MayoTestCatalog Rochester SortedByTestName Duplex Interpretive

Rochester
2022 Interpretive Handbook
Sorted By Test Name
Current as of July 20, 2022 12:05 pm CDT
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Definition of Specimen "Minimum Volume"

Defines the amount of specimen required to perform an assay once, including instrument and container dead
space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory
or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not
sufficient) result, requiring a second specimen to be collected.
Current as of July 20, 2022 12:05 pm CDT 800-533-1710 or 507-266-5700 or mayocliniclabs.com Page 1
Effective Date: 11/12/2018
Policies
Mayo Clinic Laboratories
POLICY STATEMENTS
Animal Specimens
We do not accept animal specimens for laboratory testing.
Billing
Client—Each month you will receive an itemized invoice/ statement which will indicate the date of service,
patient name, CPT code, test name, and test charge. Payment terms are net 30 days. When making payment,
please include our invoice number on your check to ensure proper credit to your account.
Patient—Mayo Clinic Laboratories does not routinely bill patient’s insurance; however, if you have made
advanced arrangements to have Mayo Clinic Laboratories bill your patient’s insurance, please include the
following required billing information: responsible party, patient’s name, current address, zip code, phone
number, Social Security number, and diagnosis code. Providing this information will avoid additional
correspondence to your office at some later date. Please advise your patients that they will receive a bill for
laboratory services from Mayo Clinic Laboratories for any personal responsibility after insurance payment.
VISA® and MasterCard® are acceptable forms of payment.
Billing—CPT Coding
It is your responsibility to determine correct CPT codes to use for billing. While this catalog lists CPT codes in
an effort to provide some guidance, CPT codes listed only reflect our interpretation of CPT coding requirements
and are not necessarily correct. Particularly, in the case of a test involving several component tests, this catalog
attempts to provide a comprehensive list of CPT codes for all of the possible components of the test. Only a
subset of component tests may be performed on your specimen. You should verify accuracy of codes listed.
Where multiple codes are listed, you should select codes for tests actually performed on your specimen. MAYO
CLINIC LABORATORIES ASSUMES NO RESPONSIBILITY FOR BILLING ERRORS DUE TO
RELIANCE ON CPT CODES LISTED IN THIS CATALOG. For further reference, please consult the CPT
Coding Manual published by the American Medical Association. If you have any questions regarding use of a
code, please contact your local Medicare carrier.
Business Continuity and Contingency Planning

In the event of a local, regional, or national disaster, Mayo Clinic and Mayo Clinic Laboratories’ performing
sites have comprehensive contingency plans in place in each location to ensure that the impact on laboratory
practice is minimized. With test standardization between our performing sites and medical practice locations
throughout the country, we have worked to ensure that patient care will not be compromised.
Cancellation of Tests
Cancellations received prior to test setup will be honored at no charge. Requests received following test setup
cannot be honored. A report will be issued automatically and charged appropriately.
Chain-of-Custody
Chain-of-custody, a record of disposition of a specimen to document who collected it, who handled it, and who
performed the analysis, is necessary when results are to be used in a court of law. Mayo Clinic Laboratories has
developed packaging and shipping materials that satisfy legal requirements for chain-of-custody. This service is
only offered for drug testing.
Compliance Policies
Mayo Clinic Laboratories is committed to compliance with applicable laws and regulations such as the Clinical
Laboratory Improvement Amendments (CLIA). Regulatory agencies that oversee our compliance include, but
are not limited to, the Centers for Medicare and Medicaid Services (CMS), the Food and Drug Administration
(FDA), and the Department of Transportation (DOT). Mayo Clinic Laboratories develops, implements, and
maintains policies, processes, and procedures throughout our organization which are designed to meet relevant
requirements. We expect clients utilizing our services will ensure their compliance with patient confidentiality,
diagnosis coding, anti-kick back statutes, professional courtesy, CPT-4 coding, CLIA proficiency testing, and
other similar regulatory requirements. Also see “Accreditation and Licensure,” “HIPAA Compliance,” and
“Reportable Disease.”
Confidentiality of Results
Mayo Clinic Laboratories is committed to maintaining confidentiality of patient information. To ensure Health
Insurance Portability and Accountability Act of 1996 (HIPAA) and the College of American Pathologists
(CAP) compliance for appropriate release of patient results, Mayo Clinic Laboratories has adopted the
following policies:
Phone Inquiry Policy—One of the following unique identifiers will be required:

• Mayo Clinic Laboratories’ accession ID number for specimen; or
• Client account number from Mayo Clinic Laboratories along with patient name; or
• Client accession ID number interfaced to Mayo Clinic Laboratories; or
• Identification by individual that he or she is, in fact, “referring physician” identified on requisition form
by Mayo Clinic Laboratories’ client
Under federal regulations, we are only authorized to release results to ordering physicians or health care
providers responsible for the individual patient’s care. Third parties requesting results including requests
directly from the patient are directed to the ordering facility. We appreciate your assistance in helping Mayo
Clinic Laboratories preserve patient confidentiality. Provision of appropriate identifiers will greatly assist
prompt and accurate response to inquiries and reporting.
Critical Values
The “Critical Values Policy” of the Department of Laboratory Medicine and Pathology (DLMP), Mayo Clinic,
Rochester, Minnesota is described below. These values apply to Mayo Clinic patients as well as external clients
of Mayo Clinic Laboratories. Clients should provide “Critical Value” contact information to Mayo Laboratory
Inquiry to facilitate call-backs. To facilitate this process, a customized form is available at mayocliniclabs.com.
Definition of Critical Value—A critical value is defined as a value that represents a pathophysiological state at
such variance with normal (expected values) as to be life-threatening unless something is done promptly and for
which some corrective action could be taken.
Abnormals are Not Considered Critical Values— Most laboratory tests have established reference ranges,
which represent results that are typically seen in a group of healthy individuals. While results outside these
reference ranges may be considered abnormal, “abnormal” results and “critical values” are not synonymous.
Analytes on the DLMP Critical Values List represent a subgroup of tests that meet the above definition.
Action Taken when a Result is Obtained that Exceeds the Limit Defined by the DLMP Critical Values List—In
addition to the normal results reporting (eg, fax, interface), Mayo Clinic Laboratories’ staff telephone the
ordering physician or the client-provided contact number within 60 minutes following laboratory release of the
critical test result(s). In the event that contact is not made within the 60-minute period, we continue to telephone
until the designated party is reached and the result is conveyed in compliance and adherence to the CAP.
Semi-Urgent Results— Semi-Urgent Results are defined by Mayo Clinic as those infectious disease-related
results that are needed promptly to avoid potentially serious health consequences for the patient (or in the case
of contagious diseases, potentially serious health consequences to other persons exposed to the patient) if not
acknowledged and/or treated by the physician. While not included on the Critical Values List, this information
is deemed important to patient care in compliance and adherence to the CAP.
To complement Mayo Clinic Laboratories’ normal reporting mechanisms (eg, fax, interface), Mayo Clinic
Laboratories’ staff will telephone results identified as significant microbiology findings to the ordering facility
within 2 hours following laboratory release of the result(s). In the event that contact is not made within the 2-
hour period, we will continue to telephone until the responsible party is reached and the result is conveyed. In
addition, in most instances, you will see the comment SIGNIFICANT RESULT appear on the final report.
For information regarding the Mayo Clinic Critical Value List, contact Mayo Laboratory Inquiry at
800-533-1710 or 507-266-5700 or visit mayocliniclabs.com.
Disclosures of Results
Under federal regulations, we are only authorized to release results to ordering physicians or other health care
providers responsible for the individual patient’s care. Third parties requesting results, including requests
directly from the patient, are directed to the ordering facility.
Extracted Specimens
Mayo Clinic Laboratories will accept extracted nucleic acid for clinical testing, provided it is an acceptable
specimen source for the ordered test, if the isolation was performed in a CLIA-certified laboratory or a
laboratory meeting equivalent requirements as determined by the CAP and/or the CMS.
Fee Changes
Fees are subject to change without notification and complete pricing per accession number is available once
accession number is final. Specific client fees are available by calling Mayo Laboratory Inquiry at 800-533-
1710 or 507-266-5700 or by visiting mayocliniclabs.com.
Framework for Quality

“Framework for Quality” is the foundation for the development and implementation of the quality program for
Mayo Clinic Laboratories. Our framework builds upon the concepts of quality control and quality assurance
providing an opportunity to deliver consistent, high-quality and cost-effective service to our clients. In addition,
our quality program enhances our ability to meet and exceed the requirements of regulatory/ accreditation
agencies and provide quality service to our customers.
A core principle at Mayo Clinic Laboratories is the continuous improvement of all processes and services that
support the care of patients. Our continuous improvement process focuses on meeting the needs of you, our
client, to help you serve your patients.
“Framework for Quality” is composed of 12 “Quality System Essentials.” The policies, processes, and
procedures associated with the “Quality System Essentials” can be applied to all operations in the path of
workflow (eg, pre-analytical, analytical, and post-analytical). Performance is measured through constant
monitoring of activities in the path of workflow and comparing performance through benchmarking internal and
external quality indicators and proficiency testing.
Data generated by quality indicators drives process improvement initiatives to seek resolutions to system-wide
problems. Mayo Clinic Laboratories utilizes “Failure Modes and Effects Analysis (FMEA),” “Plan Do Study
Act (PDSA),” “LEAN,” “Root Cause Analysis,” and “Six Sigma” quality improvement tools to determine
appropriate remedial, corrective, and preventive actions.
Quality Indicators—Mayo Clinic Laboratories produces hundreds of Key Performance Indicators for our
business and operational areas, and we review them regularly to ensure that we continue to maintain our high
standards. A sampling of these metrics includes:
• Pre-analytic performance indicators
o Lost specimens*
o On-time delivery
o Special handling calls
o Specimen acceptability*
o Specimen identification*
o Incoming defects*
• Analytic performance indicators
o Proficiency testing
o Quality control
o Turnaround (analytic) times
o Quantity-not-sufficient (QNS) specimens*
• Post-analytic performance indicators
o Revised reports*
o Critical value reports*
• Operational performance indicators
o Incoming call resolution*
o Incoming call abandon rate
o Call completion rate
o Call in-queue monitoring
o Customer complaints
o Customer satisfaction surveys
The system provides a planned, systematic program for defining, implementing, monitoring, and evaluating
our services.
*Measured using Six Sigma defects per million (dpm) method.
HIPAA Compliance
Mayo Clinic Laboratories is fully committed to compliance with all privacy, security, and electronic transaction
code requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). All services
provided by Mayo Clinic Laboratories that involve joint efforts will be done in a manner which enables our
clients to be HIPAA and the College of American Pathologists (CAP) compliant.
Infectious Material
The Centers for Disease Control (CDC) in its regulations of July 21, 1980, has listed organisms and diseases for
which special packaging and labeling must be applied. Required special containers and packaging instructions
can be obtained from us by using the “Request for Supplies” form or by ordering from the online Supply
Catalog at mayocliniclabs.com/customer-service/supplies/index.php.
Shipping regulations require that infectious substances affecting humans be shipped in a special manner. See
“Infectious Material.” A copy of the regulations can be requested from the International Air Transport
Association (IATA); they may be contacted by phone at 514-390-6770 or by fax at 514-874-2660.
Informed Consent Certification

Submission of an order for any tests contained in this catalog constitutes certification to Mayo Clinic
Laboratories by ordering physician that: (1) ordering physician has obtained “Informed Consent” of subject
patient as required by any applicable state or federal laws with respect to each test ordered; and (2) ordering
physician has obtained from subject patient authorization permitting Mayo Clinic Laboratories to report results
of each test ordered directly to ordering 800-533-1710
physician. or 507-266-5700 or mayocliniclabs.com Page 5
On occasion, we forward a specimen to an outside reference laboratory. The laws of the state where the
reference laboratory is located may require written informed consent for certain tests. Mayo Clinic Laboratories
will request that ordering physician pursue and provide such consent. Test results may be delayed or denied if
consent is not provided.
Non-Biologic Specimens
Due to the inherent exposure risk of non-biologic specimens, their containers, and the implied relationship to
criminal, forensic, and medico-legal cases, Mayo Clinic Laboratories does not accept nor refer non-biologic
specimen types. Example specimens include: unknown solids and liquids in the forms of pills, powder,
intravenous fluids, or syringe contents.
Patient Safety Goals

One of The Joint Commission National Patient Safety goals for the Laboratory Services Program is to improve
the accuracy of patient identification by using at least 2 patient identifiers when providing care, treatment, or
services.
Mayo Clinic Laboratories uses multiple patient identifiers to verify the correct patient is matched with the
correct specimen and the correct order for the testing services. As a specimen is received at Mayo Clinic
Laboratories, the client number, patient name, and patient age date of birth are verified by comparing the labels
on the specimen tube or container with the electronic order and any paperwork (batch sheet or form) which may
accompany the specimen to be tested. When discrepancies are identified, Mayo Laboratory Inquiry will call the
client to verify discrepant information to assure Mayo Clinic Laboratories is performing the correct testing for
the correct patient. When insufficient or inconsistent identification is submitted, Mayo Clinic Laboratories will
recommend that a new specimen be obtained, if feasible.
In addition, Anatomic Pathology consultation services require the Client Pathology Report. The pathology
report is used to match the patient name, patient age and/or date of birth, and pathology case number.
Since tissue blocks and slides have insufficient space to print the patient name on the block, the pathology
report provides Mayo Clinic Laboratories another mechanism to confirm the patient identification with the
client order and labels on tissue blocks and slides.
Parallel Testing
Parallel testing may be appropriate in some cases to re-establish patient baseline results when converting to a
new methodology at Mayo Clinic Laboratories. Contact your Regional Manager at 800-533-1710 or 507-266-
5700 for further information.
Proficiency Testing
We are a College of American Pathologists (CAP)-accredited, CLIA-licensed facility that voluntarily
participates in many diverse external and internal proficiency testing programs. It is Mayo Clinic Laboratories’
expectation that clients utilizing our services will adhere to CLIA requirements for proficiency testing (42 CFR
493.801), including a prohibition on discussion about samples or results and sharing of proficiency testing
materials with Mayo Clinic Laboratories during the active survey period.
Mayo Clinic Laboratories’ proficiency testing includes participation in CMS-approved programs. Mayo Clinic
Laboratories also performs alternative assessment using independent state, national, and international programs
when proficiency testing is not available. Mayo Clinic Laboratories also conducts comparability studies to
ensure the accuracy and reliability of patient testing, when necessary. We comply with the regulations set forth
in Clinical Laboratory Improvement Amendments (CLIA-88), the Occupational Safety and Health
Administration (OSHA), or the Centers for Medicare & Medicaid Services (CMS).
It is Mayo Clinic Laboratories’ expectation that clients utilizing our services will adhere to CLIA requirements
for proficiency testing including a prohibition
on discussion about samples or results and sharing of proficiency
800-533-1710 or 507-266-5700 or mayocliniclabs.com Page 6
testing materials with Mayo Clinic Laboratories during the active survey period. Referring of specimens is
acceptable for comparison purposes when an approved proficiency-testing program is not available for a given
analyte.
Radioactive Specimens
Specimens from patients receiving radioactive tracers or material should be labeled as such. All incoming
shipments arriving at Mayo Clinic Laboratories are routed through a detection process in receiving to determine
if the samples have any levels of radioactivity. If radioactive levels are detected, the samples are handled via
an internal process that assures we do not impact patient care and the safety of our staff. This radioactivity may
invalidate the results of radioimmunoassays (RIA).
Record Retention
Mayo Clinic Laboratories retains all test requisitions and patient test results at a minimum for the retention
period required to comply with and adhere to the CAP. A copy of the original report can be reconstructed
including reference ranges, interpretive comments, flags, and footnotes with the source system as the
Department of Laboratory Medicine’s laboratory information system.
Referral of Tests to Another Laboratory

Mayo Clinic Laboratories forwards tests to other laboratories as a service to its clients. This service should in no
way represent an endorsement of such test or referral laboratory or warrant any specific performance for such
test. Mayo Clinic Laboratories will invoice for all testing referred to another laboratory at the price charged to
Mayo Clinic Laboratories. In addition, Mayo Clinic Laboratories will charge an administrative fee per test for
such referral services.
Reflex Testing
Mayo Clinic Laboratories identifies tests that reflex when medically appropriate. In many cases, Mayo Clinic
Laboratories offers components of reflex tests individually as well as together. Clients should familiarize
themselves with the test offerings and make a decision whether to order a reflex test or an individual
component. Clients, who order a reflex test, can request to receive an “Additional Testing Notification Report”
which indicates the additional testing that has been performed. This report will be faxed to the client. Clients
who wish to receive the “Additional Testing Notification Report” should contact their Regional Manager or
Regional Service Representative.
Reportable Disease
Mayo Clinic Laboratories, in compliance with and adherence to the College of American Pathologists (CAP)
Laboratory General Checklist (CAP GEN. 20373) strives to comply with laboratory reporting requirements for
each state health department regarding reportable disease conditions. We report by mail, fax, and/or
electronically, depending upon the specific state health department regulations. Clients shall be responsible for
compliance with any state specific statutes concerning reportable conditions, including, but not limited to, birth
defects registries or chromosomal abnormality registries. This may also include providing patient
address/demographic information. Mayo Clinic Laboratories’ reporting does not replace the client or physician
responsibility to report as per specific state statues.
Request for Physician Name and Number

Mayo Clinic Laboratories endeavors to provide high quality, timely results so patients are able to receive
appropriate care as quickly as possible. While providing esoteric reference testing, there are times when we
need to contact the ordering physician directly. The following are 2 examples:
When necessary to the performance of a test, the ordering physician’s name and phone number are
requested as part of “Specimen Required.” This information is needed to allow our physicians to make
timely consultations or seek clarification of requested services. If this information is not provided at the time
of specimen receipt, we will call you to obtain the information. By providing this information up front,
delays in patient care are avoided.
In some situations, additional information from ordering physician is necessary to clarify or interpret a test
result. At that time, Mayo Clinic Laboratories will request physician’s name and phone number so that one
of our staff can consult with the physician.
We appreciate your rapid assistance in supplying us with the ordering physician’s name and phone number
when we are required to call. Working together, we can provide your patients with the highest quality testing
services in the shortest possible time.
Special Handling
Mayo Clinic Laboratories serves as a reference laboratory for clients around the country and world. Our test
information, including days and time assays are performed as well as analytic turnaround time, is included
under each test listing in the Test Catalog on mayocliniclabs.com. Unique circumstances may arise with a
patient resulting in a physician request that the specimen or results receive special handling. There are several
options available. These options can only be initiated by contacting Mayo Laboratory Inquiry at
800-533-1710 or 507-266-5700 and providing patient demographic information.
There is a nominal charge associated with any special handling.
• Hold: If you would like to send us a specimen and hold that specimen for testing pending initial test
results performed at your facility, please call Mayo Laboratory Inquiry. We will initiate a hold and
stabilize the specimen until we hear from you.
• Expedite: If you would like us to expedite the specimen to the performing laboratory, you can call Mayo
Laboratory Inquiry and request that your specimen be expedited. Once the shipment is received in our
receiving area, we will deliver the specimen to the performing laboratory for the next scheduled analytic
run. We will not set up a special run to accommodate an expedite request.
• STAT: In rare circumstances, STAT testing from the reference laboratory may be required for patients
who need immediate treatment. These cases typically necessitate a special analytic run to turn results
around as quickly as possible. To arrange STAT testing, please have your pathologist, physician, or
laboratory director call Mayo Laboratory Inquiry. He/she will be connected with one of our medical
directors to consult about the patient’s case. Once mutually agreed upon that there is a need for a STAT,
arrangements will be made to assign resources to run the testing on a STAT basis when the specimen is
received.
Specimen Identification Policy

In compliance with and adherence to the CAP and the Joint Commission’s 2008 Patient Safety Goals (1A),
Mayo Clinic Laboratories’ policy states that all specimens received for testing must be correctly and adequately
labeled to assure positive identification. Specimens must have 2 person-specific identifiers on the patient label.
Person-specific identifiers may include: accession number, patient’s first and last name, unique identifying
number (eg, medical record number), or date of birth. Specimens are considered mislabeled when there is a
mismatch between the person-specific identifiers on the specimen and information accompanying the specimen
(eg, computer system, requisition form, additional paperwork).
When insufficient or inconsistent identification is submitted, Mayo Clinic Laboratories will recommend that a
new specimen be obtained, if feasible.
Specimen Rejection
All tests are unique in their testing requirements. To avoid specimen rejection or delayed turnaround times,
please check the “Specimen Required” field within each test. You will be notified of rejected or problem
specimens upon receipt.
Please review the following conditions prior to submitting a specimen to Mayo Clinic Laboratories:
• Full 24 hours for timed urine collection
• pH of urine
• Lack of hemolysis/lipemia
• Specimen type (plasma, serum, whole blood, etc.)
• Specimen volume
• Patient information requested
• Proper identification of patient/specimen
• Specimen container (metal-free, separation gel, appropriate preservative, etc.)
• Transport medium
• Temperature (ambient, frozen, refrigerated)
Specimen Volume
The “Specimen Required” section of each test includes 2 volumes - preferred volume and minimum volume.
Preferred volume has been established to optimize testing and allows the laboratory to quickly process
specimen containers, present containers to instruments, perform test, and repeat test, if necessary. Many of our
testing processes are fully automated; and as a result, this volume allows hands-free testing and our quickest
turnaround time (TAT). Since patient values are frequently abnormal, repeat testing, dilutions, or other
specimen manipulations often are required to obtain a reliable, reportable result. Our preferred specimen
requirements allow expeditious testing and reporting.
When venipuncture is technically difficult or the patient is at risk of complications from blood loss (eg,
pediatric or intensive care patients), smaller volumes may be necessary. Specimen minimum volume is the
amount of sample necessary to provide a clinical relevant result as determined by the Testing Laboratory.
When patient conditions do not mandate reduced collection volumes, we ask that our clients submit preferred
volume to facilitate rapid, cost-effective, reliable test results. Submitting less than preferred volume may
negatively impact quality of care by slowing TAT, increasing the hands-on personnel time (and therefore cost)
required to perform test.
Mayo Clinic Laboratories makes every possible effort to successfully test your patient’s specimen. If you have
concerns about submitting a specimen for testing, please call Mayo Laboratory Inquiry at 800-533-1710 or
507-266-5700. Our staff will discuss the test and specimen you have available. While in some cases specimens
are inadequate for desired test, in other cases, testing can be performed using alternative techniques.
Supplies
Shipping boxes, specimen vials, special specimen collection containers, and request forms are supplied without
charge. Supplies can be requested using one of the following methods: use the online ordering functionality
available at mayocliniclabs.com/supplies or call Mayo Laboratory Inquiry at 800-533-1710 or 507-266-5700.
Test Classifications
Analytical tests offered by Mayo Clinic Laboratories are classified according to the FDA labeling of the test kit
or reagents and their usage. Where appropriate, analytical test listings contain a statement regarding these
classifications, test development, and performance characteristics.
Test Development Process

Mayo Clinic Laboratories serves patients and health care providers from Mayo Clinic, Mayo Health System,
and our reference laboratory clients worldwide. We are dedicated to providing clinically useful, cost-effective
testing strategies for patient care. Development, validation, and implementation of new and improved laboratory
methods are major components of that commitment.
Each assay utilized at Mayo Clinic, whether developed on site or by others, undergoes an extensive validation
and performance documentation period before the test becomes available for clinical use. Validations follow a
standard protocol that includes:
• Accuracy
• Precision
• Sensitivity
• Specificity and interferences
• Reportable range
• Specimen stability
• Specimen type comparisons, if applicable
• Urine preservative studies: stability at ambient, refrigerated, and frozen temperatures and with 7
preservatives; at 1, 3, and 7 days
• Comparative evaluation with current and potential methods, if applicable
• Reference intervals: reference intervals provided by Mayo Clinic Laboratories are derived from studies
performed in our laboratories or adopted from the manufacturer package insert after internal verification.
When reference intervals are obtained from other sources, the source is indicated in the “Reference
Values” field.
• Workload recording
• Limitations of the assay
• Clinical utility and interpretation: written by Mayo Clinic medical experts, electronically available
(MayoAccess™)
Test Result Call-Backs

Results will be phoned to a client when requested from the client (either on Mayo Clinic Laboratories’ request
form or from a phone call to Mayo Clinic Laboratories from the client).
Time-Sensitive Specimens
Please contact Mayo Laboratory Inquiry at 800-533-1710 or 507-266-5700 prior to sending a specimen for
testing of a time-sensitive nature. Relay the following information: facility name, account number, patient name
and/or Mayo Clinic Laboratories’ accession number, shipping information (ie, courier service, FedEx®, etc.),
date to be sent, and test to be performed. Place specimen in a separate Mayo Clinic Laboratories’ temperature
appropriate bag. Please write “Expedite” in large print on outside of bag.
Turnaround Time (TAT)

Mayo Clinic Laboratories’ extensive test menu reflects the needs of our own health care practice. We are
committed to providing the most expedient TAT possible to improve diagnosis and treatment. We consider
laboratory services as part of the patient care continuum wherein the needs of the patient are paramount. In that
context, we strive to fulfill our service obligations. Our history of service and our quality metrics will document
our ability to deliver on all areas of service including TAT.
Mayo Clinic Laboratories defines TAT as the analytical test time (the time from which a specimen is received at
the testing location to time of result) required. TAT is monitored continuously by each performing laboratory
site within the Mayo Clinic Department of Laboratory Medicine and Pathology. For the most up-to-date
information on TAT for individual tests, please visit us at mayocliniclabs.com or contact Mayo Laboratory
Inquiry at 800-533-1710 or 507-266-5700.
Unlisted Tests
Mayo Clinic Laboratories does not list all available test offerings in the paper catalog. New procedures are
developed throughout the year; therefore, some tests are not listed in this catalog. Although we do not usually
accept referred tests of a more routine type, special arrangements may be made to provide your
laboratory with temporary support during times of special need such as sustained instrumentation failure. For
information about unlisted tests, please call Mayo Laboratory Inquiry at 800-533-1710 or 507-266-5700.
DHVD 1,25-Dihydroxyvitamin D, Serum
8822 Clinical Information: Vitamin D is a generic designation for a group of fat-soluble, structurally
similar sterols, which act as hormones. In the presence of renal disease or hypercalcemia, testing of
1,25-dihydroxy vitamin D (DHVD) might be needed to adequately assess vitamin D status. The
25-hydroxyvitamin D (25HDN) test (25HDN / 25-Hydroxyvitamin D2 and D3, Serum) in serum is
otherwise the preferred initial test for assessing vitamin D status and most accurately reflects the body's
vitamin D stores. Vitamin D compounds in the body are exogenously derived by dietary means; from
plants as 25-hydroxyvitamin D2 (ergocalciferol or calciferol) or from animal products as
25-hydroxyvitamin D3 (cholecalciferol or calcidiol). Vitamin D may also be endogenously derived by
conversion of 7-dihydrocholesterol to 25-hydroxyvitamin D3 in the skin upon ultraviolet exposure.
25HDN is subsequently formed by hydroxylation (CYP2R1) in the liver. 25HDN is a prohormone that
represents the main reservoir and transport form of vitamin D, being stored in adipose tissue and tightly
bound by a transport protein while in circulation. Biological activity is expressed in the form of DHVD,
the active metabolite of 25HDN. 1-Alpha-hydroxylation (CYP27B1) occurs on demand, primarily in the
kidneys, under the control of parathyroid hormone (PTH) before expressing biological activity. Like
other steroid hormones, DHVD binds to a nuclear receptor, influencing gene transcription patterns in
target organs. 25HDN may also be converted into the inactive metabolite 24,25-dihydroxyvitamin D
(24,25D) by (CYP24A1) hydroxylation. This process, regulated by parathyroid hormone (PTH), might
increase DHVD synthesis at the expense of the alternative hydroxylation (CYP24A1) product 24,25D.
Inactivation of 25HDN and DHVD by CYP24A1 is a crucial process that prevents over production of
DHVD and resultant vitamin D toxicity. DHVD stimulates calcium absorption in the intestine and its
production is tightly regulated through concentrations of serum calcium, phosphorus, and PTH. DHVD
promotes intestinal calcium absorption and, in concert with PTH, skeletal calcium deposition, or less
commonly, calcium mobilization. Renal calcium and phosphate reabsorption are also promoted, while
prepro-PTH mRNA expression in the parathyroid glands is downregulated. The net result is a positive
calcium balance, increasing serum calcium and phosphate levels, and falling PTH concentrations. In
addition to its effects on calcium and bone metabolism, DHVD regulates the expression of a multitude
of genes in many other tissues including immune cells, muscle, vasculature, and reproductive organs.
DHVD levels are decreased in hypoparathyroidism and in chronic renal failure. DHVD levels may be
high in primary hyperparathyroidism and in physiologic hyperparathyroidism secondary to low calcium
or vitamin D intake. Some patients with granulomatous diseases (eg, sarcoidosis) and malignancies
containing nonregulated 1-alpha hydroxylase in the lesion might have hypercalcemia that appears
vitamin D mediated with normal or high serum phosphate (hyperphosphatemia) and hypercalcemia
(both of which might be severe) in addition to low PTH and absent parathyroid hormone-related peptide
(PTHRP). Assessment of 24,25D might also be required in patients with hypercalcemia that does not
appear to be driven by PTH or PTHRP, and may be helpful in assessment of patients with loss of
function inactivating CYP24A1 mutations. Differential diagnostic considerations include vitamin D
intoxication and CYP24A1 deficiency.
Useful For: As a second-order test in the assessment of vitamin D status, especially in patients with
renal disease Investigation of some patients with clinical evidence of vitamin D deficiency (eg, vitamin
D-dependent rickets due to hereditary deficiency of renal 1-alpha hydroxylase or end-organ resistance
to 1,25-dihydroxyvitamin D) Differential diagnosis of hypercalcemia
Interpretation: 1,25-Dihydroxyvitamin D (DVHD) concentrations are low in chronic renal failure

and hypoparathyroidism. DVHD concentrations are high in sarcoidosis and other granulomatous
diseases, some malignancies, primary hyperparathyroidism, and physiologic hyperparathyroidism.
DVHD concentrations are not a reliable indicator of vitamin D toxicity; normal (or even low) results
may be seen in such cases.
Reference Values:
Males:
<16 years: 24-86 pg/mL
> or =16 years: 18-64 pg/mL
Females:
<16 years: 24-86 pg/mL
> or =16 years: 18-78 pg/mL
For SI unit Reference Values, see https://www.mayocliniclabs.com/order-tests/si-unit-conversion.html
Clinical References: 1. Endres DB, Rude RK: Vitamin D and its metabolites. In Tietz Textbook of
Clinical Chemisty. Third edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders
Company, 1999, pp 1417-1423 2. Bringhurst FR, Demay MB, Kronenberg HM: Vitamin D (calciferols):
metabolism of vitamin D. In Williams Textbook of Endocrinology. Ninth edition. Edited by JD Wilson,
DW Foster, HM Kronenberg, PR Larsen. Philadelphia, WB Saunders Company, 1998, pp 1166-1169
SFUNG 1,3-Beta-D-Glucan (Fungitell), Serum

604094 Clinical Information: Invasive fungal infections (IFI) due to opportunistic fungal pathogens are a
significant cause of morbidity and mortality, particularly among patients who are significantly
immunosuppressed including hematopoietic stem cell transplant recipients, solid organ transplant
recipients, and those with hematologic or immune deficiencies. Patient recovery and survival following an
IFI is directly related to the timely clinical recognition and prompt administration of antifungal therapy.
Laboratory diagnosis of IFI is largely based on direct microscopic examination of patient specimens,
histopathologic examination of tissue biopsies, isolation of fungi via culture, and, more recently, through
molecular methods. However, these techniques commonly require invasive sample collection methods
(eg, biopsy, bronchoalveolar lavage), which may be contraindicated in certain patients. Additionally, both
microscopy and culture are frequently insensitive, with prior studies showing the sensitivity of culture for
invasive Aspergillus infections ranges from 40% to 85%, and some fungi require prolonged incubation
times, limiting the utility of culture in the acute patient setting. Due to these limitations, use of fungal
biomarkers, including detection of (1,3)-beta-D-glucan (BDG), have emerged as useful adjunct tests
available for detection of IFI. BDG is found in the cell walls of most fungi (eg, Candida, Aspergillus,
Fusarium, Pneumocystis jirovecii) with the notable exception of Cryptococcus species, Blastomyces
species, and the Mucorales (eg, Lichtheimia, Mucor, Rhizopus), which either lack BDG entirely or
produce it in very low amounts. Elevated serum BDG levels have been associated with the presence of a
fungal infection. The BDG levels may be, detected prior to the development of clinical symptoms and
before isolation or identification of the fungal organism via routine methods. The sensitivity and
specificity of BDG detection in patients with proven or probable IFI ranges from 64% to 93% and 87% to
100%, respectively, among different studies. Importantly, the BDG assay should not be used alone to
diagnose an IFI, but rather in conjunction with careful evaluation of patient risk factors for infection, other
laboratory testing, and radiologic findings.
Useful For: Aiding in the diagnosis of invasive fungal infections caused by various fungi, including
Aspergillus species, Fusarium species, Candida species, and Pneumocystis jirovecii, among others
Interpretation: The Fungitell assay should be used in conjunction with other diagnostic procedures,
such as routine bacterial/fungal cultures, histologic examination of biopsy material and radiologic studies.
Positive: (1,3)-Beta-D-glucan detected. A single positive result should be interpreted with caution and
correlated alongside consideration of patient risk for invasive fungal disease, results of routine laboratory
tests (eg, bacterial and fungal culture, histopathologic evaluation) and radiologic findings. Repeat testing
on a new sample (collected in 3-4 days) is recommended as serially positive samples are associated with a
higher diagnostic odds ratio for invasive fungal infection compared to a single positive result.
False-positive results may occur in patients who have recently (in the past 3-4 days) undergone
hemodialysis, treatment with certain fractionated blood products (eg, serum albumin, immunoglobulins),
or those who have had significant exposure to glucan-containing gauze during surgery. Indeterminate:
Repeat testing on a new sample is recommended in patients at risk for an invasive fungal infection.
Negative: No (1,3)-Beta-D-glucan detected. This assay does not detect certain fungi, including
Cryptococcus species, which produce very low levels of (1,3)-beta-D-glucan (BDG) and the Mucorales
(eg, Lichtheimia, Mucor, and Rhizopus), which are not known to produce BDG. Additionally, the yeast
phase of Blastomyces dermatitidis produces little BDG and may not be detected by this assay.
Reference Values:
FUNGITELL QUANTITATIVE VALUE:
<60 pg/mL
FUNGITELL QUALITATIVE RESULT:

Negative
Reference values apply to all ages.
Clinical References: 1. Theel ES, Doern CD: Beta-D-glucan testing is important for diagnosis of
invasive fungal infections. J Clin Microbiol. 2013 Nov;51(11):3478-3483 2. Karageorgopoulos DE,
Vouloumanou EK, Ntziora F, Michalopoulos A, Rafailidis PI, Falagas ME: Beta-D-glucan assay for the
diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis. 2011 March;52(6):750-770 3.
Lamoth F, Cruciani M, Mengoli C, et al: Beta-glucan antigenemia assay for the diagnosis of invasive
fungal infections in patients with hematological malignancies: a systematic review and meta-analysis of
cohort studies from the Third European Conference on Infections in Leukemia (ECIL-3). Clin Infect
Dis. 2012;54:633-643
DOCS 11-Deoxycorticosterone, Serum

46919 Clinical Information: The adrenal glands, ovaries, testes, and placenta produce steroid hormones,
which can be subdivided into 3 major groups: mineral corticoids, glucocorticoids and sex steroids.
Synthesis proceeds from cholesterol along 3 parallel pathways, corresponding to these 3 major groups
of steroids, through successive side-chain cleavage and hydroxylation reactions. At various levels of
each pathway, intermediate products can move into the respective adjacent pathways via additional,
enzymatically catalyzed reactions (see Steroid Pathways in Special Instructions).
11-Deoxycorticosterone represents the last intermediate in the mineral corticoid pathway that has
negligible mineral corticoid activity. It is converted by 11-beta-hydroxylase 2 (CYP11B2) or by
11-beta-hydroxylase 1 (CYP11B1) to the first mineral corticoids with significant activity,
corticosterone. Corticosterone is in turn converted to 18-hydroxycorticosterone and finally to
aldosterone, the most active mineral corticoid. Both of these reactions are catalyzed by CYP11B2,
which, unlike its sister enzyme CYP11B1, also possesses 18-hydroxylase and 18-methyloxidase
activity. The major diagnostic utility of measurement of steroid synthesis intermediates is in diagnosing
disorders of steroid synthesis, in particular, congenital adrenal hyperplasia (CAH). All types of CAH are
associated with cortisol deficiency with the exception of CYP11B2 deficiency and isolated impairments
of the 17-lyase activity of CYP17A1 (this enzyme also has 17-alpha-hydroxylase activity). In cases of
severe illness or trauma, CAH predisposes patients to poor recovery or death. Patients with the most
common form of CAH (21-hydroxylase deficiency, >90% of cases), with the third most common form
of CAH (3-beta-steroid dehydrogenase deficiency, <3% of cases), and those with the extremely rare
StAR (steroidogenic acute regulatory protein) or 20,22 desmolase deficiencies, might also suffer
mineral corticoid deficiency, as the enzyme blocks in these disorders are proximal to potent mineral
corticoids. These patients might suffer salt-wasting crises in infancy. By contrast, patients with the
second most common form of CAH, 11-hydroxylase deficiency (<5% of cases), are normotensive or
hypertensive, as the block affects either CYP11B1 or CYP11B2, but rarely both, thus ensuring that at
least corticosterone is still produced. In addition, patients with all forms of CAH might suffer the effects
of substrate accumulation proximal to the enzyme block. In the 3 most common forms of CAH, the
accumulating precursors spill over into the sex steroid pathway, resulting in virilization of females or, in
milder cases, in hirsutism, polycystic ovarian syndrome, or infertility, as well as in possible premature
adrenarche and pubarche in both genders. Measurement of the various precursors of mature mineral
corticoids and glucocorticoids, in concert with the determination of sex steroid concentrations, allows
diagnosis of CAH and its precise type, and serves as an aid in monitoring steroid replacement therapy
and other therapeutic interventions. Measurement of 11-deoxycorticosterone and its glucocorticoid
pendant, 11-deoxycortisol (also known as compound S), is aimed at diagnosing: -CYP11B1 deficiency
(associated with cortisol deficiency) -The rarer CYP11B2 deficiency (no cortisol deficiency) -The yet
less common glucocorticoid-responsive hyperaldosteronism (where expression of the gene CYP11B2 is
driven by the CYP11B1 promoter, thus making it responsive to adrenocorticotrophic hormone: ACTH
rather than renin) For other forms of CAH, the following tests might be relevant: -11-Hydroxylase
deficiency: - DOC / 11-Deoxycortisol, Serum - CORTC / Corticosterone, Serum - HYD18 /
Hydroxycorticosterone, 18 - PRA / Renin Activity, Plasma - ALDS / Aldosterone, Serum
-3-Beta-steroid-dehydrogenase deficiency: - 17PRN / Pregnenolone and 17-Hydroxypregnenolone,
Serum -17-Hydroxylase deficiency or 17-lyase deficiency (CYP17A1 has both activities): - PREGN /
Pregnenolone, Serum - 17OHP / 17-Hydroxypregnenolone, Serum - PGSN / Progesterone, Serum -
OHPG / 17-Hydroxyprogesterone, Serum - DHEA_ / Dehydroepiandrosterone (DHEA), Serum - ANST
/ Androstenedione, Serum Cortisol should be measured in all cases of suspected CAH. In the diagnosis
of suspected 11-hydroxylae deficiency and glucocorticoid-responsive hyperaldosteronism, this test
should be used in conjunction with measurements of 11-deoxycortisol, corticosterone,
18-hydroxycorticosterone, cortisol, renin, and aldosterone.
Useful For: Diagnosis of suspected 11-hydroxylase deficiency, including the differential diagnosis of
11 beta-hydroxylase 1 (CYP11B1) versus 11 beta-hydroxylase 2 (CYP11B2) deficiency Diagnosis of
glucocorticoid-responsive hyperaldosteronism Evaluating congenital adrenal hyperplasia newborn
screen-positive children, when elevations of 17-hydroxyprogesterone are only moderate, suggesting
possible 11-hydroxylase deficiency
Interpretation: In 11 beta-hydroxylase 1 (CYP11B1) deficiency, serum concentrations of cortisol will

be low (usually <7 microgram/dL for a morning draw). 11-Deoxycortisol and 11-deoxycorticosterone are
elevated, usually to at least 2 to 3 times (more typically 20-300 times) the upper limit of the normal
reference range on a morning blood draw. Elevations in 11-deoxycortisol are usually relatively greater
than those of 11-deoxycorticosterone, because of the presence of intact 11 beta-hydroxylase 2
(CYP11B2). For this reason, serum concentrations of all potent mineral corticoids (corticosterone,
18-hydroxycorticosterone, and aldosterone) are typically increased above the normal reference range.
Plasma renin activity is correspondingly low or completely suppressed. Caution needs to be exercised in
interpreting the mineral corticoid results in infants younger than 7 days; mineral corticoid levels are often
substantially elevated in healthy newborns in the first few hours of life and only decline to near-adult
levels by week 1. Mild cases of CYP11B1 deficiency might require adrenocorticotrophic hormone
(ACTH)1-24 stimulation testing for definitive diagnosis. In affected individuals, the observed serum
11-deoxycortisol concentration 60 minutes after intravenous or intramuscular administration of 250
microgram of ACTH1-24 will usually exceed 20 ng/mL, or demonstrate at least a 4-fold rise. Such
increments are rarely, if ever, observed in unaffected individuals. The corresponding cortisol response
will be blunted (<18 ng/mL peak). In CYP11B2 deficiency, serum cortisol concentrations are usually
normal, including a normal response to ACTH1-24. 11-Deoxycorticosterone will be elevated, often more
profoundly than in CYP11B1 deficiency, while 11-deoxycortisol may or may not be significantly
elevated. Serum corticosterone concentrations can be low, normal, or slightly elevated, while serum
18-hydroxycorticosterone and aldosterone concentrations will be low in the majority of cases. However, if
the underlying genetic defect has selectively affected 18-hydroxylase activity, corticosterone
concentrations will be substantially elevated. Conversely, if the deficit affects aldosterone synthase
function primarily, 18-hydroxycorticosterone concentrations will be very high. Expression of the
CYP11B2 gene is normally regulated by renin and not ACTH. In glucocorticoid-responsive
hyperaldosteronism, the ACTH-responsive promoter of CYP11B1 exerts aberrant control over CYP11B2
gene expression. Consequently, corticosterone, 18-hydroxycorticosterone, and aldosterone are
significantly elevated in these patients and their levels follow a diurnal pattern, governed by the rhythm of
ACTH secretion. In addition, the high levels of CYP11B2 lead to 18-hydroxylation of 11-deoxycortisol
(an event that is ordinarily rare, as CYP11B1, which has much greater activity in 11-deoxycortisol
conversion than CYP11B2, lacks 18-hydroxylation activity). Consequently, significant levels of
18-hydroxycortisol, which normally is only present in trace amounts, might be detected in these patients.
Ultimate diagnostic confirmation comes from showing direct responsiveness of mineral corticoid
production to ACTH1-24 injection. Normally, this has little if any effect on corticosterone,
18-hydroxycorticosterone, and aldosterone levels. This testing may then be further supplemented by
showing that mineral corticoid levels fall after administration of dexamethasone. Sex steroid levels are
moderately to significantly elevated in CYP11B1 deficiency and much less, or minimally, pronounced in
CYP11B2 deficiency. Sex steroid levels in glucocorticoid-responsive hyperaldosteronism are usually
normal. Most untreated patients with 21-hydroxylase deficiency have serum 17-hydroxyprogesterone
concentrations well in excess of 1000 ng/dL. For the few patients with levels in the range of higher than
630 ng/dL (upper limit of reference range for newborns) to 2000 or 3000 ng/dL, it might be prudent to
consider 11-hydroxylase deficiency as an alternative diagnosis. This is particularly true if serum
androstenedione concentrations are also only mildly to modestly elevated, and if the phenotype is not salt
wasting but either simple virilizing (female) or normal (female or male). 11-Hydroxylase deficiency, in
particular if it affects CYP11B1, can be associated with modest elevations in serum
17-hydroxyprogesterone concentrations. In these cases, testing for CYP11B1 deficiency and CYB11B2
deficiency should be considered and interpreted as described above. Alternatively, measurement of
21-deoxycortisol might be useful. This minor pathway metabolite accumulates in CYP21A2 deficiency,
as it requires 21-hydroxylaion to be converted to cortisol, but is usually not elevated in CYP11B1
deficiency, since its synthesis requires via 11-hydroxylation of 17-hydroxyprogesterone. Cautions At
birth, the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis are activated
and all adrenal steroids are high, including mineral corticoids and sex steroids and their precursors. In
preterm infants, elevations can be even more pronounced due to illness and stress. In doubtful cases, when
the initial test was performed on a just-born baby, repeat testing a few days or weeks later is advised.
Adrenocorticotrophic hormone (ACTH)1-24 testing has a low, but definite risk of drug and allergic
reactions and should, therefore, only be performed under the supervision of a physician in an environment
that guarantees the patient's safety, typically an endocrine, or other centralized, testing center.
Interpretation of ACTH1-24 testing in the context of diagnosis of congenital adrenal hyperplasia (CAH)
requires considerable experience, in particular for the less common variants of CAH, such as
11-hydroxylase deficiency or 3-beta-hydroxysteroid dehydrogenase (3beta-HSD deficiency), for which
very few, if any, reliable normative data exist. For the even rarer enzyme defects, such as deficiencies of
StAR (steroidogenic acute regulatory protein), 20,22 desmolase, 17a-hydroxylase/17-lyase, and
17-beta-hydroxysteroid dehydrogenase (17beta-HSD), there are only case reports. Expert opinion from a
pediatric endocrinologist with experience in CAH should, therefore, be sought.
Reference Values:
< or =18 years: <30 ng/dL
>18 years: <10 ng/dL
Clinical References: 1. Von Schnakenburg K, Bidlingmaier F, Knorr D: 17-hydroxyprogesterone,

androstenedione, and testosterone in normal children and in prepubertal patients with congenital adrenal
hyperplasia. Eur J Pediatr. 1980;133(3):259-267 2. Therrell BL: Newborn screening for congenital
adrenal hyperplasia. Endocrinol Metab Clin North Am. 2001;30(1):15-30 3. Collett-Solberg PF:
Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part I. Clin Pediatr.
2001;40:1-16 4. Forest MG: Recent advances in the diagnosis and management of congenital adrenal
hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update. 2004;10:469-485 5.
Tonetto-Fernandes V, Lemos-Marini SH, Kuperman H, Ribeiro-Neto LM, Verreschi JTN, Kater CE:
Serum 21-deoxycortisol, 17-hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal
hyperplasia: clinical and hormonal correlations and identification of patients with 11 beta-hydroxylase
deficiency among a large group with alleged 21-hydroxylase deficiency. J Clin Endocrinol Metab.
2006;91:2179-2184 6. Lashanske G, Sainger P, Fishman K, et al: Normative data for adrenal
steroidogenesis in a healthy pediatric population: age-and sex-related changes after adrenocorticotropin
stimulation. J Clin Endocrinol Metab. 1991;73:674-686 7. Holst JP, Soldin SJ, Tractenberg RE, et al:
Use of steroid profiles in determining the cause of adrenal insufficiency. Steroids. 2007;72:71-84 8.
Berneis K, Staub JJ, Gessler A, Meier C, Girard J, Muller B: Combined stimulation of
adrenocorticotropin and compound-S by single dose metyrapone test as an outpatient procedure to
assess hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab. 2002;87(12):5470-5475 9.
Sciarra F, Tosti-Croce C, Toscano V: Androgen-secreting adrenal tumors. Minerva Endocrinol.
1995;20:63-68 10. Speiser PW, Arlt W, Auchus RJ, et al: Congenital adrenal hyperplasia due to steroid
21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab.
2018 Nov;103(11):4043-4088. doi: 10.1210/jc.2018-01865 Correction in: J Clin Endocrinol Metab.
2019 Jan;104(1):39â€“40 11. Khattab A, Haider S, Kumar A, et al: Clinical, genetic, and structural
basis of congenital adrenal hyperplasia due to 11ÃŸ-hydroxylase deficiency. Proc Natl Acad Sci U S A.
2017 Mar 7;114(10):E1933â€“E1940 doi: 10.1073/pnas.1621082114
DCORT 11-Deoxycortisol, Serum

46920 Clinical Information: 11-Deoxycortisol (Compound S) is the immediate precursor of cortisol:
Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â
Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â 11 beta-hydroxylase Â
11-deoxycortisol--------------------------->cortisol Compound S is typically increased when
adrenocorticotropic hormone (ACTH) levels are increased (eg, Cushing disease, ACTH-producing
tumors) or in 11 beta-hydroxylase deficiency, a rare subform of congenital adrenal hyperplasia (CAH).
In CAH due to 11 beta-hydroxylase deficiency, cortisol levels are low, resulting in increased pituitary
ACTH production and increased serum and urine 11-deoxycortisol levels. Pharmacological blockade of
11 beta-hydroxylase with metyrapone can be used to assess the function of the
hypothalamic-pituitary-adrenal axis (HPA). In this procedure metyrapone is administered to patients,
and serum 11-deoxycortisol levels or urinary 17-hydroxy steroid levels are measured either at baseline
(midnight) and 8 hours later (overnight test), or at baseline and once per day during a 2-day metyrapone
test (4-times a day metyrapone administration over 2 days). Two-day metyrapone testing has been
largely abandoned because of the logistical problems of multiple timed urine and blood collections and
the fact that overnight testing provides very similar results. In either case, the normal response to
metyrapone administration is a fall in serum cortisol levels, triggering a rise in pituitary ACTH
secretion, which, in turn, leads to a rise in 11-deoxycortisol levels due to the ongoing
11-deoxycortisol-to-cortisol conversion block. In the diagnostic workup of suspected adrenal
insufficiency, the results of overnight metyrapone testing correlate closely with the gold standard of
HPA-axis assessment, insulin hypoglycemia testing. Combining 11-deoxycortisol measurements with
ACTH measurements during metyrapone testing further enhances the performance of the test.
Impairment of any component of the HPA-axis results in a subnormal rise in 11-deoxycortisol levels.
By contrast, standard-dose or low-dose ACTH(1-24) (cosyntropin)-stimulation testing, which forms the
backbone for diagnosis of primary adrenal failure (Addison disease), only assess the ability of the
adrenal cells to respond to ACTH stimulation. While this allows unequivocal diagnosis of primary
adrenal failure, in the setting of secondary or tertiary adrenal insufficiency, metyrapone testing is more
sensitive and specific than either standard-dose or low-dose ACTH(1-24)-stimulation testing.
Metyrapone testing is also sometimes employed in the differential diagnosis of Cushing syndrome. In
Cushing disease (pituitary-dependent ACTH overproduction), the ACTH-hypersecreting pituitary tissue
remains responsive to the usual feedback stimuli, just at a higher "set-point" than in the normal state,
resulting in increased ACTH secretion and 11-deoxycortisol production after metyrapone
administration. By contrast, in Cushing syndrome due to primary adrenal corticosteroid oversecretion or
ectopic ACTH secretion, pituitary ACTH production is appropriately shut down and there is usually no
further rise in ACTH and, hence 11-deoxycortisol, after metyrapone administration. The metyrapone
test has similar sensitivity and specificity to the high-dose dexamethasone suppression test in the
differential diagnosis of Cushing disease, but is less widely used because of the lack of availability of an
easy, automated 11-deoxycortisol assay. In recent years, both tests have been supplanted to some degree
by corticotropin-releasing hormone (CRH)-stimulation testing with petrosal sinus serum ACTH
sampling. See Steroid Pathways in Special Instructions.
Useful For: Diagnostic workup of patients with congenital adrenal hyperplasia Part of metyrapone
testing in the workup of suspected secondary or tertiary adrenal insufficiency Part of metyrapone testing
in the differential diagnostic workup of Cushing syndrome
Interpretation: In a patient suspected of having congenital adrenal hyperplasia (CAH), elevated serum
11-deoxycortisol levels indicate possible 11 beta-hydroxylase deficiency. However, not all patients will
show baseline elevations in serum 11-deoxycortisol levels. In a significant proportion of cases, increases
in 11-deoxycortisol levels are only apparent after adrenocorticotropic hormone (ACTH)(1-24)
stimulation.(1) Serum 11-deoxycortisol levels below 1,700 ng/dL 8 hours after metyrapone administration
is indicative of probable adrenal insufficiency. The test cannot reliably distinguish between primary and
secondary or tertiary causes of adrenal failure, as neither patients with pituitary failure, nor those with
primary adrenocortical failure, tend to show an increase of 11-deoxycortisol levels after metyrapone is
administered. See Steroid Pathways in Special Instructions.
Reference Values:
< or =18 years: <344 ng/dL
>18 years: 10-79 ng/dL
Clinical References: 1. Tonetto-Fernandes V, Lemos-Marini SH, Kuperman H, et al: Serum
21-deoxycortisol, 17-hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal
hyperplasia: clinical and hormonal correlations and identification of patients with 11 beta-hydroxylase
deficiency among a large group with alleged 21-hydroxylase deficiency. J Clin Endocrinol Metab 2006
Jun;91(6):2179-2184 2. Lashanske G, Sainger P, Fishman K, et al: Normative data for adrenal
steroidogenesis in a healthy pediatric population: age- and sex-related changes after adrenocorticotropin
stimulation. J Clin Endocrinol Metab 1991 Sep;73(3):674-686 3. Holst JP, Soldin SJ, Tractenberg RE,
et al: Use of steroid profiles in determining the cause of adrenal insufficiency. Steroids 2007
Jan;72(1):71-84 4. Berneis K, Staub JJ, Gessler A, et al: Combined stimulation of adrenocorticotropin
and compound-S by single dose metyrapone test as an outpatient procedure to assess
hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab 2002 Dec;87(12):5470-5475
F11DX 11-Desoxycortisol
75673 Reference Values:
Age Range (ng/dL)

Premature (26 - 28 weeks) Day 4 110-1376
Premature (31 - 35 weeks) Day 4 48-579
Newborn Day 3 13-147
Newborn 1 to 11 months
Prepubertal 8 AM 20-155
Prepubertal Children and Adults 8 AM 12-158
THCMX 11-nor-Delta-9-Tetrahydrocannabinol-9-Carboxylic Acid

62744 (Carboxy-THC) Confirmation, Chain of Custody, Meconium
Clinical Information: Marijuana and other psychoactive products obtained from the plant Cannabis
sativa are the most widely used illicit drugs in the world.(1) Marijuana has unique behavioral effects
that include feelings of euphoria and relaxation, altered time perception, impaired learning and memory,
lack of concentration, and mood changes (eg, panic reactions and paranoia). Cannabis sativa produces
numerous compounds collectively known as cannabinoids including delta-9-tetrahydrocannabinol
(THC), which is the most prevalent and produces most of the characteristic pharmacological effects of
smoked marijuana.(2) THC undergoes rapid hydroxylation by the cytochrome (CYP) enzyme system to
form the active metabolite 11-hydroxy-THC. Subsequent oxidation of 11-hydroxy-THC produces the
inactive metabolite 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH;
carboxy-THC). THC-COOH and its glucuronide conjugate have been identified as the major
end-products of metabolism. THC is highly lipid soluble, resulting in its concentration and prolonged
retention in fat tissue.(3) Cannabinoids cross the placenta, but a dose-response relationship or
correlation has not been established between the amount of marijuana use in pregnancy and the levels of
cannabinoids found in meconium, the first fecal matter passed by the neonate.(4,5) The disposition of
drug in meconium is not well understood. The proposed mechanism is that the fetus excretes drug into
bile and amniotic fluid. Drug accumulates in meconium either by direct deposition from bile or through
swallowing amniotic fluid.(5) The first evidence of meconium in the fetal intestine appears at
approximately the 10th to 12th week of gestation, and slowly moves into the colon by the 16th week of
gestation.(6) Therefore, the presence of drugs in meconium has been proposed to be indicative of in
utero drug exposure during the final 4 to 5 months of pregnancy, a longer historical measure than is
possible by urinalysis.(5) Chain of custody is a record of the disposition of a specimen to document
each individual who collected, handled, and performed the analysis. When a specimen is submitted in
this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.
Useful For: Detection of in utero drug exposure up to 5 months before birth Chain of custody is
required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights
of the individual contributing the specimen by demonstrating that it was under the control of personnel
involved with testing the specimen at all times; this control implies that the opportunity for specimen
tampering would be limited. Since the evidence of illicit drug use during pregnancy can be cause for
separating the baby from the mother, a complete chain of custody ensures that the test results are
appropriate for legal proceedings.
Interpretation: The presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid > or =5 ng/g is

indicative of in utero drug exposure up to 5 months before birth.
Reference Values:
Negative
Positives are reported with a quantitative liquid chromatography-tandem mass spectrometry result.
Cutoff concentration: 5 ng/g
Clinical References: 1. Huestis MA: Marijuana. In: Levine B, ed. Principles of Forensic
Toxicology. 2nd ed. AACC Press; 2003:229-264 2. O'Brein CP: Drug addiction and drug abuse. In:
Burton LL, Lazo JS,Â Parker KL, eds. Goodman and Gilman's The Pharmacological Basis of
Therapeutics. 11th ed. McGraw-Hill Companies Inc; 2006 3. Baselt RC: Tetrahydrocannabinol. In: Baselt
RC, ed. Disposition of Toxic Drugs and Chemical in Man. Biomedical Publications; 2008:1513-1518 4.
Ostrea EM Jr, Knapop DK, Tannenbaum L, et al: Estimates of illicit drug use during pregnancy by
maternal interview, hair analysis, and meconium analysis. J Pediatr. 2001;138:344-348 5. Ostrea EM Jr,
Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers: an
alternative to urine testing. J Pediatr. 1989;115:474-477 6. Ahanya SN, Lakshmanan J, Morgan BL, Ross
MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv.
2005;60:45-56 7. Langman LJ, Bechtel LK, Meier BM, Holstege C: Clinical toxicology. In: Rifai N,
Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed.
Elsevier;2018:883-884
THCM 11-nor-Delta-9-Tetrahydrocannabinol-9-Carboxylic Acid

84284 (Carboxy-THC) Confirmation, Meconium
Clinical Information: Marijuana and other psychoactive products obtained from the plant Cannabis
sativa are the most widely used illicit drugs in the world.(1) Marijuana has unique behavioral effects that
include feelings of euphoria and relaxation, altered time perception, impaired learning and memory, lack
of concentration, and mood changes (eg, panic reactions and paranoia). Cannabis sativa produces
numerous compounds collectively known as cannabinoids including delta-9-tetrahydrocannabinol (THC),
which is the most prevalent and produces most of the characteristic pharmacological effects of smoked
marijuana.(2) THC undergoes rapid hydroxylation by the cytochrome (CYP) enzyme system to form the
active metabolite 11-hydroxy-THC. Subsequent oxidation of 11-hydroxy-THC produces the inactive
metabolite 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH; carboxy-THC).
THC-COOH and its glucuronide conjugate have been identified as the major end-products of metabolism.
THC is highly lipid soluble, resulting in its concentration and prolonged retention in fat tissue.(3)
Cannabinoids cross the placenta, but a dose-response relationship or correlation has not been established
between the amount of marijuana use in pregnancy and the levels of cannabinoids found in meconium, the
first fecal matter passed by the neonate.(4,5) The disposition of drug in meconium is not well understood.
The proposed mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in
meconium either by direct deposition from bile or through swallowing amniotic fluid.(5) The first
evidence of meconium in the fetal intestine appears at approximately the tenth to twelfth week of
gestation, and slowly moves into the colon by the sixteenth week of gestation.(6) Therefore, the presence
of drugs in meconium has been proposed to be indicative of in utero drug exposure during the final 4 to 5
months of pregnancy, a longer historical measure than is possible by urinalysis.(5)
Useful For: Detection of in utero drug exposure to marijuana (tetrahydrocannabinol) up to 5 months

before birth
Interpretation: The presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid at 5 ng/g or
greater is indicative of in utero drug exposure up to 5 months before birth.
Reference Values:
Negative
Clinical References: 1. Huestis MA: Marijuana. In: Levine B ed. Principles of Forensic
Toxicology. 2nd ed. AACC Press; 2003:229-264 2. O'Brein CP: Drug addiction and drug abuse. In:
Burton LL, Lazo JS, ParkerKL, eds. Goodman and Gilman's The Pharmacological Basis of
Therapeutics. 11th ed. McGraw-Hill Companies Inc; 2006 3. Baselt RC: Tetrahydrocannabinol. In:
Baselt RC, ed. Disposition of Toxic Drugs and Chemical in Man. Biomedical Publications;
2008:1513-1518 4. Ostrea EM Jr, Knapop DK, Tannenbaum L, et al: Estimates of illicit drug use during
pregnancy by maternal interview, hair analysis, and meconium analysis. J Pediatr. 2001;138:344-348 5.
Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent
mothers: an alternative to urine testing. J Pediatr. 1989;115:474-477 6. Ahanya SN, Lakshmanan J,
Morgan BL, Ross MG: Meconium passage in utero: mechanisms, consequences, and management.
Obstet Gynecol Surv. 2005;60:45-56 7. Langman LJ, Bechtel LK, Meier BM, Holstege C. Clinical
toxicology. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier;2018:883-884
F143P 14-3-3 eta Protein

75516 Clinical Information: The 14-3-3 protein appears to contribute to the pathologic process of joint
erosion and, as such, is an emerging biomarker of joint damage in rheumatoid arthritis (RA) and
psoriatic arthritis. Concentrations are significantly higher in people with active joint disease than in
those with inactive RA or psoriasis without arthritis. Measurement of 14-3-3 complements RF and CCP
antibody tests and may improve diagnostic sensitivity.
Reference Values:
<0.2 ng/mL
17OHP 17-Hydroxypregnenolone, Serum

81151 Clinical Information: Congenital adrenal hyperplasia (CAH) is caused by inherited defects in
steroid biosynthesis. Deficiencies in several enzymes cause CAH including 21-hydroxylase (CYP21A2
mutations; 90% of cases), 11-hydroxylase (CYP11A1 mutations; 5%-8%), 3-beta-hydroxy
dehydrogenase (HSD3B2 mutations; <5%), and 17-alpha-hydroxylase (CYP17A1 mutations; 125 cases
reported to date). The resulting hormone imbalances (reduced glucocorticoids and mineralocorticoids,
and elevated steroid intermediates and androgens) can lead to life-threatening, salt-wasting crises in the
newborn period and incorrect gender assignment of virilized females. The adrenal glands, ovaries,
testes, and placenta produce steroid intermediates, which are hydroxylated at the position 21 (by
21-hydroxylase) and position 11 (by 11-hydroxylase) to produce cortisol. Deficiency of either
21-hydroxylase or 11-hydroxylase results in decreased cortisol synthesis and loss of feedback inhibition
of adrenocorticotropic hormone (ACTH) secretion. The consequent increased pituitary release of ACTH
drives increased production of steroid intermediates. Â The steroid intermediates are oxidized at
position 3 (by 3-beta-hydroxy dehydrogenase: 3-beta-HSD). The 3-beta-HSD enzyme allows formation
of 17-hydroxyprogesterone (17-OHPG) from 17-hydroxypregnenolone and progesterone from
pregnenolone. When 3-beta-HSD is deficient, cortisol is decreased, 17-hydroxypregnenolone and
pregnenolone levels may increase, and 17-OHPG and progesterone levels, respectively, are low.
Dehydroepiandrosterone (DHEA) is also converted to androstenedione by 3-beta-HSD and may be
elevated in patients affected with 3-beta-HSD deficiency. The best screening test for CAH, most often
caused by either 21- or 11-hydroxylase deficiency, is the analysis of 17-hydroxyprogesterone (along
with cortisol and androstenedione). CAH21 / Congenital Adrenal Hyperplasia (CAH) Profile for
21-Hydroxylase Deficiency allows the simultaneous determination of these 3 analytes. Alternatively,
these tests may be ordered individually: OHPG / 17-Hydroxyprogesterone, Serum; CINP / Cortisol,
Serum, LC-MS/MS; and ANST / Androstenedione, Serum. If both 21- and 11-hydroxylase deficiency
have been ruled out, analysis of 17-hydroxypregnenolone and pregnenolone may be used to confirm the
diagnosis of 3-beta-HSD or 17-alpha-hydroxylase deficiency. See Steroid Pathways in Special
Instructions.
Useful For: As an ancillary test for congenital adrenal hyperplasia (CAH), particularly in situations in
which a diagnosis of 21-hydroxylase and 11-hydroxylase deficiency have been ruled out Confirming a
diagnosis of 3-beta-hydroxy dehydrogenase (3-beta-HSD) deficiency Analysis for
17-hydroxypregnenolone is also useful as part of a battery of tests to evaluate females with hirsutism or
infertility; both can result from adult-onset CAH.
Interpretation: Diagnosis and differential diagnosis of congenital adrenal hyperplasia (CAH) always
requires the measurement of several steroids. Patients with CAH due to steroid 21-hydroxylase gene
(CYP21A2) mutations usually have very high levels of androstenedione, often 5-fold to 10-fold
elevations. 17-hydroxyprogesterone (17-OHPG) levels are usually even higher, while cortisol levels are
low or undetectable. All 3 analytes should be tested. For the HSD3B2 mutation, cortisol, 17-OHPG and
progesterone levels will be will be decreased; 17-hydroxypregnenolone and pregnenolone and
dehydroepiandrosterone (DHEA) levels will be increased. In the much less common CYP11A1 mutation,
androstenedione levels are elevated to a similar extent as in CYP21A2 mutation, and cortisol is also low,
but OHPG is only mildly, if at all, elevated. In the also very rare 17-alpha-hydroxylase deficiency,
androstenedione, all other androgen-precursors (17-alpha-hydroxypregnenolone, OHPG,
dehydroepiandrosterone sulfate), androgens (testosterone, estrone, estradiol), and cortisol are low, while
production of mineral corticoid and its precursors (in particular pregnenolone, 11-dexycorticosterone,
corticosterone, and 18-hydroxycorticosterone) are increased. See Steroid Pathways in Special Instructions.
Reference Values:
CHILDREN*
Males
Premature (26-28 weeks): 1,219-9,799 ng/dL
Premature (29-36 weeks): 346-8,911 ng/dL
Full term (1-5 months): 229-3,104 ng/dL
6 months-364 days: 221-1,981 ng/dL
1-2 years: 35-712 ng/dL
3-6 years: <277 ng/dL
10-12 years: <393 ng/dL
13-15 years: 35-465 ng/dL
16-17 years: 32-478 ng/dL
TANNER STAGES
Stage I: <209 ng/dL
Stage II: <356 ng/dL
Stage III: <451 ng/dL
Stage IV-V: 35-478 ng/dL
Females
Premature (26-28 weeks): 1,219-9,799 ng/dL
Premature (29-36 weeks): 346-8,911 ng/dL
Full term (1-5 months): 229-3,104 ng/dL
6 months-364 days: 221-1,981 ng/dL
1-2 years: 35-712 ng/dL
10-12 years: <399 ng/dL
13-15 years: <408 ng/dL
16-17 years: <424 ng/dL
TANNER STAGES
Stage I: <236 ng/dL
Stage II: <368 ng/dL
Stage III: <431 ng/dL
Stage IV-V: <413 ng/dL
ADULTS
Males
> or =18 years: 55-455 ng/dL
Females
> or =18 years: 31-455 ng/dL
*Kushnir MM, Rockwood AL, Roberts WL, et al: Development and performance evaluation of a tandem
mass spectrometry assay for 4 adrenal steroids. Clin Chem 2006;52(8):1559-1567
Clinical References: 1. Wudy SA, Hartmann M, Svoboda M: Determination of

17-hydroxypregnenolone in plasma by stabile isotope dilution/benchtop liquid chromatography-tandem
mass spectrometry. Horm Res 2000;53(2):68-71 2. Therrell BL: Newborn screening for congenital
adrenal hyperplasia Endocrinol Metab Clin North Am 2001;30(1):15-30 3. Bachega TA, Billerbeck AE,
Marcondes JA, et al: Influence of different genotypes on 17-hydroxyprogesterone levels in patients with
nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol
2000;52(5):601-607 4. Kao P, Machacek DA, Magera MJ, at al: Diagnosis of adrenal cortical
dysfunction by liquid chromatography-tandem mass spectrometry. Ann Clin Lab Sci
2001;31(2):199-204 5. Sciarra F, Tosti-Croce C, Toscano V: Androgen-secreting adrenal tumors.
Minerva Endocrinol 1995;20(1):63-68 6. Collett-Solberg PF: Congenital adrenal hyperplasia: from
genetics and biochemistry to clinical practice, part I. Clin Pediatr 2001:40(1):1-16
OHPG 17-Hydroxyprogesterone, Serum

9231 Clinical Information: Congenital adrenal hyperplasia (CAH) is caused by inherited defects in
steroid biosynthesis. The resulting hormone imbalances with reduced glucocorticoids and
mineralocorticoids and elevated 17-hydroxyprogesterone (OHPG) and androgens can lead to
life-threatening, salt-wasting crisis in the newborn period and incorrect gender assignment of virtualized
females. Adult-onset CAH may result in hirsutism or infertility in females. The adrenal glands, ovaries,
testes, and placenta produce OHPG. It is hydroxylated at the 11 and 21 position to produce cortisol.
Deficiency of either 11- or 21-hydroxylase results in decreased cortisol synthesis, and feedback
inhibition of adrenocorticotropic hormone (ACTH) secretion is lost. Consequent increased pituitary
release of ACTH increases production of OHPG. But, if 17-alpha-hydroxylase (which allows formation
of OHPG from progesterone) or 3-beta-hydroxysteroid dehydrogenase type 2 (which allows formation
of 17-hydroxyprogesterone formation from 17-hydroxypregnenolone) are deficient, OHPG levels are
low with possible increase in progesterone or pregnenolone respectively. OHPG is bound to both
corticosteroid binding globulin and albumin and total OHPG is measured in this assay. OHPG is
converted to pregnanetriol, which is conjugated and excreted in the urine. In all instances, more specific
tests are available to diagnose disorders or steroid metabolism than pregnanetriol measurement. Most
(90%) cases of CAH are due to variants in the steroid 21-hydroxylase gene (CYP21A2). CAH due to
21-hydroxylase deficiency is diagnosed by confirming elevations of OHPG and androstenedione
(ANST / Androstenedione, Serum) with decreased cortisol (CINP / Cortisol, Mass Spectrometry,
Serum). By contrast, in 2 less common forms of CAH, due to 17-hydroxylase or 11-hydroxylase
deficiency, OHPG and androstenedione levels are not significantly elevated and measurement of
progesterone (PGSN / Progesterone, Serum) and deoxycorticosterone (FDOC / Deoxycorticosterone
[DOC], Serum), respectively, are necessary for diagnosis. CAH21 / Congenital Adrenal Hyperplasia
(CAH) Profile for 21-Hydroxylase Deficiency allows the simultaneous determination of OHPG,
androstenedione, and cortisol. See Steroid Pathways in Special Instructions.
Useful For: The analysis of 17-hydroxyprogesterone (17-OHPG) is 1 of the 3 analytes along with
cortisol and androstenedione, that constitutes the best screening test for congenital adrenal hyperplasia
(CAH), caused by either 11- or 21-hydroxylase deficiency. Analysis for 17-OHPG is also useful as part
of a battery of tests to evaluate females with hirsutism or infertility; both can result from adult-onset
CAH
requires the measurement of several steroids. Patients with CAH due to steroid 21-hydroxylase gene
(CYP21A2) variants usually have very high levels of androstenedione, often 5- to 10-fold elevations.
17-hydroxyprogesterone (OHPG) levels are usually even higher, while cortisol levels are low or
undetectable. All 3 analytes should be tested. In the much less common CYP11A1 variant,
androstenedione levels are elevated to a similar extent as in CYP21A2 variant, and cortisol is also low,
but OHPG is only mildly, if at all, elevated. In the also very rare 17-alpha-hydroxylase deficiency,
androstenedione, all other androgen-precursors (17-alpha-hydroxypregnenolone, OHPG,
dehydroepiandrosterone sulfate), androgens (testosterone, estrone, estradiol), and cortisol are low, while
production of mineral corticoid and its precursors, in particular progesterone, 11-deoxycorticosterone,
and 18-hydroxycorticosterone, are increased. The goal of CAH treatment is normalization of cortisol
levels and ideally also of sex-steroid levels. Traditionally, OHPG and urinary pregnanetriol or total
ketosteroid excretion are measured to guide treatment, but these tests correlate only modestly with
androgen levels. Therefore, androstenedione and testosterone should also be measured and used to
guide treatment modifications. Normal prepubertal levels may be difficult to achieve, but if testosterone
levels are within the reference range, androstenedione levels of up to 100 ng/dL are usually regarded as
acceptable. See Steroid Pathways in Special Instructions.
Reference Values:
Children:
Preterm infants
Preterm infants may exceed 630 ng/dL, however, it is uncommon to see levels reach 1,000 ng/dL.
Term infants
0-28 days: <630 ng/dL
Levels fall from newborn (<630 ng/dL) to prepubertal gradually within 6 months.
Prepubertal males: <110 ng/dL
Prepubertal females: <100 ng/dL
Adults:
Males: <220 ng/dL
Females
Follicular: <80 ng/dL
Luteal: <285 ng/dL
Postmenopausal: <51 ng/dL
Note: For pregnancy reference ranges, see: Soldin OP, Guo T, Weiderpass E, et al: Steroid hormone
levels in pregnancy and 1 year postpartum using isotope dilution tandem mass spectrometry. Fertil Steril.
2005 Sept;84(3):701-710
Clinical References: 1. Therrell BL: Newborn screening for congenital adrenal hyperplasia.
Endocrinol Metab Clin North Am. 2001;30(1):15-30 2. Bachega TA, Billerbeck AE, Marcondes JA, et al:
Influence of different genotypes on 17-hydroxyprogesterone levels in patients with non-classical
congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol. 2000;52(5):601-607 3.
Von Schnaken K, Bidlingmaier F, Knorr D: 17-hydroxyprogesterone, androstenedione, and testosterone
in normal children and in prepubertal patients with congenital adrenal hyperplasia. Eur J Pediatr.
1980;133(3):259-267 4. Sciarra F, Tosti-Croce C, Toscano V: Androgen-secreting adrenal tumors.
Minerva Ednocrinol. 1995;20(1):63-68 5. Collett-Solberg PF: Congenital adrenal hyperplasia: from
genetics and biochemistry to clinical practice, part I. Clin Pediatr. 2001;40(1):1-16 6. Soldin OP, Guo T,
Weiderpass E, et al: Steroid hormone levels in pregnancy and 1 year postpartum using isotope dilution
tandem mass spectrometry. Fertil Steril. 2005 Sept;84(3):701-710 7. Speiser PW, Azziz R, Baskin LS, et
al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society
Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(9):4133-4160 Available at:
jcem.endojournals.org
FHC18 18-Hydroxycorticosterone, Serum

Age Range (ng/dL)
Premature (26 - 28 weeks) Day 4 10 - 670
Premature (31 - 35 weeks) Day 4 57 - 410
Full-term Day 3 31 - 546
31 days to 11 months 5 - 220
12 - 23 months 18 - 155
24 months to 9 years 6 - 85
10 - 14 years 10 - 72
Adults 9 - 58
Adults 8:00 AM Supine 4 - 21
Adults 8:00 AM Upright 5 - 46
GLIOF 1p/19q Deletion in Gliomas, FISH, Tissue

35272 Clinical Information: Astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas are the
major histologic types of human gliomas; histologic differentiation among these tumors can be difficult.
It has been shown that specific genetic alterations are highly associated with specific morphologic types
of gliomas. In addition, specific genetic alterations seem to predict prognosis (survival), as well as
response to specific chemotherapeutic and radiotherapeutic regimens, irrespective of tumor
morphology. Deletions of the short arm of chromosome 1(1p) and long arm of chromosome 19 (19q),
are strongly correlated with gliomas of oligodendroglial morphology. Approximately 70%, 50%, and
50% of oligodendrogliomas have deletions of 19q, 1p, and of both 19q and 1p, respectively. Combined
1p and 19q loss is infrequent in gliomas of astrocytic origin. Thus, the presence of combined 1p/19q
loss is strongly suggestive that a glioma is of oligodendroglioma lineage. Gains of chromosome 19 and
of the 19 q-arm are associated with gliomas of astrocytic origin. Deletions of 1p and of both 1p and 19q
also have been associated with response to various chemotherapeutic and radiotherapeutic regimens.
These responses have been especially associated with high-grade oligodendrogliomas (anaplastic
oligodendrogliomas). Chromosomal microarray (CMAPT / Chromosomal Microarray, Tumor,
Formalin-Fixed Paraffin-Embedded), rather than fluorescence in situ hybridization, may be of benefit to
evaluate for acquired alterations associated with the molecular classification of glioma.(1) See
Cytogenetic Analysis of Glioma.
Useful For: Aids in diagnosing oligodendroglioma tumors and predicting the response of an
oligodendroglioma to therapy May be useful in tumors with a complex "hybrid" morphology requiring
differentiation from pure astrocytomas to support the presence of oligodendroglial
differentiation/lineage Indicated when a diagnosis of oligodendroglioma, both low-grade World Health
Organization (WHO, grade II) and anaplastic (WHO, grade III) is rendered Strongly recommended
when a diagnosis of mixed oligoastrocytomas is rendered
Interpretation: The presence of short arm of chromosome 1(1p) deletion and combined 1p and long
arm of chromosome 19 deletion supports a diagnosis of oligodendroglioma may indicate that the patient
may respond to chemotherapy and radiation therapy. The presence of gain of chromosome 19 supports a
diagnosis of high-grade astrocytoma (glioblastoma multiforme). A negative result does not exclude a
diagnosis of oligodendroglioma or high-grade astrocytoma.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. WHO Classification of Tumours Editorial Board. Central Nervous System
Tumours: WHO Classification of Tumours. Vol 6. 5th ed. IARC Press; 2022:19-55 2. Ball MK,
Kollmeyer TM, Praska CE, et al. Frequency of false-positive FISH 1p/19q codeletion in adult diffuse
astrocytic gliomas. Neurooncol Adv. 2020 Aug 27;2(1):vdaa109. doi: 10.1093/noajnl/vdaa109
BPGMM 2,3-Bisphosphoglycerate Mutase, Full Gene Sequencing

63208 Analysis, Varies
Clinical Information: Erythrocytosis (ie, increased red blood cell mass and elevated hemoglobin and
hematocrit) may be primary, due to an intrinsic defect of bone marrow stem cells as in polycythemia vera
(PV), or secondary, in response to increased serum erythropoietin (EPO) levels. Secondary erythrocytosis
is associated with a number of disorders including chronic lung disease, chronic increase in carbon
monoxide, cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other
EPO-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable
cause involving hemoglobin or erythrocyte regulatory mechanism may be suspected. Unlike PV,
hereditary erythrocytosis is not associated with the risk of clonal evolution and most commonly presents
as isolated erythrocytosis that has been present since childhood. Hereditary erythrocytosis may be caused
by alterations in one of several genes and inherited in either an autosomal dominant or autosomal
recessive manner. Genetic variants causing hereditary erythrocytosis have been found in genes coding for
alpha and beta hemoglobins, hemoglobin stabilization proteins (eg, 2,3-bisphosphoglycerate mutase:
BPGM), the erythropoietin receptor (EPOR), and oxygen-sensing pathway enzymes (hypoxia-inducible
factor: HIF, prolyl hydroxylase domain: PHD, and von Hippel Lindau: VHL), see table.
High-oxygen-affinity hemoglobin variants and BPGM abnormalities result in a decreased p50 result,
whereas those affecting EPOR, HIF, PHD, and VHL have normal p50 results. The true prevalence of
variants causing hereditary erythrocytosis is unknown; however, very few cases of 2,3-BPG
deficiency-associated hereditary erythrocytosis have been identified and this disorder is thought to be rare.
Erythrocytosis Testing Gene Inheritance Serum Epo p50 JAK2 V617F Acquired Decreased Normal JAK2
exon 12 Acquired Decreased Normal EPOR Dominant Decreased Normal PHD2/EGLN1 Dominant
Normal Normal to mildly decreased BPGM Recessive Normal Decreased Beta globin Dominant Normal
to increased Decreased Alpha globin Dominant Normal to increased Decreased HIF2A/EPAS1 Dominant
Normal to increased Normal VHL Recessive Normal to increased Normal
Useful For: Diagnosis of 2,3-bisphosphoglycerate mutase deficiency in individuals with lifelong,

unexplained erythrocytosis Identifying genetic variant carriers in family members of an affected
individual for the purposes of preconception genetic counseling This test is not intended for prenatal
diagnosis.
Interpretation: An interpretive report will be provided and will include specimen information, assay
information, and whether the specimen was positive for any variations in the gene. If positive, the
alteration will be correlated with clinical significance, if known.
Reference Values:
Clinical References: 1. Petousi N, Copley RR, Lappin TR, et al: Erythrocytosis associated with a
novel missense mutation in the BPGM gene. Haematologica. 2014 Oct;99:e201-e204 2. Hoyer JD, Allen
SL, Beutler E, et al: Erythrocytosis due to bisphosphoglycerate mutase deficiency with concurrent
glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Am J Hematol. 2004;75(4):205-208 3. Rosa R,
Prehu MO, Beuzard Y, Rosa J: The first case of a complete deficiency of diphosphoglycerate mutase in
human erythrocytes. J Clin Invest. 1978;62(5):907-915
23BPT 2,3-Dinor 11 Beta-Prostaglandin F2 Alpha, 24 Hour, Urine

606357 Clinical Information: 2,3-Dinor-11beta-prostaglandin F2 alpha (2,3 BPG) is the most abundant
metabolic product of prostaglandins released by activated mast cells. Systemic mastocytosis (SM) is a
disease in which clonally derived mast cells accumulate in peripheral tissues. Degranulation of these mast
cells releases large amounts of histamines, prostaglandins, leukotrienes, and tryptase. World Health
Organization diagnostic criteria for SM require the presence of elevated mast cell counts on a bone
marrow biopsy and 1 of the following minor criteria: -Abnormal mast cell morphology -KIT Asp816Val
variant -CD25-positive mast cells -Serum tryptase greater than 20 ng/mL Alternatively, SM diagnosis can
be made with the presence of 3 minor criteria in the absence of abnormal bone marrow studies.
Measurement of mast cell mediators in blood or urine is less invasive and is advised for the initial
evaluation of suspected cases. Elevated levels of serum tryptase, urinary N-methylhistamine, 2,3 BPG, or
leukotriene E4 are consistent with the diagnosis of systemic mast cell disease.
Useful For: Screening for mast cell activation disorders including systemic mastocytosis using
24-hour urine specimens
Interpretation: Elevated urine 2,3-dinor-11beta-prostaglandin F2 alpha is consistent with systemic

mastocytosis.
Reference Values:
<1802 pg/mg creatinine
Clinical References: 1. Gotlib J, Pardanani A, Akin C, et al: International Working

Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Competence
Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis.
Blood. 2013 Mar 28;121(13):2393-2401. doi: 10.1182/blood-2012-09-458521 2. Butterfield JH:
Increased leukotriene E4 excretion in systemic mastocytosis. Prostaglandins Other Lipid Mediat. 2010
Jun;92(1-4):73-76. doi: 10.1016/j.prostaglandins.2010.03.003 3. Roberts LJ II, Sweetman BJ, Lewis
RA, Austen KF, Oates JA: Increased production of prostaglandin D2 in patients with systemic
mastocytosis. N Engl J Med. 1980 Dec 11;303(24):1400-1404. doi: 10.1056/NEJM198012113032405
4. Metcalfe DD: Mastocytosis syndromes. In: Middleton E Jr, Reed CE, Ellis EF, et al. eds. Allergy
Principles and Practice. Vol II. 4th ed. Mosby Yearbook Inc; 1993:1537-1551
23BPR 2,3-Dinor 11 Beta-Prostaglandin F2 Alpha, Random, Urine

606356 Clinical Information: 2,3-Dinor-11beta-prostaglandin F2 alpha (2,3 BPG) is the most abundant
metabolic product of prostaglandins released by activated mast cells. Systemic mastocytosis (SM) is a
disease in which clonally derived mast cells accumulate in peripheral tissues. Degranulation of these
mast cells releases large amounts of histamines, prostaglandins, leukotrienes, and tryptase. World
Health Organization diagnostic criteria for SM require the presence of elevated mast cell counts on a
bone marrow biopsy and 1 of the following minor criteria: -Abnormal mast cell morphology -KIT
Asp816Val variant -CD25-positive mast cells -Serum tryptase greater than 20 ng/mL Alternatively, SM
diagnosis can be made with the presence of 3 minor criteria in the absence of abnormal bone marrow
studies. Measurement of mast cell mediators in blood or urine is less invasive and is advised for the
initial evaluation of suspected cases. Elevated levels of serum tryptase, urinary N-methylhistamine, 2,3
BPG, or leukotriene E4 are consistent with the diagnosis of systemic mast cell disease.
Useful For: Screening for mast cell activation disorders including systemic mastocytosis using
random urine specimens
Interpretation: Elevated urine 2,3-dinor-11beta-prostaglandin F2 alpha is consistent with systemic

mastocytosis.
Reference Values:
<1802 pg/mg creatinine
Clinical References: 1. Gotlib J, Pardanani A, Akin C, et al: International Working

Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Competence
Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis.
Blood. 2013 Mar 28;121(13):2393-2401. doi: 10.1182/blood-2012-09-458521 2. Butterfield JH:
Increased leukotriene E4 excretion in systemic mastocytosis. Prostaglandins Other Lipid Mediat. 2010
Jun;92(1-4):73-76. doi: 10.1016/j.prostaglandins.2010.03.003 3. Roberts LJ 2nd, Sweetman BJ, Lewis
RA, Austen KF, Oates JA: Increased production of prostaglandin D2 in patients with systemic
mastocytosis. N Engl J Med. 1980 Dec 11;303(24):1400-1404. doi: 10.1056/NEJM198012113032405
4. Metcalfe DD: Mastocytosis syndromes. In: Middleton E Jr, Reed CE, Ellis EF, et al. eds. Allergy
Principles and Practice. Vol II. 4th ed. Mosby Yearbook Inc; 1993:1537-1551
2HGA 2-Hydroxyglutaric Acid Chiral Analysis, Quantitative, Random,
614603 Urine
Clinical Information: 2-Hydroxyglutaric aciduria disorders are a group of cerebral organic acidurias
that present biochemically with an elevation of 2-hydroxyglutaric acid (2-HGA) in the urine. There are 2
enantiomers or forms of 2-HGA, the D-form and the L-form. Depending on the genetic defect, individuals
may have an elevation of one or both forms of 2-HGA. Routine organic acid analysis (OAU / Organic
Acids Screen, Random, Urine), while able to detect 2-HGA, is unable to distinguish between the 2
enantiomers; however, they can be separated with this more specialized biochemical test.
L-2-hydroxyglutaric aciduria (L-2-HGA) is caused by defects in L2HGDH and is characterized by
progressive cerebellar ataxia and intellectual disability, seizures, and macrocephaly beginning in infancy
or early childhood. Symptoms worsen over time leading to severe disability by early adulthood. Magnetic
resonance imaging (MRI) findings include subcortical leukoencephalopathy, generalized cerebellar and
cerebral atrophy, and atrophy of the corpus callosum. D-2-hydroxylglutaric aciduria (D-2-HGA) is
characterized by elevated levels of D-2-hydroxyglutaric acid (D-2-HG) and typically manifests with
developmental delay, seizures, and hypotonia, though can vary widely from asymptomatic to severe.
There are 2 types of D-2-HGA depending on the genetic cause. D-2-HGA can either be autosomal
recessive, resulting from variants in D2HGDH causing reduced enzymatic activity (type I), or autosomal
dominant gain-of-function variants in IDH2 causing overproduction of D-2-HG (type II). Combined
D,L-2-hydroxylglutaric aciduria (D,L-2-HGA) is the most severe of the 3 types and is caused by defects
in SLC25A1, which encodes the mitochondrial citrate carrier. It is characterized by neonatal-onset
encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of
psychomotor development resulting in early death. Molecular genetic testing is available (2OHGP /
2-Hydroxyglutaric Aciduria Gene Panel, Varies), which includes analysis of D2HGDH, L2HGDH, IDH2,
and SLC25A1 and can be used to confirm abnormal urine results.
Useful For: Determining type of 2-hydroxyglutaric aciduria by chiral analysis of urine

Interpretation: The values for the D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid
concentrations are reported. The interpretation of the result must be correlated with clinical and other
laboratory findings.
Reference Values:
Age D-2-hydroxyglutaric acid (mmol/mol creatinine) L-2-hydroxyglutaric acid (mmol/mol creatinine)
0-11 months < or =14.11 < or =17.38
12-23 months < or =13.76 < or =17.03
24-35 months < or =13.38 < or =16.63
3 years < or =12.96 < or =16.18
4 years < or =12.20 < or =15.35
5 years < or =11.40 < or =14.44
6 years < or =10.56 < or =13.46
7 years < or =9.71 < or =12.43
8 years < or =8.93 < or =11.44
9 years < or =8.21 < or =10.50
10 years < or =7.56 < or =9.66
11 years < or =6.99 < or =8.94
12 years < or =6.47 < or =8.33
13 years < or =6.01 < or =7.83
14 years < or =5.60 < or =7.44
15 years < or =5.23 < or =7.14
16 years < or =4.91 < or =6.93
17 years < or =4.63 < or =6.78
18 years < or =4.40 < or =6.69
19 years < or =4.21 < or =6.63
20 years < or =4.07 < or =6.60
21 years < or =3.96 < or =6.59
22 years < or =3.88 < or =6.58
23 years < or =3.81 < or =6.56
24 years < or =3.76 < or =6.54
25 years < or =3.71 < or =6.50
26 years < or =3.67 < or =6.44

27 years < or =3.63 < or =6.37
28 years < or =3.59 < or =6.27
29 years < or =3.56 < or =6.15
30 years < or =3.54 < or =6.02
31 years < or =3.52 < or =5.87
32 years < or =3.50 < or =5.72
33 years < or =3.49 < or =5.57
34 years < or =3.48 < or =5.41
35 years < or =3.46 < or =5.26
36 years < or =3.45 < or =5.13
37 years < or =3.43 < or =5.00
38 years < or =3.42 < or =4.88
39 years < or =3.40 < or =4.78
40 years < or =3.39 < or =4.70
41 years < or =3.37 < or =4.62
42 years < or =3.35 < or =4.55
43 years < or =3.33 < or =4.50
44 years < or =3.30 < or =4.44
45 years < or =3.28 < or =4.40
46 years < or =3.24 < or =4.35
47 years < or =3.21 < or =4.31
48 years < or =3.17 < or =4.27
49 years < or =3.13 < or =4.23
50 years < or =3.10 < or =4.19
51 years < or =3.07 < or =4.16
52 years < or =3.04 < or =4.12
53 years < or =3.01 < or =4.10
54 years < or =2.99 < or =4.07
55 years < or =2.97 < or =4.04
56 years < or =2.95 < or =4.01
57 years < or =2.93 < or =3.98
58 years < or =2.91 < or =3.94
59 years < or =2.89 < or =3.91
60 years < or =2.87 < or =3.87
61 years < or =2.85 < or =3.84
62 years < or =2.83 < or =3.80
63 years < or =2.79 < or =3.78
64 years < or =2.76 < or =3.75

65 years < or =2.71 < or =3.73
66 years < or =2.67 < or =3.72
67 years < or =2.61 < or =3.71
68 years < or =2.56 < or =3.69
69 years < or =2.50 < or =3.68
70 years < or =2.44 < or =3.66
71 years < or =2.38 < or =3.64
72 years < or =2.32 < or =3.61
73 years < or =2.26 < or =3.56
74 years < or =2.21 < or =3.50
75 years < or =2.16 < or =3.43
76 years < or =2.10 < or =3.35
77 years < or =2.05 < or =3.26
78 years < or =2.00 < or =3.17
79 years < or =1.94 < or =3.08
80 years < or =1.89 < or =2.99
81 years < or =1.84 < or =2.91
82 years < or =1.80 < or =2.84
83 years < or =1.75 < or =2.78
84 years < or =1.71 < or =2.73
85 years < or =1.68 < or =2.69
86 years < or =1.65 < or =2.67
87 years < or =1.64 < or =2.65
88 years < or =1.63 < or =2.64
> or =89 years < or =1.62 < or =2.64
Clinical References: 1. Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C:
Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis. 2012 Jul;35(4):571-587.
doi: 10.1007/s10545-012-9462-5 2. Muhlhausen C, Salomons GS, Lukacs Z, et al: Combined
D2-/L2-hydroxyglutaric aciduria (SLC25A1 deficiency): clinical course and effects of citrate treatment.
J Inherit Metab Dis. 2014 Sep;37(5):775-781. doi: 10.1007/s10545-014-9702-y 3. Struys EA:
D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. J Inherit
Metab Dis. 2006 Feb;29(1):21-29. doi: 10.1007/s10545-006-0317-9 4. Perales-Clemente E, Hewitt AL,
Studinski AL, et al: Bilateral subdural hematomas and retinal hemorrhages mimicking nonaccidental
trauma in a patient with D-2-hydroxyglutaric aciduria. JIMD Rep. 2020 Nov 20;58(1):21-28. doi:
10.1002/jmd2.12188
2OHGP 2-Hydroxyglutaric Aciduria Gene Panel, Varies

608030 Clinical Information: The 2-hydroxyglutaric aciduria disorders are a group of cerebral organic
acidurias that present biochemically with an elevation of 2-hydroxyglutaric acid (2-HG) in the urine.
There are two enantiomers or forms of 2-hydroxyglutaric acid, the D-form and the L-form. Depending
on the genetic defect, individuals may have an elevation of one or both forms of 2-HG. Routine organic
acid analysis (OAU / Organic Acids Screen, Random, Urine), while able to detect 2-HG, is unable to
distinguish between the two enantiomers; however, they can be separated with more specialized
biochemical testing. L-2-hydroxyglutaric aciduria (L-2-HGA) is caused by defects in L2HGDH and is
characterized by progressive cerebellar ataxia and intellectual disability, seizures, and macrocephaly
beginning in infancy or early childhood. Symptoms worsen over time leading to severe disability by
early adulthood. Magnetic resonance imaging findings include subcortical leukoencephalopathy,
generalized cerebellar and cerebral atrophy, and atrophy of the corpus callosum. D-2-hydroxylglutaric
aciduria (D-2-HGA) is characterized by elevated levels of D-2-hydroxyglutaric acid and typically
manifests with developmental delay, seizures, and hypotonia, though can vary widely from
asymptomatic to severe. There are 2 types of D-2-HGA depending on the genetic cause. D-2-HGA can
either be autosomal recessive, resulting from variants in D2HGDH causing reduced enzymatic activity
(Type I) or autosomal dominant gain-of-function variants in IDH2 causing overproduction of D-2-HG
(Type II). D,L-2-hydroxylglutaric aciduria is the most severe of the 3 and caused by defects in
SLC25A1, which encodes the mitochondrial citrate carrier. It is characterized by neonatal-onset
encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of
psychomotor development resulting in early death. Because of the genetic heterogeneity of the
2-hydroxyglutaric acidurias and the specialized biochemical testing needed to distinguish among the
conditions, this genetic panel, which incorporates D2HGDH, L2HGDH, IDH2, and SLC25A1, is an
efficient way to diagnose these conditions.
Useful For: Follow up for abnormal biochemical results suggestive of 2-hydroxyglutaric aciduria
Establishing a molecular diagnosis for patients with 2-hydroxyglutaric aciduria Identifying variants
within genes known to be associated with 2-hydroxyglutaric aciduria, allowing for predictive testing of
at-risk family members
Interpretation: All detected alterations are evaluated according to American College of Medical
Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known,
predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or
known significance.
Reference Values:
Clinical References: 1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the
interpretation of sequence variants: a joint consensus recommendation of the American College of
Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015
May;17(5):405-424 2. Nota B, Struys EA, Pop A, et al: Deficiency in SLC25A1, encoding the
mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria. Am J Hum
Genet. 2013;92:627-631. doi: 10.1016/j.ajhg.2013.03.009 3. Kranendijk M, Struys EA, van Schaftingen
E, et al: IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 2010 Oct
15;330(6002):336. doi: 10.1126/science.1192632 4. Kranendijk M, Struys EA, Salomons GS, Van der
Knaap MS, Jakobs C: Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis.
2012;35(4):571-587. doi: 10.1007/s10545-012-9462-5 5. Pop A, Struys EA, Jansen EEW, et al:
D-2-hydroxyglutaric aciduria Type I: functional analysis of D2HGDH missense variants. Hum Mutat.
2019; 40(7):975-982. doi: 10.1002/humu.23751
21DOC 21-Deoxycortisol, Serum

89477 Clinical Information: The adrenal glands, ovaries, testes, and placenta produce steroid hormones,
which can be subdivided into 3 major groups: mineral corticoids, glucocorticoids, and sex steroids.
Synthesis proceeds from cholesterol along 3 parallel pathways, corresponding to these 3 major groups of
steroids, through successive side-chain cleavage and hydroxylation reactions. At various levels of each
pathway, intermediate products can move into the respective adjacent pathways via additional,
enzymatically catalyzed reactions (see Steroid Pathways in Special Instructions). 21-Deoxycortisol is an
intermediate steroid in the glucocorticoid pathway. While the main substrate flow in glucocorticoid
synthesis proceeds from 17-hydroxyprogesterone via 21-hydroxylation to 11-deoxycortisol and then,
ultimately, to cortisol, a small proportion of 17-hydroxyprogesterone is also hydroxylated at carbon
number 11 by 11-beta-hydroxylase 1 (CYP11B1), yielding 21-deoxycortisol. This in turn can also serve
as a substrate for 21-hydroxylase (CYP21A2), resulting in formation of cortisol. The major diagnostic
utility of measurements of steroid synthesis intermediates lies in the diagnosis of disorders of steroid
synthesis, in particular congenital adrenal hyperplasia (CAH). All types of CAH are associated with
cortisol deficiency with the exception of CYP11B2 deficiency and isolated impairments of the 17-lyase
activity of CYP17A1 (this enzyme also has 17-alpha-hydroxylase activity). In case of severe illness or
trauma, CAH predisposes patients to poor recovery or death. Patients with the most common form of
CAH (21-hydroxylase deficiency, >90% of cases), with the third most common form of CAH
(3-beta-steroid dehydrogenase deficiency, <3% of cases) and those with the extremely rare StAR
(steroidogenic acute regulatory protein) or 20,22 desmolase deficiencies, might also suffer mineral
corticoid deficiency, as the enzyme blocks in these disorders are proximal to potent mineral corticoids.
These patients might suffer salt-wasting crises in infancy. By contrast, patients with the second most
common form of CAH, 11-hydroxylase deficiency (<5% of cases), are normotensive or hypertensive, as
the block affects either CYP11B1 or CYP11B2, but rarely both, thus ensuring that at least corticosterone
is still produced. In addition, patients with all forms of CAH might suffer the effects of substrate
accumulation proximal to the enzyme block. In the 3 most common forms of CAH the accumulating
precursors spill over into the sex steroid pathway, resulting in virilization of females or, in milder cases, in
hirsutism, polycystic ovarian syndrome or infertility, as well as in possible premature adrenarche and
pubarche in both genders. Measurement of the various precursors of mature mineral corticoids and
glucocorticoids, in concert with the determination of sex steroid concentrations, allows diagnosis of CAH
and its precise type, and serves as an aid in monitoring steroid replacement therapy and other therapeutic
interventions. Measurement of 21-deoxycortisol can supplement or confirm 17-hydroxyprogesterone and
androstenedione measurements in the diagnosis of difficult cases of CAH presumed to be due to
CYP21A2 deficiency. 11-Hydroxylation remains intact in such patients. However, since the CYP21A2
enzyme block prevents formation of 11-deoxycortisol, while simultaneously increasing the concentrations
of the precursor, 17-hydroxyprogesterone, unoccupied CYP11B1 starts to 11-hydroxylate the abundant
17-hydroxyprogesterone substrate into 21-deoxycortisol. The 21-deoxycortisol accumulates, as the
diminished or absent CYP21A2 activity slows or prevents its conversion into cortisol. For other forms of
CAH the following tests might be relevant: -11-Hydroxylase deficiency: Â - DOC / 11-Deoxycortisol,
Serum Â - CORTC / Corticosterone, Serum Â - PRA / Renin Activity, Plasma Â - ALDS / Aldosterone,
Serum -3-Beta-steroid-dehydrogenase deficiency: Â - 17PRN / Pregnenolone and
17-Hydroxypregnenolone -17-Hydroxylase deficiency or 17-lyase deficiency (CYP17A1 has both
activities): Â - PREGN / Pregnenolone, Serum Â - 17OHP / 17-Hydroxypregnenolone, Serum Â - PGSN /
Progesterone, Serum Â - OHPG / 17-Hydroxyprogesterone, Serum Â - DHEA_ / Dehydroepiandrosterone
(DHEA), Serum Â - ANST / Androstenedione, Serum Cortisol should be measured in all cases of
suspected CAH. It has been suggested that in the pubertal patient with 21-hydroxylase deficiency,
21-deoxycortisol may be useful and better then 17-hydroxyprogesterone for therapeutic decisions.
Useful For: As an adjunct to measurement of 17-hydroxyprogesterone, androstenedione, and cortisol

in the diagnosis of difficult cases of suspected 21-hydroxylase (CYP21A2) deficiency Identifying
heterozygote CYP21A2 deficiency carriers As an adjunct to measurements of 17-hydroxyprogesterone,
androstenedione, testosterone, and, in females, estradiol in the follow-up of children with CYP21A2
deficiency
Interpretation: In untreated 21-hydroxylase (CYP21A2) deficiency, 21-deoxycortisol serum

concentrations on average exceed the upper limit of the reference range 30-fold to 40-fold.
21-Hydroxycortisol measurements are particularly useful in equivocal cases of suspected
21-hydroxylase deficiency. Most untreated patients with 21-hydroxylase deficiency have serum
17-hydroxyprogesterone concentrations well in excess of 1,000 ng/dL. For the few patients with levels
in the range of greater than 630 ng/dL (upper limit of reference range for newborns) to 2,000 ng/dL or
3,000 ng/dL, it might be prudent to consider 11-hydroxylase deficiency as an alternative diagnosis. This
is particularly true if serum androstenedione concentrations are also only mildly-to-modestly elevated,
and if the phenotype is not salt wasting but either simple virilizing (female) or normal (female or male).
11-Hydroxylase deficiency, in particular if it affects 11 beta-hydroxylase 1 (CYP11B1), can be
associated with modest elevations in serum 17-hydroxyprogesterone concentrations. In these cases
testing for CYP11B1 deficiency and 11 beta-hydroxylase 2 (CYP11B2) deficiency should be considered
and interpreted as described above. Alternatively, measurement of 21-deoxycortisol might be useful in
such cases. This minor pathway metabolite accumulates in CYP21A2 deficiency, as it requires
21-hydroxylation to be converted to cortisol, but is usually not elevated in CYP11B1 deficiency, since
its synthesis requires via 11-hydroxylation of 17-hydroxyprogesterone. For genetic counseling purposes,
identification of asymptomatic carriers of CYP21A2 mutations and deletions is sometimes required.
The gold-standard is full DNA sequencing of CYP21A2, its pseudogene CYP21A1P, and, if possible,
recombinants of gene and pseudogene, along with deletion detection. Such a procedure is costly and
complex, and often has a slow turnaround time. Therefore, many laboratories perform less complex, but
also less complete, mutation and deletion assessments, which may miss a significant minority of
heterozygote carriers. Biochemical testing using adrenocorticotropic hormone (ACTH) ACTH1-24
adrenal stimulation represents an alternative. However, for 17-hydroxyprogesterone and
androstenedione measurements there is significant overlap between poststimulation results in normals
and in heterozygote carriers. By contrast, poststimulation 21-deoxycortisol concentrations of 55 ng/dL
identify virtually all heterozygote carriers, with minimal overlap with normal subjects. The goal of
congenital adrenal hyperplasia (CAH) treatment is normalization of cortisol levels and ideally also of
sex steroid levels. Serum 17-hydroxyprogesterone, androstenedione, and testosterone should be
measured and used to guide treatment modifications. Normal prepubertal androgen levels may be
difficult to achieve, but if testosterone levels are within the reference range, androstenedione levels up
to 100 ng/dL are usually regarded as acceptable. 17-Hydroxyprogesterone levels should not
significantly exceed the normal reference range at any time of the day. However, during puberty, the
changing levels of sex steroid production may make 17-hydroxyprogesterone measurements less
reliable. Since 21-deoxycortisol is not a sex-steroid precursor, its levels appear more reliable during the
pubertal period, again, the aim being not to exceed the reference range significantly.
Reference Values:
<5.0 ng/dL

hyperplasia. Eur J Pediatr 1980;133(3):259-267 2. Therrell BL: Newborn screening for congenital
adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30(1):15-30 3. Collett-Solberg PF:
Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part I. Clin Pediatr
2001;40:1-16 4. Forest MG: Recent advances in the diagnosis and management of congenital adrenal
hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update 2004;10:469-485 5.
Tonetto-Fernandes V, Lemos-Marini SH, Kuperman H, et al: Serum 21-deoxycortisol,
17-hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and
hormonal correlations and identification of patients with 11beta-hydroxylase deficiency among a large
group with alleged 21-hydroxylase deficiency. J Clin Endocrinol Metab 2006;91:2179-2184
21OH 21-Hydroxylase Antibodies, Serum

607788as of July 20, 2022 12:05 pm CDT
Current 800-533-1710 or 507-266-5700 or mayocliniclabs.com Page 31
Clinical Information: Adrenal insufficiency is caused by failure of the adrenal cortex to produce
cortisol. This failure can result from loss of function of the adrenal glands (ie, primary adrenal
insufficiency). This is most frequently caused by autoimmune adrenalitis or Addison disease accounting
for 68% to 94% of cases. It can occur sporadically or in combination with other autoimmune endocrine
diseases that together comprise Type I or Type II autoimmune polyglandular syndrome (APS). Antibodies
that react with several steroidogenic enzymes (most often 21-hydroxylase) are present in the serum of up
to 86% of patients with autoimmune primary adrenal insufficiency, but only rarely in patients with other
causes of adrenal insufficiency. Therefore, anti-21-hydroxylase autoantibodies (21-OH Abs) are markers
of autoimmune Addison disease, whether itâ€™s present alone, or as part of Type I or Type II APS. The
measurement of 21-OH Abs is an important step in the investigation of adrenal insufficiency, and may
also aid in the detection of those at risk of developing autoimmune adrenal failure in the future.
Useful For: Investigation of adrenal insufficiency Aid in the detection of those at risk of developing
autoimmune adrenal failure in the future
Interpretation: This is a qualitative test. A positive result indicates the presence of autoantibodies to
21-hydroxylase and is consistent with Addison disease. Utilizing an index value of <45 as a negative
cutoff, this assay has a clinical sensitivity and specificity of 87.0% (95% CI: 79.4%-92.2%) and 99.3%
(95% CI: 97.5%-99.8%), respectively.
Reference Values:
Negative
Clinical References: 1. Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. Lancet
2014;383(9935):2152-2167 2. Bancos I, Hahner S, Tomlinson J, Arlt W: Diagnosis and management of
adrenal insufficiency. Lancet Diabetes Endocrinol 2015;3(3):216-226 3. Bornstein SR, Allolio B, Arlt W,
et al: Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2016;101(2):364-389
CYPZ 21-Hydroxylase Gene, CYP21A2, Full Gene Analysis, Varies

37445 Clinical Information: Congenital adrenal hyperplasia (CAH), with an incidence rate of 1 in 10,000 to
18,000 live births, is one of the most common inherited syndromes. The condition is characterized by
impaired cortisol production due to inherited defects in steroid biosynthesis. The clinical consequences of
CAH, besides diminished cortisol production, depend on which enzyme is affected and whether the loss
of function is partial or complete. In greater than 90% of CAH cases, the affected enzyme is 21-steroid
hydroxylase, encoded by the CYP21A2 gene located on chromosome 6 within the highly recombinant
human histocompatibility complex locus. 21-hydroxylase deficient CAH is inherited in an autosomal
recessive pattern and has a spectrum of clinical phenotypes depending upon residual enzyme activity.
Excessive adrenal androgen biosynthesis results in varying degrees of virilization. If there is some
residual enzyme activity, a non-classical phenotype results, with signs of hyperandrogenism typically
starting in later childhood or adolescence. Individuals with severe enzyme deficiency have classical CAH,
with prenatal onset of virilization. Classical CAH is subdivided into simple-virilizing (minimal residual
enzyme activity) and salt-wasting (no residual enzyme activity) forms. Patients with salt-wasting CAH
have both cortisol and mineral corticosteroid deficiency and are at risk for life-threatening salt-wasting
crises if untreated. Because of its high incidence rate, 21-hydroxylase deficiency is screened for in most
US newborn screening programs, typically by measuring 17-hydroxyprogesterone concentrations in blood
spots by immunoassay. Confirmation by other testing strategies (eg, liquid chromatography tandem mass
spectrometry: LC-MS/MS), CAH2T / Congenital Adrenal Hyperplasia Newborn Screen, Blood Spot), or
retesting after several weeks, is required for most positive screens because of the high false-positive rates
of the immunoassays (due to physiological elevations of 17-hydroxyprogesterone in premature babies and
immunoassay cross-reactivity with other steroids). In a small percentage of cases, additional testing will
fail to provide a definitive diagnosis. In addition, screening strategies can miss many non-classical cases,
which may present later in childhood or adolescence and require more extensive steroid hormone
profiling, including testing before and after adrenal stimulation with adrenocorticotropic hormone
(ACTH)-1-24. For these reasons, genetic diagnosis plays an important ancillary role in both classical and
nonclassical cases. In addition, the high carrier frequency (approximately 1 in 50) for CYP21A2 variant
makes genetic diagnosis important for genetic counseling. Genetic testing can also play a role in prenatal
diagnosis of 21-hydroxylase deficiency. However, accurate genetic diagnosis continues to be a challenge
because most of the variants arise from recombination events between CYP21A2 and its highly
homologous pseudogene, CYP21A1P (transcriptionally inactive). In particular, partial or complex
rearrangements (with or without accompanying gene duplication events), which lead to reciprocal
exchanges between gene and pseudogene, can present severe diagnostic challenges. Comprehensive
genetic testing strategies must therefore allow accurate assessment of most, or all, known rearrangements
and variants, as well as unequivocal determination of whether the observed changes are located within a
potentially transcriptionally active genetic segment. Testing of additional family members is often needed
for clarification of genetic test results.
Useful For: Carrier screening and diagnosis of 21-hydroxylase deficient congenital adrenal
hyperplasia (CAH) in individuals with a personal or family history of 21-hydroxylase deficiency, or as
follow-up to positive CAH newborn screens and/or measurement of basal and adrenocorticotropic
hormone- 1-24 stimulated 17-hydroxyprogesterone, androstenedione, and other adrenal steroid levels
May be used to identify CYP21A2 variant in individuals with a suspected diagnosis of 21-hydroxylase
deficient CAH when a common variant panel is negative or only identifies 1 variant. In prenatal cases of
ambiguous genitalia detected by ultrasound, particularly when the fetus is confirmed XX female by
chromosome analysis. This test should also be used for known/familial variant analysis for CYP21A2.
Due to the complexity of the CYP21A2 locus, site specific testing for known/familial variants is not
offered for this gene.
Interpretation: All detected alterations will be evaluated according to American College of Medical
Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known,
known significance.
Reference Values:
May;17(5):405-424 2. Collett-Solberg PF: Congenital adrenal hyperplasias: from clinical genetics and
biochemistry to clinical practice, part I. Clin Pediatr. 2001;40:1-16 3. Mercke DP, Bornstein SR, Avila
NA, Chrousos GP: NIH conference: future directions in the study and management of congenital
adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Intern Med. 2002;136:320-334 4. Speiser
PW, White PC: Medical progress: congenital adrenal hyperplasia. N Engl J Med. 2003;349:776-788
DD22F 22q11.2 Deletion/Duplication, FISH, Varies

35246 Clinical Information: The 22q deletion syndrome and 22q duplication syndrome have overlapping
phenotypes. Deletions of 22q are associated with DiGeorge and velocardiofacial syndrome. These
syndromes are manifested by the presence of growth deficiency, global developmental delay, heart
defect, and hearing loss. The major birth defects include palatal clefting or insufficiency and thymus
aplasia. Prominent facial features are widely spread eyes, superior placement of eyebrows, downward
slanting palpebral fissures with or without ptosis (droopy upper eyelid), mild micrognathia (small jaw),
and a long, narrow face. FISH studies are highly specific and do not exclude other chromosome
abnormalities.
Useful For: Establishing a diagnosis of 22q deletion/duplication syndromes Detecting cryptic

rearrangements involving 22q11.2 or 22q11.3 that are not demonstrated by conventional chromosome
studies
Interpretation: Any individual with a normal signal pattern in each metaphase is considered
negative for this probe. Any patient with a FISH signal pattern indicating loss of the critical region (1
signal) will be reported as having a deletion of the region tested by this probe. This is consistent with a
diagnosis of 22q deletion syndrome. Any patient with a FISH signal pattern indicating duplication of the
critical region (3 signals) will be reported as having a duplication of the region tested by this probe. This
is consistent with a diagnosis 22q duplication syndrome.
Reference Values:
Clinical References: 1. Ensenauer RE, Adeyinka A, Flynn HC, et al: Microduplication 22q11.2 an
emerging syndrome: clinical, cytogenetic and molecular analysis of thirteen patients. Am J Hum Genet
2003;73:1027-1040 2. Yobb TM, Sommerville MJ, Willatt L, et al: Microduplication and triplication of
22q11.2: a highly variable syndrome. Am J Hum Genet 2005;76:865-876 3. Bassett AS, Chow EWC,
Husted J, et al: Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet
2005;138A:307-313 4. Manji A, Roberson JR, Wiktor A, et al: Prenatal diagnosis of 22q11.2 deletion
when ultrasound examination reveals a heart defect. Genet Med 2001;3:65-66 5. McDonald-McGinn DM,
Emanuel BS, Zackai EH: 22q11.2 Deletion Syndrome. GeneReviews, Accessed 05/22/2013, Available at
www.ncbi.nlm.nih.gov/books/NBK1523/
25HDN 25-Hydroxyvitamin D2 and D3, Serum

similar sterols, which act as hormones. This test is the preferred initial test for assessing vitamin D status
and most accurately reflects the body's vitamin D stores. In the presence of renal disease, testing
1,25-dihydroxyvitamin D (DHVD) levels might be needed to adequately assess vitamin D status. DHVD
testing alone may not clearly indicate deficiencies of vitamin D stores. Vitamin D compounds in the body
are exogenously derived by dietary means; from plants as 25-hydroxyvitamin D2 (ergocalciferol or
calciferol) or from animal products as 25-hydroxyvitamin D3 (cholecalciferol or calcidiol). Vitamin D
may also be endogenously derived by conversion of 7-dihydrocholesterol to 25-hydroxyvitamin D3 in the
skin upon ultraviolet exposure. 25HDN is subsequently formed by hydroxylation (CYP2R1) in the liver.
25HDN is a prohormone that represents the main reservoir and transport form of vitamin D, being stored
in adipose tissue and tightly bound by a transport protein while in circulation. Biological activity is
expressed in the form of DHVD, the active metabolite of 25HDN. 1-Alpha-hydroxylation (CYP27B1)
occurs on demand, primarily in the kidneys, under the control of parathyroid hormone (PTH) before
expressing biological activity. Like other steroid hormones, DHVD binds to a nuclear receptor,
influencing gene transcription patterns in target organs. 25HDN may also be converted into the inactive
metabolite 24,25-dihydroxyvitamin D (24,25D) by (CYP24A1) hydroxylation. This process, regulated by
PTH, might increase DHVD synthesis at the expense of the alternative hydroxylation (CYP24A1) product
24,25D. Inactivation of 25HDN and DHVD by CYP24A1 is a crucial process that prevents over
production of DHVD and resultant vitamin D toxicity. Based on these considerations circulating 25HDN
is the best indicator of optimal vitamin D body stores. The exact levels of optimal circulating 25HDN
concentrations remain a matter of debate. Mild-to-modest deficiency can be associated with osteoporosis
or secondary hyperparathyroidism. Severe deficiency may lead to failure to mineralize newly formed
osteoid in bone, resulting in rickets in children and osteomalacia in adults. The consequences of vitamin D
deficiency on organs other than bone are not fully known, but might include increased susceptibility to
infections, muscular discomfort, and an increased risk of colon, breast, and prostate cancer. Modest
25HDN deficiency is common; in institutionalized elderly, its prevalence may be greater than 50%.
Although much less common, severe deficiency is not rare either. Reasons for suboptimal 25HDN levels
include lack of sunshine exposure, a particular problem in Northern latitudes during winter; inadequate
intake; malabsorption (eg, due to celiac disease); depressed hepatic vitamin D 25-hydroxylase activity,
secondary to advanced liver disease; and enzyme-inducing drugs, in particular many antiepileptic drugs,
including phenytoin, phenobarbital, and carbamazepine, which increase 25HDN metabolism.
Useful For: Diagnosis of vitamin D deficiency Differential diagnosis of causes of rickets and
osteomalacia Monitoring vitamin D replacement therapy Diagnosis of hypervitaminosis D
Interpretation: Based on animal studies and large human epidemiological studies, 25-hydroxyvitamin
D2 and D3 (25-OH-VitD) levels below 25 ng/mL are associated with an increased risk of secondary
hyperparathyroidism, reduced bone mineral density, and fractures, particularly in the elderly. Intervention
studies support this clinical cutoff, showing a reduction of fracture risk with 25-OH-VitD replacement.
Levels less than 10 ng/mL may be associated with more severe abnormalities and can lead to inadequate
mineralization of newly formed osteoid, resulting in rickets in children and osteomalacia in adults. In
these individuals, serum calcium levels may be marginally low, and parathyroid hormone (PTH) and
serum alkaline phosphatase are usually elevated. Definitive diagnosis rests on the typical radiographic
findings or bone biopsy/histomorphometry. Baseline biochemical work-up of suspected cases of rickets
and osteomalacia should include measurement of serum calcium, phosphorus, PTH, and 25-OH-VitD. In
patients where testing is not completely consistent with the suspected diagnosis, in particular, if serum
25-OH-VitD levels are greater than 10 ng/mL, an alternative cause for impaired mineralization should be
considered. Possible differential diagnosis includes: partly treated vitamin D deficiency, extremely poor
calcium intake, vitamin D resistant rickets, renal failure, renal tubular mineral loss with or without renal
tubular acidosis, hypophosphatemic disorders (eg, X-linked or autosomal dominant hypophosphatemic
rickets), congenital hypoparathyroidism, activating calcium sensing receptor mutations, and osteopetrosis.
Measurement of serum urea, creatinine, magnesium, and 1,25-dihydroxyvitamin D (DHVD) is
recommended as a minimal additional workup for these patients. 25-OH-VitD replacement in the United
States typically consists of vitamin D2. Lack of clinical improvement and no reduction in PTH or alkaline
phosphatase may indicate patient noncompliance, malabsorption, resistance to 25-OH-VitD, or additional
factors contributing to the clinical disease. Measurement of serum 25-OH-VitD levels can assist in further
evaluation, in particular as the liquid chromatography-tandem mass spectrometry methodology allows
separate measurement of 25-OH-VitD3 and of 25-OH-VitD2, which is derived entirely from dietary
sources or supplements. Â Patients who present with hypercalcemia, hyperphosphatemia, and low PTH
may suffer either from ectopic, unregulated conversion of 25-OH-VitD to 1,25-OH-VitD, as can occur in
granulomatous diseases, particular sarcoid, or from nutritionally-induced hypervitaminosis D. Serum
1,25-OH-VitD levels will be high in both groups, but only patients with hypervitaminosis D will have
serum 25-OH-VitD concentrations of greater than 80 ng/mL, typically greater than 150 ng/mL.
Reference Values:
TOTAL 25-HYDROXYVITAMIN D2 AND D3 (25-OH-VitD)
<10 ng/mL (severe deficiency)*
10-19 ng/mL (mild to moderate deficiency)**
20-50 ng/mL (optimum levels)***
51-80 ng/mL (increased risk of hypercalciuria)****
>80 ng/mL (toxicity possible)*****
*Could be associated with osteomalacia or rickets
**May be associated with increased risk of osteoporosis or secondary hyperparathyroidism
***Optimum levels in the healthy population; patients with bone disease may benefit from higher
levels within this range
****Sustained levels >50 ng/mL 25OH-VitD along with prolonged calcium supplementation may lead
to hypercalciuria and decreased renal function
*****80 ng/mL is the lowest reported level associated with toxicity in patients without primary
hyperparathyroidism who have normal renal function. Most patients with toxicity have levels >150
ng/mL. Patients with renal failure can have very high 25-OH-VitD levels without any signs of toxicity,
as renal conversion to the active hormone 1,25-OH-VitD is impaired or absent.
These reference ranges represent clinical decision values, based on the 2011 Institute of Medicine
report, that apply to males and females of all ages, rather than population-based reference values.
Population reference ranges for 25-OH-VitD vary widely depending on ethnic background, age,
geographic location of the studied populations, and the sampling season. Population-based ranges
correlate poorly with serum 25-OH-VitD concentrations that are associated with biologically and
clinically relevant vitamin D effects and are therefore of limited clinical value.
Clinical References: 1. Jones G, Strugnell SA, DeLuca HF: Current understanding of the
molecular actions of vitamin D. Physiol Rev 1998 Oct;78(4):1193-1231 2. Miller WL, Portale AA:
Genetic causes of rickets. Curr Opin Pediatr 1999 Aug;11(4):333-339 3. Vieth R: Vitamin D
supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999
May;69(5):842-856 4. Vieth R, Ladak Y, Walfish PG: Age-related changes in the 25-hydroxyvitamin D
versus parathyroid hormone relationship suggest a different reason why older adults require more
vitamin D. J Clin Endocrinol Metab 2003 Jan;88(1):185-191 5. Wharton B, Bishop N: Rickets. Lancet
2003 Oct 25;362(9393):1389-1400 6. Institute of Medicine (US) Committee to Review Dietary
Reference Intakes for Vitamin D and Calcium; Edited by AC Ross, CL Taylor, AL Yaktine, HB Del
Valle. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC. National Academies
Press (US), 2011 Available from: www.ncbi.nlm.nih.gov/books/NBK56070
2425D 25-Hydroxyvitamin D:24,25-Dihydroxyvitamin D Ratio, Serum

similar sterols. The 25HDN / 25-Hydroxyvitamin D2 and D3, Serum assay is the preferred initial test for
assessing vitamin D status and most accurately reflects the body's vitamin D stores. In the presence of
renal disease, DHVD / 1,25-Dihydroxyvitamin D, Serum testing might be needed to adequately assess
vitamin D status. For patients with loss of function inactivating CYP24A1 mutations, this test (2425D /
25-Hydroxyvitamin D2 and D3:24,25-Dihydroxyvitamin D Ratio, Serum) may be helpful Loss of
function mutations in the CYP24A1 gene have been shown to lead to insufficient deactivation of
bioactive vitamin D metabolites, resulting in a phenotype characterized by suppressed serum parathyroid
hormone (PTH), increased serum 1,25-dihydroxyvitamin D (DHVD) concentrations, hypercalcemia, and
hypercalciuria or nephrolithiasis. Vitamin D compounds in the body are exogenously derived by dietary
means; from plants as 25-hydroxyvitamin D2 (ergocalciferol or calciferol) or from animal products as
25-hydroxyvitamin D3 (cholecalciferol or calcidiol). Vitamin D may also be endogenously derived by
conversion of 7-dihydrocholesterol to 25-hydroxyvitamin D3 in the skin upon ultraviolet exposure.
25-Hydroxyvitamin D (25HDN) is subsequently formed by hydroxylation (CYP2R1) in the liver. 25HDN
is a prohormone that represents the main reservoir and transport form of vitamin D, being stored in
adipose tissue and tightly bound by a transport protein while in circulation. Biological activity is
expressed in the form of DHVD the active metabolite of 25HDN. 1-Alpha-hydroxylation (CYP27B1)
occurs on demand, primarily in the kidneys, under the control of parathyroid hormone (PTH) before
expressing biological activity. Like other steroid hormones, DHVD binds to a nuclear receptor,
influencing gene transcription patterns in target organs. 25HDN may also be converted into the inactive
metabolite 24,25-dihydroxyvitamin D (24,25D) by (CYP24A1) hydroxylation. This process regulated by
parathyroid hormone (PTH) might increase DHVD synthesis at the expense of the alternative
hydroxylation (CYP24A1) product 24,25D. Inactivation of 25HDN and DHVD by CYP24A1 is a crucial
process that prevents over production of DHVD and resultant vitamin D toxicity. DHVD stimulates
calcium absorption in the intestine and its production is tightly regulated through concentrations of serum
calcium, phosphorus, and PTH. DHVD promotes intestinal calcium absorption and, in concert with PTH,
skeletal calcium deposition, or less commonly, calcium mobilization. Renal calcium and phosphate
reabsorption are also promoted, while prepro-PTH mRNA expression in the PTH glands is
downregulated. The net result is a positive calcium balance, increasing serum calcium and phosphate
levels, and falling PTH concentrations. In addition to its effects on calcium and bone metabolism, DHVD
regulates the expression of a multitude of genes in many other tissues including immune cells, muscle,
vasculature, and reproductive organs. DHVD levels are decreased in hypoparathyroidism and in chronic
renal failure. DVHD levels may be high in primary hyperparathyroidism and in physiologic
hyperparathyroidism secondary to low calcium or vitamin D intake. Some patients with granulomatous
diseases (eg, sarcoidosis) and malignancies containing nonregulated 1-alpha hydroxylase in the lesion
might have hypercalcemia that appears vitamin D mediated with normal or high serum phosphate
(hyperphosphatemia) and hypercalcemia (both of which might be severe), in addition to low parathyroid
hormone (PTH) and absent parathyroid hormone-related peptide (PTHRP). Differential diagnostic
considerations include vitamin D intoxication and CYP24A1 deficiency
Useful For: As a screening test for inactivating CYP24A1 mutations in patients with symptoms, signs,
or biochemical findings of parathyroid hormone (PTH)-independent hypercalcemia or hypercalciuria
Interpretation: Results should be interpreted in the context of other biochemical findings including
serum calcium, parathyroid hormone (PTH), and 1,25 dihydroxyvitamin D (DHVD) concentrations. If
25-hydroxyvitamin D (25HDN) result is less than 20 ng/mL, the ratio of 25-OH-D to
24,25-dihydroxyvitamin D (24,25D) will be falsely elevated since there is no inactivation of 25-OH-D to
24,25D. 24,25D formation by CYP24A1 is dependent on CYP24A1 activity and the concentrations of its
substrate, 25HDN. The ratio of 25HDN to 24,25D, therefore, allows the most reliable estimation of
CYP24A1 activity. Ratios of 25HDN to 24.25D less than 25 may be interpreted as normal, though ratio of
less than 25 may also be observed in heterozygous carriers of CYP24A1 mutations. Ratios of 25HDN to
24.25D between the 25 and 80 range may be seen in patients with low vitamin D or heterozygous
CYP24A1 mutations. Confirmation with molecular testing is recommended. Confirmation with molecular
testing is also recommended for ratios of 25HDN to 24.25D greater than 80, as this may indicate a
probable biallelic CYP24A1 mutation or deletion.
Reference Values:
Interpretative commentary provided based on 25-hydroxyvitamin D (25HDN) to
24,25-dihydroxyvitamin D (24,25D) ratio result.
25HDN to 24,25D ratio less than 25*

*Interpretation: Normal (Ratio of less than 25 may also be observed in heterozygous carriers of
CYP24A1 mutations)
25HDN to 24,25D ratio between 25-80**

**Interpretation: Ratios in the 25 to 80 range can be seen in patients with low vitamin D or
heterozygous CYP24A1 mutations. Confirmation with molecular testing is recommended.
25HDN to 24,25D ratio greater than 80***

***Interpretation: Ratios greater than 80 indicate probable biallelic CYP24A1 mutation or deletion.
Confirmation with molecular testing is recommended.
Reference values not applicable for 24,25 Dihydroxyvitamin D Total result.
Results should be interpreted in the context of other biochemical findings including serum calcium,
parathyroid hormone, and 1,25 dihydroxyvitamin D concentrations. If 25-OH-D is less than 20 ng/ml
the ratio of 25-OH-D to 24,25-dihydroxyvitamin D will be falsely elevated since there is no inactivation
25-OH-D to 24,25-dihydroxyvitamin D.
Clinical References: 1. Kaufmann M, Gallagher JC, Peacock M, et al: Clinical utility of

simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/MS
involving derivatization with DMEQ-TAD. J Clin Endocrinol Metab 2014;July 99(7):2567-2574. doi:
10.1210/jc.2013-4388 2. Ketha H, Kumar R, Singh RJ: LC-MS/MS for Identifying Patients with
CYP24A1 Mutations. Clin Chem 2016 Jan;62(1):236-242
HMGCR 3-Hydroxy-3-Methylglutaryl Coenzyme-A (HMG-CoA)

607414 Reductase, Serum
Clinical Information: Necrotizing autoimmune myopathy (NAM) is a serious but rare muscle
disease strongly associated with autoantibodies to either signal recognition protein (SRP) or
3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR).(1) NAM typically manifests with subacute
proximal limb muscle weakness and persistently elevated serum creatine kinase (CK) concentrations,
but slower onsets can occur and complicate diagnosis. Muscle biopsies in affected patients can
demonstrate necrotic and regenerating myofibers without inflammatory infiltrates, suggesting the
diagnosis.(2) However, sampling issues and lack of access to persons having expertise in obtaining,
preparing, and interpreting muscle biopsy specimens may delay a diagnosis.(3) Early identification of
NAM and subsequent aggressive immune-modulating therapy is critical.(1,3) Discovery of SRP- or
HMGCR-IgG autoantibodies can aid in establishing an earlier diagnosis and treatment initiation. In
addition, the discovery of SRP or HMGCR autoantibodies should prompt a search for an underlying
malignancy.(4) Serial testing for these autoantibodies can delay diagnosis with the discovery of either
antibody aiding in establishing an earlier diagnosis and treatment initiation.(1,3) The clinical onsets are
not specific to NAM, consisting of proximal limb weakness in association with an elevated serum
creatinine kinase, with or without exposure to lipid-lowering statin medications.(1,3-9) The clinical
presentation can be confused with forms of inflammatory (dermatomyositis, polymyositis), toxic,
metabolic, or even neurodegeneration (ie, muscular dystrophy) and the diagnosis delayed without
serological testing by SRP- or HMGCR-autoantibody testing. Panel testing of both HMGCR and SRP
autoantibodies is the preferred strategy for the best patient care.
Useful For: Evaluating patients with suspected necrotizing autoimmune myopathy Measuring
3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies
Interpretation: Seropositivity for 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)

autoantibodies supports the clinical diagnosis of necrotizing autoimmune myopathy (NAM).
Confirmation with muscle biopsy is recommended. A paraneoplastic basis should be considered,
according to age, sex, and other risk factors.(4) In cases of NAM, immune therapy is required and often
multiple simultaneously utilized immunotherapies are needed to successfully treat patients.
Reference Values:
<20.0 CU
Clinical References: 1. Kassardjian CD, Lennon VA, Alfugham NB, et al: Clinical Features and
Treatment Outcomes of Necrotizing Autoimmune Myopathy. JAMA Neurol 2015 Sep;72(9):996-1003 2.
Emslie-Smith A M, Engel A G: Necrotizing myopathy with pipestem capillaries, microvascular
deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration.
Neurology 1991;41(6):936-939 3. Ramanathan S, Langguth D, Hardy T, et al: Clinical course and
treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy. Neurol
Neuroimmunol Neuroinflamm 2015 June;2(3):e96 4. Allenbach Y, Keraen J, Bouvier AM, et al: High
risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody. Brain
2016 Aug;139(Pt 8):2131-2135 5. Christopher-Stine L, Casciola-Rosen L, Hong G, et al: A novel
autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing
myopathy. Arthritis Rheum 2010 May;62(9):2757-2766 6. Mammen AL, Chung T, Christopher-Stine L,
et al: Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with
statin-associated autoimmune myopathy. Arthritis Rheum 2011 Mar;63(3):713-721 7. Hengstman GJ, ter
Laak HJ, Vree Egberts WT, et al: Anti-signal recognition particle autoantibodies: marker of a necrotising
myopathy. Ann Rheum Dis 2006;65(12):1635-1638 8. Miller T, Al-Lozi MT, Lopate G, Pestronk A:
Myopathy with antibodies to the signal recognition particle: clinical and pathological features. J Neurol
Neurosurg Psychiatry 2002 Oct;73(4):420-428 9. Watanabe Y, Uruha A, Suzuki S, et al: Clinical features
and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry 2016
Oct;87(10):1038-1044
3MT 3-Methoxytyramine, 24 Hour, Urine

65157 Clinical Information: Pheochromocytoma is a rare, though potentially lethal, tumor of chromaffin
cells of the adrenal medulla that produces episodes of hypertension with palpitations, severe headaches,
and sweating (spells). Patients with pheochromocytoma may also be asymptomatic and present with
sustained hypertension or an incidentally discovered adrenal mass. Pheochromocytomas and other tumors
derived from neural crest cells (eg, paragangliomas and neuroblastomas) secrete catecholamines
(epinephrine, norepinephrine, and dopamine). Dopamine secreting tumors are rarer than norepinephrine
and epinephrine secreting tumors. 3-Methoxytyramine (3MT), metanephrine, and normetanephrine are the
metabolites of dopamine, epinephrine, and norepinephrine, respectively. These metabolites are further
metabolized to vanillylmandelic acid. Pheochromocytoma cells also have the ability to oxymethylate
catecholamines into metanephrines that are secreted into circulation. This test may be used as the first test
for low-suspicion cases and as a confirmatory study in patients with less than a 2-fold elevation in plasma
free fractionated catecholamines. This is highly desirable, as the very low population incidence rate of
pheochromocytoma (<1:100,000 population per year) will otherwise result in large numbers of
unnecessary, costly, and sometimes risky imaging procedures.
Useful For: A first- and second-order screening test for the presumptive diagnosis of
catecholamine-secreting pheochromocytomas and paragangliomas Testing in conjunction or as an
alternative to plasma metanephrines (PMET / Metanephrines, Fractionated, Free, Plasma) or plasma
catecholamine (CATP / Catecholamine Fractionation, Free, Plasma) testing
Interpretation: Further clinical investigation (eg, radiographic studies) and genetic studies are
warranted in patients whose 3-methoxytyramine (3MT) levels are elevated and there is a very high
clinical index of suspicion. Increased 3MT levels are found in patients with pheochromocytoma and
dopamine-secreting tumors. 3MT levels of 306 mcg/24 hours or less in males and 242 mcg/24 hours or
less in females can be detected in non-pheochromocytoma hypertensive patients.
Reference Values:
Males: < or =306 mcg/24 hours
Females: < or =242 mcg/24 hours
Clinical References: 1. van Duinen N, Corssmit EPM, de Jong WHA, Brookman D, Kema IP,
Romijn JA: Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of
biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites. Eur J
Endocrinol. 2013 Aug 28;169(3):377-382. doi: 10.1530/EJE-13-0529 2. van Duinen N, Steenvoorden
D, Kema IP, et al: Increased urinary excretion of 3-methoxytyramine in patients with head and neck
paragangliomas. J Clin Endocrinol Metab. 2010 Jan:95(1):209-214. doi: 10.1210/jc.2009-1632 3.
Kantorovich V, Pacak K: Interest of urinary dosage of 3- methoxytyramine in the diagnosis of
pheochromocytoma and paraganglioma: report of 28 cases. Ann Clin Biol. 2011;69(5):555-559. doi:
10.1684 /abc.2011.0612 4. Muskiet FA, Thomasson CG, Gerding AM, Fremouw-Ottevangers DC,
Nagel GT, Wolthers BG: Determination of catecholamines and their 3-O-methylated metabolites in
urine by mass fragmentography with use of deuterated internal standards. Clin Chem. 1979
Mar;25(3):453-460 5. Shen Y, Cheng L: Biochemical diagnosis of pheochromocytoma and
paraganglioma. In: Mariani-Costantini R, ed. Paraganglioma: A Multidisciplinary Approach. Codon
Publications; 2019. doi: 10.15586/paraganglioma.2019.ch2. Accessed: April 2020. Available at:
3MGAP 3-Methylglutaconic Aciduria Panel, Varies

608034 Clinical Information: The 3-methylglutaconic acidurias (3-MGA) are a heterogeneous group of
metabolic conditions characterized by increased urinary excretion of 3-MGA. Primary 3-MGA type I is
an organic aciduria caused by defective leucine catabolism due to variants in 3-methylglutaconyl-CoA
hydratase (AUH). Four more types of 3-MGA have been described where 3-MGA is a consistent
feature. These are characterized by various degrees of mitochondrial dysfunction, very remotely, if at
all, linked to leucine degradation and include Barth syndrome (type II), Costeff syndrome (type III), and
type V or dilated cardiomyopathy with ataxia (DCMA) syndrome. The remaining cases (type IV) with
increased 3-MGA encompass a variety of disorders affecting mitochondrial function. Genes known to
be associated with elevations of 3-MGA are included on this panel.
Useful For: Follow up for abnormal biochemical results suggestive of 3-methylglutaconic aciduria
(3-MGA) Establishing a molecular diagnosis for patients with 3-MGA Identifying variants within genes
known to be associated with3-MGA, allowing for predictive testing of at-risk family members
known significance.
Reference Values:
May;17(5):405-424 2. Wortmann SB, Kluijtmans LA, Engelke UF, Wevers RA, Morava E: The
3-methylglutaconic acidurias: what's new?. J Inherit Metab Dis. 2012;35(1):13-22. doi:
10.1007/s10545-010-9210-7 3. Manoli I, Venditti CP: Disorders of branched chain amino acid
metabolism. Transl Sci Rare Dis. 2016;1(2):91-110. doi: 10.3233/TRD-160009 4. Wortmann SB, Duran
M, Anikster Y, et al: Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative
feature: proper classification and nomenclature. J Inherit Metab Dis. 2013;36:923-928. doi:
10.1007/s10545-012-9580-0
F5NUL 5'Nucleotidase
57285 Useful For:
Reference Values:
0 - 15 U/L
FLUC 5-Flucytosine, Serum

82741 Clinical Information: Flucytosine is a broad-spectrum antifungal agent generally used in combined
therapy (often with amphotericin B) for treatment of fungal infections such as cryptococcal meningitis.
Concerns with toxicity (ie, bone marrow suppression, hepatic dysfunction) and development of fungal
resistance limit the use of flucytosine, particularly as a monotherapy. The drug is well-absorbed orally but
can also be administered intravenously (available outside of the United States). There is good correlation
between serum concentrations of flucytosine with both efficacy and risk for toxicity. Because of the drug's
short half-life (3-6 hours), therapeutic monitoring is typically performed at peak levels approximately 2
hours after an oral dose or 30 minutes after an intravenous administration. Flucytosine is eliminated
primarily as unmetabolized drug in urine. Patients with kidney dysfunction may require dose adjustments
or more frequent monitoring to ensure that serum concentrations do not accumulate to excessive levels.
Nephrotoxicity associated with use of amphotericin B can affect elimination of flucytosine when the
drugs are coadministered.
Useful For: Monitoring serum concentration during therapy Evaluating potential toxicity May aid in
evaluating patient compliance
Interpretation: Most individuals display optimal response to flucytosine when peak serum levels (1-2
hours after oral dosing) are greater than 25.0 mcg/mL. Some infections may require higher concentrations
for efficacy. Toxicity is more likely when peak serum concentrations are greater than 100.0 mcg/mL
Reference Values:
Therapeutic concentration:
Peak >25.0 mcg/mL (difficult infections may require higher concentrations)
Toxic concentration:
Peak >100.0 mcg/mL
Clinical References: 1. Rifai N, Horvath AR, Wittwer CT, eds: Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018 2. Goodwin ML, Drew RH: Antifungal
serum concentration monitoring: an update. J Antimicrob Chemother. 2008 Jan;61(1):17-25. doi:
10.1093/jac/dkm389 3. Andes D, Pascual A, Marchetti O: Antifungal therapeutic drug monitoring:
established and emerging indications. Antimicrob Agents Chemother. 2009 Jan;53(1):24-34. doi:
10.1128/AAC.00705-08
FHIAA 5-HIAA (5-Hydroxyindoleacetic acid), Plasma

75515 Clinical Information: The ISI plasma 5-HIAA assay correlates well with the 24-hour urinary
5-HIAA assays. This test has been clinically validated for NETS patients who previously relied on the
24-hour urinary 5-HIAA. The plasma 5-HIAA saves time, alleviates the need to collect urine in a
container for 24 hours, and provides equivalent clinical information.
Reference Values:
Up to 22 ng/mL
Clinical References: 1. Tellez MR, Mamikunian G, O'Dorisio TM et al. A single fasting plasma
5-HIAA value correlates with 24-hour urinary 5-HIAA values and other biomarkers in midgut
neuroendocrine tumors (NETs). Pancreas. 2013:42(3): 405-410. 2. Cai H-L, Zhu R-H, Li H-D, et al.
MultiSimplex optimization of chromatographic separation and dansyl derivatization conditions in the
ultra performance liquid chromatography-tandem mass spectrometry analysis of neurotransmitters in
human urine. J Chromato B 2011;879:1993-1999. 3. Gonzalez RR, Fernandez RF, Vidal JLM et al.
Development and validation of an ultra-high performance liquid chromatography-tandem mass
spectrometry (UHPLC-MS/MS) method for the simultaneous determination of neurotransmitters in rat
brain samples. J Neuro Meth 2011;198: 187-194. 4. Stephanson N, Helander A, Beck O. Alcohol
biomarker analysis: simultaneous determination of 5-hydroxytryptophol glucuronide and
5-hydroxyindoleacetic acid by direct injection of urine using ultra-performance liquid
chromatographytandem mass spectrometry. J Mass Spect 2007;42: 940-949.
HIAA 5-Hydroxyindoleacetic Acid, 24 Hour, Urine

9248 Clinical Information: 5-Hydroxyindoleacetic acid (5-HIAA) is the major metabolite of serotonin
and is excreted in the urine. Intestinal carcinoid tumors, along with neuroendocrine tumors, can produce
excess amounts of 5-HIAA and serotonin, especially in individuals with carcinoid syndrome. Carcinoid
syndrome is characterized by carcinoid tumors, flushing, heart disease, and hepatomegaly.
Measurement of 5-HIAA in a 24-hour urine specimen can diagnose carcinoid disease with a high
specificity.
Useful For: Biochemical diagnosis and monitoring of intestinal carcinoid syndrome using 24-hour
urine specimens
Interpretation: If pharmacological and dietary artifacts have been ruled out, an elevated excretion of
5-hydroxyindoleacetic acid is a probable indicator of the presence of a serotonin-producing tumor.
Reference Values:
5-HIAA, mg/24 hour 99th percentile cutoff
Age Female Male
< or =23 months < or =2.7 < or =2.3
24-35 months < or =3.0 < or =2.6
3 years < or =3.2 < or =2.9
4 years < or =3.4 < or =3.2
5 years < or =3.6 < or =3.6
6 years < or =3.8 < or =3.9
7 years < or =4.0 < or =4.2
8 years < or =4.2 < or =4.5
9 years < or =4.5 < or =4.8
10 years < or =4.7 < or =5.1
11 years < or =4.9 < or =5.3
12 years < or =5.2 < or =5.6
13 years < or =5.4 < or =5.8
14 years < or =5.6 < or =6.1
15 years < or =5.7 < or =6.3
16 years < or =5.9 < or =6.4
17 years < or =6.0 < or =6.6
18 years < or =6.0 < or =6.7
19 years < or =6.1 < or =6.8
20 years < or =6.1 < or =6.9
21 years < or =6.2 < or =6.9
22 years < or =6.2 < or =7.0
23 years < or =6.2 < or =7.0
24 years < or =6.3 < or =7.1
25 years < or =6.3 < or =7.2
26 years < or =6.3 < or =7.2
27 years < or =6.4 < or =7.3
28 years < or =6.4 < or =7.4
29 years < or =6.5 < or =7.5
30 years < or =6.6 < or =7.5
31 years < or =6.6 < or =7.6
32 years < or =6.7 < or =7.7
33 years < or =6.8 < or =7.7

34 years < or =6.8 < or =7.8
35 years < or =6.9 < or =7.9
36 years < or =6.9 < or =7.9
37 years < or =7.0 < or =8.0
38 years < or =7.0 < or =8.1
39 years < or =7.0 < or =8.2
40 years < or =7.1 < or =8.2
41 years < or =7.1 < or =8.3
42 years < or =7.2 < or =8.4
43 years < or =7.3 < or =8.5
44 years < or =7.4 < or =8.6
45 years < or =7.4 < or =8.7
46 years < or =7.5 < or =8.8
47 years < or =7.6 < or =8.9
48 years < or =7.6 < or =9.0
49 years < or =7.7 < or =9.1
50 years < or =7.7 < or =9.2
51 years < or =7.8 < or =9.3
52 years < or =7.8 < or =9.4
53 years < or =7.9 < or =9.5
54 years < or =8.0 < or =9.6
55 years < or =8.1 < or =9.7
56 years < or =8.1 < or =9.7
57 years < or =8.2 < or =9.8
58 years < or =8.3 < or =9.8
59 years < or =8.3 < or =9.8
60 years < or =8.3 < or =9.9
61 years < or =8.3 < or =9.9
62 years < or =8.4 < or =9.9
63 years < or =8.4 < or =10.0
64 years < or =8.4 < or =10.0
65 years < or =8.4 < or =10.0
66 years < or =8.5 < or =10.1
67 years < or =8.5 < or =10.1
68 years < or =8.5 < or =10.1
69 years < or =8.5 < or =10.2
70 years < or =8.5 < or =10.2
71 years < or =8.6 < or =10.2

72 years < or =8.6 < or =10.2
73 years < or =8.5 < or =10.1
74 years < or =8.5 < or =10.1
75 years < or =8.6 < or =10.1
76 years < or =8.6 < or =10.0
77 years < or =8.6 < or =10.0
78 years < or =8.6 < or =10.0
79 years < or =8.6 < or =10.0
80 years < or =8.7 < or =9.9
81 years < or =8.7 < or =9.9
82 years < or =8.7 < or =9.9
83 years < or =8.7 < or =9.9
84 years < or =8.7 < or =9.9
85 years < or =8.6 < or =9.8
86 years < or =8.5 < or =9.8
87 years < or =8.4 < or =9.7
88 years < or =8.3 < or =9.7
89 years < or =8.1 < or =9.5
90 years < or =7.9 < or =9.4
91 years < or =7.6 < or =9.2
92 years < or =7.4 < or =9.0
93 years < or =7.1 < or =8.8
94 years < or =7.0 < or =8.7
= 95 years < or =6.9 < or =8.6 For SI unit Reference Values, see
www.mayocliniclabs.com/order-tests/si-unit-conversion.html
Clinical References: 1. Grimaldi F, Fazio N, Attanasio R, et al: Italian Association of Clinical
Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of
gastroenteropancreatic neuroendocrine neoplasms. J Endocrinol Invest. 2014;37(9):875-909.
doi:10.1007/s40618-014-0119-0 2. Vinik A, Hughes MS. Feliberti E, et al: Carcinoid tumors. In: Feingold
KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. MDText.com Inc; 2000. Updated February 5,
2018. Accessed May 5, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK279162/ 3. Shah D, Mandot
A, Cerejo C, et al: The outcome of primary hepatic neuroendocrine tumors: A single-center experience. J
Clin Exp Hepatol. 2019 Nov-Dec;9(6):710-715. doi: 10.1016/j.jceh.2019.08.002 4. Perry D, Hayek SS:
Carcinoid heart disease: A guide for clinicians. Cardiol Clin. 2019 Nov;37(4):497-503. doi:
10.1016/j.ccl.2019.07.014 5. Degnan AJ, Tocchio S, Kurtom W, Tadros SS: Pediatric neuroendocrine
carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr
Blood Cancer. 2017 Sep;64(9). doi: 10.1002/pbc.26477 6. Corcuff JB, Chardon L, El Hajji Ridah I,
Brossaud J: Urinary sampling for 5HIAA and metanephrines determination: revisiting the
recommendations. Endocr Connect. 2017 Aug;6(6):R87-R98. doi:10.1530/EC-17-0071
HIAAR 5-Hydroxyindoleacetic Acid, Random, Urine

616090 Clinical Information: 5-Hydroxyindoleacetic acid (5-HIAA) is the major metabolite of serotonin and
is excreted in the urine. Intestinal carcinoid tumors, along with neuroendocrine tumors, can produce
excess amounts of 5-HIAA and serotonin, especially in individuals with carcinoid syndrome. Carcinoid
syndrome is characterized by carcinoid tumors, flushing, heart disease, and hepatomegaly. Measurement
of 5-HIAA in a random urine specimen can diagnose carcinoid disease with a high specificity.
Useful For: Biochemical diagnosis and monitoring of intestinal carcinoid syndrome using random
urine specimens
Interpretation: If pharmacological and dietary artifacts have been ruled out, an elevated excretion of
5-hydroxyindoleacetic acid is a probable indicator of the presence of a serotonin-producing tumor.
Reference Values:
5-HIAA, mg/g creatinine 99th percentile cutoff
Age Female Male
< or =23 months < or =17.53 < or =16.42
24-35 months < or =17.07 < or =15.96
3 years < or =16.70 < or =15.60
4 years < or =16.03 < or =14.93
5 years < or =15.26 < or =14.17
6 years < or =14.40 < or =13.34
7 years < or =13.47 < or =12.43
8 years < or =12.52 < or =11.52
9 years < or =11.58 < or =10.63
10 years < or =10.67 < or =9.79
11 years < or =9.81 < or =9.00
12 years < or =9.02 < or =8.29
13 years < or =8.32 < or =7.65
14 years < or =7.70 < or =7.08
15 years < or =7.16 < or =6.59
16 years < or =6.72 < or =6.15
17 years < or =6.36 < or =5.78
18 years < or =6.08 < or =5.45
19 years < or =5.88 < or =5.17
20 years < or =5.73 < or =4.93
21 years < or =5.64 < or =4.73
22 years < or =5.59 < or =4.55
23 years < or =5.57 < or =4.40
24 years < or =5.57 < or =4.28
25 years < or =5.58 < or =4.19
26 years < or =5.61 < or =4.11
27 years < or =5.64 < or =4.06
28 years < or =5.67 < or =4.03

29 years < or =5.70 < or =4.02
30 years < or =5.72 < or =4.01
31 years < or =5.75 < or =4.02
32 years < or =5.77 < or =4.03
33 years < or =5.78 < or =4.05
34 years < or =5.79 < or =4.06
35 years < or =5.80 < or =4.08
36 years < or =5.80 < or =4.09
37 years < or =5.80 < or =4.11
38 years < or =5.80 < or =4.12
39 years < or =5.81 < or =4.14
40 years < or =5.82 < or =4.17
41 years < or =5.85 < or =4.22
42 years < or =5.89 < or =4.27
43 years < or =5.95 < or =4.35
44 years < or =6.04 < or =4.43
45 years < or =6.14 < or =4.53
46 years < or =6.26 < or =4.63
47 years < or =6.40 < or =4.75
48 years < or =6.55 < or =4.86
49 years < or =6.71 < or =4.99
50 years < or =6.86 < or =5.11
51 years < or =7.01 < or =5.24
52 years < or =7.15 < or =5.37
53 years < or =7.29 < or =5.51
54 years < or =7.41 < or =5.64
55 years < or =7.52 < or =5.78
56 years < or =7.62 < or =5.91
57 years < or =7.71 < or =6.05
58 years < or =7.80 < or =6.17
59 years < or =7.88 < or =6.29
60 years < or =7.95 < or =6.41
61 years < or =8.02 < or =6.51
62 years < or =8.09 < or =6.60
63 years < or =8.15 < or =6.69
64 years < or =8.21 < or =6.76
65 years < or =8.28 < or =6.82
66 years < or =8.34 < or =6.88

67 years < or =8.40 < or =6.93
68 years < or =8.46 < or =6.97
69 years < or =8.52 < or =7.00
70 years < or =8.58 < or =7.03
71 years < or =8.65 < or =7.06
72 years < or =8.71 < or =7.08
73 years < or =8.77 < or =7.10
74 years < or =8.82 < or =7.11
75 years < or =8.86 < or =7.11
76 years < or =8.90 < or =7.11
77 years < or =8.92 < or =7.10
78 years < or =8.93 < or =7.09
79 years < or =8.93 < or =7.07
80 years < or =8.92 < or =7.05
81 years < or =8.90 < or =7.02
82 years < or =8.88 < or =7.00
83 years < or =8.86 < or =6.98
84 years < or =8.85 < or =6.97
85 years < or =8.84 < or =6.95
86 years < or =8.84 < or =6.94
87 years < or =8.84 < or =6.94
88 years < or =8.84 < or =6.94
>or= 89 years < or =8.85 < or =6.93
Clinical References: 1. Grimaldi F, Fazio N, Attanasio R, et al. Italian Association of Clinical

Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of
gastroenteropancreatic neuroendocrine neoplasms. J Endocrinol Invest. 2014;37(9):875-909.
doi:10.1007/s40618-014-0119-0 2. Vinik A, Hughes MS. Feliberti E, et al: Carcinoid tumors. In: Feingold
KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. MDText.com, Inc; 2000. Updated February 5,
2018. Accessed May 5, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK279162/ 3. Shah D, Mandot
A, Cerejo C, et al: The outcome of primary hepatic neuroendocrine tumors: A single-center experience. J
Clin Exp Hepatol. 2019 Nov-Dec;9(6):710-715. doi: 10.1016/j.jceh.2019.08.002 4. Perry D, Hayek SS:
Carcinoid heart disease: A guide for clinicians. Cardiol Clin. 2019 Nov;37(4):497-503. doi:
10.1016/j.ccl.2019.07.014 5. Degnan AJ, Tocchio S, Kurtom W, Tadros SS: Pediatric neuroendocrine
carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr
Blood Cancer. 2017 Sep;64(9). doi: 10.1002/pbc.26477 6. Corcuff JB, Chardon L, El Hajji Ridah I,
Brossaud J. Urinary sampling for 5HIAA and metanephrines determination: revisiting the
recommendations. Endocr Connect. 2017;6(6):R87-R98. doi:10.1530/EC-17-0071
F5M 5-Methyltetrahydrofolate
57101 Clinical Information: CSF 5-Methyltetrahydrofolate (NC01) is useful for determining a deficiency
of folate in the central nervous system. CSF 5-Methyltetrahydrofolate (NC01) may also be used for
assessment of Variants of Uncertain Significance (VUS) identified during genetic testing (e.g. Next
Generation Sequencing or Capillary Sequencing Testing). CLINICAL 5-Methyltetrahydrofolate
(5-MTHF) is the predominant form of folate in cerebrospinal fluid (CSF). Low CSF 5-MTHF levels are
associated with inborn errors of metabolism affecting folate metabolism , dietary deficiency of folate,
cerebral folate syndromes and Kearns-Sayre syndrome. Symptoms may include, anemia, developmental
delay, seizures, depression and dementia.
Reference Values:
5-Methyltetrahydrofolate
Age 5MTHF
(years) (nmol/L)
0-0.2 40-240
0.2-0.5 40-240
0.5-2.0 40-187
2.0-5.0 40-150
5.0-10 40-128
10-15 40-120
Adults 40-120
Note: If test results are inconsistent with the clinical presentation, please call our laboratory to discuss
the case and/or submit a second sample for confirmatory testing.
DISCLAIMER required by the FDA for high complexity clinical laboratories: HPLC testing was
developed and its performance characteristics determined by Medical Neurogenetics. These HPLC tests
have not been cleared or approved by the U.S. FDA.
MAMMX 6-Monoacetylmorphine (6-MAM) Confirmation, Chain of

62732 Custody, Meconium
Clinical Information: Heroin (diacetylmorphine) is a semisynthetic opiate that is closely related to
morphine. It is no longer used clinically in the United States, though it is used elsewhere for rapid relief
of pain.(1) Like morphine and other opiates, its relaxing and euphoric qualities make heroin a popular
drug of abuse. Heroin is commonly injected intravenously, although it can be administered by other
means such as snorting, smoking, or inhaling vapors. Heroin shares the core structure of morphine, with
the addition of 2 acetyl groups, which are thought to enhance its permeation into the central nervous
system.(2,3) Heroin is metabolized by sequential removal of these acetyl groups; loss of the first acetyl
converts heroin into 6-monoacetylmorphine (6-MAM).(2,3) Heroin is rarely found in meconium since
only 0.1% of a dose is excreted unchanged. 6-MAM is a unique metabolite of heroin, and its presence is
a definitive indication of heroin use. Like heroin, 6-MAM has a very short half-life; however, its
detection time in meconium, the first fecal material passed by the neonate, is uncharacterized. 6-MAM
is further metabolized into morphine, the dominant metabolite of heroin, and morphine will typically be
found in a specimen containing 6-MAM. Opiates, including heroin, have been shown to readily cross
the placenta and distribute widely into many fetal tissues.(4) Opiate use by the mother during pregnancy
increased the risk of prematurity and being small for gestational age. Furthermore, heroin-exposed
infants exhibit an early onset of withdrawal symptoms compared with methadone-exposed infants.
Heroin-exposed infants demonstrate a variety of symptoms including irritability, hypertonia,
wakefulness, diarrhea, yawning, sneezing, increased hiccups, excessive sucking, and seizures.
Long-term intrauterine drug exposure may lead to abnormal neurocognitive and behavioral
development as well as an increased risk of sudden infant death syndrome.(5) The disposition of drug in
meconium is not well understood. The proposed mechanism is that the fetus excretes drug into bile and
amniotic fluid. Drug accumulates in meconium either by direct deposit from bile or through swallowing
of amniotic fluid.(6) The first evidence of meconium in the fetal intestine appears at approximately the
10th to 12th week of gestation, and it slowly moves into the colon by the 16th week of gestation.(7)
Therefore, the presence of drugs in meconium has been proposed to be indicative of in utero drug
exposure during the final 4 to 5 months of pregnancy, a longer historical measure than is possible by
urinalysis.(6) Chain of custody is a record of the disposition of a specimen to document each individual
who collected, handled, and performed the analysis. When a specimen is submitted in this manner,
analysis will be performed in such a way that it will withstand regular court scrutiny.
Useful For: Detection of in utero heroin exposure up to 5 months before birth Chain of custody is
separating the baby from the mother, a complete chain-of-custody ensures that the test results are
Interpretation: The presence of 6-monoacetylmorphine (6-MAM) in meconium is definitive for

heroin use by the mother. However, the absence of 6-MAM does not rule-out heroin use because of its
short half-life.
Reference Values:
Negative
Clinical References: 1. Giovannelli M, Bedforth N, Aitkenhead A: Survey of intrathecal opioid

usage in the UK. Eur J Anaesthesiol. 2008;25:118-122 2. Principles of Forensic Toxicology. 2nd ed.
AACC Press; 2003:187-205 3. Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 10th
ed. McGraw-Hill; 2001:590-592 4. Szeto HH: Kinetics of drug transfer to the fetus. Clin Obstet Gynecol.
1993;36:246-254 5. Kwong TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn
drug testing. Clin Chem. 1997;43(1):235-242 6. Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening
of meconium in infants of drug-dependent mothers: an alternative to urine testing. J Pediatr. 1989
Sep;115(3):474-477 7. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium passage in utero
mechanisms, consequences, and management. Obstet Gynecol Surv. 2005 Jan;60(1):45-56; quiz 73-74 8.
Langman LJ Bechtel LK, Meier BM, Holstege C: Clinical toxicology. In: Rifai N, Horvath AR, Wittwer
CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887
9. Baselt RC: Disposition of Toxic Drugs and Chemical in Man. 10th ed. Biomedical Publications; 2014
6MAMM 6-Monoacetylmorphine (6-MAM), Confirmation, Meconium

89659 Clinical Information: Heroin (diacetylmorphine) is a semisynthetic opiate that is closely related to
morphine. It is no longer used clinically in the United States, though it is used elsewhere for rapid relief of
pain.(1) Like morphine and other opiates, its relaxing and euphoric qualities make heroin a popular drug
of abuse. Heroin is commonly injected intravenously, although it can be administered by other means
such as snorting, smoking, or inhaling vapors. Heroin shares the core structure of morphine, with the
addition of 2 acetyl groups, which are thought to enhance its permeation into the central nervous
system.(2,3) Heroin is metabolized by sequential removal of these acetyl groups; loss of the first acetyl
converts heroin into 6-monoacetylmorphine (6-MAM).(2,3) Heroin is rarely found in meconium since
only 0.1% of a dose is excreted unchanged. 6-MAM is a unique metabolite of heroin, and its presence is a
definitive indication of heroin use. Like heroin, 6-MAM has a very short half-life; however, its detection
time in meconium, the first fecal material passed by the neonate, is uncharacterized. 6-MAM is further
metabolized into morphine, the dominant metabolite of heroin, and morphine will typically be found in a
specimen containing 6-MAM. Opiates, including heroin, have been shown to readily cross the placenta
and distribute widely into many fetal tissues.(4) Opiate use by the mother during pregnancy increased the
risk of prematurity and being small for gestational age. Furthermore, heroin-exposed infants exhibit an
early onset of withdrawal symptoms compared with methadone-exposed infants. Heroin-exposed infants
demonstrate a variety of symptoms including irritability, hypertonia, wakefulness, diarrhea, yawning,
sneezing, increased hiccups, excessive sucking, and seizures. Long-term intrauterine drug exposure may
lead to abnormal neurocognitive and behavioral development as well as an increased risk of sudden infant
death syndrome.(5) The disposition of drug in meconium is not well understood. The proposed
mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in meconium
either by direct deposit from bile or through swallowing of amniotic fluid.(6) The first evidence of
meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation, and it slowly
moves into the colon by the 16th week of gestation.(7) Therefore, the presence of drugs in meconium has
been proposed to be indicative of in utero drug exposure during the final 4 to 5 months of pregnancy, a
longer historical measure than is possible by urinalysis.(6)
Useful For: Detection of in utero heroin exposure up to 5 months before birth

Interpretation: The presence of 6-monoacetylmorphine (6-MAM) in meconium is definitive for
heroin use by the mother. However, the absence of 6-MAM does not rule-out heroin use because of its
short half-life and stability.
Reference Values:
Negative

usage in the UK. Eur J Anaesthesiol. 2008;25:118-122 2. Levine B, ed. Principles of Forensic
Toxicology. 4th ed. AACC Press; 2013 3. Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman
and Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill; 2018 4. Szeto HH:
Kinetics of drug transfer to the fetus. Clin Obstet Gynecol. 1993;36:246-254 5. Kwong TC, Ryan RM:
Detection of intrauterine illicit drug exposure by newborn drug testing. Clin Chem. 1997;43(1):235-242
6. Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent
mothers: an alternative to urine testing. J Pediatr. 1989 Sep;115(3):474-477 7. Ahanya SN, Lakshmanan
J, Morgan BL, Ross MG: Meconium passage in utero mechanisms, consequences, and management.
Obstet Gynecol Surv. 2005 Jan;60(1):45-56; quiz 73-74 8. Langman LJ Bechtel LK, Meier BM,
Holstege C: Clinical toxicology. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 9. Baselt RC: Disposition of
Toxic Drugs and Chemical in Man. 12th ed. Biomedical Publications; 2020
6MAMU 6-Monoacetylmorphine Confirmation, Random, Urine

morphine. It is no longer used clinically in the United States, though elsewhere it is used for rapid relief
of pain.(1) Like morphine and other opiates, its relaxing and euphoric qualities make heroin a popular
drug of abuse. Heroin is commonly injected intravenously, although it can be administered by other
means such as snorting, smoking, or inhaling vapors. Heroin shares the core structure of morphine, with
the addition of 2 acetyl groups, which are thought to enhance its permeation into the central nervous
system.(2,3) Heroin is metabolized by sequential removal of these acetyl groups; loss of first acetyl
group converts heroin into 6-monoacetylmorphine (6-MAM) and loss of the second acetyl group
converts 6-MAM to morphine, the dominant metabolite of heroin.(2,3) Heroin is rarely found intact in
urine, since only 0.1% of a dose is excreted unchanged. 6-MAM is a unique metabolite of heroin, and
its presence is a definitive indication of recent heroin use. Like heroin, 6-MAM has a very short half-life
and detection window.
Useful For: Determination of heroin use

Interpretation: The presence of 6-monoacetylmorphine (6-MAM) in urine is definitive for recent
heroin use. However, the absence of 6-MAM does not rule-out heroin use because of its short half-life.
6-MAM is typically only detectable within 24 hours of heroin use. 6-MAM is further metabolized into
morphine, which may be detected 1 to 2 days after 6-MAM is no longer measurable. Morphine will
typically be found in a specimen containing 6-MAM.(2,3)
Reference Values:
Negative
Cutoff concentrations:
6-MAM
<5 ng/mL

usage in the UK. Eur J Anaesthesiol 2008;25:118-1122 2. Principles of Forensic Toxicology. Second
edition. Washington DC. AACC Press, 2003, pp 187-205 3. Hardman JG, Limbird LE, Gilman AG:
Goodman and Gilman's. The Pharmacological Basis of Therapeutics. 10th edition McGraw-Hill Book
Company, 2001 pp 590-592 4. Principles of Forensic Toxicology. Fourth edition. AACC Press, 2013 5.
Langman LJ, Bechtel LK, Meier BM, Holstege C: Chapter 41: Clinical Toxicology. In Tietz Textbook of
Clinical Chemistry and Molecular Diagnostics. Edited by N Rifai, AR Horvath, CT Wittwer. Sixth
edition. Elsevier, 2018 p 872
6MAMX 6-Monoacetylmorphine, Chain of Custody, Random, Urine

morphine. It is no longer used clinically in the United States, though elsewhere it is used for rapid relief of
pain.(1) Like morphine and other opiates, its relaxing and euphoric qualities make heroin a popular drug
of abuse. Heroin is commonly injected intravenously, although it can be administered by other means
such as snorting, smoking, or inhaling vapors. Heroin shares the core structure of morphine, with the
addition of 2 acetyl groups, which are thought to enhance its permeation into the central nervous
system.(2,3) Heroin is metabolized by sequential removal of these acetyl groups; loss of first acetyl group
converts heroin into 6-monoacetylmorphine (6-MAM) and loss of the second acetyl group converts
6-MAM to morphine, the dominant metabolite of heroin.(2,3) Heroin is rarely found intact in urine, since
only 0.1% of a dose is excreted unchanged. 6-MAM is a unique metabolite of heroin, and its presence is a
definitive indication of recent heroin use. Like heroin, 6-MAM has a very short half-life and detection
window. Chain of custody is required whenever the results of testing could be used in a court of law. Its
purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was
under the control of personnel involved with testing the specimen at all times; this control implies that the
opportunity for specimen tampering would be limited. This includes a record of the disposition of a
specimen to document the personnel who collected it, who handled it, and who performed the analysis.
When a specimen is submitted in this manner, analysis will be performed in such a way that it will
withstand regular court scrutiny.
Useful For: Determination of heroin use in urine specimens handled through the chain-of-custody
process
Interpretation: The presence of 6-monoacetylmorphine (6-MAM) in urine is definitive for recent

heroin use. However, the absence of 6-MAM does not rule out heroin use because of its short half-life.
6-MAM is typically only detectable within 24 hours of heroin use. 6-MAM is further metabolized into
morphine, which may be detected 1 to 2 days after 6-MAM is no longer measurable. Morphine will
typically be found in a specimen containing 6-MAM.(2,3)
Reference Values:
Negative
6-MAM
<5 ng/mL

usage in the UK. Eur J Anaesthesiol 2008;25:118-1122 2. Principles of Forensic Toxicology. Second
edition. AACC Press, 2003, pp 187-205 3. Hardman JG, Limbird LE, Gilman AG: Goodman and
Gilman's. The Pharmacological Basis of Therapeutics. 10th edition McGraw-Hill Book Company, 2001
pp 590-592 4. Principles of Forensic Toxicology. Fourth edition. AACC Press, 2013 5. Langman LJ,
Bechtel LK, Meier BM, Holstege C: Chapter 41: Clinical Toxicology. In Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. Edited by N Rifai, AR Horvath, CT Wittwer. Sixth edition.
Elsevier, 2018 p 872
F68KD 68kD (hsp-70)

91494 Interpretation: Antibodies to inner ear antigen (68kD) occur in approximately 70% of patients with
autoimmune hearing loss. The antibody tests to this 68kD antigen parallel with disease activity. In
addition, a majority of patients positive for antibodies to 68kd are responsive to corticosteroid treatment.
(Hirose et al: The Laryngoscope 109:1769 Ã¢â‚¬â€œ 1999)
Reference Values:
Qualitative test Ã¢â‚¬â€œ Positive or Negative
7AC4 7AC4, Bile Acid Synthesis, Serum

607699 Clinical Information: Bile acids are synthesized from cholesterol in the liver and released into the
digestive tract where they function to emulsify dietary fats and facilitate lipid absorption in the small
intestine. More than 95% of bile acids are then reabsorbed primarily by active uptake in the distal ileum,
while less than 5% are excreted in stool. The synthesis of bile acids in the liver is regulated by a
negative feedback mechanism from the bile acids reabsorbed from the intestine. 7
Alpha-hydroxy-4-cholesten-3-one (7aC4) is an intermediate in the biosynthesis pathway of cholesterol
to bile acids. The concentration of 7aC4 in serum is a surrogate for the amount of bile acid synthesis in
the liver. There is some diurnal variation in 7aC4 serum concentrations, so measurement should be
performed on a fasting morning sample. Patients with increased bile acid in their stool suffer from
chronic diarrhea termed bile acid diarrhea (BAD). Approximately 10% to 33% of patients with irritable
bowel syndrome with primarily diarrhea (IBS-D) have BAD. Identifying patients with BAD can be
done by measuring total and fractionated bile acids in stool. The increased bile acids in feces can be
caused by an inability to reabsorb bile acids in the terminal ileum (bile acid malabsorption: BAM). The
loss of intestinal reabsorption leads to increase synthesis of bile acids in the liver. Recent studies have
shown that serum concentrations of 7aC4 are elevated in patients with BAD and can be used as a
surrogate to the timed fecal collection. Several intestinal diseases or functional abnormalities can lead to
BAD. Identification of these patients can influence treatment decisions that could include the use of bile
acid sequestrants. Conversely, patients with IBS with predominately constipation (IBS-C) may have
lower circulating 7aC4 as compared to healthy individuals.
Useful For: Screening for bile acid malabsorption in patients with irritable bowel syndrome-diarrhea
(IBS-D)
Interpretation: In patients with irritable bowel syndrome-diarrhea (IBS-D), elevated

7alpha-hydroxy-4-cholesten-3-one (7aC4) is consistent with bile acid diarrhea (BAD). A result of 17.6
ng/mL or greater is 83% sensitive and 53% specific for BAD. In these cases, a confirmatory 48-hour
fecal bile acid test could be considered. A result above 52.5 ng/mL is 40% sensitive and 85% specific
for BAD. Interpretation in patients with chronic diarrhea (bile acid malabsorption: BAM):
-------------------------------------------------17.6------------------------------------------52.5------------------------
-- BAM unlikely Indeterminate BAM likely (consider other (consider confirmatory (consider bile acid
conditions) fecal bile acids test or trial sequestrant therapy) of bile acid sequestrant)
Reference Values:
> or =18 years: 2.5-63.2 ng/mL
Reference values have not been established for patients who are <18 years of age.
Clinical References: 1. Vijayvargiya P, Camilleri M, Carlson P, et al: Performance characteristics of

serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and
functional diarrhoea. Aliment Pharmacol Ther. 2017;46(6):581-588. doi: 10.1111/apt.14214 2.
Vijayvargiya P, Camilleri M, Shin A, et al: Methods for diagnosis of bile acid malabsorption in clinical
practice. Clin Gastroenterol Hepatol. 2013;11(10):1232-1239 3. Camilleri M, Nadeau A, Tremaine WJ, et
al: Measurement of serum 7 alpha-hydroxy-4-cholesten-3-one (or 7AC4), a surrogate test for bile acid
malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem
mass spectrometry. Neurogastroenterol Motil. 2009;21(7):734-743 4. Wong BS, Camilleri M, Carlson P,
et al: Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea. Clin
Gastroenterol Hepatol. 2012 Sep;10(9):1009-1015.e3
A1R A1 Antigen Subtype, Blood

113437 Clinical Information: The presence or absence of a cellular antigen is an inherited trait. As a general
rule, individuals will not make antibody directed against an antigen present on their own red blood cells.
Useful For: Additional proof of alloantibody specificity Assessment of solid organ transplantation
donor compatibility This test is not useful for the purpose of establishing paternity.
Interpretation: A1 antigen type will be resulted as "pos" indicating that the antigen is present, or by
"neg" indicating that the antigen is absent.
Reference Values:
Reported as Negative or Positive
Clinical References: Fung MK, Eder AF, Spitalnik SL, Westhoff CM: Technical Manual. 19th ed.
AABB; 2017
_G111 Abnormal Transferrin CDG Panel (Bill Only)

This test is for billing purposes only.
This is not an orderable test.
ABONR ABO/Rh Newborn, Blood

113498 Clinical Information: The ABO and Rh typing indicates the presence of 2 of the various blood group
systems. The identification of antigens in the ABO and Rh system has its major application in the
selection of blood and blood products of the appropriate ABO/Rh type for transfusion therapy and in the
determination of the mother's candidacy for Rh immune globulin therapy. Weak D testing will be
performed on all Rh-negative babies.
Useful For: Selecting compatible blood products for transfusion therapy Determining the need for Rh
immune globulin in mother of baby
Interpretation: Agglutination of red cells with an antiserum represents the presence of the
corresponding antigen on the red cells.
Reference Values:
ABO and Rh blood group antigens identified
Clinical References: Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. Technical Manual. 19th
ed. AABB; 2017
ABOMR ABO/Rh, Blood

113490 Clinical Information: This ABO and Rh blood typing test identifies the presence of specific red
cell antigens and antibodies to determine the ABO/Rh type.
Useful For: Determining blood group ABO and Rh only

Interpretation: Standard ABO/Rh type will be reported. Routine types include: O pos, O neg, A pos,
A neg, B pos, B neg, AB pos and AB neg.Â Any relevant discrepancies will be noted.
Reference Values:
ABO and Rh blood group antigens identified
Clinical References: Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. Technical Manual.
19th ed. AABB; 2017
ACAC Acacia, IgE, Serum

82757 Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are
caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from
immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE
antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the
immune response to allergens that may be associated with allergic disease. The allergens chosen for
testing often depend upon the age of the patient, history of allergen exposure, season of the year, and
clinical manifestations. In individuals predisposed to develop allergic disease, the sequence of
sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and
bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and
wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to
sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).
Useful For: Establishing the diagnosis of an allergy to acacia Defining the allergen responsible for
eliciting signs and symptoms Identifying allergens: -Responsible for allergic disease and/or
anaphylactic episode -To confirm sensitization prior to beginning immunotherapy -To investigate the
specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens
Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased

likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be
responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with
the concentration of IgE antibodies expressed as a class score or kU/L.
Reference Values:
Class IgE kU/L Interpretation
0 Negative
1 0.35-0.69 Equivocal
2 0.70-3.49 Positive
4 17.5-49.9 Strongly positive
6 > or =100 Strongly positive Reference values

apply to all ages.
Clinical References: Homburger HA, Hamilton RG: Chapter 55: Allergic diseases. In Henry's
Clinical Diagnosis and Management by Laboratory Methods. 23rd edition. Edited by RA McPherson, MR
Pincus. Elsevier, 2017, pp 1057-1070
ACARP Acanthamoeba species Molecular Detection, PCR, Ocular

64717 Clinical Information: Acanthamoeba are ubiquitous, free-living, microscopic amebae that cause rare,
but severe, infections of the eye, skin, lungs, and central nervous system (CNS). They are found
worldwide in water and soil and may enter the body through inhalation, contamination of wounds, and
contact lens use. As many as 24 species comprising 18 genotypes (T1-T18) have been described, although
most human infections are due to genotype T4. Given their widespread distribution in the environment,
many people will be exposed to Acanthamoeba during their lifetime, but very few will become sick from
this exposure. The most common form of Acanthamoeba infection is amebic keratitis (AK). Infection
occurs primarily in contact lens wearers due to contamination of lenses, cleaning solutions, or storage
cases. Amebae can also enter the cornea following trauma. AK is a painful, subacute corneal infection
associated with extensive scarring and blindness if untreated. Cases generally respond to treatment but
relapse is common. Compared to corneal infection, involvement of the CNS is rare and seen primarily in
severely immunocompromised individuals such as organ transplant recipients and patients with AIDS.
CNS infection may also be caused by a related ameba, Balamuthia mandrillaris. AK is usually clinically
suspected based on symptoms and confocal ophthalmologic examination. Confirmation of infection is
classically identified by microscopic examination and culture of corneal tissue and contact lenses or
equipment using tap water agar plate overlain with bacteria as a food source for the amebae.
Unfortunately, it must be held and examined for 7 days for maximum sensitivity. A polymerase chain
reaction assay provides a more rapid result with similar sensitivity to culture and is, therefore, the
preferred method for confirming the clinical diagnosis of AK.
Useful For: Aids in the diagnosis of amebic keratitis in conjunction with clinical findings
Interpretation: A positive result indicates the presence of Acanthamoeba species DNA and is
consistent with active or recent infection. While positive results are highly specific indicators of disease,
they should be correlated with symptoms, clinical findings, and confocal ophthalmologic examination.
Reference Values:
Negative
Clinical References: 1. Trabelsi H, Dendana A, Sellami A, et al: Pathogenic free-living amoebae:

epidemiology and clinical review. Pathol Biol (paris). 2012 Dec;60(6):399-405 2. Thompson PP,
Kowalski RP, Shanks RMQ, Gordon YJ: Validation of real-time PCR for laboratory diagnosis of
Acanthamoeba keratitis. J Clin Microbiol. 2008 Oct;46(10):3232-3236
ACAR Acarus siro, IgE, Serum

bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat
proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to
Useful For: Establishing the diagnosis of an allergy to Acarus siro (flour mites) Defining the allergen
responsible for eliciting signs and symptoms Identifying allergens: -Responsible for allergic disease
and/or anaphylactic episode -To confirm sensitization prior to beginning immunotherapy -To investigate
the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens

Reference Values:
0 Negative

apply to all ages.
Clinical Diagnosis and Management by Laboratory Methods. 23rd edition. Edited by RA McPherson,
MR Pincus. Elsevier, 2017, pp 1057-1070
FACET Acetaminophen (Tylenol, Datril), Urine

Units: ug/mL
Note: Analysis performed on urine.

Reference ranges have not been established for urine specimens.
ACMA Acetaminophen, Serum

37030 Clinical Information: Acetaminophen (found in Anacin-3, Comtrex, Contac, Datril, Dristan,
Excedrin, Nyquil, Sinutab, Tempera, Tylenol, Vanquish, and many others) is an analgesic, antipyretic
drug lacking significant anti-inflammatory activity. It is metabolized by the liver with a normal
elimination half-life of less than 4 hours. In normal therapeutic doses, a minor metabolite, possessing
electrophilic alkylating activity, readily reacts with glutathione in the liver to yield a detoxified product.
In overdose situations, liver glutathione is consumed and the toxic metabolite (postulated metabolite:
benzoquinone) reacts with cellular proteins resulting in hepatotoxicity, characterized by centrilobular
necrosis and possible death if untreated. N-acetylcysteine can substitute for glutathione and serves as an
antidote. Serum concentration and half-life are the only way to assess degree of intoxication in early
stages since other liver function studies (eg, bilirubin, liver function enzymes) will not show clinically
significant increases until after tissue damage has occurred, at which point therapy is ineffective.
Useful For: Monitoring toxicity in overdose cases

Interpretation: The normal half-life is less than 4 hours, while the toxic half-life is greater than 4
hours. The toxic level is dependent on half-life. When the half-life is 4 hours, hepatotoxicity generally
will not occur unless the concentration is above 150 mcg/mL. The level at which toxicity occurs
decreases with increasing half-life until it is encountered at values as low as 50 mcg/mL when the
half-life reaches 12 hours. For half-life determination, draw 2 specimens at least 4 hours apart and note
the exact time of each draw. Half-life can be calculated from the concentrations and the time interval.
Clinical References: Rumack BH, Peterson RG: Acetaminophen overdose: incidence, diagnosis,
and management in 416 patients. Pediatrics Nov 1978;62:898-903
FACES Acetoacetate, Serum

Reporting limit determined each analysis.
Acetoacetate
Normal range for adults: 5-30 mcg/mL
FCDU3 Acetyl Fentanyl, Umbilical Cord Tissue

Units: ng/g
Only orderable as part of a profile-see FCDSU.
ARBI Acetylcholine Receptor (Muscle AChR) Binding Antibody,

8338 Serum
Clinical Information: Fatigable weakness due to impaired postsynaptic transmission at the
neuromuscular junction is characteristic of myasthenia gravis (MG). A clinical diagnosis should be
supported by electrodiagnostic testing (ie, clinical-electrodiagnosis [EDX]). Positive autoimmune
serology increases certainty of MG diagnosis but needs to be interpreted in the proper clinical-EDX
context with response to anticholinesterase medications supporting the diagnosis. Most cases are
autoimmune and are caused by IgG autoantibodies binding to critical postsynaptic membrane molecules
(nicotinic muscle acetylcholine receptor [AChR] or its interacting proteins, such as muscle-specific
kinase). Serologically, the detection of AChR binding antibody provides the best diagnostic sensitivity.
However, the presence of both AChR binding and modulating activity improves diagnostic accuracy.
Autoantibody detection frequency is lowest in patients with weakness confined to extraocular muscles
(approximately 70% are positive for AChR binding antibodies) and highest in patients with generalized
weakness due to MG (approximately 90% are positive for AChR binding antibodies). In adults with MG
and AChR antibodies, approximately 20% will have thymoma and very rarely (<1%) extrathymic cancers.
Computed tomography imaging of the chest is considered the standard of care to evaluate for thymoma.
These results should only be interpreted in the appropriate clinical and electrophysiological context and
are not diagnostic in isolation. Note: Single antibody tests may be requested in the follow-up of patients
with positive results previously documented in this laboratory.
Useful For: Supporting the diagnosis of autoimmune myasthenia gravis (MG) in adults and children
Distinguishing autoimmune from congenital MG in adults and children or other acquired forms of
neuromuscular junction transmission disorders An adjunct to the test for P/Q-type calcium channel
binding antibodies as a diagnostic aid for Lambert-Eaton myasthenic syndrome
Interpretation: Positive results (>0.02 nmol/L) are indicative of autoimmune myasthenia gravis (MG).
These results should be interpreted in the appropriate clinical and electrophysiological context. With a
diagnosis of MG, a paraneoplastic basis should be considered with thymoma being the most commonly
associated tumor with MG. The clinical sensitivity of this assay is approximately 90% in
nonimmunosuppressed patients with generalized MG. The frequency of antibody detection is lower in
MG patients with weakness clinically restricted to ocular muscles (71%), and antibody titers are generally
low in ocular MG (eg, 0.03-1.0 nmol/L). Negative results do not exclude the diagnosis of MG. If clinical
suspicion remains and symptoms persist or worsen consider retesting. Results may be negative in the first
12 months after symptoms of MG appear or during immunosuppressant therapy. Note: In follow up of
seronegative patients with adult-acquired generalized MG, 17.4% seroconvert to positive at 12 months (ie,
seronegativity rate at 12 months is 8.4%). A subset of MG patients that are persistently negative for
acetylcholine receptor binding antibodies will have muscle-specific kinase (MuSK) antibodies, and
therefore, it is recommended to test for MuSK antibodies in seronegative patients with high clinical
suspicion of MG. In general, there is not a close correlation between antibody titer and severity of
weakness, but in individual patients, clinical improvement may be accompanied by a decrease in titer.
Reference Values:
< or =0.02 nmol/L
Clinical References: 1. Lennon VA: Serological profile of myasthenia gravis and distinction from
the Lambert-Eaton myasthenic syndrome. Neurology. 1997 Apr;48(Suppl 5):S23-S27. doi:
10.1212/WNL.48.Suppl_5.23S 2. Lachance DH, Lennon VA: Paraneoplastic neurological
autoimmunity. In: Kalman B, Brannagan III T, eds. Neuroimmunology in Clinical Practice. Blackwell
Publishing Ltd; 2008:210-217 3. Gilhus NE: Myasthenia gravis. N Engl J Med. 2016
Dec;375(26):2570-2581. doi: 10.1056/NEJMra1602678 4. Nicolle MW: Myasthenia gravis and
Lambert-Eaton myasthenic syndrome. Continuum (Minneap Minn). 2016;22(6, Muscle and
Neuromuscular Junction Disorders):1978-2005. doi: 10.1212/CON.0000000000000415 5. Shelly S,
Paul P, Bi H, et al. Improving accuracy of myasthenia gravis autoantibody testing by reflex algorithm.
Neurology. 2020 Dec;95(22):e3002-e3011. doi: 10.1212/WNL.0000000000010910
ACMFS Acetylcholine Receptor Modulating Antibody, Flow Cytometry

610029 Assay, Serum
Clinical Information: Fatigable weakness due to impaired postsynaptic transmission at the
neuromuscular junction is characteristic of myasthenia gravis (MG). A clinical diagnosis should be
supported by electrodiagnostic testing, ie, clinical-electrodiagnosis (EDX). Positive autoimmune
serology increases certainty of MG diagnosis but needs to be interpreted in the proper clinical-EDX
context with response to anticholinesterase medications supporting the diagnosis. Most cases are
autoimmune and are caused by IgG autoantibodies binding to critical postsynaptic membrane molecules
(nicotinic muscle acetylcholine receptor [AChR] or its interacting proteins, such as muscle-specific
kinase [MuSK]). Serologically, the detection of AChR binding antibody provides the best diagnostic
sensitivity. However, the presence of both AChR binding and modulating activity improves diagnostic
accuracy. Autoantibody detection frequency is lowest in patients with weakness confined to extraocular
muscles (72% are positive for AChR binding antibodies) and highest in patients with generalized
weakness due to MG (92% are positive for AChR binding antibodies). In adults with MG and AChR
antibodies, approximately 20% will have thymoma and very rarely (<1%) extrathymic cancers.
Computed tomography (CT) imaging of the chest is considered the standard of care to evaluate for
thymoma. These results should only be interpreted in the appropriate clinical and electrophysiological
context and are not diagnostic in isolation. Note: Single antibody tests may be requested in the
follow-up of patients with positive results previously documented in this laboratory.
Useful For: Diagnosis for autoimmune myasthenia gravis (MG) in adults and children Distinguishing
autoimmune from congenital MG in adults and children or other acquired forms of neuromuscular
junction transmission disorders. This test is a qualitative assay and should not be used for monitoring
purposes.
Interpretation: This assay shows strong qualitative concordance with the previous modulating
assay. Positive results in this antibody evaluation are indicative of autoimmune myasthenia gravis
(MG). These results should be interpreted in the appropriate clinical and electrophysiological context.
The presence of acetylcholine receptor (AChR) modulating antibodies along with AChR binding
antibodies as compared to AChR binding antibodies alone, improves the diagnostic accuracy for MG. In
the presence of AChR modulating antibodies, a paraneoplastic basis should be considered with
thymoma being the most commonly associated tumor with MG. Negative results do not exclude the
diagnosis of MG. If clinical suspicion remains and symptoms persistent or worsen consider re-testing.
Reference Values:
Only orderable as part of a profile. For more information see:
MGLE / Myasthenia Gravis/Lambert-Eaton Myasthenic Syndrome Evaluation, Serum
MGMR / Myasthenia Gravis Evaluation with Muscle-Specific Kinase (MuSK) Reflex, Serum
PAVAL / Paraneoplastic, Autoantibody Evaluation, Serum
Negative
Clinical References: 1. Lozier BK, Haven TR, Astill ME, Hill HR: Detection of acetylcholine
receptor modulating antibodies by flow cytometry. Am J Clin Pathol. 2015 Feb;143(2):186-192 2. Keefe
D, Hess D, Bosco J, et al: A rapid, fluorescence-based assay for detecting antigenic modulation of the
acetylcholine receptor on human cell lines. Cytometry B Clin Cytom. 2009 May;76(3):206-212
ACHE_ Acetylcholinesterase, Amniotic Fluid

9287 Clinical Information: Neural tube defects (NTD) are a type of birth defect involving openings along
the brain and spine. They develop in the early embryonic period when the neural tube fails to close
completely. NTD can vary widely in severity. Anencephaly represents the most severe type of NTD,
which occurs when the cranial end fails to develop properly, resulting in an absence of the forebrain, the
area of the skull that covers the brain, and the skin. Most infants with anencephaly are stillborn or die
shortly after birth. NTD along the spine are referred to as spina bifida. Individuals with spina bifida may
experience hydrocephalus, urinary and bowel dysfunction, club foot, lower body weakness, and loss of
feeling or paralysis. Severity varies depending upon whether the NTD is covered by skin, whether
herniation of the meninges and spinal cord are present, and the location of the lesion. NTD not covered by
skin are referred to as open NTD and are typically more severe than closed NTD. Likewise, those
presenting with herniation and higher on the spinal column are typically more severe. Most NTD occur as
isolated birth defects with an incidence of approximately 1 to 2 in 1000 live births in the United States.
Rates vary by geographic region with lower rates being observed in the North and West than the South
and East. A fetus is at higher risk when the pregnancy is complicated by maternal diabetes, exposed to
certain anticonvulsants, or there is a family history of NTD. Studies have shown a dramatic decrease in
risk as a result of maternal dietary supplementation with folic acid. The March of Dimes currently
recommends that all women of childbearing age take 400 mcg of folic acid daily, increasing the amount to
600 mcg/day during pregnancy. For women who have had a prior pregnancy affected by an NTD, the
recommended dose is at least 4000 mcg/day starting at least 1-month preconception and continuing
through the first trimester. When an NTD is suspected based upon maternal serum alpha-fetoprotein
(AFP) screening results or diagnosed via ultrasound, analysis of AFP and acetylcholinesterase (AChE) in
amniotic fluid are useful diagnostic tools. AChE is primarily active in the central nervous system with
small amounts of enzyme found in erythrocytes, skeletal muscle, and fetal serum. Normal amniotic fluid
does not contain AChE, unless contributed by the fetus as a result of an open NTD.
Useful For: Diagnosing open neural tube defects and, to a lesser degree, ventral wall defects
Interpretation: The presence of acetylcholinesterase in amniotic fluid is consistent with open neural
tube defects and, to a lesser degree, ventral wall defects.
Reference Values:
Negative (reported as negative [normal] or positive [abnormal] for inhibitable acetylcholinesterase)
Reference values were established in conjunction with alpha-fetoprotein testing and include only
amniotic fluids from pregnancies between 14 and 21 weeks gestation.
Clinical References: 1. Wilson RD, Audibert F, Brock JA, et al: Prenatal screening, diagnosis, and
pregnancy management of fetal neural tube defects. J Obstet Gynaecol Can 2014 Oct;36(10):927-939 2.
Palomaki GE, Bupp C, Gregg AR, et al: Laboratory screening and diagnosis of open neural tube defects,
2019 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).
Genet Med 2020 Mar;22(3):462-474
ACHS Acetylcholinesterase, Erythrocytes
614475 Clinical Information: Erythrocyte acetylcholinesterase (AChE) activity is measured to evaluate
possible exposure to organophosphate insecticides. Organophosphates act by irreversible inhibition of
AChE. Inhibition of AChE in humans causes a variety of acute symptoms including dizziness, nausea,
difficulty breathing, and even death. The presence and severity of these symptoms depend, in part, on
the degree of AChE depression. Occupational pesticide handlers are at an elevated risk for exposure to
these chemicals through skin contact, inhalation, or accidental ingestion. Organophosphate intoxication
can be a result of one or more high exposure events or through chronic lower-level exposure. Both
serum and erythrocyte cholinesterase activity are inhibited by these insecticides, which are among the
most commonly used pesticides in the United States. The half-life of serum cholinesterase (eg,
pseudocholinesterase) is about 8 days, while the half-life of AChE in erythrocytes is between 2 and 3
months. Therefore, erythrocyte AChE is an indicator of chronic and temporally distant exposures to
organophosphates.
Useful For: Detecting effects of chronic or remote (months) past exposure to cholinesterase
inhibitors (organophosphate insecticide poisoning)
Interpretation: Activities less than normal are suspect for exposure to certain insecticides. For
occupational high-risk individuals, a pre-exposure "baseline" is recommended.
Reference Values:
31.2-61.3 U/g of hemoglobin
Reference values have not been established for patients younger than 18 years of age.
Clinical References: 1. Brahmi N, Mokline A, Kouraichi N, et al: Prognostic value of human

erythrocyte acetylcholinesterase in acute organophosphate poisoning. Am J Emerg Med. Nov
2006;24(7):822-827. doi: 10.1016/j.ajem.2006.05.009 2. Strelitz J, Engel LS, Keifer MC: Blood
acetylcholinesterase and butyrylcholinesterase as biomarkers of cholinesterase depression among
pesticide handlers. Occup Environ Med. 2014;71(12):842-847. doi: 10.1136/oemed-2014-102315 3.
Mason HJ: The recovery of plasma cholinesterase and erythrocyte acetylcholinesterase activity in
workers after over-exposure to dichlorvos. Occup Med (Lond). 2000;50(5):343-347. doi:
10.1093/occmed/50.5.343 4. Assis CR, Linhares AG, Cabrera MP, et al: Erythrocyte
acetylcholinesterase as a biomarker of pesticide exposure: new and forgotten insights. Environ Sci
Pollut Res. 2018;25:18364-18376. doi: 10.1007/s11356-018-2303-9 5. Robinson DG, Trites DG,
Banister EW: Physiological effects of work stress and pesticide exposure in tree planting by British
Columbia silviculture workers. Ergonomics. 1993 Aug;36:951-961. doi: 10.1080/00140139308967959
6. Fuortes LJ, Ayebo AD, Kross BC: Cholinesterase-inhibiting insecticide toxicity. Am Fam Phys. 1993
May;47:1613-1620
ASCL1 Achaete-Scute Homolog 1 Immunostain, Technical

71355 Component Only
Clinical Information: Achaete-scute homolog 1 (ACSL1), alternatively titled hASH1 or MASH1,
is a member of the basic helix-loop-helix family of transcription factors. ACSL1 may play a role at
early stages of development of specific neural lineages in most regions of the central nervous system,
and of several lineages in the peripheral nervous system. The protein has been shown to be highly
expressed in medullary thyroid cancer and small cell lung cancer and may be a useful marker for these
cancers.
Useful For: Identification of the presence of achaete-scute homolog 1 (ASCL1)

Interpretation: This test does not include pathologist interpretation only technical performance of
the stain. If interpretation is required order PATHC / Pathology Consultation for a full diagnostic
evaluation or second opinion of the case. The positive and negative controls are verified as showing
appropriate immunoreactivity and documentation is retained at Mayo Clinic Rochester. If a control
tissue is not included on the slide, a scanned image of the relevant quality control tissue is available
upon request, call 855-516-8404. Interpretation of this test should be performed in the context of the
patient's clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Au NH, Cheang M, Huntsman DG, et al: Evaluation of

immunohistochemical markers in non-small cell lung cancer by unsupervised hierarchical clustering
analysis: a tissue microarray study of 284 cases and 18 markers. J Pathol. 2004;204:101-109 2. Kosari F,
Ida CM, Aubry M-C, et al: ASCL1 and RET expression defines a clinically relevant subgroup of lung
adenocarcinoma characterized by neuroendocrine differentiation. Oncogene. 2014;33:3776-3783 3.
Ralston J, Chiriboga L, Nonaka D: MASH1: a useful marker in differentiating pulmonary small cell
carcinoma from merkel cell carcinoma. Mod Pathol. 2008 Nov;21(11):1357-1362 4. Somasundaram K,
Reddy SP, Vinnakota K, et al: Upregulation of ASCL1 and inhibition of Notch signaling pathway
characterize progressive astrocytoma. Oncogene. 2005;24:7073-7083
GAAWR Acid Alpha-Glucosidase Reflex, Leukocytes

606281 Clinical Information: Pompe disease, also known as glycogen storage disease type II, is an
autosomal recessive disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase
(GAA; acid maltase) due to variants in the GAA gene. The estimated incidence is 1 in 40,000 live births.
In Pompe disease, glycogen that is taken up by lysosomes during physiologic cell turnover accumulates,
causing lysosomal swelling, cell damage, and organ dysfunction. This leads to progressive muscle
weakness, cardiomyopathy, and eventually, death. Individuals with Pompe disease, especially those with
infantile, childhood, and juvenile onset, can have elevations of serum enzymes (eg, creatine kinase)
secondary to cellular dysfunction. The clinical phenotype of Pompe disease lies on a spectrum dependent
on age of onset and residual enzyme activity. Complete loss of enzyme activity causes onset in infancy
leading to death, typically within the first year of life when left untreated. Juvenile and adult-onset forms,
as the names suggest, are characterized by later onset and longer survival. All disease variants are
eventually associated with progressive muscle weakness and respiratory insufficiency. Cardiomyopathy is
associated almost exclusively with the infantile form. Treatment with enzyme replacement therapy is
available, making early diagnosis of Pompe disease desirable, as early initiation of treatment may improve
prognosis. Newborn screening can identify individuals with all forms of Pompe disease, even before onset
of symptoms. Unaffected individuals with GAA pseudodeficiency alleles and carriers may also be
identified by newborn screening. Determination of GAA enzyme activity in leukocytes can help
distinguish between infantile and later onset Pompe disease, but it may also be deficient in individuals
with pseudodeficiency alleles and in some carriers. Urine glucotetrasaccharides (HEX4 /
Glucotetrasaccharides, Random, Urine) have been shown to be elevated in some individuals, particularly
those with infantile onset, and may aid in the initial diagnosis and treatment monitoring. Molecular
genetic analysis of the GAA gene (GAAZ / Pompe Disease, Full Gene Analysis, Varies) is necessary for
differentiating alterations from disease-causing variants in affected individuals and for carrier detection in
family members.
Useful For: Diagnosis of Pompe disease as a confirmatory reflex of the 6-enzyme panel
Interpretation: When abnormal results are detected, a detailed interpretation is given, including an
overview of the results and of their significance, a correlation to available clinical information, elements
of differential diagnosis, recommendations for additional biochemical testing and in vitro, confirmatory
studies (enzyme assay, molecular analysis), and a phone number to reach one of the laboratory directors
in case the referring physician has additional questions.
Reference Values:
Only orderable as a reflex. For more information see LSD6W / Lysosomal Storage Disorders,
Six-Enzyme Panel, Leukocytes.
> or =1.50 nmol/hour/mg protein
Clinical References: 1. Elliott S, Buroker N, Cournoyer JJ, et al: Pilot study of newborn screening
for six lysosomal storage diseases using tandem mass spectrometry. Mol Genet Metab. 2016
Aug;118(4):304-309. doi: 10.1016/j.ymgme.2016.05.015 2. Matern D, Gavrilov D, Oglesbee D, Raymond
K, Rinaldo P, Tortorelli S: Newborn screening for lysosomal storage disorders. Semin Perinatol. 2015
Apr;39(3):206-216. doi: 10.1053/j.semperi.2015.03.005 3. Reuser AJ, Hirschhorn R, Kroos MA: Pompe
disease: Glycogen storage disease type II, acid a-glucosidase (acid maltase) deficiency. In: Valle DL,
Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. Online Metabolic and Molecular Bases of
Inherited Disease. McGraw-Hill; 2019. Accessed June 30, 2020. Available at:
https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225890450 4. Lin N, Huang J,
Violante S, et al: Liquid chromatography-tandem mass spectrometry assay of leukocyte acid
alpha-glucosidase for post-newborn screening evaluation of Pompe disease. Clin Chem. 2017
Apr;63(4):842-851. doi: 10.1373/clinchem.2016.259036 5. Leslie N, Bailey L: Pompe disease. In: Adam
MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle;
2007. Updated May 11, 2017. Accessed March 23, 2022. Available at
GAAW Acid Alpha-Glucosidase, Leukocytes

606267 Clinical Information: Pompe disease, also known as glycogen storage disease type II, is an
autosomal recessive disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase
(GAA; acid maltase) due to variants in the GAA gene. The estimated incidence is 1 in 40,000 live
births. In Pompe disease, glycogen that is taken up by lysosomes during physiologic cell turnover
accumulates, causing lysosomal swelling, cell damage, and organ dysfunction. This leads to progressive
muscle weakness, cardiomyopathy, and, eventually, death. Individuals with Pompe disease, especially
those with infantile, childhood, and juvenile onset, can have elevations of serum enzymes (eg, creatine
kinase) secondary to cellular dysfunction. The clinical phenotype of Pompe disease lies on a spectrum
dependent on age of onset and residual enzyme activity. Complete loss of enzyme activity causes onset
in infancy leading to death, typically within the first year of life when left untreated. Juvenile and
adult-onset forms, as the names suggest, are characterized by later onset and longer survival. All disease
variants are eventually associated with progressive muscle weakness and respiratory insufficiency.
Cardiomyopathy is associated almost exclusively with the infantile form. Treatment with enzyme
replacement therapy is available, making early diagnosis of Pompe disease desirable, as early initiation
of treatment may improve prognosis. Newborn screening can identify individuals with all forms of
Pompe disease, even before onset of symptoms. Unaffected individuals with GAA pseudodeficiency
alleles and carriers may also be identified by newborn screening. Determination of GAA enzyme
activity in leukocytes can help distinguish between infantile and later onset Pompe disease, but it may
also be deficient in individuals with pseudodeficiency alleles and in some carriers. Urine
glucotetrasaccharides (HEX4 / Glucotetrasaccharides, Random, Urine) have been shown to be elevated
in some individuals, particularly those with infantile onset, and may aid in the initial diagnosis and
treatment monitoring. Molecular genetic analysis of the GAA gene (GAAZ / Pompe Disease, Full Gene
Analysis, Varies) is necessary for differentiating alterations from disease-causing variants in affected
individuals and for carrier detection in family members.
Useful For: Diagnosis of Pompe disease

of differential diagnosis, recommendations for additional biochemical testing and in vitro, confirmatory
studies (enzyme assay, molecular analysis), and a phone number to reach one of the laboratory directors
Reference Values:
An interpretive report is provided.
for six lysosomal storage diseases using tandem mass spectrometry. Mol Genet Metab. 2016
Aug;118(4):304-309. doi: 10.1016/j.ymgme.2016.05.015 2. Matern D, Gavrilov D, Oglesbee D,
Raymond K, Rinaldo P, Tortorelli S: Newborn screening for lysosomal storage disorders. Semin
Perinatol. 2015 Apr;39(3):206-216. doi: 10.1053/j.semperi.2015.03.005 3. Reuser AJJ, Hirschhorn R,
Kroos MA: Pompe disease: Glycogen storage disease type II, acid a-glucosidase (acid maltase)
deficiency. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. Online Metabolic
and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed June 30, 2020. Available at
https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225890450 4. Lin N, Huang J,
Violante S, et al: Liquid chromatography-tandem mass spectrometry assay of leukocyte acid
alpha-glucosidase for post-newborn screening evaluation of Pompe disease. Clin Chem. 2017
Apr;63(4):842-851. doi: 10.1373/clinchem.2016.259036 5. Leslie N, Bailey L: Pompe disease. In:
Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews [Internet]. University of Washington, Seattle;
2007. Updated May 11, 2017. Accessed March 23, 2022. Available at
ASMW Acid Sphingomyelinase, Leukocytes

606264 Clinical Information: Niemann-Pick disease (NPD) types A (NPA) and B (NPB) are autosomal
recessive lysosomal storage disorders affecting metabolism of specific lipids within cells. NPA and NPB
are caused by a deficiency of sphingomyelinase, which results in extensive storage of sphingomyelin and
cholesterol in the liver, spleen, lungs, and, to a lesser degree, brain. NPA disease is more severe than NPB
and is characterized by early onset with feeding problems, dystrophy, persistent jaundice, development of
hepatosplenomegaly, neurological deterioration, deafness, and blindness, leading to death by age 3. NPB
disease is limited to visceral symptoms with survival into adulthood. Some patients have been described
with intermediary phenotypes. Large lipid-laden foam cells are characteristic of the disease.
Approximately 50% of cases have cherry-red spots in the macula. The combined prevalence of NPA and
NPB is estimated to be 1 in 250,000. NPA and NPB are inherited in an autosomal recessive manner and
are caused by variants in the SMPD1 gene. Although there is a higher frequency of type A among the
Ashkenazi Jewish population, both types are panethnic. Individuals with NPD types A and B typically
have elevations of lyso-sphingomyelin and lyso-sphingomyelin 509 combined with elevations of the
oxysterols cholestane-3 beta, 5 alpha, 6 beta-triol (COT) and 7-ketocholesterol (7-KC). (OXNP /
Oxysterols, Plasma; OXYWB / Oxysterols, Blood; OXYBS / Oxysterols, Blood Spot). Molecular genetic
testing for NPA and NPB disease is also available (CGPH / Custom Gene Panel, Hereditary,
Next-Generation Sequencing, Varies; specifcy SMPD1 Gene List ID: IEMCP-W6S9XD).
Useful For: Investigation of possible diagnosis of Niemann-Pick disease types A and B This test is not
recommended for carrier detection because of the wide range of enzymatic activities observed in carriers
and noncarriers.
Interpretation: Values below the reference range are consistent with a diagnosis for Niemann-Pick
types A and B. When abnormal results are detected, a detailed interpretation is given, including an
of differential diagnosis, recommendations for additional biochemical testing, and in vitro, confirmatory
studies (enzyme assay, molecular analysis), name and phone number of key contacts who may provide
these studies, and a phone number to reach one of the laboratory directors in case the referring physician
has additional questions.
Reference Values:
An interpretative report will be provided.
for six lysosomal storage diseases using Tandem Mass Spectrometry. Mol Genet Metab. 2016
Aug;118(4):304-309 2. Matern D, Gavrilov D, Oglesbee D, Raymond K, Rinaldo P, Tortorelli S:Â
Newborn screening for lysosomal storage disorders. Semin Perinatol. 2015 Apr;39(3):206-216 3.
Schuchman EH, Desnick RJ: Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies.
In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic Bases of
Inherited Disease. McGraw-Hill; 2019. Accessed May 26, 2021. Available
athttps://ommbid.mhmedical.com/content.aspx?sectionid=225545671&bookid=2709 4. Wasserstein MP,
Schuchman EH: Acid sphingomyelinase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds.
GeneReviews. [Internet]. University of Washington, Seattle; 2006. Updated February 25, 2021. Accessed
May 26, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1370/ 5. Schuchman EH, Desnick RJ:
Types A and B Niemann-Pick disease. Mol Genet Metab. 2017 Jan-Feb;120(1-2)27-33
SAFB Acid-Fast Smear for Mycobacterium, Varies

8213 Clinical Information: Mycobacterium tuberculosis is a leading infectious disease cause of death
worldwide. The Centers for Disease Control and Prevention has reported a rise in the incidence of
tuberculosis associated with AIDS, foreign-born cases, and increased transmission in high-risk
populations. There has also been a rise in the number of M tuberculosis strains that exhibit resistance to
one or more antituberculosis drugs. The public health implications of these facts are considerable.
Because M tuberculosis is readily spread by airborne particles, rapid diagnosis and isolation of infected
persons is important. Nontuberculous mycobacteria infections also cause significant morbidity and
mortality in humans, particularly in immunocompromised persons. Detection of acid-fast bacilli in
sputum specimens allows rapid identification of individuals who are likely to be infected with
mycobacteria while definitive diagnosis and treatment are pursued.
Useful For: Detection of acid-fast bacilli in clinical specimens

Interpretation: Patients whose sputum specimens are identified as acid-fast positive should be
considered potentially infected with Mycobacterium tuberculosis, pending definitive diagnosis by
molecular methods or mycobacterial culture.
Reference Values:
Negative (reported as positive or negative)
Clinical References: 1. American Thoracic Society/Centers for Disease Control and

Prevention/Infectious Diseases Society of America: Controlling Tuberculosis in the United States. Am J
Respir Crit Care Med. 2005;172:1169-1227 2. American Thoracic Society: An Official ATS/IDSA
Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am J
Respir Crit Care Med. 2007;175:367-416
SMACN Actin, Smooth Muscle (SMActin) Immunostain, Technical

Clinical Information: Smooth muscle actin reacts with the alpha-smooth muscle isoform of actin,
and labels the smooth muscle cells of vessels, myoepithelial cells, pericytes, some stromal cells in the
intestine, testis, and ovary, and tumors derived from smooth muscle cells. The antibody does not react
with actin from fibroblasts, striated muscle, and myocardium. This immunostain is a useful tool in the
identification of leiomyomas, leiomyosarcomas, and pleomorphic adenomas.
Useful For: Identification of cells expressing the alpha-smooth muscle isoform of actin
Interpretation: This test includes only technical performance of the stain (no pathologist
interpretation is performed). Mayo Clinic cannot provide an interpretation of tech only stains outside the
context of a pathology consultation. If an interpretation is needed, refer to PATHC / Pathology
Consultation for a full diagnostic evaluation or second opinion of the case. All material associated with
the case is required. Additional specific stains may be requested as part of the pathology consultation,
and will be performed as necessary at the discretion of the Mayo pathologist. The positive and negative
controls are verified as showing appropriate immunoreactivity and documentation is retained at Mayo
Clinic Rochester. If a control tissue is not included on the slide, a scanned image of the relevant quality
control tissue is available upon request. Contact 855-516-8404. Interpretation of this test should be
performed in the context of the patient's clinical history and other diagnostic tests by a qualified
pathologist.
Clinical References: 1. Arora G, Girdhar M, Gaghla A, et al: Comparing the expression of

myoepithelial cell markers CD10 and smooth muscle actin with the estrogen receptor status in the
invasive carcinoma breast: An immunohistochemical study. Clin Cancer Invest J 2013;2:20-24 2.
Nishio J, Iwasaki H, Skashita N, et al: Undifferentiated (embryonal) sarcoma of the liver in middle-aged
adults: smooth muscle differentiation determined by immunohistochemistry and electron microscopy.
Hum Pathol 2003;34(3):246-252. 3. Tse GM, Tan PH, Lui PC, et al: The role of immunohistochemistry
for smooth-muscle actin, p63, CD10 and cytokeratin 14 in the differential diagnosis of papillary lesions
of the breast. J Clin Pathol 2007;60(3):315-320
ACT Actinomyces Culture, Varies

8221 Clinical Information: Anaerobic Actinomyces are nonsporeforming, thin branching, gram-positive
bacilli that are part of the normal flora of the human oral cavity and may also colonize the gastrointestinal
and female genital tracts. Their presence is important in preserving the usual bacterial populations of the
mouth and in preventing infection with pathogenic bacteria. Actinomyces are generally of low
pathogenicity but may be an important factor in the development of periodontal disease and may cause
soft tissue infections in colonized areas of the body following trauma (surgical or otherwise). The typical
lesion consists of an outer zone of granulation around central purulent loculations containing masses of
tangled organisms ("sulfur granule"). Chronic burrowing sinus tracts develop. Typical actinomycotic
infections occur around the head and neck, in the lung and chest wall, and in the peritoneal cavity and
abdominal wall. Actinomycosis of the female genital tract occurs in association with the use of
intrauterine contraceptive devices. Purulent collections containing "sulfur granules" may drain from some
sinus tracts opening to the skin.
Useful For: Diagnosing anaerobic Actinomyces involved in infections

Interpretation: Isolation of anaerobic Actinomyces in significant numbers from well collected
specimens including blood, other normally sterile body fluids, or closed collections of purulent fluid
indicates infection with the identified organism.
Reference Values:
No growth
Identification of probable pathogens
Clinical References: 1. Summanen P, Baron EJ, Citron DM, Jousimies-Somer HR, et al: Wadsworth
Anaerobic Bacteriology Manual, Sixth edition. Belmont CA, Star Publishing Co. 2002 2. Butler-Wu SM,
She RC: Actinomyces, Lactobacillus, Cutibacterium, and Other Non-Spore-Forming Anaerobic
Gram-Positive Rods. In Manual of Clinical Microbiology. 12th edition. Edited by KC Carroll, MA
Pfaller. Washington DC, ASM Press, 2019 Chapters 54, pp 938-967 3. Hall, GS: Anaerobic
Gram-Positive Bacilli. In Clinical Microbiology Procedures Handbook. Fourth edition. Vol. 1. Edited by
AL Leber. Washington DC, ASM Press, 2016
APMSC Activated Partial Thromboplastin Time (APTT) Mix 1:1, Plasma

602182 Clinical Information: The activated partial thromboplastin time (APTT) mix is only performed when
the APTT is abnormally prolonged. Refer to APTSC / Activated Partial Thromboplastin Time (APTT),
Plasma for interpretation of results. The APTT mixing test is used to evaluate a prolonged APTT test
result, especially when mixing test results are combined with results of other coagulation tests and clinical
information, to assist in differentiating coagulation factor deficiencies from coagulation inhibitors.
Useful For: Screening for certain coagulation factor deficiencies and abnormalities (eg, factor VIII, IX,
XI, or XII). Detection of coagulation inhibitors such as lupus anticoagulant, antiphospholipid antibodies,
specific factor inhibitors, and nonspecific inhibitors
Interpretation: Prolongation of the activated partial thromboplastin time (APTT) can occur as a result
of deficiency of 1 or more coagulation factors (acquired or congenital in origin), or the presence of an
inhibitor of coagulation such as heparin, a lupus anticoagulant, a "nonspecific" inhibitor such as a
monoclonal immunoglobulin, or a specific coagulation factor inhibitor. The APTT mixing study, using
equal volumes of patient and normal pool plasma, may be performed on specimens with a prolonged
APTT to assist in differentiating coagulation factor deficiencies from coagulation inhibitors of all types
(1-4). Correction of the APTT mix to within the normal reference range usually indicates a coagulation
factor deficiency (normal plasma in the mixture ensures at least 50% activity of all coagulation factors). If
the prolonged APTT is due to an inhibitor (eg, specific coagulation factor inhibitor, lupus anticoagulant,
heparin), the APTT mix typically fails to correct a prolonged APTT. However, the presence of a weak
inhibitor may be missed by the APTT mixing study. Accurate interpretation of both APTT and APTT
mixing study results may often require additional testing. For example, the thrombin time (TT) test is
helpful for identifying or excluding the presence of heparin, the platelet neutralization procedure (PNP,
using a modified APTT method) for identifying or excluding lupus anticoagulant, the prothrombin time
(PT) and dilute Russell viper venom time (DRVVT) for further assessment of the common procoagulant
pathway, and coagulation factor assays to detect and identify deficient or abnormal factors. These assays
are available as components of reflexive and interpretive testing panels in the Special Coagulation
Laboratory (eg, APROL / Prolonged Clot Time Profile, Plasma). Shortening of the APTT usually reflects
either elevation of factor VIII activity secondary to acute or chronic illness or inflammation, or spurious
results from suboptimal venipuncture, specimen collection or processing. A normal or shortened APTT
result does not exclude a hemostatic defect; and specific clotting factor assays should be performed
despite a normal APTT when there is clinical impression of bleeding diathesis.
Reference Values:
Only orderable as a reflex. For more information see:
ALUPP / Lupus Anticoagulant Profile, Plasma
ALBLD / Bleeding Diathesis Profile, Limited, Plasma
AATHR / Thrombophilia Profile, Plasma
APROL / Prolonged Clot Time Profile, Plasma
ADIC / Disseminated Intravascular Coagulation/Intravascular Coagulation and Fibrinolysis (DIC/ICF)
Profile, Plasma
25-37 seconds
Clinical References: 1. Miletich JP: Activated partial thromboplastin time. In Williams

Hematology. Fifth edition. Edited by E Beutler, MA Lichtman, BA Coller, TJ Kipps. New York,
McGraw-Hill, 1995, pp L85-86 2. Greaves M, Preston FE: Approach to the bleeding patient. In
Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by RW
Colman, J Hirsh, VJ Marder, et al: Philadelphia, JB Lippincott Co, 2001, pp 1197-1234 3. Kaczor, DA,
Bickford NN, Triplett DA: Evaluation of different mixing study reagents and dilution effect in lupus
anticoagulant testing. Am J Clin Pathol 1991;95:408-411 4. Brandt JT, Triplett DA, Alving B, Scharrer
I: Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995;74(5):1185-1190
5. Olson JD, Arkin CF, Brandt JT, et al: Laboratory monitoring of heparin therapy. Arch Pathol Lab
Med 1998;122:782-798
APTSC Activated Partial Thromboplastin Time (APTT), Plasma

602172 Clinical Information: The activated partial thromboplastin time (APTT) measures the integrity of
the intrinsic (factors VIII, IX, XI and XII) and common (factors II, V, X, and I [fibrinogen]) pathway
coagulation factors as well as contact factors, prekallikrein (PK) and high-molecular-weight kininogen
(HMWK). The APTT assay depends on the phospholipid (a partial thromboplastin), contact activator
(eg, silica), and ionic calcium supplied in the reagents. A prolonged APTT may be caused by congenital
or acquired coagulation factor deficiencies, anticoagulant effect such as heparin anticoagulation therapy,
and inhibition due to lupus anticoagulants as well as other nonspecific coagulation inhibitors (eg,
monoclonal immunoglobulins). Although the APTT is commonly used as an initial test for detecting
coagulation factor deficiencies, various reagents differ considerably in their sensitivity to deficiencies of
coagulation factor proteins. The reagents are generally most sensitive to deficiencies of "contact factors"
(XII, PK and HMWK) and factor XI, less sensitive to deficiencies of factors VIII and IX (the
"antihemophilic factors"), and least sensitive to deficiencies of common procoagulant pathway factors
(X, V, II, I). The APTT prolongs typically when the activities of factors XI and XII are below the
hemostatically adequate level of 40% to 50%. Although factor XII deficiency does not cause bleeding,
it is a relatively common cause of APTT prolongation. Nevertheless, an APTT may still be normal
when the factor VIII level is as low as 25% to 35%; factor IX as low as 20% to 30%, as seen in some
patients with mild hemophilia A or B, respectively a shortened APTT due to increased factor VIII
activity secondary to inflammation, pregnancy, or estrogen use, or other conditions may masquerade
deficiencies of other factors. The APTT also has divergent sensitivity to nonspecific inhibitors of the
intrinsic and common coagulation pathways, such as lupus anticoagulant (LAC) and specific
coagulation factor inhibitors. LAC's are antibodies directed towards neoepitopes presented by
complexes of phospholipid and proteins, such as prothrombin (factor II) or beta 2 glycoprotein I, instead
of coagulation factors. They interfere with the in vitro phospholipid component of APTT assay, and
result in a prolonged clotting time. Clinically, lupus anticoagulant represents an important marker of
thrombotic tendency. In contrast, patients with specific coagulation inhibitors, such as factor VIII
inhibitor antibodies, have a significant risk of hemorrhage and often require specific treatment for
effective management.
Useful For: Screening for certain coagulation factor deficiencies and abnormalities (eg, factor VIII, IX,
XI or XII) Detecting coagulation inhibitors such as lupus anticoagulant, antiphospholipid antibodies,
specific factor inhibitors, and nonspecific inhibitors Evaluating a prolonged APTT test result to assist in
differentiating coagulation factor deficiencies from coagulation inhibitors, especially when the activated
partial thromboplastin time (APTT) mixing test results are combined with results of other coagulation
tests and clinical information Monitoring heparin (unfractionated) therapy
Interpretation: Prolongation of the activated partial thromboplastin time (APTT) can occur as a result
of deficiency of 1 or more coagulation factors (acquired or congenital in origin), or the presence of an
inhibitor of coagulation such as heparin, a lupus anticoagulant, a "nonspecific" inhibitor such as a
monoclonal immunoglobulin, or a specific coagulation factor inhibitor. The APTT mixing study, which
uses equal volumes of patient and normal pool plasma, may be performed on specimens with a prolonged
APTT to assist in differentiating coagulation factor deficiencies from coagulation inhibitors of all
types.(1-4) Correction of the APTT mix to within the normal reference range usually indicates a
coagulation factor deficiency (normal plasma in the mixture ensures at least 50% activity of all
coagulation factors). If the prolonged APTT is due to an inhibitor (eg, specific coagulation factor
inhibitor, lupus anticoagulant, heparin), the APTT mix typically fails to correct a prolonged APTT.
However, the presence of a weak inhibitor may be missed by the APTT mixing study. Accurate
interpretation of both APTT and APTT mixing study results may often require additional testing. For
example, the thrombin time (TT) test is helpful for identifying or excluding the presence of heparin, the
platelet neutralization procedure (PNP, using a modified APTT method) for identifying or excluding
lupus anticoagulant, the prothrombin time (PT) and dilute Russell's viper venom time (DRVVT) for
further assessment of the common procoagulant pathway, and coagulation factor assays to detect and
identify deficient or abnormal factors. These assays are available as components of reflexive and
interpretive testing panels in the Special Coagulation Laboratory (eg, APROL / Prolonged Clot Time
Profile). The APTT test is frequently used to monitor therapy with unfractionated heparin (UFH). Since
APTT reagents can vary greatly in their sensitivity to UFH, it is important to establish a relationship
between APTT response and heparin concentration.(1) The therapeutic APTT range in seconds should
correspond with a UFH concentration of 0.3 to 0.7 U/mL as assessed by a heparin assay (inhibition of
factor Xa activity with detection by a chromogenic substrate [1]). We have established the therapeutic
APTT range to be approximately 70 to 120 seconds. Shortening of the APTT usually reflects either
elevation of factor VIII activity secondary to acute or chronic illness or inflammation, or spurious results
from suboptimal venipuncture, specimen collection or processing. A normal or shortened APTT result
does not exclude a hemostatic defect; and specific clotting factor assays should be performed despite a
normal APTT when there is clinical impression of bleeding diathesis.
Reference Values:
Only orderable as part of a special coagulation profile or as a reflex. For more information see:
Profile, Plasma
25â€“37 seconds
The APTT may be 35% longer in full-term newborns that reach adult reference range by age 3 months
and twice the adult upper limit in premature infants reaching adult reference range by age 6 months.
Clinical References: 1. Olson JD, Arkin CF, Brandt JT, et al: Laboratory monitoring of heparin
therapy. Arch Pathol Lab Med 1998;122:782-798 2. Miletich JP: Activated partial thromboplastin time.
In Williams Hematology. Fifth edition. Edited by E Beutler, MA Lichtman, BA Coller, TJ Kipps. New
York, McGraw-Hill, 1995, pp L85-86 3. Greaves M, Preston FE: Approach to the bleeding patient. In
Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by RW
Colman, J Hirsh, VJ Marder, et al: Philadelphia, JB Lippincott Co, 2001, pp 1197-1234 4. Kaczor, DA,
Bickford NN, Triplett DA: Evaluation of different mixing study reagents and dilution effect in lupus
anticoagulant testing. Am J Clin Pathol 1991;95:408-411 5. Brandt JT, Triplett DA, Alving B, Scharrer
I: Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995;74(5):1185-1190
APTTP Activated Partial Thromboplastin Time, Plasma

40935 Clinical Information: The activated partial thromboplastin time (APTT) assay is used as a
screening test to evaluate the overall integrity of the intrinsic/common coagulation pathway and to
monitor patients on heparin therapy. This test reflects the activities of most of the coagulation factors in
the intrinsic and common procoagulant pathway, but not the extrinsic procoagulant pathway, which
includes factor VII and tissue factor, nor the activity of factor XIII (fibrin stabilizing factor).
Useful For: Monitoring heparin therapy (unfractionated heparin) Screening for certain coagulation
factor deficiencies Detection of coagulation inhibitors such as lupus anticoagulant, specific factor
inhibitors, and nonspecific inhibitors
Interpretation: Prolongation of the activated partial thromboplastin time (APTT) can occur as a
result of deficiency of one or more coagulation factors (acquired or congenital in origin), or the
presence of an inhibitor of coagulation such as heparin, a lupus anticoagulant, a nonspecific inhibitor
such as a monoclonal immunoglobulin, or a specific coagulation factor inhibitor. Prolonged clotting
times may also be observed in cases of fibrinogen deficiency, liver disease, and vitamin K deficiency.
Shortening of the APTT usually reflects either elevation of factor VIII activity in vivo that most often
occurs in association with acute or chronic illness or inflammation, or spurious results associated with
either difficult venipuncture and specimen collection or suboptimal specimen processing.
Reference Values:
25-37 seconds
Clinical References: 1. Clinical and Laboratory Standards Institute (CLSI). One-stage PT and
APTT test; Approved Guideline Second Edition. H47-A2, 2008 2. Greaves M, Preston FE: Approach to
the bleeding patient. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth
edition. Edited by RW Colman, J Hirsh, VJ Marder, et al. Philadelphia, JB Lippincott Co, 2001, pp
1197-1234 3. Boender J, Kruip MJ, Leebeek FW: A Diagnostic Approach to Mild Bleeding Disorders. J
Thromb Haemost 2016;Aug;14(8):1507-1516. doi: 10.1111/jth.13368
APCRV Activated Protein C Resistance V (APCRV), Plasma

81967 Clinical Information: Protein C, a part of the natural anticoagulant system, is a vitamin
K-dependent protein zymogen (molecular weight=62,000 da) that is synthesized in the liver and
circulates at a plasma concentration of approximately 5 mcg/mL. Protein C is activated to activated
protein C (APC) via proteolytic cleavage by thrombin bound to thrombomodulin, an endothelial cell
surface membrane protein. APC downregulates the procoagulant system by proteolytically inactivating
procoagulant factors Va and VIIIa. Protein S, another vitamin K-dependent coagulation protein,
catalyzes APC inactivation of factors Va and VIIIa. APC interacts with and proteolyses factors V/Va
and VIII/VIIIa at specific APC binding and cleavage sites, respectively. Resistance to activated protein
C (APC resistance) is a term used to describe abnormal resistance of human plasma to the anticoagulant
effects of human APC. APC resistance is characterized by a reduced anticoagulant response of patient
plasma after adding a standard amount of APC. For this assay, the activated partial thromboplastin time
clotting test fails to prolong significantly after the addition of APC. The vast majority of individuals
with familial APC resistance have a specific point mutation in the procoagulant factor V gene
(1691G-A, factor V Leiden) encoding for a glutamine (Q) substitution for arginine (R)-506 in the heavy
chain of factor V (factor V R506Q). This amino acid change alters an APC cleavage site on factor V
such that factor V/Va is partially resistant to inactivation by APC. The carrier frequency for the factor V
Leiden mutation varies depending on the population. Approximately 5% of asymptomatic white
Americans of non-Hispanic ancestry are heterozygous carriers, while the carrier frequency among
African Americans, Asian Americans, and Native Americans is less than 1%, and the carrier frequency
for Hispanics is intermediate (2.5%). The carrier frequency can be especially high (up to 14%) among
whites of Northern European or Scandinavian ancestry. Homozygosity for factor V Leiden is much less
common, but may confer a substantially increased risk for thrombosis. The degree of abnormality of the
APC-resistance assay correlates with heterozygosity or homozygosity for the factor V Leiden mutation;
homozygous carriers have a very low APC-resistance ratio (eg, 1.1-1.4), while the ratio for
heterozygous carriers is usually 1.5 to 1.8.
Useful For: Evaluation of patients with incident or recurrent venous thromboembolism (VTE)
Evaluation of individuals with a family history of VTE
Interpretation: An activated protein C (APC) resistance ratio of less than 2.3 suggests abnormal
resistance to APC of hereditary origin. If the APC resistance test is abnormal, DNA-based testing for the
factor V Leiden mutation (F5DNA / Factor V Leiden [R506Q] Mutation, Blood) may be helpful in
confirming or excluding hereditary APC resistance.
Reference Values:
APCRV RATIO
> or =2.3
Pediatric reference range has neither been established nor is available in scientific literature. The adult
reference range likely would be applicable to children older than 6 months.
Clinical References: 1. Nichols WL, Heit JA: Activated protein C resistance and thrombosis. Mayo
Clin Proc 1996;71:897-898 2. Dahlback B: Resistance to activated protein C as risk factor for thrombosis:
molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol
1997;34(3):217-234 3. Rodeghiero F, Tosetto A: Activated protein C resistance and Factor V Leiden
mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999;130:643-650 4.
Grody WW, Griffin JH, Taylor AK, et al: American College of Medical Genetics consensus statement on
factor V Leiden mutation testing. Genet Med 2001;3:139-148 5. Press RD, Bauer KA, Kujovich JL, Heit
JA: Clinical utility of factor V Leiden (R506Q) testing for the diagnosis and management of
thromboembolic disorders. Arch Pathol Lab Med 2002;126:1304-1318
APCRR Activated Protein C Resistance V, with Reflex to Factor V

60547 Leiden, Blood and Plasma
Clinical Information: Protein C, a part of the natural anticoagulant system, is a vitamin K-dependent
protein zymogen (molecular weight=62,000 Da) that is synthesized in the liver and circulates at a plasma
concentration of approximately 5 mcg/mL. Protein C is activated to activated protein C (APC) via
proteolytic cleavage by thrombin bound to thrombomodulin, an endothelial cell surface membrane
protein. APC downregulates the procoagulant system by proteolytically inactivating procoagulant factors
Va and VIIIa. Protein S, another vitamin K-dependent coagulation protein, catalyzes APC inactivation of
factors Va and VIIIa. APC interacts with and proteolyzes factors V/Va and VIII/VIIIa at specific APC
binding and cleavage sites, respectively. Resistance to activated protein C (APC resistance) is a term used
to describe abnormal resistance of human plasma to the anticoagulant effects of human APC. APC
resistance is characterized by a reduced anticoagulant response of patient plasma after adding a standard
amount of APC. For this assay, the activated partial thromboplastin time fails to prolong significantly
after the addition of APC. The vast majority of individuals with familial APC resistance have a specific
alteration in the procoagulant factor V gene (F5) encoding for a p.Arg534Gln substitution in the heavy
chain of factor V (formerly R506Q). This glutamine to arginine amino acid change alters an APC
cleavage site on factor V such that factor V/Va is partially resistant to inactivation by APC. The carrier
frequency for the factor V Leiden variant varies depending on the population. Approximately 5% of
asymptomatic white Americans of non-Hispanic ancestry are heterozygous carriers, while the carrier
frequency among African Americans, Asian Americans, and Native Americans is less than 1%, and the
carrier frequency for Hispanics is intermediate (2.5%). The carrier frequency can be especially high (up to
14%) among whites of Northern European or Scandinavian ancestry. Homozygosity for factor V Leiden is
much less common but may confer a substantially increased risk for thrombosis. The degree of
abnormality of the APC-resistance assay correlates with heterozygosity or homozygosity for the factor V
Leiden variant; homozygous carriers have a very low APC-resistance ratio (eg, 1.1-1.4), while the ratio
for heterozygous carriers is usually 1.5 to 1.8.
Useful For: Evaluation of patients with incident or recurrent venous thromboembolism (VTE)
Evaluation of individuals with a family history of VTE
Interpretation: An activated protein C (APC) resistance ratio below 2.3 suggests abnormal
resistance to APC of hereditary origin. If the screening APC resistance test is abnormal, DNA-based
testing for the factor V Leiden variant (p.Arg534Gln, formerly R506Q) is performed to confirm or
exclude hereditary APC-resistance.
Reference Values:
APCRV RATIO
> or =2.3
Pediatric reference range has neither been established nor is available in scientific literature. The adult
reference range likely would be applicable to children older than 6 months.
Clinical References: 1. Nichols WL, Heit JA: Activated protein C resistance and thrombosis.
Mayo Clin Proc. 1996;71:897-898 2. Dahlback B: Resistance to activated protein C as risk factor for
thrombosis: molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol.
1997;34(3):217-234 3. Rodeghiero F, Tosetto A: Activated protein C resistance and Factor V Leiden
mutation are independent risk factors for venous thromboembolism. Ann Intern Med.
1999;130:643-650. doi: 10.7326/0003-4819-130-8-199904200-00004. 4. Grody WW, Griffin JH,
Taylor AK, et al: American College of Medical Genetics consensus statement on factor V Leiden
mutation testing. Genet Med. 2001;3:139-148. doi: 10.1097/00125817-200103000-00009.Â 5. Press
RD, Bauer KA, Kujovich JL, Heit JA: Clinical utility of factor V Leiden (R506Q) testing for the
diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med. 2002;126:1304-1318.
doi: 10.5858/2002-126-1304-CUOFVL. 6.Â Yohe S, Olson J: Thrombophilia: Assays and
interpretation. In: Kottke-Marchant K, ed: Laboratory Hematology Practice. Wiley Blackwell
Publishing; 2012:492-508
AHEP Acute Hepatitis Profile, Serum

56105 Clinical Information: Hepatitis A: Hepatitis A virus (HAV) is an RNA virus that accounts for 20%
to 25% of the viral hepatitis in United States adults. HAV infection is spread by the oral/fecal route and
produces acute hepatitis, which follows a benign, self-limited course. Spread of the disease is usually
associated with contaminated food or water caused by poor sanitary conditions. Outbreaks frequently
occur in overcrowded situations and in institutions or high-density centers such as prisons and health
care centers. Epidemics may occur following floods or other disaster situations. Chronic carriers of
HAV have never been observed. Hepatitis B: Hepatitis B virus (HBV) is a DNA virus that is endemic
throughout the world. The infection is spread primarily through percutaneous contact with infected
blood products (eg, blood transfusion, sharing of needles by drug addicts). The virus is also found in
virtually every type of human body fluid and is known to be spread through oral and genital contact.
HBV can be transmitted from mother to child during delivery through contact with blood and vaginal
secretions; it is not commonly transmitted transplacentally. After a course of acute illness, HBV persists
in approximately 10% of patients. Some of these chronic carriers are asymptomatic; others develop
chronic liver disease, including cirrhosis and hepatocellular carcinoma. Hepatitis C: Hepatitis C virus
(HCV) is an RNA virus that is a significant cause of morbidity and mortality worldwide. HCV is
transmitted through contaminated blood or blood products or through other close, personal contacts. It is
recognized as the cause of most cases of posttransfusion hepatitis. HCV shows a high rate of
progression (>50%) to chronic disease. In the United States, HCV infection is quite common, with an
estimated 3.5 to 4 million chronic HCV carriers. Cirrhosis and hepatocellular carcinoma are sequelae of
chronic HCV. The following algorithms are available: -Hepatitis B: Testing Algorithm for Screening,
Diagnosis, and Management -Hepatitis C: Testing Algorithm for Screening and Diagnosis -Viral
Hepatitis Serologic Profiles
Useful For: Differential diagnosis of recent acute viral hepatitis

Interpretation: Hepatitis A: Antibody against hepatitis A antigen is usually detectable by the onset of
symptoms (usually 15-45 days after exposure). The initial antibody consists almost entirely of IgM
subclass antibody. Antibody to hepatitis A virus (anti-HAV) IgM usually falls to undetectable levels 3 to
6 months after infection. Hepatitis B: Hepatitis B surface antigen (HBsAg) is the first serologic marker
appearing in the serum 6 to 16 weeks following hepatitis B virus (HBV) infection. In acute cases, HBsAg
usually disappears 1 to 2 months after the onset of symptoms. Hepatitis B surface antibody (anti-HBs)
appears with the resolution of HBV infection after the disappearance of HBsAg. Anti-HBs also appears as
the immune response following a course of inoculation with the hepatitis B vaccine. Initially, hepatitis B
core antibody (anti-HBc) consists almost entirely of the IgM subclass. Anti-HBc, IgM can be detected
shortly after the onset of symptoms and is usually present for 6 months. Anti-HBc may be the only marker
of a recent HBV infection detectable following the disappearance of HBsAg, and prior to the appearance
of anti-HBs, ie, window period. Hepatitis C: Hepatitis C antibody is usually not detectable during the
early months following infection and is almost always detectable by the late convalescent stage of
infection. Hepatitis C antibody is not neutralizing and does not provide immunity. If HBsAg, anti-HAV
(IgM), and anti-HCV are negative and patient's condition warrants, consider testing for Epstein-Barr virus
or cytomegalovirus. The following algorithms are available in Special Instructions: -Hepatitis B: Testing
Algorithm for Screening, Diagnosis, and Management -Hepatitis C: Testing Algorithm for Screening and
Diagnosis
Reference Values:
HEPATITIS B SURFACE ANTIGEN
Negative
HEPATITIS B SURFACE ANTIGEN CONFIRMATION

Negative
HEPATITIS B CORE IgM ANTIBODY

Negative
HEPATITIS A IgM ANTIBODY

Negative
HEPATITIS C ANTIBODY
Negative
HEPATITIS C VIRUS RNA DETECTION and QUANTIFICATION by REAL-TIME RT-PCR

Undetected
Interpretation depends on clinical setting. See Viral Hepatitis Serologic Profiles in Special Instructions.
Clinical References: 1. Roque-Afonso AM, Desbois D, Dussaix E: Hepatitis A virus: serology and
molecular diagnostics. Future Virology. 2010;5(2):233-242 2. de Paula VS: Laboratory diagnosis of
hepatitis A. Future Virology. 2012;7(5):461-472 3. Bonino F, Piratvisuth T, Brunetto MR, Liaw YF
Diagnostic markers of chronic hepatitis B infection and disease. Antivir Ther. 2010;15(Suppl. 3):35-44 4.
Wasley A, Fiore A, Bell BP: Hepatitis A in the era of vaccination. Epidemiol Rev. 2006;28:101-111 5.
American Association for the Study of Liver Diseases/Infectious Diseases Society of
America/International Antiviral Society-USA: Recommendations for Testing, Managing, and Treating
Hepatitis C. Accessed September 29, 2020. Available at www.hcvguidelines.org/contents 6. LeFebre ML,
U.S. Preventive Services Task Force: Screening for hepatitis B virus infection in nonpregnant adolescents
and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med.
2014;161:58-66. doi:10.7326/M14-1018 7. Jackson K, Locarnini S, Gish R: Diagnostics of hepatitis B
virus: Standard of care and investigational. Clin Liver Dis (Hoboken). 2018;12(1):5-11. doi:
10.1002/cld.729 8. Coffin CS, Zhou K, Terrault NA: New and old biomarkers for diagnosis and
management of chronic hepatitis B virus infection. Gastroenterol. 2019;156:355-368. doi:
10.1053/j.gastro.2018.11.037 9. WHO Guidelines Development Group: World Health Organization
guidelines on hepatitis B and C testing. World Health Organization; 2017. Available at
www.who.int/hepatitis/publications/guidelines-hepatitis-c-b-testing/en/ 10. Centers for Disease Control
and Prevention. Testing and public health management of persons with chronic hepatitis B virus infection.
Accessed April 8, 2020. Available at www.cdc.gov/hepatitis/hbv/testingchronic.htm
HPAM Acute Hepatitis Profile, Serum

616066 Clinical Information: Hepatitis A: Hepatitis A virus (HAV) is an RNA virus that accounts for 20%
to 25% of the viral hepatitis in United States adults. HAV infection is spread by the oral/fecal route and
produces acute hepatitis, which follows a benign, self-limited course. Spread of the disease is usually
associated with contaminated food or water caused by poor sanitary conditions. Outbreaks frequently
occur in overcrowded situations and in institutions or high-density centers such as prisons and health
care centers. Epidemics may occur following floods or other disaster situations. Chronic carriers of
HAV have never been observed. Hepatitis B: Hepatitis B virus (HBV) is a DNA virus that is endemic
in approximately 10% of patients. Some of these chronic carriers are asymptomatic; others develop
chronic liver disease, including cirrhosis and hepatocellular carcinoma. Hepatitis C: Hepatitis C virus
(HCV) is an RNA virus and is a significant cause of morbidity and mortality worldwide. HCV is
transmitted through contaminated blood or blood products or through other close, personal contacts. It is
recognized as the cause of most cases of posttransfusion hepatitis. HCV shows a high rate of
progression (>50%) to chronic disease. In the United States, HCV infection is quite common, with an
estimated 3.5 to 4 million chronic HCV carriers. Cirrhosis and hepatocellular carcinoma are sequelae of
chronic HCV. The following algorithms are available in Special Instructions: -Hepatitis B: Testing
Algorithm for Screening, Diagnosis, and Management -Hepatitis C: Testing Algorithm for Screening
and Diagnosis
Useful For: Differential diagnosis of recent acute viral hepatitis

Interpretation: Hepatitis A: Antibody against hepatitis A antigen is usually detectable by the onset
of symptoms (usually 15-45 days after exposure). The initial antibody consists almost entirely of IgM
subclass antibody. Antibody to hepatitis A virus (anti-HAV) IgM usually falls to undetectable levels 3
to 6 months after infection. Hepatitis B: Hepatitis B surface antigen (HBsAg) is the first serologic
marker appearing in the serum 6 to 16 weeks following hepatitis B virus (HBV) infection. In acute
cases, HBsAg usually disappears 1 to 2 months after the onset of symptoms. Hepatitis B surface
antibody (anti-HBs) appears with the resolution of HBV infection after the disappearance of HBsAg.
Anti-HBs also appears as the immune response following a course of inoculation with the hepatitis B
vaccine. Initially, hepatitis B core antibody (anti-HBc) consists almost entirely of the IgM subclass.
Anti-HBc, IgM can be detected shortly after the onset of symptoms and is usually present for 6 months.
Anti-HBc may be the only marker of a recent HBV infection detectable following the disappearance of
HBsAg, and prior to the appearance of anti-HBs, ie, window period. Hepatitis C: Hepatitis C antibody is
usually not detectable during the early months following infection and is almost always detectable by
the late convalescent stage of infection. Hepatitis C antibody is not neutralizing and does not provide
immunity. If HBsAg, anti-HAV (IgM), and anti-HCV are negative and patient's condition warrants,
consider testing for Epstein-Barr virus or cytomegalovirus. The following algorithms are available in
Special Instructions: -Hepatitis B: Testing Algorithm for Screening, Diagnosis, and Management
-Hepatitis C: Testing Algorithm for Screening and Diagnosis
Reference Values:
HEPATITIS B SURFACE ANTIGEN:
Negative
HEPATITIS B CORE ANTIBODY, IgM:
Negative
HEPATITIS A IgM ANTIBODY:

Negative
HEPATITIS C ANTIBODY SCREEN:

Negative
Clinical References: 1. Roque-Afonso AM, Desbois D, Dussaix E: Hepatitis A virus: serology and
molecular diagnostics. Future Virology. 2010 Mar 1;5(2):233-242 2. de Paula VS: Laboratory diagnosis
of hepatitis A. Future Virology. 2012;7(5):461-472 3. Bonino F, Piratvisuth T, Brunetto MR, Liaw YF:
Diagnostic markers of chronic hepatitis B infection and disease. Antivir Ther. 2010;15(Suppl. 3):35-44 4.
Wasley A, Fiore A, Bell BP: Hepatitis A in the era of vaccination. Epidemiol Rev. 2006;28:101-111 5.
American Association for the Study of Liver Diseases/Infectious Diseases Society of
America/International Antiviral Society-USA. Recommendations for Testing, Managing, and Treating
Hepatitis C. Accessed September 29, 2020. Available at www.hcvguidelines.org/contents
COGMF Acute Myeloid Leukemia (AML), Children's Oncology Group

113528 Enrollment Testing, FISH, Varies
Clinical Information: Acute myeloid leukemia (AML) is one of the most common adult leukemias,
with almost 10,000 new cases diagnosed per year. AML also comprises 15% of pediatric acute leukemia
and accounts for the majority of infant (<1 year old) leukemia. Several recurrent chromosomal
abnormalities have been identified in AML. The most common chromosome abnormalities associated
with AML include t(8;21), t(15;17), inv(16), and abnormalities of the MLL (KMT2A) gene at 11q23. The
most common genes juxtaposed with MLL through translocation events in AML include
MLTT4(AFDN)- t(6;11), MLLT3- t(9;11), MLLT10- t(10;11), and ELL- t(11;19p13.1). AML can also
evolve from myelodysplasia (MDS). Thus, the common chromosome abnormalities associated with MDS
can also be identified in AML, which include: inv(3), -5/5q-, -7/7q-, and 17p. Overall, the recurrent
chromosome abnormalities identified in patients with AML are observed in approximately 60% of
diagnostic AML cases. Conventional chromosome analysis is the gold standard for identification of the
common, recurrent chromosome abnormalities in AML. However, some of the subtle rearrangements can
be missed by karyotype, including inv(16) and MLL rearrangements. Fluorescence in situ hybridization
(FISH) analysis of nonproliferating (interphase) cells can be used to detect the common chromosome
abnormalities observed in patients with AML. The abnormalities have diagnostic and prognostic
relevance, and FISH testing can also be used to track response to therapy. Metaphase FISH confirmation
of classic translocations that are cryptic and not visually detectable by chromosome analysis [ie, t(6;11)
associated with KMT2A/MLLT4(AFDN) fusion] is performed as required by Children's Oncology Group
(COG) and is included as part of the electronic case submission by the Mayo Clinic Genomics Laboratory
to COG for central review. Additional cytogenetic techniques such as chromosomal microarray (CMAH /
Chromosomal Microarray, Hematologic Disorders, Varies) may be helpful to resolve questions related to
ploidy (hyperdiploid clone vs doubled hypodiploid clone).
Useful For: Evaluation of pediatric bone marrow and peripheral blood specimens by fluorescence in
situ hybridization (FISH) probe analysis for classic rearrangements and chromosomal copy number
changes associated with acute myeloid leukemia (AML) in patients being considered for enrolment in
Children's Oncology Group (COG) clinical trials and research protocols As an adjunct to conventional
chromosome studies in performed in pediatric patients with AML being considered for enrollment in
COG protocols
Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds
the normal reference range for any given probe. The absence of an abnormal clone does not rule out the
presence of a neoplastic disorder.
Reference Values:
Clinical References: 1. Grimwade D, Hills RK, Moorman AV, et al: Refinement of cytogenetics
classification in acute myeloid leukemia: determination of prognostic significance or rare recurring
chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom
Research Council trials. Blood. 2010 Jul 22;116(3):354-365 2. Swerdlow SH, Campo E, Harris NL, et
al. eds: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press; 2017
3. Dohner H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN
recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi:
10.1182/blood-2016-08-733196
AMLAF Acute Myeloid Leukemia (AML), FISH, Adult, Varies

609517 Clinical Information: Acute myeloid leukemia (AML) is one of the most common adult leukemias,
with almost 10,000 new cases diagnosed per year. AML also comprises 15% of pediatric acute
leukemia and accounts for the majority of infant (<1 year old) leukemia. Several recurrent chromosomal
abnormalities have been identified in AML with associated clinical significance. The most common
chromosome abnormalities associated with AML include t(8;21), t(15;17), inv(16), and abnormalities of
the MLL (KMT2A) gene at 11q23. The most common genes juxtaposed with MLL through
translocation events in AML include MLLT3- t(9;11), MLLT4)- t(6;11), MLLT10- t(10;11), and ELL-
t(11;19p13.1). Other recurrent chromosome abnormalities associated with AML include inv(3) or t(3;3),
t(6;9) and t(9;22). In addition, AML can also evolve from myelodysplasia (MDS). Thus, the common
chromosome abnormalities associated with MDS can also be identified in AML, which include: -5/5q-,
-7/7q-, and 17p-. Overall, the recurrent chromosome abnormalities identified in patients with AML are
observed in approximately 60% of diagnostic AML cases. Conventional chromosome analysis is the
gold standard for identification of the common, recurrent chromosome abnormalities in AML.
However, some of the subtle rearrangements can be missed by karyotype, including inv(16) and MLL
rearrangements. Fluorescence in situ hybridization (FISH) analysis of nonproliferating (interphase) cells
can be used to detect the common diagnostic and prognostic chromosome abnormalities observed in
patients with AML. When recurrent translocations or inversions are identified, FISH testing can also be
used to track response to therapy.
Useful For: Detecting a neoplastic clone associated with recurrent chromosome abnormalities seen in
adult patients with acute myeloid leukemia (AML) or other myeloid malignancies An adjunct to
conventional chromosome studies in patients with AML Evaluating specimens in which standard
cytogenetic analysis is unsuccessful
Reference Values:
Clinical References: 1. Swerdlow SH, Campo E, Harris NL, et al, eds: WHO Classification of
Tumour of Haematopoietic and Lymphoid Tissues. 4th ed. IARC Press; 20172. 2. Dohner H, Estey E,
Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN recommendations from an
international expert panel. Blood. 2017;129(4):424-447 doi:10.1182/blood-2016-08-733196
AMLPF Acute Myeloid Leukemia (AML), FISH, Pediatric, Varies

with almost 10,000 new cases diagnosed per year. AML also comprises 15% of pediatric acute
leukemia and accounts for the majority of infant (<1 year old) leukemia. Several recurrent chromosomal
abnormalities have been identified in AML. The most common chromosome abnormalities associated
with AML include t(8;21), t(15;17), inv(16), and abnormalities of the MLL (KMT2A) gene at 11q23.
The most common genes juxtaposed with MLL through translocation events in AML include
MLTT4(MLLT4)- t(6;11), MLLT3- t(9;11), MLLT10- t(10;11), and ELL- t(11;19p13.1). AML can also
evolve from myelodysplasia (MDS). Thus, the common chromosome abnormalities associated with
MDS can also be identified in AML, which include: inv(3), -5/5q-, -7/7q-. Overall, the recurrent
chromosome abnormalities identified in patients with AML are observed in approximately 60% of
diagnostic AML cases. Conventional chromosome analysis is the gold standard for identification of the
common, recurrent chromosome abnormalities in AML. However, some of the subtle rearrangements
can be missed by karyotype, including inv(16) and MLL rearrangements. Fluorescence in situ
hybridization (FISH) analysis of nonproliferating (interphase) cells can be used to detect the common
diagnostic and prognostic chromosome abnormalities observed in patients with AML. When recurrent
translocations or inversions are identified, FISH testing can also be used to track response to therapy.
Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities and
classic rearrangements seen in pediatric/young adult patients with acute myeloid leukemia (AML) An
adjunct to conventional chromosome studies in patients with AML Evaluating specimens in which
standard cytogenetic analysis is unsuccessful
presence of neoplastic disorder.
Reference Values:
chromosomal abnormalities among 5879 younger adult patients treated in the United Kingdom Research
Council trials. Blood. 2010 Jul;116(3):354-365 2. Swerdlow SH, Campo E, Harris NL, et al. eds: WHO
Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. IARC Press; 2017 3. Dohner
H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN
recommendations from an international expert panel. Blood. 2017;129(4):424-447 doi:
10.1182/blood-2016-08-733196
AMLMF Acute Myeloid Leukemia (AML), Specified FISH, Varies

with almost 10,000 new cases diagnosed per year. AML also comprises 15% of pediatric acute leukemia
and accounts for the majority of infant (<1 year old) leukemia. Several recurrent chromosomal
abnormalities have been identified in AML with associated clinical significance. The most common
chromosome abnormalities associated with AML include t(8;21), t(15;17), inv(16), and abnormalities of
the MLL (KMT2A) gene at 11q23. The most common genes juxtaposed with MLL through translocation
events in AML include MLLT3- t(9;11), MLLT4- t(6;11), MLLT10- t(10;11), and ELL- t(11;19p13.1).
Other recurrent chromosome abnormalities associated with AML include inv(3) or t(3;3), t(6;9) and
t(9;22). In addition, AML can also evolve from myelodysplasia (MDS). Thus, the common chromosome
abnormalities associated with MDS can also be identified in AML, which include: inv(3), -5/5q-, -7/7q-,
and 17p. Overall, the recurrent chromosome abnormalities identified in patients with AML are observed
in approximately 60% of diagnostic AML cases. Conventional chromosome analysis is the gold standard
for identification of the common, recurrent chromosome abnormalities in AML. However, some of the
subtle rearrangements can be missed by karyotype, including inv(16) and MLL rearrangements.
Fluorescence in situ hybridization (FISH) analysis of nonproliferating (interphase) cells can be used to
detect the common diagnostic and prognostic chromosome abnormalities observed in patients with AML.
When recurrent translocations or inversions are identified, FISH testing can also be used to track response
to therapy.
Useful For: Detecting a neoplastic clone associated with the recurrent chromosome abnormalities seen
in patients with acute myeloid leukemia (AML) or other myeloid malignancies using a client specified
probe set An adjunct to conventional chromosome studies in patients with AML Evaluating specimens in
which standard cytogenetic analysis is unsuccessful
Reference Values:
chromosomal abnormalities among 5879 younger adult patients treated in the United Kingdom
Research Council trials. Blood. 2010 Jul;116(3):354-365 2. Swerdlow SH, Campo E, Harris NL, et al,
eds: WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues. 4th ed. IARC Press;
2017 3. Dohner H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017
ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447 doi:
10.1182/blood-2016-08-733196
APGP Acute Porphyria Gene Panel, Varies

608015 Clinical Information: Acute porphyria is caused by variants in 1 of 4 genes: -HMBS is associated
with acute intermittent porphyria (AIP) -CPOX is associated with hereditary coproporphyria (HCP)
-PPOX is associated with variegate porphyria (VP) -ALAD is associated with aminolevulinic acid
dehydratase deficiency porphyria Variants in these genes show incomplete penetrance, and patients with
a confirmed deleterious variant may be asymptomatic. Clinical manifestations of acute porphyria
include attacks of neurologic dysfunction, commonly characterized as abdominal pain. However, these
acute attacks are variable and can include vomiting, diarrhea, constipation, urinary retention, acute
episodes of neuropathic symptoms, psychiatric symptoms, seizures, respiratory paralysis, tachycardia,
and hypertension. Respiratory paralysis can progress to coma and death. HCP and VP are also
associated with cutaneous manifestations, including edema, sun-induced erythema, acute painful
photodermatitis, and urticaria. In some cases, patients present with isolated photosensitivity. Acute
attacks may be prevented by avoiding both endogenous and exogenous triggers. These triggers include
porphyrogenic drugs, hormonal contraceptives, fasting, alcohol, tobacco, and cannabis. Fecal
porphyrins and quantitative urinary porphyrins analyses are helpful in establishing a diagnosis of acute
porphyria.
Useful For: Establishing a molecular diagnosis for patients with acute porphyria Identifying variants
within genes known to be associated with acute porphyria, allowing for predictive testing of at-risk
family members
known significance.
Reference Values:
May;17(5):405-424 2. Siegesmund M, van Tuyll van Serooskerken AM, Poblete-Gutierrez P, Frank J:
The acute hepatic porphyrias: current status and future challenges. Best Pract Res Clin Gastroenterol.
2010 Oct;24(5):593-605 3. Anderson KE, Bloomer JR, Bonkovsky HL, et al: Recommendations for the
diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005 Mar 15;142(6):439-450
FACYS Acyclovir, Plasma

Usual therapeutic range (vs. Genital Herpes) during chronic oral daily divided dosages of 1200 - 2400
mg:
--Peak: 0.40 - 2.0 mcg/mL plasma
--Trough: 0.14 - 1.2 mcg/mL plasma
ACRN Acylcarnitines, Quantitative, Plasma

82413 Clinical Information: Acylcarnitine analysis enables the diagnosis of many disorders of fatty acid
oxidation and several organic acidurias, as relevant enzyme deficiencies cause the accumulation of
specific acyl-CoAs.(1) Fatty acid oxidation (FAO) plays a major role in energy production during periods
of fasting. When the body's supply of glucose is depleted, fatty acids are mobilized from adipose tissue,
taken up by the liver and muscles, and oxidized to acetyl-CoA. In the liver, acetyl-CoA is the building
block for the synthesis of ketone bodies, which enter the blood stream and provide an alternative substrate
for production of energy in other tissues when the supply of glucose is insufficient to maintain a normal
level of energy. The acyl groups are conjugated with carnitine to form acylcarnitines, which can be
measured by tandem mass spectrometry. Diagnostic results are usually characterized by a pattern of
significantly elevated acylcarnitine species compared to normal and disease controls. In general, more
than 20 inborn errors of metabolism can be identified using this method, including FAO disorders and
organic acidurias. The major clinical manifestations associated with individual FAO disorders include
hypoketotic hypoglycemia, variable degrees of liver disease and failure, skeletal myopathy,
dilated/hypertrophic cardiomyopathy, and sudden or unexpected death. Organic acidurias also present as
acute life-threatening events early in life with metabolic acidosis, increased anion gap, and neurologic
distress. Patients with any of these disorders are at risk of developing fatal metabolic decompensations
following the acquisition of even common infections. Once diagnosed, these disorders can be treated by
avoidance of fasting, special diets, and cofactor and vitamin supplementation. Additional confirmatory
testing is recommended. The diagnosis of an underlying FAO disorder or organic aciduria allows genetic
counseling of the family, including the possible option of future prenatal diagnosis, and testing of at-risk
family members of any age. The following disorders are detectable by acylcarnitine analysis. However,
further confirmatory testing is required for most of these conditions because an acylcarnitine profile can
be suggestive of more than one condition. Fatty Acid Oxidation Disorders: -Carnitine
palmitoyltransferase I deficiency -Medium-chain 3-ketoacyl-CoA thiolase deficiency -Dienoyl-CoA
reductase deficiency -Short-chain acyl-CoA dehydrogenase deficiency -Medium/Short-chain
3-hydroxyacyl-CoA dehydrogenase deficiency -Medium-chain acyl-CoA dehydrogenase deficiency
-Long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiency and trifunctional protein deficiency -Very
long-chain acyl-CoA dehydrogenase deficiency -Carnitine palmitoyl transferase type II deficiency
-Carnitine-acylcarnitine translocase deficiency -Electron transfer flavoprotein (ETF) deficiency,
ETF-dehydrogenase deficiency (multiple acyl-CoA dehydrogenase deficiency; glutaric acidemia type II)
Organic Acid Disorders: -Glutaryl-CoA dehydrogenase deficiency (glutaric acidemia type I) -Propionic
acidemia -Methylmalonic acidemia -Isovaleric acidemia -3-Hydroxy-3-methylglutaryl-CoA carboxylase
deficiency -3-Methylcrotonyl carboxylase deficiency -Biotinidase deficiency -Multiple carboxylase
deficiency -Isobutyryl-CoA dehydrogenase deficiency -2-Methylbutyryl-CoA dehydrogenase deficiency
-Beta-ketothiolase deficiency -Malonic aciduria -Ethylmalonic encephalopathy -Glutamate
formiminotransferase deficiency (formiminoglutamic aciduria)
Useful For: Diagnosis of fatty acid oxidation disorders and several organic acidurias using plasma
specimens Evaluating treatment during follow-up of patients with fatty acid beta-oxidation disorders and
several organic acidurias
Interpretation: An interpretive report is provided. The individual quantitative results support the
interpretation of the acylcarnitine profile but are not diagnostic by themselves. The interpretation is based
on pattern recognition. Abnormal results are typically not sufficient to conclusively establish a diagnosis
of a particular disease. To verify a preliminary diagnosis based on an acylcarnitine analysis, independent
biochemical or molecular genetic analyses are required. For information on the follow-up of specific
acylcarnitine elevations, see the following algorithms: -Newborn Screening Follow-up for Elevations of
C8, C6, and C10 Acylcarnitines (also applies to any plasma or serum C8, C6, and C10 acylcarnitine
elevations) -Newborn Screening Follow-up for Isolated C4 Acylcarnitine Elevations (also applies to any
plasma or serum C4 acylcarnitine elevation) -Newborn Screening Follow-up for Isolated C5 Acylcarnitine
Elevations (also applies to any plasma or serum C5 acylcarnitine elevation)
Reference Values:
< or =7 days 8 days-7 years > or =8 years

(nmol/mL) (nmol/mL) (nmol/mL)
Acetylcarnitine, C2 2.14-15.89 2.00-27.57 2.00-17.83
Acrylylcarnitine, C3:1
Propionylcarnitine, C3
Formiminoglutamate, FIGLU
Iso-/Butyrylcarnitine, C4
Tiglylcarnitine, C5:1
Isovaleryl-/2-Methylbutyrylcarn C5
3-OH-iso-/butyrylcarnitine, C4-OH
Hexenoylcarnitine, C6:1
Hexanoylcarnitine, C6
3-OH-isovalerylcarnitine, C5-OH
Benzoylcarnitine
Heptanoylcarnitine, C7
3-OH-hexanoylcarnitine, C6-OH
Phenylacetylcarnitine
Salicylcarnitine
Octenoylcarnitine, C8:1
Octanoylcarnitine, C8
Malonylcarnitine, C3-DC
Decadienoylcarnitine, C10:2
Decenoylcarnitine, C10:1
Decanoylcarnitine, C10
Methylmalonyl-/succinylcarn, C4-DC
3-OH-decenoylcarnitine, C10:1-OH
Glutarylcarnitine, C5-DC
Dodecenoylcarnitine, C12:1
Dodecanoylcarnitine, C12
3-Methylglutarylcarnitine, C6-DC
3-OH-dodecenoylcarnitine, C12:1-OH
3-OH-dodecanoylcarnitine, C12-OH
Tetradecadienoylcarnitine, C14:2
Tetradecenoylcarnitine, C14:1
Tetradecanoylcarnitine, C14
Octanedioylcarnitine, C8-DC
3-OH-tetradecenoylcarnitine C14:1OH
3-OH-tetradecanoylcarnitine, C14-OH
Hexadecenoylcarnitine, C16:1
Hexadecanoylcarnitine, C16
3-OH-hexadecenoylcarnitine,C16:1-OH
3-OH-hexadecanoylcarnitine, C16-OH
Octadecadienoylcarnitine, C18:2
Octadecenoylcarnitine, C18:1
Octadecanoylcarnitine, C18
Dodecanedioylcarnitine, C12-DC
3-OH-octadecadienoylcarn, C18:2-OH
3-OH-octadecenoylcarnitine C18:1-OH
3-OH-octadecanoylcarnitine, C18-OH
Clinical References: 1. Miller MJ, Cusmano-Ozog K, Oglesbee D, Young S; ACMG Laboratory

Quality Assurance Committee. Laboratory analysis of acylcarnitines, 2020 update: a technical standard
of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021
Feb;23(2):249-258 2. Matern D: Acylcarnitines, including in vitro loading tests. In: Blau N, Duran M,
Gibson KM, eds: Laboratory Guide to the Methods in Biochemical Genetics. Springer Verlag;
2008:171-206 3. Rinaldo P, Cowan TM, Matern D: Acylcarnitine profile analysis. Genet Med. 2008
Feb;10(2):151-156 4. Smith EH, Matern D: Acylcarnitine analysis by tandem mass spectrometry. Curr
Protoc Hum Genet. 2010 Jan;Chap 17:Unit 17.8.1-20 5. Elizondo G, Matern D, Vockley J, Harding CO,
Gillingham MB. Effects of fasting, feeding and exercise on plasma acylcarnitines among subjects with
CPT2D, VLCADD and LCHADD/TFPD. Mol Genet Metab. 2020 Sep-Oct;131(1-2):90-97
ACRNS Acylcarnitines, Quantitative, Serum

60644 Clinical Information: Acylcarnitine analysis enables the diagnosis of many disorders of fatty acid
oxidation and several organic acidurias, as relevant enzyme deficiencies cause the accumulation of
specific acyl-CoAs.(1) Fatty acid oxidation (FAO) plays a major role in energy production during periods
of fasting. When the body's supply of glucose is depleted, fatty acids are mobilized from adipose tissue,
taken up by the liver and muscles, and oxidized to acetyl-CoA. In the liver, acetyl-CoA is the building
block for the synthesis of ketone bodies, which enter the blood stream and provide an alternative substrate
for production of energy in other tissues when the supply of glucose is insufficient to maintain a normal
level of energy. The acyl groups are conjugated with carnitine to form acylcarnitines, which can be
measured by tandem mass spectrometry. Diagnostic results are usually characterized by a pattern of
significantly elevated acylcarnitine species compared to normal and disease controls. In general, more
than 20 inborn errors of metabolism can be identified using this method including FAO disorders and
organic acidurias. The major clinical manifestations associated with individual FAO disorders include
hypoketotic hypoglycemia, variable degrees of liver disease or failure, skeletal myopathy,
dilated/hypertrophic cardiomyopathy, and sudden or unexpected death. Organic acidurias also present as
acute life-threatening events early in life with metabolic acidosis, increased anion gap, and neurologic
distress. Patients with any of these disorders are at risk of developing fatal metabolic decompensations
following the acquisition of even common infections. Once diagnosed, these disorders can be treated by
avoidance of fasting, special diets, and cofactor/vitamin supplementation. Analysis of acylcarnitines in
blood and bile spots represents the first level of evaluation of a complete postmortem investigation of a
sudden or unexpected death of an individual. Additional confirmatory testing is recommended. The
diagnosis of an underlying FAO disorder or organic aciduria allows genetic counseling of the family,
including the possible option of future prenatal diagnosis, and testing of at-risk family members of any
age. The following disorders are detectable by acylcarnitine analysis. However, further confirmatory
testing is required for most of these conditions because an acylcarnitine profile can be suggestive of more
than one condition. Fatty Acid Oxidation Disorders: -Carnitine palmitoyltransferase I deficiency
-Medium-chain 3-ketoacyl-CoA thiolase deficiency -Dienoyl-CoA reductase deficiency -Short-chain
acyl-CoA dehydrogenase deficiency -Medium/Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
-Medium-chain acyl-CoA dehydrogenase) deficiency -Long-chain 3-hydroxyacyl-CoA dehydrogenase)
deficiency and trifunctional protein deficiency -Very long-chain acyl-CoA dehydrogenase deficiency
-Carnitine palmitoyl transferase type II deficiency -Carnitine-acylcarnitine translocase deficiency
-Electron transfer flavoprotein (ETF) deficiency, ETF-dehydrogenase deficiency (multiple acyl-CoA
dehydrogenase deficiency; glutaric acidemia type II) Organic Acid Disorders: -Glutaryl-CoA
dehydrogenase deficiency (glutaric acidemia type I) -Propionic acidemia -Methylmalonic acidemia
-Isovaleric acidemia -3-Hydroxy-3-methylglutaryl-CoA carboxylase deficiency -3-Methylcrotonyl
carboxylase deficiency -Biotinidase deficiency -Multiple carboxylase deficiency -Isobutyryl-CoA
dehydrogenase deficiency -2-Methylbutyryl-CoA dehydrogenase deficiency -Beta-ketothiolase deficiency
-Malonic aciduria -Ethylmalonic encephalopathy Glutamate formiminotransferase deficiency
(formiminoglutamic aciduria)
Useful For: Diagnosis of fatty acid oxidation disorders and several organic acidurias using serum
specimens Evaluating treatment during follow-up of patients with fatty acid beta-oxidation disorders
and several organic acidurias
Interpretation: An interpretive report will be provided. The individual quantitative results support
the interpretation of the acylcarnitine profile but are not diagnostic by themselves. The interpretation is
based on pattern recognition. Abnormal results are not sufficient to conclusively establish a diagnosis of
a particular disease. To verify a preliminary diagnosis based on an acylcarnitine analysis, independent
biochemical (eg, in vitro enzyme assay) or molecular genetic analyses are required. For information on
the follow-up of specific acylcarnitine elevations, see the following algorithms: -Newborn Screening
Follow-up for Elevations of C8, C6, and C10 Acylcarnitines (also applies to any plasma or serum C8,
C6, and C10 acylcarnitine elevations) -Newborn Screening Follow-up for Isolated C4 Acylcarnitine
Elevations (also applies to any plasma or serum C4 acylcarnitine elevation) -Newborn Screening
Follow-up for Isolated C5 Acylcarnitine Elevations (also applies to any plasma or serum C5
acylcarnitine elevation)
Reference Values:
< or =7 days 8 days-7 years > or =8 years

(nmol/mL) (nmol/mL) (nmol/mL)
Acetylcarnitine, C2 2.14-15.89 2.00-27.57 2.00-17.83
Acrylylcarnitine, C3:1
Propionylcarnitine, C3
Formiminoglutamate, FIGLU
Iso-/Butyrylcarnitine, C4
Tiglylcarnitine, C5:1
Isovaleryl-/2-Methylbutyrylcarn C5
3-OH-iso-/butyrylcarnitine, C4-OH
Hexenoylcarnitine, C6:1
Hexanoylcarnitine, C6
3-OH-isovalerylcarnitine, C5-OH
Benzoylcarnitine
Heptanoylcarnitine, C7
3-OH-hexanoylcarnitine, C6-OH
Phenylacetylcarnitine
Salicylcarnitine
Octenoylcarnitine, C8:1
Octanoylcarnitine, C8
Malonylcarnitine, C3-DC
Decadienoylcarnitine, C10:2
Decenoylcarnitine, C10:1
Decanoylcarnitine, C10
Methylmalonyl-/succinylcarn, C4-DC
3-OH-decenoylcarnitine, C10:1-OH
Glutarylcarnitine, C5-DC
Dodecenoylcarnitine, C12:1
Dodecanoylcarnitine, C12
3-Methylglutarylcarnitine, C6-DC
3-OH-dodecenoylcarnitine, C12:1-OH
3-OH-dodecanoylcarnitine, C12-OH
Tetradecadienoylcarnitine, C14:2
Tetradecenoylcarnitine, C14:1
Tetradecanoylcarnitine, C14
Octanedioylcarnitine, C8-DC
3-OH-tetradecenoylcarnitine C14:1OH
3-OH-tetradecanoylcarnitine, C14-OH
Hexadecenoylcarnitine, C16:1
Hexadecanoylcarnitine, C16
3-OH-hexadecenoylcarnitine,C16:1-OH
3-OH-hexadecanoylcarnitine, C16-OH
Octadecadienoylcarnitine, C18:2
Octadecenoylcarnitine, C18:1
Octadecanoylcarnitine, C18
Dodecanedioylcarnitine, C12-DC
3-OH-octadecadienoylcarn, C18:2-OH
3-OH-octadecenoylcarnitine C18:1-OH
3-OH-octadecanoylcarnitine, C18-OH

Quality Assurance Committee. Laboratory analysis of acylcarnitines, 2020 update: a technical standard
Feb;23(2):249-258 2. Matern D: Acylcarnitines, including in vitro loading tests. In: Blau N, Duran M,
Gibson KM, eds: Laboratory Guide to the Methods in Biochemical Genetics. Springer Verlag;
2008:171-206 3. Rinaldo P, Cowan TM, Matern D: Acylcarnitine profile analysis. Genet Med. 2008
Feb;10(2):151-156 4. Smith EH, Matern D: Acylcarnitine analysis by tandem mass spectrometry. Curr
Protoc Hum Genet. 2010 Jan;Chap 17:Unit 17.8.1-20 5. Elizondo G, Matern D, Vockley J, Harding CO,
Gillingham MB. Effects of fasting, feeding and exercise on plasma acylcarnitines among subjects with
CPT2D, VLCADD and LCHADD/TFPD. Mol Genet Metab. 2020 Sep-Oct;131(1-2):90-97
AGU20 Acylglycines, Quantitative, Random, Urine

608909 Clinical Information: Acylglycines are glycine conjugates of acyl-CoA species, which occur as
normal intermediates of amino acid and fatty acid metabolism. In abnormal concentrations, acylglycines
are biochemical markers of selected inborn errors of metabolism (IEM). Analysis of acylglycines is
useful for the diagnosis and monitoring for specific fatty acid oxidation disorders and organic acidurias,
although is recommended to use this testing in conjunction with urine organic acids and plasma
acylcarnitines testing in order to establish a diagnosis. In particular, acylglycine analysis is more
sensitive and specific for the identification of asymptomatic patients and those who may experience
mild or intermittent biochemical phenotypes that could be missed by organic acid analysis alone.
Useful For: Diagnosis and monitoring for patients affected with 1 of the following inborn errors of
metabolism: Fatty Acid Oxidation Disorders -Glutaric acidemia type II -Medium-chain 3-ketoacyl-CoA
thiolase (MCKAT) deficiency -Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency -Short
chain acyl-CoA dehydrogenase (SCAD) deficiency Organic Acidurias
-2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (2M3HBD) deficiency -2-Methylbutyryl-CoA
dehydrogenase deficiency -3-Methylcrotonyl-CoA carboxylase deficiency
-3-Methylglutaconyl-CoA-hydratase deficiency -Aminoacylase 1 deficiency -Beta-ketothiolase
deficiency -Ethylmalonic encephalopathy -Glutaryl-CoA dehydrogenase deficiency -Isobutyryl-CoA
dehydrogenase (IBD) deficiency -Isovaleryl-CoA dehydrogenase deficiency -Multiple carboxylase
deficiency -Propionic acidemia
Interpretation: When abnormal results are detected, a detailed interpretation is given including an
overview of the results and of their significance; a correlation to available clinical information; elements
of differential diagnosis; recommendations for additional biochemical testing and in vitro confirmatory
studies (enzyme assay, molecular analysis); name and phone number of key contacts who may provide
these studies at Mayo Clinic or elsewhere; and a phone number to reach one of the laboratory directors
Reference Values:
Reference Values; Expressed as mg/g creatinine
< or =11 Months 12-23 Months 24-35 Months
Female Male Female Male Female Male
n-Acetylglycine 0.18-1.30 0.18-1.30 0.17-1.29 0.17-1.29 0.17-1.28 0.17-1.28
n-Propionylglycine 0.16-0.91 0.16-0.91 0.16-0.91 0.16-0.91 0.16-0.90 0.16-0.90
Isobutyrylglycine 0.17-2.50 0.17-2.50 0.17-2.49 0.17-2.49 0.17-2.47 0.17-2.47
Ethylmalonic acid 2.18-15.29 2.06-17.30 2.15-15.13 2.03-17.08 2.11-14.94 2.00-16.82
n-Butyrylglycine 0.20-1.37 0.19-1.29 0.20-1.36 0.19-1.28 0.20-1.34 0.19-1.26
2-Methylsuccinic acid 1.16-5.97 1.09-6.10 1.14-5.89 1.07-6.01 1.13-5.79 1.05-5.91
2-Methylbutyrylglycine 0.10-1.42 0.09-1.40 0.10-1.40 0.09-1.39 0.10-1.38 0.09-1.37
Isovalerylglycine 0.47-7.15 0.47-7.15 0.48-7.13 0.48-7.13 0.48-7.10 0.48-7.10
Glutaric acid 0.45-6.20 0.47-6.02 0.45-6.11 0.46-5.92 0.44-6.00 0.46-5.81
3-Methylcrotonylglycine 0.28-1.55 0.28-1.55 0.28-1.53 0.28-1.53 0.28-1.50 0.28-1.50
n-Tiglylglycine 1.05-5.76 1.05-5.76 1.05-5.67 1.05-5.67 1.05-5.56 1.05-5.56
3-Methylglutaconic acid 2.79-12.73 2.79-12.73 2.77-12.60 2.77-12.60 2.75-12.43 2.75-12.43
n-Hexanoylglycine 0.35-1.70 0.36-1.67 0.35-1.69 0.36-1.66 0.35-1.68 0.35-1.65
n-Octanoylglycine 0.16-1.60 0.16-1.60 0.16-1.59 0.16-1.59 0.16-1.58 0.16-1.58
3-Phenylpropionylglycine 0.08-1.10 0.07-1.06 0.08-1.09 0.07-1.05 0.08-1.09 0.07-1.05
trans-Cinnamoylglycine 0.41-4.81 0.40-4.73 0.41-4.81 0.40-4.73 0.41-4.81 0.40-4.73
Suberylglycine 0.38-3.09 0.38-3.09 0.38-3.05 0.38-3.05 0.37-3.01 0.37-3.01
Dodecanedioic acid 0.01-0.09 0.01-0.09 0.01-0.09 0.01-0.09 0.01-0.09 0.01-0.09
Tetradecanedioic acid 0.01-0.07 0.01-0.07 0.01-0.07 0.01-0.07 0.01-0.06 0.01-0.06
Hexadecanedioic acid 0.01-0.04 0.01-0.04 0.01-0.04 0.01-0.04 0.01-0.04 0.01-0.04
3 Years 4 Years 5 Years
n-Acetylglycine 0.17-1.26 0.17-1.26 0.17-1.24 0.17-1.24 0.17-1.21 0.17 - 1.21

Glutaric acid 0.43-5.88 0.45-5.68 0.42-5.65 0.44-5.44 0.41-5.39 0.43-5.17
n-Tiglylglycine 1.05-5.44 1.05-5.44 1.04-5.22 1.04-5.22 1.03-4.98 1.03-4.98
Suberylglycine 0.37-2.97 0.37-2.97 0.36-2.90 0.36-2.90 0.35-2.82 0.35-2.82
n-Acetylglycine 0.16-1.18 0.16-1.18 0.16-1.15 0.16-1.15 0.15-1.12 0.15-1.12
Glutaric acid 0.40-5.10 0.42-4.87 0.39-4.79 0.40-4.54 0.37-4.47 0.39-4.21
n-Tiglylglycine 1.01-4.73 1.01-4.73 0.99-4.46 0.99-4.46 0.96-4.22 0.96-4.22
Suberylglycine 0.34-2.74 0.34-2.74 0.32-2.66 0.32-2.66 0.31-2.58 0.31-2.58

n-Acetylglycine 0.15-1.09 0.15-1.09 0.15-1.07 0.15 1.07 0.14-1.04 0.14-1.04
Glutaric acid 0.36-4.16 0.37-3.88 0.36-3.87 0.36-3.57 0.35-3.60 0.35-3.28
n-Tiglylglycine 0.93-4.00 0.93-4.00 0.90-3.80 0.90-3.80 0.87-3.64 0.87-3.64
Suberylglycine 0.30-2.52 0.30-2.52 0.29-2.46 0.29-2.46 0.28-2.42 0.28-2.42
n-Acetylglycine 0.14-1.01 0.14-1.01 0.14-0.98 0.14-0.98 0.13-0.95 0.13-0.95
Glutaric acid 0.35-3.35 0.35-3.00 0.34-3.13 0.34-2.75 0.34-2.94 0.34-2.53
n-Tiglylglycine 0.84-3.51 0.84-3.51 0.82-3.40 0.82-3.40 0.80-3.30 0.80-3.30

Suberylglycine 0.28-2.38 0.28-2.38 0.27-2.35 0.27-2.35 0.27-2.33 0.27-2.33
Hexadecanedioic acid 0.01-0.03 0.01-0.03 Â 0.01-0.03 0.01-0.03 0.01-0.03 0.01-0.03
n-Acetylglycine 0.13-0.92 0.13-0.92 0.14-0.89 0.14-0.89 0.14-0.87 0.14-0.87
Glutaric acid 0.34-2.77 0.34-2.32 0.34-2.63 0.34-2.14 0.34-2.50 0.34-1.98
n-Tiglylglycine 0.80-3.22 0.80-3.22 0.80-3.14 0.80-3.14 0.81-3.06 0.81-3.06
Suberylglycine 0.26-2.31 0.26-2.31 0.26-2.29 0.26-2.29 0.26-2.27 0.26-2.27
n-Acetylglycine 0.14-0.85 0.14-0.85 0.14-0.83 0.14-0.83 0.14-0.81 0.14-0.81

Glutaric acid 0.34-2.39 0.34-1.83 0.35-2.29 0.35-1.70 0.35-2.20 0.35-1.59
n-Tiglylglycine 0.83-2.98 0.83-2.98 0.85-2.90 0.85-2.90 0.87-2.83 0.87-2.83
Suberylglycine 0.26-2.26 0.26-2.26 0.26-2.24 0.26-2.24 0.26-2.22 0.26-2.22
n-Acetylglycine 0.15-0.80 0.15-0.80 0.15-0.79 0.15-0.79 0.15-0.78 0.15-0.78
Glutaric acid 0.35-2.13 0.35-1.49 0.35-2.06 0.36-1.41 0.35-2.00 0.36-1.34
n-Tiglylglycine 0.90-2.76 0.90-2.76 0.93-2.70 0.93-2.70 0.95-2.64 0.95-2.64
Suberylglycine 0.26-2.21 0.26-2.21 0.26-2.19 0.26-2.19 0.26-2.17 0.26-2.17

n-Acetylglycine 0.15-0.77 0.15-0.77 0.15-0.75 0.15-0.75 0.15-0.73 0.15-0.73
Glutaric acid 0.35-1.94 0.36-1.28 0.35-1.88 0.36-1.24 0.34-1.83 0.36-1.21
n-Tiglylglycine 0.97-2.59 0.97-2.59 0.98-2.55 0.98-2.55 0.99-2.51 0.99-2.51
Suberylglycine 0.27-2.16 0.27-2.16 0.27-2.14 0.27-2.14 0.27-2.12 0.27-2.12
n-Acetylglycine 0.15-0.71 0.15-0.71 0.15-0.69 0.15-0.69 0.15-0.67 0.15-0.67
Glutaric acid 0.34-1.78 0.36-1.19 0.34-1.73 0.36-1.18 0.34-1.69 0.35-1.17
n-Tiglylglycine 1.00-2.48 1.00-2.48 1.00-2.45 1.00-2.45 1.00-2.43 1.00-2.43

Suberylglycine 0.28-2.10 0.28-2.10 0.28-2.08 0.28-2.08 0.29-2.06 0.29-2.06
n-Acetylglycine 0.15-0.64 0.15-0.64 0.16-0.62 0.16-0.62 0.16-0.60 0.16-0.60
Glutaric acid 0.35-1.65 0.35-1.17 0.35-1.61 0.35-1.17 0.35-1.58 0.35-1.17
n-Tiglylglycine 0.99-2.41 0.99-2.41 0.98-2.39 0.98-2.39 0.97-2.37 0.97-2.37
Suberylglycine 0.29-2.04 0.29-2.04 0.30-2.02 0.30-2.02 0.30-1.99 0.30-1.99
n-Acetylglycine 0.16-0.59 0.16-0.59 0.17-0.58 0.17-0.58 0.17-0.56 0.17-0.56
Glutaric acid 0.35-1.55 0.35-1.16 0.35-1.53 0.35-1.16 0.36-1.52 0.35-1.15

n-Tiglylglycine 0.96-2.35 0.96-2.35 0.95-2.33 0.95-2.33 0.95-2.30 0.95-2.30
Suberylglycine 0.31-1.97 0.31-1.97 0.31-1.95 0.31-1.95 0.31-1.92 0.31-1.92
n-Acetylglycine 0.17-0.56 0.17-0.56 0.18-0.55 0.18-0.55 0.18-0.54 0.18-0.54
Glutaric acid 0.36-1.50 0.35-1.14 0.36-1.50 0.35-1.13 0.36-1.49 0.36-1.12
n-Tiglylglycine 0.94-2.27 0.94-2.27 0.94-2.24 0.94-2.24 0.94-2.20 0.94-2.20
Suberylglycine 0.31-1.90 0.31-1.90 0.32-1.88 0.32-1.88 0.32-1.86 0.32-1.86
n-Acetylglycine 0.18-0.54 0.18-0.54 0.18-0.54 0.18-0.54 0.18-0.54 0.18-0.54

Glutaric acid 0.36-1.49 0.36-1.10 0.36-1.49 0.36-1.09 0.36-1.49 0.37-1.07
n-Tiglylglycine 0.95-2.16 0.95-2.16 0.95-2.12 0.95-2.12 0.96-2.09 0.96-2.09
Suberylglycine 0.32-1.84 0.32-1.84 0.32-1.83 0.32-1.83 0.33-1.81 0.33-1.81
n-Acetylglycine 0.17-0.53 0.17-0.53 0.17-0.53 0.17-0.53 0.17-0.53 0.17-0.53
Glutaric acid 0.36-1.49 0.37-1.05 0.37-1.49 0.38-1.03 0.37-1.49 0.38-1.01
n-Tiglylglycine 0.97-2.05 0.97-2.05 0.98-2.03 0.98-2.03 0.99-2.01 0.99-2.01
Suberylglycine 0.33-1.81 0.33-1.81 0.33-1.80 0.33-1.80 0.34-1.80 0.34-1.80

n-Acetylglycine 0.17-0.53 0.17-0.53 0.17-0.53 0.17-0.53 0.17-0.53 0.17-0.53
Glutaric acid 0.37-1.47 0.39-0.99 0.37-1.46 0.39-0.97 0.38-1.44 0.40-0.95
n-Tiglylglycine 1.00-2.00 1.00-2.00 1.02-1.99 1.02-1.99 1.04-1.99 1.04-1.99
Suberylglycine 0.34-1.79 0.34-1.79 0.35-1.79 0.35-1.79 0.36-1.79 0.36-1.79
n-Acetylglycine 0.18-0.53 0.18-0.53 0.19-0.53 0.19-0.53 0.19-0.53 0.19-0.53
Glutaric acid 0.38-1.41 0.41-0.94 0.38-1.38 0.41-0.92 0.39-1.34 0.41-0.91
n-Tiglylglycine 1.05-1.99 1.05-1.99 1.07-1.99 1.07-1.99 1.09-1.99 1.09-1.99

Suberylglycine 0.36-1.78 0.36-1.78 0.37-1.78 0.37-1.78 0.37-1.77 0.37-1.77
n-Acetylglycine 0.20-0.52 0.20-0.52 0.21-0.51 0.21-0.51 0.23-0.51 0.23-0.51
Glutaric acid 0.39-1.30 0.41-0.90 0.39-1.27 0.41-0.89 0.40-1.23 0.41-0.89
n-Tiglylglycine 1.11-1.99 1.11-1.99 1.12-1.98 1.12-1.98 1.12-1.97 1.12-1.97
Suberylglycine 0.38-1.76 0.38-1.76 0.38-1.75 0.38-1.75 0.39-1.74 0.39-1.74
n-Acetylglycine 0.24-0.50 0.24-0.50 0.24-0.49 0.24-0.49 0.25-0.47 0.25-0.47

Glutaric acid 0.40-1.20 0.40-0.88 0.41-1.17 0.40-0.87 0.41-1.15 0.39-0.87
n-Tiglylglycine 1.12-1.94 1.12-1.94 1.12-1.92 1.12-1.92 1.11-1.88 1.11-1.88
Suberylglycine 0.39-1.73 0.39-1.73 0.40-1.72 0.40-1.72 0.41-1.71 0.41-1.71
n-Acetylglycine 0.26-0.46 0.26-0.46 0.26-0.45 0.26-0.45 0.27-0.44 0.27-0.44
Glutaric acid 0.42-1.14 0.38-0.86 0.43-1.13 0.38-0.85 0.44-1.12 0.38-0.84
n-Tiglylglycine 1.10-1.85 1.10-1.85 1.09-1.81 1.09-1.81 1.08-1.77 1.08-1.77
Suberylglycine 0.41-1.70 0.41-1.70 0.42-1.69 0.42-1.69 0.42-1.67 0.42-1.67
n-Acetylglycine 0.28-0.43 0.28-0.43 0.28-0.42 0.28-0.42 0.29-0.42 0.29-0.42

Glutaric acid 0.45-1.11 0.37-0.82 0.46-1.10 0.37-0.81 0.47-1.09 0.37-0.79
n-Tiglylglycine 1.07-1.74 1.07-1.74 1.06-1.71 1.06-1.71 1.06-1.70 1.06-1.70
Suberylglycine 0.43-1.66 0.43-1.66 0.43-1.64 0.43-1.64 0.43-1.62 0.43-1.62
n-Acetylglycine 0.29-0.41 0.29-0.41 0.29-0.41 0.29-0.41 0.30-0.41 0.30-0.41
Glutaric acid 0.48-1.08 0.37-0.77 0.49-1.07 0.37-0.75 0.49-1.06 0.37-0.74
n-Tiglylglycine 1.06-1.68 1.06-1.68 1.06-1.67 1.06-1.67 1.06-1.67 1.06-1.67
Suberylglycine 0.43-1.59 0.43-1.59 0.43-1.57 0.43-1.57 0.42-1.55 0.42-1.55

> or = 66 Years
Female Male
n-Acetylglycine 0.30-0.41 0.30-0.41
n-Propionylglycine 0.29-0.38 0.29-0.38
Isobutyrylglycine 0.46-0.92 0.24-0.97
Ethylmalonic acid 1.84-4.42 1.67-2.86
n-Butyrylglycine 0.33-0.62 0.27-0.56
2-Methylsuccinic acid 1.07-2.02 0.66-1.43
2-Methylbutyrylglycine 0.19-0.65 0.13-0.45
Isovalerylglycine 0.61-2.31 0.61-2.31
Glutaric acid 0.49-1.06 0.38-0.73
3-Methylcrotonylglycine 0.30-0.48 0.30-0.48
n-Tiglylglycine 1.07-1.67 1.07-1.67
3-Methylglutaconic acid 3.11-3.75 3.11-3.75
n-Hexanoylglycine 0.43-0.94 0.38-0.71
n-Octanoylglycine 0.21-0.82 0.21-0.82
3-Phenylpropionylglycine 0.21-0.69 0.16-0.56
trans-Cinnamoylglycine 0.75-2.58 0.50-1.43
Suberylglycine 0.42-1.52 0.42-1.52
Dodecanedioic acid 0.01-0.03 0.01-0.03
Tetradecanedioic acid 0.01-0.02 0.01-0.02
Hexadecanedioic acid 0.01-0.01 0.01-0.01
Clinical References: 1. Rinaldo P, Hahn SH, Matern D: Inborn errors of amino acid, organic acid,
and fatty acid metabolism. In: Burtis CA, Ashwood ER, Bruns DE eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 4th ed. WB Saunders Company; 2005:2207-2247 2. Roe CR,
Ding J. Mitochondrial fatty acid oxidation disorders. In: Valle D, Antonarakis S, Ballabio A, Beaudet
A, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill;
2019. Accessed March 30, 2020.
http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225087274 3. Kolker S, Cazorla
AG, Valayannopoulos, et al: The phenotypic spectrum of organic acidurias and urea cycle disorders.
Part 1: the initial presentation. J Inherit Metab Dis. 2015;38:1041-1057. doi:
10.1007/s10545-015-9839-3 4. Tuncel AT, Boy N, Morath MA, Horster F, Mutze U, Kolker S: Organic
acidurias in adults: late complications and management. J Inherit Metab Dis. 2018;41:765-776. doi:
10.1007/s10545-017-0135-2
ADALX Adalimumab Quantitative with Reflex to Antibody, Serum

64863 Clinical Information: Adalimumab, sold under the brand name Humira, is a medication used to
treat rheumatoid arthritis, psoriatic arthritis, Crohn disease, ulcerative colitis, chronic psoriasis, amongst
others. Adalimumab is a tumor necrosis factor (TNF)-inhibiting, antiinflammatory, biologic medication.
It binds to TNF-alpha, which normally binds to TNF-alpha receptors, leading to the inflammatory
response of autoimmune diseases. By binding to TNF-alpha, adalimumab reduces inflammatory
response. Because TNF-alpha is also part of the immune system that protects the body from infection,
treatment with adalimumab may increase the risk of infections. Treatment with adalimumab is effective
in reducing disease activity, offers significant benefits in quality of life, and may have the potential to
change the progression of the disease when given early. However, over 30% of patients fail to respond
to anti-TNF-alpha therapy, and approximately 60% of patients who responded initially lose the response
over time and require either drug dose-escalation or switch to an alternative therapy in order to maintain
response.(1) Reasons for primary loss of response are not well understood but may include disease
processes mediated by proinflammatory molecules other than TNF. Secondary loss of response, on the
other hand, is associated with low serum albumin, high body-mass index, the degree of systemic
inflammation and development of an immune response to therapy, or immunogenicity.(2,3) Antidrug
antibody formation may increase drug clearance in treated patients or neutralize the drug effect, thereby
potentially contributing to the loss of response. Antidrug antibodies could also cause adverse events
such as serum sickness and hypersensitivity reactions.(4) Currently, adalimumab quantitation is
commonly performed in conjunction with immunogenicity assessment for antibodies to adalimumab
(ATA). Most often, this testing is ordered in patients on therapy who are experiencing partial or
complete loss of response. TNF inhibitor therapies are expensive and adverse events include greater risk
for infections, such as reactivation of latent tuberculosis or hepatitis B, infusion or injection site
reactions, cutaneous reactions, and reports of hepatoxicity, demyelinating disease, and higher incidence
of mortality and hospitalization in heart failure patients have been documented.
Useful For: Therapeutic drug monitoring of adalimumab concentration

Interpretation: Currently, adalimumab quantitation is one of the most commonly tested monoclonal
antibodies in routine clinical practice; this testing is generally performed in conjunction with
immunogenicity assessment for antibodies to adalimumab (ATA). Most often, this testing is ordered for
patients with inflammatory bowel disease (IBD) who are on adalimumab therapy and who are
experiencing loss of response (reactive monitoring),(5) but the testing may be ordered for anyone on
adalimumab-even when treatment is going well (proactive monitoring).(6-8) Results from adalimumab
and ATA testing play an important role in patient management. In the setting of loss of response to
adalimumab therapy, for adults with active inflammatory bowel disease (IBD), a clinical decision tool
from the American Gastroenterology Association(9,10) suggests the following scenarios for a blood
draw that occurred at trough, immediately before the next injection dose: For patients who have
undetectable or low concentrations of adalimumab (<8 mcg/mL) but no detectable ATA, the patient
care team may choose to increase the dose of adalimumab in an attempt to increase the amount of the
drug in circulation. If the patient has subtherapeutic adalimumab concentrations (<8 mcg/mL) in the
presence of an ATA, in many cases, the patient care team may switch the patient to another TNF
inhibitor. For patients with increased trough concentrations of adalimumab (therapeutic or greater),
whether an ATA is present or not, it may be necessary to switch the patient to a therapy with a different
mechanism of action such as the anti-alpha4-beta-7-integrin antibody vedolizumab or the IL12/IL23
antibody ustekinumab. Low trough concentrations may be correlated with loss of response to
adalimumab. For adalimumab trough concentrations of 8.0 mcg/mL or less, testing for ATA is
suggested. For adalimumab trough concentrations above 8.0 mcg/mL, the presence of ATA is unlikely;
patients experiencing loss of response to adalimumab may benefit from a therapy with a different
mechanism of action such as the anti-alpha4-beta-7-integrin antibody vedolizumab or the IL12/IL23
antibody ustekinumab. Adalimumab concentration results above 35 mcg/mL are suggestive of a blood
draw at a time-point in treatment other than trough. Test interpretation relies on clinical presentation and
may differ from the statements above, which were designed for adults with IBD experiencing loss of
response. For individuals on adalimumab therapy for other conditions such as rheumatoid arthritis, or
pediatric patient populations or proactive monitoring, drug concentration therapeutic targets and patient
management decision may be individualized.
Reference Values:
ADALIMUMAB QUANTITATIVE
Limit of quantitation is 0.8 mcg/mL. Optimal therapeutic ranges are disease specific.
ADALIMUMAB ANTIBODY
<14.0 AU/mL
Clinical References: 1. Willrich MA, Murray DL, Snyder MR: Tumor necrosis factor inhibitors:
clinical utility in autoimmune diseases. Transl Res. 2015 Feb;165(2):270-282 2. Ordas I, Mould DR,
Feagan BG, Sandborn WJ: Anti-TNF monoclonal antibodies in inflammatory bowel disease:
pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012 Apr;91(4):635-646 3. Ordas I,
Feagan BG, Sandborn WJ: Therapeutic drug monitoring of tumor necrosis factor antagonists in
inflammatory bowel disease. Clin Gastroenterol Hepatol. 2012 Oct;10(10):1079-1087; quiz e85-86 4.
Restellini S, Chao CY, Lakatos PL, et al: Therapeutic drug monitoring guides the management of Crohn's
patients with secondary loss of response to adalimumab. Inflamm Bowel Dis. 2018 Jun
8;24(7):1531-1538 5. American Gastroenterological Association: Therapeutic drug monitoring in
inflammatory bowel disease: Clinical decision support tool. Gastroenterology. 2017 Sep;153(3):858-859.
doi:10.1053/j.gastro.2017.07.039 6. D'Haens GR, Sandborn WJ, Loftus EV Jr, et al: Higher vs standard
adalimumab induction dosing regimens and 2 maintenance strategies: Randomized SERENE CD trial
results. Gastroenterology. 2022 Feb 3;S0016-5085(22)00099-3. doi: 10.1053/j.gastro.2022.01.044 7. Yao
J, Jiang X, You JHS: Proactive therapeutic drug monitoring of adalimumab for pediatric Crohn's disease
patients: A cost-effectiveness analysis. J Gastroenterol Hepatol. 2021 Sep;36(9):2397-2407.
doi:10.1111/jgh.15373 8. Kato M, Sugimoto K, Ikeya K, et al: Therapeutic monitoring of adalimumab at
non-trough levels in patients with inflammatory bowel disease. PLoS One. 2021 Jul 9;16(7):e0254548 9.
Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S: American Gastroenterological Association
Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory
bowel diseases. Gastroenterology. 2017 Sep;153(3):835-857.e6. doi: 10.1053/j.gastro.2017.07.031 10.
Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S: American Gastroenterological
Association Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease.
Gastroenterology. 2017 Sep;153(3):827-834. doi: 10.1053/j.gastro.2017.07.032 11. Sejournet L, Kerever
S, Mathis T, Kodjikian L, Jamilloux Y, Seve P: Therapeutic drug monitoring guides the management of
patients with chronic non-infectious uveitis treated with adalimumab: a retrospective study. Br J
Ophthalmol. 2021 Apr 19;bjophthalmol-2021-319072 12. Gomez-Arango C, Gorostiza I, Ucar E, et al:
Cost-effectiveness of therapeutic drug monitoring-guided adalimumab therapy in rheumatic diseases: A
Prospective, Pragmatic Trial. Rheumatol Ther. 2021 Sep;8(3):1323-1339.
doi:10.1007/s40744-021-00345-5 13. Abdalla T, Mansour M, Bouazzi D, Lowes MA, Jemec GBE, Alavi
A: Therapeutic drug monitoring in patients with suboptimal response to adalimumab for hidradenitis
suppurativa: A retrospective case series. Am J Clin Dermatol. 2021 Mar;22(2):275-283.
doi:10.1007/s40257-020-00575-3
ADM13 ADAMTS13 Activity and Inhibitor Profile, Plasma

61212 Clinical Information: Thrombotic thrombocytopenic purpura (TTP), a rare (estimated incidence of
3.7 cases per million) and potentially fatal thrombotic microangiopathy syndrome, is characterized by a
pentad of symptoms: thrombocytopenia, microangiopathic hemolytic anemia (intravascular hemolysis and
presence of peripheral blood schistocytes), neurological symptoms, fever, and kidney dysfunction. A large
majority of patients initially present with thrombocytopenia and peripheral blood evidence of
microangiopathy and, in the absence of any other potential explanation for such findings, satisfy criteria
for early initiation of plasma exchange, which is critical for patient survival. TTP may rarely be
congenital (Upshaw-Shulman syndrome) but, far more commonly, is acquired. Acquired TTP may be
considered primary or idiopathic (the most frequent type) or associated with distinctive clinical conditions
(secondary TTP) such as medications, hematopoietic stem cell or solid organ transplantation, sepsis, and
malignancy. The isolation and characterization of an IgG autoantibody frequently found in patients with
idiopathic TTP clarified the basis of this entity and led to the isolation and characterization of a
metalloprotease called ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motif
13 repeats), which is the target for the IgG autoantibody, leading to a functional deficiency of
ADAMTS-13. ADAMTS-13 cleaves the ultra-high-molecular-weight multimers of von Willebrand factor
(VWF) at the peptide bond Tyr1605-Met1606 to disrupt VWF-induced platelet aggregation. The IgG
antibody prevents this cleavage and leads to TTP. Although the diagnosis of TTP may be confirmed with
ADAMTS-13 activity and inhibition studies, the decision to initiate plasma exchange should not be
delayed pending results of this assay.
Useful For: Assisting with the diagnosis of congenital or acquired thrombotic thrombocytopenic
purpura
Interpretation: Less than 10% ADAMTS-13 activity is highly indicative of thrombotic

thrombocytopenic purpura (TTP) in an appropriate clinical setting. The presence of ADAMTS-13
inhibition (positive inhibitor screen) with a measurable antibody titer is most consistent with an
acquired TTP.
Reference Values:
ADAMTS13 ACTIVITY ASSAY
> or =70%
ADAMTS13 INHIBITOR SCREEN

Negative
ADAMTS13 BETHESDA TITER

<0.4 BU
Clinical References: 1. Sadler JE: Von Willebrand factor, ADAMTS13, and thrombotic
thrombocytopenic purpura. Blood. 2008 Jul 1;112(1):11-18. doi: 10.1182/blood-2008-02-078170 2.
George JN: How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010 Nov
18;116(20):4060-4069. doi: 10.1182/blood-2010-07-271445 3. Upshaw JD Jr: Congenital deficiency of
a factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J
Med. 1978 Jun 15;298(24):1350-1352. doi: 10.1056/NEJM197806152982407 4. Chiasakul T, Cuker A:
Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology Am Soc Hematol Educ
Program. 2018 Nov 30;2018(1):530-538. doi: 10.1182/asheducation-2018.1.530
ADMBU ADAMTS13 Inhibitor Bethesda Titer, Plasma

3.7 cases per million) and potentially fatal thrombotic microangiopathy (TMA) syndrome, is
characterized by a pentad of symptoms: thrombocytopenia, microangiopathic hemolytic anemia
(intravascular hemolysis and presence of peripheral blood schistocytes), neurological symptoms, fever,
and kidney dysfunction. A large majority of patients initially present with thrombocytopenia and
peripheral blood evidence of microangiopathy, and in the absence of any other potential explanation for
such findings, satisfy criteria for early initiation of plasma exchange, which is critical for patient
survival. TTP may rarely be congenital (Upshaw-Shulman syndrome) but, far more commonly, is
acquired. Acquired TTP may be considered primary or idiopathic (the most frequent type) or associated
with distinctive clinical conditions (secondary TTP) such as medications, hematopoietic stem cell or
solid organ transplantation, sepsis, and malignancy. The isolation and characterization of an IgG
autoantibody frequently found in patients with idiopathic TTP, clarified the basis of this entity and led
to the isolation and characterization of a metalloprotease called ADAMTS-13 (a disintegrin and
metalloprotease with thrombospondin type 1 motif 13 repeats), which is the target for the IgG
autoantibody, leading to a functional deficiency of ADAMTS-13. ADAMTS-13 cleaves the
ultra-high-molecular-weight multimers of von Willebrand factor (VWF) at the peptide bond
Tyr1605-Met1606 to disrupt VWF-induced platelet aggregation. The IgG antibody prevents this
cleavage and leads to TTP. Although the diagnosis of TTP may be confirmed with ADAMTS-13
activity and inhibition studies, the decision to initiate plasma exchange should not be delayed pending
results of this assay.
purpura as a part of a profile

inhibition (positive inhibitor screen) with a measurable antibody titer is most consistent with an acquired
TTP.
Reference Values:
Only orderable as part of a profile. For more information see ADM13 / ADAMTS13 Activity and
Inhibitor Profile, Plasma.
<0.4 BU
thrombocytopenic purpura. Blood. 2008 Jul 1;112(1):11-18. doi.org/10.1182/blood-2008-02-078170 2.
18;116(20):4060-4069. doi: 10.1182/blood-2010-07-271445 3. Upshaw JD: Congenital deficiency of a
factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J Med.
1978 Jun 15;298(24):1350-1352. doi: 10.1056/NEJM197806152982407 4. Chiasakul T, Cuker A: Clinical
and laboratory diagnosis of TTP: an integrated approach. Hematology Am Soc Hematol Educ Program.
2018 Nov 30;2018(1):530-538. doi: 10.1182/asheducation-2018.1.530
ADMIS ADAMTS13 Inhibitor Screen Assay, Plasma

3.7 cases per million) and potentially fatal thrombotic microangiopathy (TMA) syndrome, is characterized
by a pentad of symptoms: thrombocytopenia, microangiopathic hemolytic anemia (intravascular
hemolysis and presence of peripheral blood schistocytes), neurological symptoms, fever, and kidney
dysfunction. A large majority of patients initially present with thrombocytopenia and peripheral blood
evidence of microangiopathy, and in the absence of any other potential explanation for such findings,
satisfy criteria for early initiation of plasma exchange, which is critical for patient survival. TTP may
rarely be congenital (Upshaw-Shulman syndrome) but, far more commonly, is acquired. Acquired TTP
may be considered primary or idiopathic (the most frequent type) or associated with distinctive clinical
conditions (secondary TTP) such as medications, hematopoietic stem cell or solid organ transplantation,
sepsis, and malignancy. The isolation and characterization of an IgG autoantibody frequently found in
patients with idiopathic TTP, clarified the basis of this entity and led to the isolation and characterization
of a metalloprotease called ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1
motif 13 repeats), which is the target for the IgG autoantibody, leading to a functional deficiency of
ADAMTS-13. ADAMTS-13 cleaves the ultra-high-molecular-weight multimers of von Willebrand factor
(VWF) at the peptide bond Tyr1605-Met1606 to disrupt VWF-induced platelet aggregation. The IgG
antibody prevents this cleavage and leads to TTP. Although the diagnosis of TTP may be confirmed with
ADAMTS-13 activity and inhibition studies, the decision to initiate plasma exchange should not be
delayed pending results of this assay.
purpura as a part of a profile
inhibition (positive inhibitor screen) with a measurable antibody titer is most consistent with an
acquired TTP.
Reference Values:
Only orderable as part of a profile. For more information see ADM13 / ADAMTS13 Activity and
Inhibitor Profile, Plasma.
Negative
thrombocytopenic purpura. Blood. 2008 Jul 1;112(1):11-18. doi.org/10.1182/blood-2008-02-078170 2.
18;116(20):4060-4069. doi: 10.1182/blood-2010-07-271445 3. Upshaw JD: Congenital deficiency of a
factor in normal plasma that reverses microangiopathic hemolysis and thrombocytopenia. N Engl J
Med. 1978 Jun 15;298(24):1350-1352. doi: 10.1056/NEJM197806152982407 4. Chiasakul T, Cuker A:
Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology Am Soc Hematol Educ
Program. 2018 Nov 30;2018(1):530-538. doi: 10.1182/asheducation-2018.1.530
ADMPU Addiction Medicine Profile with Reflex, 22 Drug Classes, High

615908 Resolution Mass Spectrometry and Immunoassay Screen,
Random, Urine
Clinical Information: This test uses screening techniques that involves immunologic testing and
high-resolution accurate mass spectrometry screening for drugs by class. All positive immunoassay
screening results are confirmed by gas chromatography-mass spectrometry (GC-MS) or liquid
chromatography-tandem mass spectrometry (LC-MS/MS), and quantitated, before a positive result is
reported. The following drugs/drug classes are tested by immunoassay and confirmed by GC-MS:
-Barbiturates -Cocaine -Tetrahydrocannabinol Ethyl glucuronide is also screened using an immunoassay
and confirmation of ethyl glucuronide/ethyl sulfate is performed using LC-MS/MS. The targeted opioid,
benzodiazepine, and stimulant screen portions are performed using liquid chromatography-tandem mass
spectrometry, high-resolution accurate massÂ and are completed for all opioids, benzodiazepines, and
stimulants. Opioids are a large class of medications commonly used to relieve acute and chronic pain or
help manage opioid abuse and dependence. Medications that fall into this class include: buprenorphine,
codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone,
tapentadol, tramadol, and others. Opioids work by binding to the opioid receptors that are found in the
brain, spinal cord, gastrointestinal tract, and other organs. Common side effects include drowsiness,
confusion, nausea, constipation, and, in severe cases, respiratory depression depending on the dose.
These medications can also produce physical and psychological dependence and have a high risk for
abuse and diversion, which is one of the main reasons many professional practice guidelines
recommend compliance testing in patients prescribed these medications. Opioids are readily absorbed
from the gastrointestinal tract, nasal mucosa, lungs, and after subcutaneous or intermuscular injection.
Opioids are primarily excreted from the kidney in both free and conjugated forms. This assay doesn't
hydrolyze the urine sample and looks for both parent drugs and metabolites (including glucuronide
forms). The detection window for most opioids in urine is approximately 1 to 3 days with longer
detection times for some compounds (ie, methadone). Benzodiazepines represent a large family of
medications used to treat a wide range of disorders from anxiety to seizures and are also used in pain
management. With a high risk for abuse and diversion, professional practice guidelines recommend
compliance monitoring for these medications using urine drug tests. However, traditional
benzodiazepine immunoassays suffer from a lack of cross-reactivity with all the benzodiazepines, so
many compliant patients taking clonazepam (Klonopin) or lorazepam (Ativan) may screen negative by
immunoassay but are positive when confirmatory testing is done. The new targeted benzodiazepine
screening test provides a more sensitive and specific test to check for compliance to all the commonly
prescribed benzodiazepines and looks for both parent and metabolites in the urine. Stimulants are
sympathomimetic amines that stimulate the central nervous system activity and, in part, suppress the
appetite. Amphetamine and methamphetamine are also prescription drugs used in the treatment of
narcolepsy and attention-deficit disorder/attention-deficit hyperactivity disorder (ADHD).
Methylphenidate is another stimulant used to treat ADHD. Phentermine is indicated for the management
of obesity. All of the other amphetamines (eg, methylenedioxymethamphetamine: MDMA) are Drug
Enforcement Administration (DEA) scheduled Class I compounds. Due to their stimulant effects, the
drugs are commonly sold illicitly and abused. Physiological symptoms associated with very high
amounts of ingested amphetamine or methamphetamine include elevated blood pressure, dilated pupils,
hyperthermia, convulsions, and acute amphetamine psychosis. Ethyl glucuronide is a direct metabolite
of ethanol that is formed by enzymatic conjugation of ethanol with glucuronic acid. Alcohol in urine is
normally detected for only a few hours, whereas ethyl glucuronide can be detected in the urine for 1 to 3
days. This procedure uses immunoassay reagents that are designed to produce a negative result when no
drugs are present in a natural (eg, unadulterated) specimen of urine; the assay is designed to have a high
true-negative rate. Like all immunoassays, it can have a false-positive rate due to cross-reactivity with
natural chemicals and drugs other than those they were designed to detect. The immunoassay also has a
false-negative rate to the antibody's ability to cross-react with different drugs in the class being screened
for. NICOU: Tobacco use is the leading cause of death in the United States. Nicotine, coadministered in
tobacco products such as cigarettes, pipe, cigar, or chew, is an addicting substance that causes
individuals to continue use of tobacco despite concerted efforts to quit. Nicotine stimulates dopamine
release and increases dopamine concentration in the nucleus accumbens, a mechanism that is thought to
be the basis for addiction for drugs of abuse. Nicotine is rapidly metabolized in the liver to cotinine,
exhibiting an elimination half-life of 2 hours. Cotinine exhibits an apparent elimination half-life of 15
hours. Patients using tobacco products excrete nicotine in urine in the concentration range of 1000 to
5000 ng/mL. Cotinine accumulates in urine in proportion to dose and hepatic metabolism (which is
genetically determined); most tobacco users excrete cotinine in the range of 1000 to 8000 ng/mL. Urine
concentrations of nicotine and metabolites in these ranges indicate the subject is using tobacco or is
receiving high-dose nicotine patch therapy. In addition to nicotine and metabolites, tobacco products
also contain other alkaloids that can serve as unique markers of tobacco use. Two such markers are
anabasine and nornicotine. Anabasine is present in tobacco products, but not nicotine replacement
therapies. Nornicotine is present as an alkaloid in tobacco products and as a metabolite of nicotine. The
presence of anabasine greater than 10 ng/mL or nornicotine greater than 30 ng/mL in urine indicates
current tobacco use, irrespective of whether the subject is on nicotine replacement therapy. The
presence of nornicotine without anabasine is consistent with use of nicotine replacement products.
Heavy tobacco users who abstain from tobacco for 2 weeks exhibit urine nicotine values below 30
ng/mL, cotinine values below 50 ng/mL, anabasine levels below 2 ng/mL, and nornicotine levels below
2 ng/mL. Passive exposure to tobacco smoke can cause accumulation of nicotine metabolites in
nontobacco users. Urine cotinine has been observed to accumulate up to 20 ng/mL from passive
exposure. Neither anabasine nor nornicotine accumulates from passive exposure. Tobacco users
engaged in programs to abstain from tobacco require support in the form of counseling,
pharmacotherapy, and continuous encouragement. Occasionally, counselors may elect to monitor
abstinence by biochemical measurement of nicotine and metabolites in a random urine specimen to
verify abstinence. If results of biologic testing indicate the patient is actively using a tobacco product
during therapy, additional counseling or intervention may be appropriate. Quantification of urine
nicotine and metabolites while a patient is actively using a tobacco product is useful to define the
concentrations that a patient achieves through self-administration of tobacco. Nicotine replacement dose
can then be tailored to achieve the same concentrations early in treatment to assure adequate nicotine
replacement so the patient may avoid the strong craving they may experience early in the withdrawal
phase. This can be confirmed by measurement of urine nicotine and metabolite concentrations at
steady-state (2-3 days after replacement therapy is started). Once the patient is stabilized on the dose
necessary to achieve complete replacement and responding well to therapy, the replacement dose can be
slowly tapered to achieve complete withdrawal. This test is intended to be used in a setting where the
test results can be used to make a definitive diagnosis.
Useful For: Detecting drug use involving stimulants, barbiturate, benzodiazepines, cocaine, opioids,
tetrahydrocannabinol, alcohol, and nicotine This test is not intended for use in employment-related
testing.
Interpretation: A positive result derived by this testing indicates that the patient has used one of the
drugs detected by these techniques in the recent past. See individual tests (eg, COKEU / Cocaine and
Metabolite Confirmation, Random, Urine) for more information. For information about drug testing,
including estimated detection times, see Specific Drug Groups at
https://www.mayocliniclabs.com/test-info/drug-book/index.html
Reference Values:
ADULTERANT SURVEY:
Cutoff concentrations
Oxidants: 200 mg/L
Nitrites: 500 mg/L
DRUG IMMUNOASSAY PANEL:

Negative
Screening cutoff concentrations:
Barbiturates: 200 ng/mL
Cocaine (benzoylecgonine-cocaine metabolite): 150 ng/mL
Tetrahydrocannabinol carboxylic acid: 50 ng/mL
This report is intended for use in clinical monitoring or management of patients. It is not intended for
use in employment-related testing.
TARGETED OPIOID SCREEN:

Not Detected
Codeine: 25 ng/mL
Codeine-6-beta-glucuronide: 100 ng/mL
Morphine: 25 ng/mL
Morphine-6-beta-glucuronide: 100 ng/mL
6-monoacetylmorphine: 25 ng/mL
Hydrocodone: 25 ng/mL
Norhydrocodone: 25 ng/mL
Dihydrocodeine: 25 ng/mL
Hydromorphone: 25 ng/mL
Hydromorphone-3-beta-glucuronide: 100 ng/mL
Oxycodone: 25 ng/mL
Noroxycodone: 25 ng/mL
Oxymorphone: 25 ng/mL
Oxymorphone-3-beta-glucuronide: 100 ng/mL
Noroxymorphone: 25 ng/mL
Fentanyl: 2 ng/mL
Norfentanyl: 2 ng/mL
Meperidine: 25 ng/mL
Normeperidine: 25 ng/mL
Naloxone: 25 ng/mL
Naloxone-3-beta-glucuronide: 100 ng/mL
Methadone: 25 ng/mL
EDDP: 25 ng/mL
Propoxyphene: 25 ng/mL
Norpropoxyphene: 25 ng/mL
Tramadol: 25 ng/mL
O-desmethyltramadol: 25 ng/mL
Tapentadol: 25 ng/mL
N-desmethyltapentadol: 50 ng/mL
Tapentadol-beta-glucuronide: 100 ng/mL
Buprenorphine: 5 ng/mL
Norbuprenorphine: 5 ng/mL
Norbuprenorphine glucuronide: 20 ng/mL
TARGETED BENZODIAZEPINE SCREEN:

Not Detected
Alprazolam: 10 ng/mL
Alpha-Hydroxyalprazolam: 10 ng/mL
Alpha-Hydroxyalprazolam Glucuronide: 50 ng/mL
Chlordiazepoxide: 10 ng/mL
Clobazam: 10 ng/mL
N-Desmethylclobazam: 200 ng/mL
Clonazepam: 10 ng/mL
7-aminoclonazepam: 10 ng/mL
Diazepam: 10 ng/mL
Nordiazepam: 10 ng/mL
Flunitrazepam: 10 ng/mL
7-aminoflunitrazepam: 10 ng/mL
Flurazepam: 10 ng/mL
2-Hydroxy Ethyl Flurazepam: 10 ng/mL
Lorazepam: 10 ng/mL
Lorazepam Glucuronide: 50 ng/mL
Midazolam: 10 ng/mL
Alpha-Hydroxy Midazolam: 10 ng/mL
Oxazepam: 10 ng/mL
Oxazepam Glucuronide: 50 ng/mL
Prazepam: 10 ng/mL
Temazepam: 10 ng/mL
Temazepam Glucuronide: 50 ng/mL
Triazolam: 10 ng/mL
Alpha-Hydroxy Triazolam: 10 ng/mL
Zolpidem: 10 ng/mL
Zolpidem Phenyl-4-Carboxylic acid: 10 ng/mL
TARGETED STIMULANT SCREEN:

Not Detected
Methamphetamine: 100 ng/mL
Amphetamine: 100 ng/mL
3,4-methylenedioxymethamphetamine (MDMA): 100 ng/mL
3,4-methylenedioxy-N-ethylamphetamine (MDEA): 100 ng/mL
3,4-methylenedioxyamphetamine (MDA): 100 ng/mL
Ephedrine: 100 ng/mL
Pseudoephedrine: 100 ng/mL
Phentermine: 100 ng/mL
Phencyclidine (PCP): 20 ng/mL
Methylphenidate: 20 ng/mL
Ritalinic acid: 100 ng/mL
ETHYL GLUCURONIDE SCREEN:

Negative

Ethyl Glucuronide: 500 ng/mL
NICOTINE AND METABOLITES:
Non-tobacco user with no passive exposure:
Nicotine: <5.0 ng/mL
Cotinine: <5.0 ng/mL
Anabasine: <2.0 ng/mL
Nornicotine: <2.0 ng/mL
Clinical References: 1. Physicians' Desk Reference; 60th ed. Medical Economics Company, 2006
2. Bruntman LL, ed. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 11th ed.
McGraw-Hill Book Company; 2006 3. Langman LJ, Bechtel L, Meier BM, Holstege CP: Clinical
toxicology In: Rifai N, Horwath AR, Wittwer CT, eds: Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 4. Gutstein HB, Akil H: Opioid analgesics. In:
Brunton LL, Lazo JS, Parker KL, eds: Goodman and Gilman's: The Pharmacological Basis of
Therapeutics. 11th ed. McGraw-Hill Companies; 2006 5. Chronic Pain in America: Roadblocks to
Relief, survey conducted for the American Pain Society, The American Academy of the Pain Medicine
and Janssen Pharmaceutical, 1999 6. Magnani B, Kwong T: Urine drug testing for pain management.
Clin Lab Med. 2012 Sep;32(32):379-390 7. Jannetto PJ, Bratanow NC, Clark WA, et al: Executive
summary: American Association of Clinical Chemistry Laboratory Medicine Practice Guideline-using
clinical laboratory tests to monitor drug therapy in pain management patients. J Appl Lab Med. 2018
Jan;2(4):489-526 8. McMillin GA, Marin SJ, Johnson-Davis KL, Lawlor BG, Strathmann FG: A hybrid
approach to urine drug testing using high-resolution mass spectrometry and select immunoassays. Am J
Clin Pathol. 2015 Feb;143(2):234-240 9. Cone EJ, Caplan YH, Black DL, Robert T, Moser F: Urine
drug testing of chronic pain patients: licit and illicit drug patterns. J Anal Toxicol. 2008
Oct;32(8):530-543
ADSTM Additional Flow Stimulant (Bill Only)

AGSTM Additional Flow Stimulant, LPAGF (Bill Only)

MGSTM Additional Flow Stimulant, LPMGF (Bill Only)

XSRM Additional Sample for Reflex Oligoclonal Banding, Serum

-MSP3 / Multiple Sclerosis (MS) Profile, Serum and Spinal Fluid
-OLIG / Oligoclonal Banding, Serum and Spinal Fluid
Not Applicable
VID2 Additional Testing Virus Ident

This test is for Billing Purposes Only.
FADCF Adenosine Deaminase in CSF
0-9 U/L
FADFL Adenosine Deaminase in Peritoneal Fluid

0 - 30 U/L
FADDP Adenosine Deaminase, Pericardial Fluid

0-40 U/L
FADPF Adenosine Deaminase, Pleural Fluid

0 - 30 U/L
FADBC Adenosine Deaminase, RBC

75553 Interpretation: Adenosine Deaminase (ADA) deficiency is an autosomal recessive disorder of purine
metabolism primarily affecting lymphocyte development, viability, and function. Affected individuals
have less than 1 percent of normal ADA catalytic activity in red cell hemolysates. ADA deficiency is the
cause of 20-30 percent of SCID cases. If the patient has been recently transfused, ADA deficiency may be
masked; interpret results with caution. Heterozygotes cannot be identified by this test.
Reference Values:
400 - 900 mU/g Hb
FADNA Adenovirus DNA, Quantitative Real-Time PCR

Not Detected
ADV Adenovirus Immunostain, Technical Component Only

70352 Clinical Information: Adenoviruses are 65 to 80 nm, nonenveloped, regular icosahedron pathogens
containing double-stranded DNA. Adenovirus infection is often associated with respiratory (HAdV-B and
C) and gastrointestinal illness (HAdV-F serotypes 40 and 41) as well as conjunctivitis (HAdV-B and D).
Over 51 types of immunologically distinct adenovirus serotypes have been categorized.
Useful For: Identification of adenovirus infection

Interpretation: The positive and negative controls are verified as showing appropriate
immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality
pathologist.
Clinical References: 1. Wu E, Nemerow GR: Virus yoga: the role of flexibility in virus host cell
recognition. Trends Microbiol 2004;124(4):162-169 2. Ohori NP, Michaels MG, Jaffe R, et al:
Adenovirus pneumonia in lung transplant recipients. Hum Pathol 1995;26(10):1073-1079 3. Koneru B,
Jaffe R, Esquivel CO, et al: Adenoviral infections in pediatric liver transplant recipients. JAMA
1987;258(4):489-492
LCADP Adenovirus, Molecular Detection, PCR, Plasma

89887 Clinical Information: Human adenoviruses cause a variety of diseases including pneumonia,
cystitis, conjunctivitis, diarrhea, hepatitis, myocarditis, and encephalitis. In humans, adenoviruses have
been recovered from almost every organ system. Infections can occur at any time of the year and in all
age groups. Currently, there are 51 adenovirus serotypes that have been grouped into 6 separate
subgenera. Culture is the gold standard for the diagnosis for adenovirus infection; however, it can take
up to 3 weeks to achieve culture results. Mayo's shell vial culture provides more rapid results, reported
at 2 and 5 days. While PCR offers a rapid, specific, and sensitive means of diagnosis by detecting
adenovirus DNA.
Useful For: Aiding in diagnosing adenovirus infections using plasma specimens

Interpretation: A positive result indicates the presence of adenovirus nucleic acid. A negative result
does not rule out the presence of adenoviruses because organisms may be present at levels below the
detection limits of this assay.
Reference Values:
Negative
Clinical References: 1. Buckwalter SP, Teo R, Espy MJ, et al: Real-time qualitative PCR for 57
human adenovirus types from multiple specimen sources. J Clin Microbiol2011;50(3):766-771
doi:10.1128/jcm.05629-11 2. Ebner K, Pinsker W, Lion T: Comparative sequence analysis of the hexon
gene in the entire spectrum of human adenovirus serotypes: phylogenetic, taxonomic, and clinical
implications. J Virol 2005;79:12635-12642 3. Ebner K, Suda M, Watzinger F, Lion T: Molecular
detection and quantitative analysis of the entire spectrum of human adenoviruses by a two-reaction
real-time PCR assay. J Clin Microbiol 2005;43:3049-3053 4. Jothikumar N, Cromeans TL, Hill VR, et
al: Quantitative real-time PCR assays for the detection of human adenoviruses and identification of
serotypes 40 and 41. Appl Environ Microbiol 2005;71:3131-3136 5. Robinson C, Echavarria M:
Adenovirus. In Manual of Clinical Microbiology. Edited by PR Murray, EJ Baron, JH, et al:
Washington, DC, ASM Press, 2007, pp 1589-1600 6. Thavagnanam S, Christie SN, Doherty GM, et al:
Respiratory viral infection in lower airways of asymptomatic children. Acta Paediatr 2010
Mar;99(3):394-398 7. Kaneko H, Maruko I, Iida T, et al: The possibility of human adenovirus detection
in the conjunctiva in asymptomatic cases during a nosocomial infection. Cornea 2008
Jun;27(5):527-530
LADV Adenovirus, Molecular Detection, PCR, Varies

89074 Clinical Information: Human adenoviruses cause a variety of diseases including pneumonia,
cystitis, conjunctivitis, diarrhea, hepatitis, myocarditis, and encephalitis. In humans, adenoviruses have
been recovered from almost every organ system. Infections can occur at any time of the year and in all
age groups. Currently, there are 57 adenovirus serotypes that have been grouped into 6 separate
subgenera. Culture is the gold standard for the diagnosis for adenovirus infection. However, it can take
up to 3 weeks to achieve culture results (Mayo Clinic's shell vial culture provides more rapid results,
reported at 2 and 5 days). Serological tests have faster turnaround times, but can be less sensitive
compared to culture. PCR offers a rapid, specific, and sensitive means of diagnosis by detecting
adenovirus DNA.
Useful For: Aiding in the diagnosis of adenovirus infections

Interpretation: A positive result indicates the presence of adenovirus DNA in the clinical sample. A
negative result does not rule out the presence of adenovirus because viral DNA may be present at levels
below the detection limits of this assay.
Reference Values:
Negative
Clinical References: 1. Buckwalter SP, Teo R, Espy MJ, et al: Real-time qualitative PCR for 57
human adenovirus types from multiple specimen sources. J Clin Microbiol2011;50(3):766-771
doi:10.1128/jcm.05629-11 2. Ebner K, Pinsker W, Lion T: Comparative sequence analysis of the hexon
gene in the entire spectrum of human adenovirus serotypes: phylogenetic, taxonomic, and clinical
implications. J Virol 2005;79:12635-12642 3. Ebner K, Suda M, Watzinger F, Lion T: Molecular
detection and quantitative analysis of the entire spectrum of human adenoviruses by a two-reaction
real-time PCR assay. J Clin Microbiol 2005;43:3049-3053 4. Jothikumar N, Cromeans TL, Hill VR, et al:
Quantitative real-time PCR assays for the detection of human adenoviruses and identification of serotypes
40 and 41. Appl Environ Microbiol 2005;71:3131-3136 5 . Robinson C, Echavarria M: Adenovirus. In
Manual of Clinical Microbiology. Edited by PR Murray, EJ Baron, JH Jorgensen, et al: Ninth edition.
Washington, DC, ASM Press, 2007, pp 1589-1600 6. Thavagnanam S, Christie SN, Doherty GM, et al:
Respiratory viral infection in lower airways o asymptomatic children. Acta Paediatr Mar;99(3):394-398 7.
Kaneko H, Maruko I, Iida T, et al: The possibility of human adenovirus detection in the conjunctiva in
asymptomatic cases during a nosocomial infection. Cornea Jun 2008;27(5):527-530
AKC Adenylate Kinase Enzyme Activity, Blood

608421 Clinical Information: Adenylate kinase (AK) is a monomeric enzyme that catalyzes the nucleotide
phosphoryl interconversion of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) to 2
molecules of adenosine diphosphate (ADP). The level of enzyme activity in neonates is normally mildly
to moderately lower than in adults. AK deficiency (OMIM 612631) is a rare cause of autosomal recessive
nonspherocytic hemolytic anemia. Although rare, AK deficient-associated anemia has been described in
multiple families of varied ethnic origin. Those individuals with heterozygous genetic alterations are
predominantly asymptomatic and show a normal phenotype. Those individuals with homozygous or
compound heterozygous genetic alterations display congenital chronic nonspherocytic hemolytic anemia
(hemoglobin [Hb] levels of 8-9 g/dL) with hyperbilirubinemia and gallstones. Patients typically present at
birth or in early childhood. Some patients have psychomotor impairment, although the pathogenesis is not
well understood. Concurrent glucose 6-phosphate dehydrogenase (G6PD) deficiency exacerbates the
anemia (Hb 6 g/dL). AK activity levels range from 0% to 44%, although most show less than 30%
activity. Carriers have normal to only mildly decreased enzyme activity (1). Patients may respond well to
splenectomy.
Useful For: Assessment of adenylate kinase activity as part of the evaluation of chronic nonspherocytic
hemolytic anemia
Interpretation: In adenylate kinase deficiency, values are expected to be less than 30% of normal
mean, although this value should be interpreted in the context of age of the patient and other enzyme
values.
Reference Values:
Only available as part of a profile. For more information see:
-HAEV1 / Hemolytic Anemia Evaluation, Blood
-EEEV1 / Red Blood Cell (RBC) Enzyme Evaluation, Blood
> or =12 months: 195-276 U/g Hb

Reference values have not been established for patients who are less than 12 months of age.
Clinical References: 1. Niizuma H, Kanno H, Sato A, Ogura H, Imaizumi M: Splenectomy resolves

hemolytic anemia caused by adenylate kinase deficiency. Pediatr Int. 2017 Feb;59(2):228-230 2. Rapley
S, Harris H: Red cell adenylate kinase activity in AK1 and AK 2-1 phenotypes. Annals of Human
Genetics. 1970;33:361-364. doi: 10.1111/j.1469-1809 3. Mohrenweiser HW. Frequency of enzyme
deficiency variants in erythrocytes of newborn infants. Proc Natl Acad Sci U S A. 1981
Aug;78(8):5046-5050 4. Corrons JL, Garcia E, Tusell JJ, Varughese KI, West C, Beutler E: Red cell
adenylate kinase deficiency: molecular study of 3 new mutations (118G>A, 190G>A, and GAC deletion)
associated with hereditary nonspherocytic hemolytic anemia. Blood. 2003 Jul 1;102(1):353-356 5. Toren
A., Brok-Simoni F, Ben-Bassat I, et al: Congenital haemolytic anaemia associated with adenylate kinase
deficiency. Brit. J. Haemat. 1994;87:376-380 6. Bianchi P, Zappa M, Bredi E, et al: A case of complete
adenylate kinase deficiency due to a nonsense mutation in AK-1 gene (arg107-to-stop, CGA-to-TGA)
associated with chronic haemolytic anaemia. Brit. J. Haemat. 1999;105:75-79 7. Lachant NA, Zerez CR,
Barredo J, et al: Hereditary erythrocyte adenylate kinase deficiency: A defect of multiple
phosphotransferases? Blood. 1991;77(12):2774-2784 8. Koralkova P, van Solinge WW, van Wijk R: Rare
hereditary red blood cell enzymopathies associated with hemolytic anemia-pathophysiology, clinical
aspects and laboratory diagnosis. Int J Lab Hematol. 2014;36:388-397
AK1 Adenylate Kinase Enzyme Activity, Blood

607455 Clinical Information: Adenylate kinase (AK) is a monomeric enzyme that catalyzes the nucleotide
phosphoryl interconversion of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) to 2
molecules of adenosine diphosphate (ADP). The level of enzyme activity in neonates is normally mildly
to moderately lower than in adults. AK deficiency (OMIM 612631) is a rare cause of autosomal
recessive nonspherocytic hemolytic anemia. Although rare, AK deficient-associated anemia has been
described in multiple families of varied ethnic origin. Those individuals with heterozygous genetic
alterations are predominantly asymptomatic and show a normal phenotype. Those individuals with
homozygous or compound heterozygous genetic alterations display congenital chronic nonspherocytic
hemolytic anemia (hemoglobin [Hb] levels of 8-9 g/dL) with hyperbilirubinemia and gallstones.
Patients typically present at birth or in early childhood. Some patients have psychomotor impairment,
although the pathogenesis is not well understood. Concurrent glucose 6-phosphate dehydrogenase
(G6PD) deficiency exacerbates the anemia (Hb 6 g/dL). AK activity levels range from 0% to 44%,
although most show less than 30% activity. Carriers have normal to only mildly decreased enzyme
activity (1). Patients may respond well to splenectomy.
Useful For: Evaluation of chronic nonspherocytic hemolytic anemia

Interpretation: In adenylate kinase deficiency, values are expected to be less than 30% of normal
mean, although this value should be interpreted in the context of age of the patient and other enzyme
values.
Reference Values:
> or =12 months: 195-276 U/g Hb
Reference values have not been established for patients who are less than 12 months of age.
Clinical References: 1. Niizuma H, Kanno H, Sato A, Ogura H, Imaizumi M: Splenectomy

resolves hemolytic anemia caused by adenylate kinase deficiency. Pediatr Int. 2017 Feb;59(2):228-230
2. Rapley S, Harris H: Red cell adenylate kinase activity in AK1 and AK 2-1 phenotypes. Annals of
Human Genetics. 1970;33:361-364. doi: 10.1111/j.1469-1809 3. Mohrenweiser HW. Frequency of
enzyme deficiency variants in erythrocytes of newborn infants. Proc Natl Acad Sci U S A. 1981
Aug;78(8):5046-5050 4. Corrons JL, Garcia E, Tusell JJ, Varughese KI, West C, Beutler E: Red cell
adenylate kinase deficiency: molecular study of 3 new mutations (118G>A, 190G>A, and GAC
deletion) associated with hereditary nonspherocytic hemolytic anemia. Blood. 2003 Jul
1;102(1):353-356 5. Toren A., Brok-Simoni F, Ben-Bassat I, et al: Congenital haemolytic anaemia
associated with adenylate kinase deficiency. Brit. J. Haemat. 1994;87:376-380 6. Bianchi P, Zappa M,
Bredi E, et al: A case of complete adenylate kinase deficiency due to a nonsense mutation in AK-1 gene
(arg107-to-stop, CGA-to-TGA) associated with chronic haemolytic anaemia. Brit. J. Haemat.
1999;105:75-79 7. Lachant NA, Zerez CR, Barredo J, et al: Hereditary erythrocyte adenylate kinase
deficiency: A defect of multiple phosphotransferases? Blood. 1991;77(12):2774-2784 8. Koralkova P,
van Solinge WW, van Wijk R: Rare hereditary red blood cell enzymopathies associated with hemolytic
anemia-pathophysiology, clinical aspects and laboratory diagnosis. Int J Lab Hematol. 2014;36:388-397
FADIO Adiponectin
75607
Reference Values:
Body Mass Index Males (mcg/mL) Females (mcg/mL)
Less than 25 kg/m2 4 - 26 5 - 37
25 - 30Â kg/m2 4 - 20 5 - 28
Greater than 30 kg/m2 2 - 20 4 - 22
ACC Adrenal Mass Panel, 24 Hour, Urine

604986 Clinical Information: Approximately 80 million computerized tomography (CT) scans are
performed in the United States every year. Adrenal tumors are found incidentally in about 5% of patients
undergoing abdominal CT. Most of these tumors will be benign, but a small fraction are adrenal cortical
carcinoma (ACC), a cancer with high mortality and frequent recurrence. Even for localized disease, the
5-year survival rates do not exceed 65%, while distant spread is associated with a greater than 90%
mortality rate. Early diagnosis of a malignant adrenal mass is therefore imperative to assure timely and
appropriate therapy. Unfortunately, CT imaging alone is very limited in its ability to distinguish benign
from malignant adrenal tumors since only very small and hypodense lesions can be easily dismissed as
benign. The sizeable group of patients with larger or denser tumors ends up with an arduous workup that
frequently includes additional imaging studies, hormonal testing, and biopsy. However, even the latter has
both a high diagnostic false-positive and false-negative rate, and ultimately the tumor is often resected,
sometimes unnecessarily. On the other hand, the delays due to the diagnostic work might compromise
optimal care for those tumors that prove malignant. In addition, patients who are believed to probably not
have adrenal cancer after their workup, and those who opt out of surgery, often still require long-term
follow up with regular re-imaging and repeated hormone testing, with resultant radiation exposure and
high health care costs. This adrenal mass panel is a noninvasive and more accurate test to diagnose
malignant adrenal tumors, via urinary steroid profiling. It differentiates ACC, a rare and lethal tumor,
from benign adrenocortical adenomas (ACA), including those that overproduce corticosteroids, or mineral
steroids, or sex steroids, or those that are hormonally inactive. The test utilizes both clinical and
laboratory data. The clinical parameters are age at diagnosis and sex of the patient, the size of the tumor
by CT scanning and its CT density in Hounsfield units, whether it was detected incidentally or not, and
whether there is evidence of hormone overproduction. All of this data are readily available for almost all
patients with an adrenal mass and are used by an algorithm to calculate the pretest probability of having
ACC. The steroid profile testing is then performed, and the results are added into the risk calculation
algorithm to generate an integrated probability. The final result will provide the referring physicians a
highly accurate probability for ACC and will thereby facilitate the optimal choice of further investigation,
if any, based on an informed discussion between doctor and patient. In addition, it allows, albeit with
lesser accuracy, the detection of malignant adrenal tumors that are not ACCs. Finally, standalone steroid
profiles can be performed for the purpose of offering the diagnosis of complex assessment of steroidal
disorders, disease monitoring of ACC patients, and for novel investigations, such as biopharma studies.
Understanding the Adrenal Glands: The human body has 2 adrenal glands, one above each kidney.
Adrenal glands influence many processes and functions of the body, mainly through production of 3 types
of steroid hormones: -Mineralocorticoids (eg, aldosterone, which helps control blood pressure)
-Glucocorticoids (eg, cortisol, which is important for metabolism, immune response, and stress) -Sex
steroids (eg, DHEAS, a precursor of testosterone and estradiol) These steroids are all synthesized from
cholesterol via enzymes in the adrenal glands. In benign ACA, near-normal levels of precursor and
bioactive steroids are produced. By contrast, ACC frequently shows abnormal patterns of steroid
production. By measuring 25 different steroid metabolites, even subtle abnormalities can be detected. This
is the basis for the assessment capability of profiling 25 steroids. In addition, catecholamines-the "flight or
fight hormones"-are also synthesized in a different portion of the adrenal glands. This portion is not
examined in the ACC panel. Epidemiology of Adrenal Tumors: Adrenal masses are found in 1% to 5% of
the adult population. The prevalence increases with age, to around 10% in 70-year-old patients. Although
the majority of these tumors are benign, around 30% of adrenal tumors (>4cm) are malignant (half are
represented by ACCs), and the survival rate for these patients is very poor unless detected early.
Useful For: Aiding in assessing malignancy in adrenal masses May aid in improving diagnostic and
prognostic prediction and dissect disease mechanisms for the following applications: -Diagnostic
assessment and follow up of adrenal cortical carcinoma (ACC) -Differential diagnostic assessment of
adrenal tumors -Additional assessment related to Cushing syndrome, mild autonomous cortisol
secretion, primary aldosteronism, inborn errors of steroidogenesis, polycystic ovary syndrome This test
is not useful for establishing eligibility for a specific treatment as results must be interpreted in
conjunction with the clinical status of the patient.
Interpretation: Test provides clinical risk values based on clinical data alone as well as integrated
risk values based on clinical data in combination with biochemical steroid data. Reported risk values
correspond to the probability of a malignant adrenal cortical carcinoma (ACC) or other malignancy (eg,
sarcoma, lymphoma) as well as the probability of a benign mass (eg, adenoma, myelolipoma, cyst). Test
results provide the referring physician with probabilities for a variety of outcomes, thereby aiding the
interpretation of clinical status and optimal paths for further investigation, if any, based on an informed
discussion between provider and patient. Test results should always be interpreted in conjunction with
all other clinical findings as they cannot be interpreted as absolute evidence for the presence or absence
of malignant disease. For more information, see Adrenal Mass Panel Clinical Data Definition of
Malignancy Predictors.
Reference Values:
Note: Due to the wide range of urine steroid metabolite concentrations seen in healthy individuals and
their skewed distribution, the reference values are based on the back calculated +/- 3SD of log
transformed data.
Males 18-49 years:

Androsterone: 182-29,212 mcg/24 hour
Etiocholanolone: 133-23,272 mcg/24 hour
Dehydroepiandrosterone: <5-81,554 mcg/24 hour
16a-OH-Dehydroepiandrosterone: 13-29,945 mcg/24 hour
5-Pregnenetriol: 23-7,328 mcg/24 hour
5-Pregnenediol: 13-2,823 mcg/24 hour
Tetrahydro-11-Corticosterone: 8-1,961 mcg/24 hour
Tetrahydro-11-Deoxycorticosterone: <5-316 mcg/24 hour
Pregnanediol: 12-3,812 mcg/24 hour
17a-OH-Pregnanolone: 15-2,466 mcg/24 hour
Pregnanetriol: 66-9,409 mcg/24 hour
Pregnanetriolone: <5-550 mcg/24 hour
Tetrahydrodeoxycortisol: 7-1520 mcg/24 hour
Cortisol: <5-903 mcg/24 hour
6B-OH-Cortisol: 13-2,303 mcg/24 hour
Tetrahydrocortisol: 152-22,723 mcg/24 hour
5a-Tetrahydrocortisol: 157-24,059 mcg/24 hour
B-Cortol: 30-5,115 mcg/24 hour
11B-OH-Androsterone: 108-11,987 mcg/24 hour
11B-OH-Etiocholanolone: 22-8,312 mcg/24 hour
Cortisone: 12-842 mcg/24 hour
Tetrahydrocortisone: 271-44,355 mcg/24 hour
a-Cortolone: 140-14,885 mcg/24 hour
B-Cortolone: 72-9,740 mcg/24 hour
11-Oxoetiocholanolone: 70-8,446 mcg/24 hour
Males > or =50 years:

Dehydroepiandrosterone: 7-4,260 mcg/24 hour
Pregnanetriolone: 5-221 mcg/24 hour
Tetrahydrodeoxycortisol: 12-1,277 mcg/24 hour
Cortisol: 12-597 mcg/24 hour
B-Cortol: 56-3,541 mcg/24 hour
Females 18-49 years:

Tetrahydrodeoxycortisol: 7-1,047 mcg/24 hour
B-Cortol: 28-4260 mcg/24 hour
Females > or =50 years:

16a-OH-Dehydroepiandrosterone: <5-9,982 mcg/24 hour
5-Pregnenediol: <5-2,732 mcg/24 hour
17a-OH-Pregnanolone: <5-571 mcg/24 hour
Tetrahydrodeoxycortisol: 8-801 mcg/24 hour
B-Cortol: 29-3289 mcg/24 hour
Reference values have not been established for patients who are younger than 18 years of age.
Clinical References: 1. Arlt W, Biehl M, Taylor AE, et al: Urine steroid metabolomics as a
biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocrinol Metab. 2011
Dec;96(12):3775-3784. doi: 10.1210/jc.2011-1565 2. Hines JM, Bancos I, Bancos C, et al:
High-resolution, accurate-mass (HRAM) mass spectrometry urine steroid profiling in the diagnosis of
adrenal disorders. Clin Chem. 2017 Dec;63(12):1824-1835. doi: 10.1373/clinchem.2017.271106 3.
Bancos I, Arlt W: Diagnosis of a malignant adrenal mass: the role of urinary steroid metabolite
profiling. Curr Opin Endocrinol Diabetes Obes. 2017 Jun;24(3):200-207. doi:
10.1097/MED.0000000000000333 4. Fassnacht M, Arlt W, Bancos I, et al: Management of adrenal
incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with
the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175(2):G1-G34.
doi: 10.1530/EJE-16-0467
ACTHI Adrenocorticotropic Hormone (ACTH) Immunostain, Technical

Clinical Information: Adrenocorticotropic hormone (ACTH) is a hormone produced and secreted
by corticotrophs in the adenohypophysis (anterior lobe) of the pituitary gland. Normal pituitary exhibits
positive staining in a large population of cells (approximately 15% to 20%). Immunohistochemical
detection of ACTH may be useful in the classification of pituitary adenomas.
Useful For: Aids in the classification of pituitary adenomas and neoplasms with ectopic hormone
production
pathologist.
Clinical References: 1. Hamid Z, Mrak RE, Ijaz MT, Faas FH: Sensitivity and Specificity of
Immunohistochemistry in Pituitary Adenomas. The Endocrinologist 2009;19(1):38-43 2. Osamura RY,
Kajiva H, Takei M, et al: Pathology of the human pituitary adenomas. Histochem Cell Biol
2008;130(3):495-507 3. Scheithauer BW, Jaap AJ, Horvath E, et al: Clinically Silent Corticotroph
Tumors of the Pituitary Gland. Neurosurgery 2000;47(3):723-730
ACTH Adrenocorticotropic Hormone, Plasma

8411 Clinical Information: Adrenocorticotropic hormone (ACTH) is synthesized by the pituitary in
response to corticotropin-releasing hormone (CRH), which is released by the hypothalamus. ACTH
stimulates adrenal cortisol production. Plasma ACTH and cortisol levels exhibit peaks (6-8 a.m.) and
troughs (11 p.m.). Disorders of cortisol production that might affect circulating ACTH concentrations
include: Hypercortisolism -Cushing syndrome: - Cushing disease (pituitary ACTH-producing tumor) -
Ectopic ACTH-producing tumor - Ectopic CRH - Adrenal cortisol-producing tumor - Adrenal
hyperplasia (non-ACTH dependent, autonomous cortisol-producing adrenal nodules) Hypocortisolism
-Addison disease-primary adrenal insufficiency -Secondary adrenal insufficiency -Pituitary
insufficiency -Hypothalamic insufficiency -Congenital adrenal hyperplasia-defects in enzymes involved
in cortisol synthesis
Useful For: Determining the cause of hypercortisolism and hypocortisolism

Interpretation: In a patient with hypocortisolism, an elevated adrenocorticotropic hormone (ACTH)
indicates primary adrenal insufficiency, whereas a value that is not elevated is consistent with secondary
adrenal insufficiency from a pituitary or hypothalamic cause. In a patient with hypercortisolism (Cushing
syndrome), a suppressed value is consistent with a cortisol-producing adrenal adenoma or carcinoma,
primary adrenal micronodular hyperplasia, or exogenous corticosteroid use. Normal or elevated ACTH in
a patient with Cushing syndrome puts the patient in the ACTH-dependent Cushing syndrome category.
This is due to either an ACTH-producing pituitary adenoma or ectopic production of ACTH (bronchial
carcinoid, small cell lung cancer, others). Further diagnostic studies such as dexamethasone suppression
testing, corticotropin-releasing hormone stimulation testing, petrosal sinus sampling, and imaging studies
are usually necessary to define the ACTH source. ACTH concentrations vary considerably depending on
physiological conditions. Therefore, ACTH results should always be evaluated with simultaneously
measured cortisol concentrations.
Reference Values:
7.2-63 pg/mL (a.m. draws)
No established reference values for p.m. draws
Pediatric reference values are the same as adults, as confirmed by peer reviewed literature.
Petersen KE: ACTH in normal children and children with pituitary and adrenal diseases. I. Measurement
in plasma by radioimmunoassay-basal values. Acta Paediatr Scand 1981;70:341-345
Clinical References: 1. Demers LM: In Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics, 2006; pp 2014-2027 2. Petersen KE: ACTH in normal children and children with pituitary
and adrenal diseases I. Measurement in plasma by radioimmunoassay-basal values. Acta Paediatr Scan
1981;70:341-345
ADLTX Adulterants Survey, Chain of Custody, Random, Urine

62710 Clinical Information: Specimen adulteration is the manipulation of a sample that may cause
false-negative test results for the presence of drugs of abuse. Common adulterants that may affect testing
are water, soap, bleach, vinegar, oxidants, and salt. The adulteration testing includes assessment of
creatinine concentration, pH, urine specific gravity, presence or absence of an oxidant, and presence or
absence of nitrite. Chain of custody is a record of the disposition of a specimen to document each
individual who collected the specimen, handled it, and performed the analysis. When a specimen is
submitted in this manner, analysis will be performed in such a way that it will withstand regular court
scrutiny.
Useful For: Assess the possible adulteration of a urine specimen submitted for drug of abuse testing, as
well as for providing the urine creatinine for "creatinine normalization" Chain of custody is required
whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the
individual contributing the specimen by demonstrating that it was under the control of personnel involved
with testing the specimen at all times; this control implies that the opportunity for specimen tampering
would be limited.
Interpretation: See Adulterant Survey Algorithm in Special Instructions.
Reference Values:
Oxidants: 200 mg/L
Nitrites: 500 mg/L
Clinical References: 1. US Department of Health and Human Services, Substance Abuse and
Mental Health Services Administration (SAMHSA): Mandatory Guidelines for Federal Workplace
Drug Testing Programs. Federal Register. 2017 January 23;82(13):FR 7920. Available at:
www.samhsa.gov/sites/default/files/workplace/frn_vol_82_7920_.pdf 2. US Department of Health and
Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA): Drug-Free
Workplace Guidelines and Resources: Substance Abuse and Mental Health Services Administration
(SAMHSA). Updated June 7, 2021. Accessed September 27, 2021. Available at:
www.samhsa.gov/workplace/resources.
ADULT Adulterants Survey, Random, Urine

29345 Clinical Information: Specimen adulteration is the manipulation of a sample that may cause falsely
negative test results for the presence of drugs of abuse. Common adulterants that may affect testing are
water, soap, bleach, vinegar, oxidants, and salt. The adulteration testing includes assessment of
creatinine concentration, pH, urine specific gravity, presence or absence of an oxidant, and presence or
absence of nitrite.
Useful For: Assessment of possible adulteration of a urine specimen submitted for drug of abuse
testing Providing the creatinine concentration for normalization purposes
Interpretation: See Adulterant Survey Algorithm in Special Instructions.

Reference Values:
Oxidants: 200 mg/L
Nitrites: 500 mg/L
Clinical References: 1. US Department of Health and Human Services, Substance Abuse and
Mental Health Services Administration (SAMHSA): Mandatory Guidelines for Federal Workplace
Drug Testing Programs. Federal Register. 2017 January 23;82(13):FR 7920. Available at:
www.samhsa.gov/sites/default/files/workplace/frn_vol_82_7920_.pdf 2. US Department of Health and
Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA): Drug-Free
Workplace Guidelines and Resources Updated June 7, 2021. Accessed September 27, 2021. Available
at: www.samhsa.gov/workplace/resources
ISAE Aerobe Identification by Sequencing (Bill Only)

This test is for billing purposes only. This is not an orderable test.
AERMC Aeromonas Culture, Feces

604916 Clinical Information: Diarrhea may be caused by a number of agents, including bacteria, viruses,
parasites, and chemicals; these agents may result in similar symptoms. A thorough patient history
covering symptoms, severity and duration of illness, age, travel history, food consumption, history of
recent antibiotic use, and illnesses in the family or other contacts will help the healthcare provider
determine the appropriate testing to be performed. Aeromonas species are associated with a range of
diarrheal presentations including acute secretory diarrhea with vomiting, chronic diarrhea lasting more
than 10 days, and travelerâ€™s diarrhea. Most cases of Aeromonas-associated diarrhea are self-limited
and may be managed with supportive therapy (eg, rehydration), but in severe cases or those in patients
with a history of immunosuppression, antimicrobial therapy may be considered. Clinical studies have
demonstrated differences in antimicrobial susceptibility profiles between Aeromonas species,
highlighting the importance of both species identification and susceptibility testing for all isolates,
particularly in serious infections.
Useful For: Determining whether Aeromonas species may be the cause of diarrhea This test is
generally not useful for patients hospitalized more than 3 days because the yield from specimens from
these patients is very low, as is the likelihood of identifying a pathogen that has not been detected
previously.
Interpretation: The growth of Aeromonas species identifies a potential cause of diarrhea.

Reference Values:
No growth of pathogen
Clinical References: 1. Pillai DR: Fecal culture for aerobic pathogens of gastroenteritis. In Clinical
Microbiology Procedures Handbook, Fourth edition. Washington, DC, ASM Press, 2016, Section 3.8.1 2.
Pillai DR: Fecal culture for Campylobacter and related organisms. In Clinical Microbiology Procedures
Handbook, Fourth edition. Washington, DC, ASM Press, 2016, Section 3.8.2 3. DuPont HL: Persistent
diarrhea: A clinical review. JAMA 2016;315(24):2712-2723 doi:10.1001/jama.2016.7833
_STAC Ag-Nor/CBL Stain (Bill Only)

AGXTZ AGXT Gene, Full Gene Analysis, Varies

35348 Clinical Information: Primary hyperoxaluria type 1 (PH1) is a hereditary disorder of glyoxylate
metabolism caused by deficiency of alanine:glyoxylate-aminotransferase (AGT), a hepatic enzyme that
converts glyoxylate to glycine. Absence of AGT activity results in conversion of glyoxylate to oxalate,
which is not capable of being degraded. Therefore, excess oxalate is excreted in the urine, causing kidney
stones (urolithiasis), nephrocalcinosis, and kidney failure. As kidney function declines, blood levels of
oxalate increase markedly, and oxalate combines with calcium to form calcium oxalate deposits in the
kidney, eyes, heart, bones, and other organs, resulting in systemic disease. Pyridoxine (vitamin B6), a
cofactor of AGT, is effective in reducing urine oxalate excretion in some PH1 patients. Presenting
symptoms of PH1 include nephrolithiasis, nephrocalcinosis, or end-stage kidney disease with or without a
history of urolithiasis. Age of symptom onset is variable; however, most individuals present in childhood
or adolescence with symptoms related to kidney stones. In some infants with a more severe phenotype,
kidney failure may be the initial presenting feature. Less frequently, affected individuals present in
adulthood with recurrent kidney stones or kidney failure. End-stage kidney disease is most often seen in
the third decade of life, but can occur at any age. The exact prevalence and incidence of PH1 are not
known, but prevalence rates of 1 to 3 per million population and incidences of 0.1 per million/year have
been estimated from population surveys. Biochemical testing is indicated in patients with possible
primary hyperoxaluria. Measurement of urinary oxalate is strongly preferred, with correction to adult
body surface area in pediatric patients (HYOX / Hyperoxaluria Panel, Urine; OXU / Oxalate, 24 Hour,
Urine). Abnormal urinary excretion of oxalate is strongly suggestive of, but not diagnostic for, this
disorder, as there are other forms of inherited (type 2 and non-PH1/PH2) hyperoxaluria and secondary
hyperoxaluria that may result in similarly elevated urine oxalate excretion rates. An elevated urine
glycolate in the presence of hyperoxaluria is suggestive of PH1. Historically, the diagnosis of PH1 was
confirmed by AGT enzyme analysis performed on liver biopsy; however, this has been replaced by
molecular testing, which forms the basis of confirmatory or carrier testing in most cases. PH1 is inherited
as an autosomal recessive disorder caused by mutations in the AGXT gene, which encodes the enzyme
AGT. Several common AGXT mutations have been identified including c.33dupC, p.Gly170Arg
(c.508G->A), and p.Ile244Thr (c.731T->C). These mutations account for at least 1 of the 2 affected
alleles in approximately 70% of individuals with PH1. Direct sequencing of the AGXT gene is predicted
to identify 99% of alleles in individuals who are known by enzyme analysis to be affected with PH1.
While age of onset and severity of disease is variable and not necessarily predictable by genotype, a
correlation between pyridoxine responsiveness and homozygosity for the p.Gly170Arg mutation has been
observed. (Note: testing for the p.Gly170Arg mutation only is available by ordering AGXTG /
Alanine:Glyoxylate Aminotransferase [AGXT] Mutation Analysis [G170R], Blood). Pyridoxine (vitamin
B6) is a known cofactor of AGT and is effective in reducing urine oxalate excretion in some PH1 patients
treated with pharmacologic doses. Individuals with 2 copies of the p.Gly170Arg mutation have been
shown to normalize their urine oxalate when treated with pharmacologic doses of pyridoxine and those
with a single copy of the mutation show reduction in urine oxalate. This is valuable because not all
patients have been shown to be responsive to pyridoxine, and strategies that help to identify the
individuals most likely to benefit from such targeted therapies are desirable.
Useful For: Confirming a diagnosis of primary hyperoxaluria type 1 Carrier testing for individuals
with a family history of primary hyperoxaluria type 1 in the absence of known mutations in the family
Genetics recommendations.(1) Variants are classified based on known, predicted, or possible
pathogenicity and reported with interpretive comments detailing their potential or known significance.
Reference Values:
Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015
May;17(5):405-424 2. Milliner DS: The primary hyperoxalurias: an algorithm for diagnosis. Am J
Nephrol 2005;25(2):154-160 3. Monico CG, Rossetti S, Olson JB, Milliner DS: Pyridoxine effect in
type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int
2005;67(5):1704-1709 4. Monico CG, Rossetti S, Schwanz HA, et al: Comprehensive mutation
screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis.
J Am Soc Nephrol 2007;18:1905-1914 5. Rumsby G, Williams E, Coulter-Mackie M: Evaluation of
mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int
2004;66(3):959-963 6. Williams EL, Acquaviva C, Amoroso, A, et al: Primary hyperoxaluria type I:
update and additional mutation analysis of the AGXT gene. Hum Mutat 2009;30:910-917 7. Williams
E, Rumsby G: Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of
patients with primary hyperoxaluria type 1. Clin Chem 2007;53(7):1216-1221 8. Communique April
2007: Laboratory and Molecular Diagnosis of Primary Hyperoxaluria and Oxalosis
ALT Alanine Aminotransferase (ALT) (GPT), Serum

8362 Clinical Information: Alanine aminotransferase (ALT) is present primarily in liver cells. In viral
hepatitis and other forms of liver disease associated with hepatic necrosis, serum ALT is elevated even
before the clinical signs and symptoms of the disease appear. Although serum levels of both aspartate
aminotransferase (AST) and ALT become elevated whenever disease processes affect liver cell
integrity, ALT is a more liver-specific enzyme. Serum elevations of ALT are rarely observed in
conditions other than parenchymal liver disease. Moreover, the elevation of ALT activity persists longer
than does AST activity.
Useful For: Diagnosis and monitoring of liver disease associated with hepatic necrosis
Interpretation: Elevated alanine aminotransferase (ALT) values are seen in parenchymal liver
diseases characterized by a destruction of hepatocytes. Values are typically at least 10 times above the
normal range. Levels may reach values as high as 100 times the upper reference limit, although 20- to
50-fold elevations are most frequently encountered. In infectious hepatitis and other inflammatory
conditions affecting the liver, ALT is characteristically as high as or higher than aspartate
aminotransferase (AST), and the ALT:AST ratio, which normally and in other condition is less than 1,
becomes greater than unity. ALT levels are usually elevated before clinical signs and symptoms of
disease appear.
Reference Values:
Males
> or =1 year: 7-55 U/L
Reference values have not been established for patients who are <12 months of age.
Females
> or =1 year: 7-45 U/L
Clinical References: Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood.

Philadelphia, WB Saunders Company, 1994
ALB24 Albumin, 24 Hour, Urine

606718 Clinical Information: Albumin excretion increases in patients with diabetes who are destined to
develop diabetic nephropathy. More importantly, at this phase of increased albumin excretion before overt
proteinuria develops, therapeutic maneuvers can be expected to significantly delay, or possibly prevent,
development of nephropathy. These maneuvers include aggressive blood pressure maintenance
(particularly with angiotensin-converting enzyme inhibitors), aggressive blood sugar control, and possibly
decreased protein intake. Thus, there is a need for addressing small amounts of urinary albumin excretion
(in the range of 30-300 mg/day, ie, microalbuminuria). The National Kidney Foundation convened an
expert panel to recommend guidelines for the management of patients with diabetes and
microalbuminuria. These guidelines recommend that all type 1 diabetic patients older than 12 years and
all type 2 diabetic patients younger than 70 years should have their urine tested for microalbuminuria
yearly when they are under stable glucose control.(1) The preferred specimen is a 24-hour collection, but
a 10-hour overnight collection (9 p.m.-7 a.m.) or a random collection are acceptable. Recent studies have
shown that correcting albumin for creatinine excretion rates has similar discriminatory value with respect
to diabetic renal involvement, and it is now suggested that an albumin/creatinine ratio from a random
urine specimen is a valid screening tool.(2) Several studies have addressed the question of whether this
needs to be a fasting urine, an exercised urine, or an overnight urine specimen. From these studies, it is
clear that the first-morning urine specimen is less sensitive, but more specific. A positive result should be
confirmed by a first-morning random or 24-hour timed urine specimen. Studies have also shown that
microalbuminuria is a marker of generalized vascular disease and is associated with stroke and heart
disease.
Useful For: Evaluating diabetic patients to assess the potential for early onset of nephropathy
Interpretation: An albumin excretion rate of more than 30 mg/24 hours is considered to be
microalbuminuric. By definition, the upper end of microalbuminuria is thought to be 300 mg/24 hours.
Although this level has not been rigorously defined, it is felt that at this level it is more difficult to change
the course of diabetic nephropathy. Laboratory normal values agree with the 30 mg/24 hour level. A
normal excretion rate of 20 mcg/minute has also been established in the literature and is consistent with
the laboratory data. Thus, microalbuminuria has been defined at 30 to 300 mg/24 hours. The literature has
defined the albumin/creatinine ratio (mg/g) below 17 as normal for males and below 25 for females(2)
and is consistent with the laboratory's normal data. A ratio of albumin to creatinine of 300 or more
indicates overt albuminuria. Thus, microalbuminuria has been defined as an albumin/creatinine ratio of 17
to 299 for males and 25 to 299 for females. Due to biologic variability, any patient who has an
albumin/creatinine ratio or urinary albumin excretion rate in the positive microalbuminuria range should
have this confirmed with a second specimen. If there is discrepancy, a third specimen is recommended. If
2 of 3 results are in the positive microalbuminuria range, this is evidence for incipient nephropathy and
warrants increased efforts at glucose control, aggressive blood pressure control, and institution of therapy
with an angiotensin-converting enzyme inhibitor (if the patient can tolerate it).
Reference Values:
24-Hour excretion: <30 mg/24 hours
Excretion rate: <20 mcg/min
Clinical References: 1. Bennett PH, Haffner S, Kasiske BL, et al: Screening and management of
microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board
of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of
the National Kidney Foundation. Am J Kidney Dis. 1995;25:107-112 2. Zelmanovitz T, Gross JL,
Oliveira JR, et al: The receiver operating characteristics curve in the evaluation of a random urine
specimen as a screening test for diabetic nephropathy. Diabetes Care. 1997;20:516-519 3. Krolewski
AS, Laffel LM, Krolewski M, et al: Glycosylated hemoglobin and the risk of microalbuminuria in
patients with insulin-dependent diabetes mellitus. N Engl J Med. 1995;332:1251-1255 4.Miller GW,
Bruns DE, Hortin GL, et al: Current Issues in Measurement and Reporting of Urinary Albumin
Excretion. Clin Chem. 2009;55(1):24-38 5. Lamb EJ, Jones GRD: Kidney functions tests. In: Rifai N,
Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th
ed. Elsevier; 2018:480-488 6. Sacks DB: Diabetes mellitus. In: Rifai N, Horvath AR, Wittwer CT,
eds.Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. In: Elsevier;
2018:1197-1199
ALBFL Albumin, Body Fluid

60622 Clinical Information: Peritoneal fluid: Ascites is the pathologic accumulation of excess fluid in the
peritoneal cavity caused by changes in vascular permeability, hydrostatic pressure, and oncotic pressure.
The most common causes of ascites in individuals are cirrhosis (80%), malignancy (10%), cardiac
failure (5%), and infection. Total protein results of 3.0 g/dL or greater, historically used to classify
ascites fluid as transudate or exudate, has a reported accuracy of only 55% in identifying exudates and
has been largely replaced with measurement of the serum-ascites albumin gradient (SAAG), calculated
as serum albumin concentration minus ascites albumin concentration. SAAG has been shown to
correlate directly with portal pressure and SAAG results of 1.1 g/dL or greater are 97% accurate at
identifying portal hypertension. Conditions associated with high SAAG include cirrhosis, acute liver
failure, fatty liver disease, alcoholic hepatitis, portal vein thrombosis, hepatic malignancy, and
veno-occlusive disease. Cardiac ascitic fluid caused by congestive heart failure has both a high SAAG
result (> or =1.1 g/dL) and total protein concentration greater than 2.5 g/dL. Conditions associated with
low SAAG measurement (<1.1 g/dL) include peritoneal malignancy, tuberculosis, pancreatitis,
connective tissue disease, and nephrotic syndrome. Pleural fluid: Pleural fluid is normally present
within the pleural cavity surrounding the lungs, serving as a lubricant between the lungs and inner chest
wall. Pleural effusion develops when the pleural cavity experiences an overproduction of fluid due to
increased capillary hydrostatic and osmotic pressure that exceeds the ability of the lymphatic or venous
system to return the fluid to circulation. Laboratory-based criteria are often used to classify pleural
effusions as either exudative or transudative. Exudative effusions form due to infection or inflammation
of the capillary membranes allowing excess fluid into the pleural cavity. Patients with these conditions
benefit from further investigation and treatment of the local cause of inflammation. Transudative
effusions form due to systemic conditions such as volume overload, end-stage renal disease, and heart
failure that can lead to excess fluid accumulation in the pleural cavity. Patients with transudative
effusions benefit from treatment of the underlying condition.(1) Dr. Richard Light derived criteria in the
1970s for patients with pleural effusions that are still used today.(2) Dr. Light's criteria were designed to
be sensitive for detecting exudates at the expense of specificity.(3) Heart failure and recent diuretic use
contribute to most misclassifications by Dr. Light's criteria (transudates falsely categorized as exudates).
Serum-to-fluid protein or albumin gradient (serum protein or albumin minus fluid protein or albumin)
may be calculated in these cases and when more than 3.1 g/dL (protein) or 1.2 g/dL (albumin) suggests
the patient has a transudative effusion.
Useful For: Aiding in identifying the cause of ascites Aiding in differentiating exudative and
transudative pleural effusions
Interpretation: Peritoneal fluid albumin is used to calculate the serum-ascites albumin gradient
(SAAG). Values of 1.1 g/dL or higher suggest portal hypertension. Pleural fluid albumin may be used to
calculate a serum-effusion albumin gradient. Values above 1.2 g/dL are most consistent with a
transudative process. For all other fluids, the albumin concentration and gradient have only been
evaluated in peritoneal and pleural fluids. All other fluid albumin concentrations should be interpreted
in conjunction with serum albumin concentration and other clinical findings.
Reference Values:
An interpretive report will be provided
Clinical References: 1. Runyon BA: The serum-ascites albumin gradient is superior to the
exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med. 1992;117:215-220 2.
Clinical and Laboratory Standards Institute: Analysis of Body Fluids in Clinical Chemistry; Approved
Guideline. Clinical and Laboratory Standards Institute, 2007, CLSI document C49-A (ISBN
1-56238-638-7) 3. Block DR, Algeciras-Schimnich A: Body fluid analysis: Clinical utility and
applicability of published studies to guide interpretation of today's laboratory testing in serous fluids. Crit
Rev Clin Lab Sci. 2013; 50(4-5):107-124 4. Heffner JE, Brown LK, Barbieri CA: Diagnostic value of
tests that discriminate between exudative and transudative pleural effusions. Chest. 1997;111:970-980
RALB Albumin, Random, Urine

603287 Clinical Information: Diabetic nephropathy is a complication of diabetes and is characterized by
proteinuria (normal urinary albumin excretion is <30 mg/day; overt proteinuria is >300 mg/day). Before
overt proteinuria develops, albumin excretion increases in those diabetic patients who are destined to
develop diabetic nephropathy. Therapeutic maneuvers (eg, aggressive blood pressure maintenance,
particularly with angiotensin-converting enzyme inhibitors; aggressive blood sugar control; and possibly
decreased protein intake) can significantly delay, or possibly prevent, development of nephropathy. Thus,
there is a need to identify small, but abnormal, increases in the excretion of urinary albumin (in the range
of 30-300 mg/day, ie, microalbuminuria). The National Kidney Foundation guidelines for the
management of patients with diabetes and microalbuminuria recommend that all type 1 diabetic patients
older than 12 years and all type 2 diabetic patients younger than 70 years have their urine tested for
microalbuminuria yearly when they are under stable glucose control.(1) The preferred specimen is a
24-hour collection, but a random collection is acceptable. Studies have shown that correcting albumin for
creatinine excretion rates has similar discriminatory value with respect to diabetic renal involvement. The
albumin:creatinine ratio from a random urine specimen is also considered a valid screening tool.(2)
Several studies have addressed whether the specimen needs to be a fasting urine, an exercised urine, or an
overnight urine specimen. These studies have shown that the first-morning urine specimen is less
sensitive, but more specific. Studies also have shown that microalbuminuria is a marker of generalized
vascular disease and is associated with stroke and heart disease.
Useful For: Assessing the potential for early onset of nephropathy in diabetic patients using random
urine specimens
Interpretation: In random urine specimens, normal urinary albumin excretion is below 17 mg/g
creatinine for males and below 25 mg/g creatinine for females.(3) Microalbuminuria is defined as an
albumin:creatinine ratio of 17 to 299 for males and 25 to 299 for females. A ratio of albumin:creatinine of
300 or higher is indicative of overt proteinuria. Due to biologic variability, positive results should be
confirmed by a second, first-morning random or 24-hour timed urine specimen. If there is discrepancy, a
third specimen is recommended. When 2 out of 3 results are in the microalbuminuria range, this is
evidence for incipient nephropathy and warrants increased efforts at glucose control, blood pressure
control, and institution of therapy with an angiotensin-converting-enzyme (ACE) inhibitor (if the patient
can tolerate it).
Reference Values:
Males: <17 mg/g creatinine
Females: <25 mg/g creatinine
microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of
the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the
National Kidney Foundation. Am J Kidney Dis. 1995 Jan;25:107-112. doi:
10.1016/0272-6386(95)90636-3 2. Krolewski AS, Laffel LM, Krolewski M, Quinn M, Warram JH:
Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes
mellitus. N Engl J Med. 1995 May 11;332:1251-1255. doi: 10.1056/NEJM199505113321902 3.
Zelmanovitz T, Gross JL, Oliveira JR, Paggi A, Tatsch M, Azevedo MJ: The receiver operating
characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic
nephropathy. Diabetes Care. 1997 April;20:516-519. doi: 10.2337/diacare.20.4.516 4. Miller GW, Bruns
DE, Hortin GL, et al: Current Issues in Measurement and Reporting of Urinary Albumin Excretion.
Clinical Chemistry. 2009 Jan;55:1(24-38). doi: 10.1373/clinchem.2008.106567 5. Lamb EJ, Jones GRD:
Kidney functions tests. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry
and Molecular Diagnostics. 6th ed. Elsevier; 2018:480-488 6. Sacks DB: Diabetes mellitus. In: Rifai N,
In: Elsevier; 2018:1197-1199
ALBR Albumin, Random, Urine

particularly with angiotensin-converting enzyme inhibitors; aggressive blood sugar control; and
possibly decreased protein intake) can significantly delay, or possibly prevent, development of
nephropathy. Thus, there is a need to identify small, but abnormal, increases in the excretion of urinary
albumin (in the range of 30-300 mg/day, ie, microalbuminuria). The National Kidney Foundation
guidelines for the management of patients with diabetes and microalbuminuria recommend that all type
1 diabetic patients older than 12 years and all type 2 diabetic patients younger than 70 years have their
urine tested for microalbuminuria yearly when they are under stable glucose control.(1) The preferred
specimen is a 24-hour collection, but a random collection is acceptable. Studies have shown that
correcting albumin for creatinine excretion rates has similar discriminatory value with respect to
diabetic renal involvement. The albumin:creatinine ratio from a random urine specimen is also
considered a valid screening tool.(2) Several studies have addressed whether the specimen needs to be a
fasting urine, an exercised urine, or an overnight urine specimen. These studies have shown that the
first-morning urine specimen is less sensitive, but more specific. Studies also have shown that
microalbuminuria is a marker of generalized vascular disease and is associated with stroke and heart
disease.
urine specimens
albumin:creatinine ratio of 17 to 299 for males and 25 to 299 for females. A ratio of albumin:creatinine
of 300 or higher is indicative of overt proteinuria. Due to biologic variability, positive results should be
confirmed by a second, first-morning random or 24-hour timed urine specimen. If there is discrepancy,
a third specimen is recommended. When 2 out of 3 results are in the microalbuminuria range, this is
can tolerate it).
Reference Values:
the National Kidney Foundation. Am J Kidney Dis. 1995 Jan;25:107-112. doi:
nephropathy. Diabetes Care. 1997 April;20:516-519. doi: 10.2337/diacare.20.4.516 4. Miller GW,
Bruns DE, Hortin GL, et al: Current issues in measurement and reporting of urinary albumin excretion.
Clin Chem. 2009 Jan;55(1):24-38. doi: 10.1373/clinchem.2008.106567 5. Lamb EJ, Jones GRD:
Kidney functions tests. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:480-488 6. Sacks DB: Diabetes mellitus.
In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics. 6th ed. In: Elsevier; 2018:1197-1199
RALB1 Albumin, Random, Urine

urine specimens
can tolerate it).
Reference Values:
-ALBR / Albumin, Random, Urine
-RALB / Albumin, Random, Urine.

microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of
the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the
National Kidney Foundation. Am J Kidney Dis. 1995 Jan;25:107-112. doi:
nephropathy. Diabetes Care. 1997 April;20:516-519. doi: 10.2337/diacare.20.4.516 4. Miller GW, Bruns
DE, Hortin GL, et al: Current issues in measurement and reporting of urinary albumin excretion. Clin
Chem 2009 Jan;55(1):24-38. doi: 10.1373/clinchem.2008.106567 5. Lamb EJ, Jones GRD: Kidney
functions tests. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:480-488 6. Sacks DB: Diabetes mellitus. In: Rifai N,
In: Elsevier; 2018:1197-1199
ALB Albumin, Serum

8436 Clinical Information: Albumin is a carbohydrate-free protein, which constitutes 55% to 65% of
total plasma protein. It maintains oncotic plasma pressure, is involved in the transport and storage of a
wide variety of ligands, and is a source of endogenous amino acids. Albumin binds and solubilizes
various compounds, including bilirubin, calcium, long-chain fatty acids, toxic heavy metal ions, and
numerous pharmaceuticals. Hypoalbuminemia is caused by several factors: impaired synthesis due
either to liver disease (primary) or due to diminished protein intake (secondary), increased catabolism as
a result of tissue damage and inflammation, malabsorption of amino acids, and increased renal excretion
(eg, nephrotic syndrome).
Useful For: Assessing nutritional status

Interpretation: Hyperalbuminemia is of little diagnostic significance except in the case of
dehydration. When plasma or serum albumin values fall below 2.0 g/dL, edema is usually present.
Reference Values:
> or =12 months: 3.5-5.0 g/dL
Clinical References: 1. Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood.

Philadelphia, WB Saunders Company, 1999 2. Peters T, Jr: Serum albumin. In The Plasma Proteins.
Vol 1. Second edition. Edited by F Putnam, New York, Academic Press, 1975
ALBS1 Albumin, Serum

610525 Clinical Information: Albumin is a carbohydrate-free protein, which constitutes 55% to 65% of
total plasma protein. It maintains oncotic plasma pressure, is involved in the transport and storage of a
wide variety of ligands, and is a source of endogenous amino acids. Albumin binds and solubilizes
various compounds, including bilirubin, calcium, long-chain fatty acids, toxic heavy metal ions, and
numerous pharmaceuticals. Hypoalbuminemia is caused by several factors: impaired synthesis due
either to liver disease (primary) or due to diminished protein intake (secondary), increased catabolism as
a result of tissue damage and inflammation, malabsorption of amino acids, and increased renal excretion
(eg, nephrotic syndrome). Measurement of albumin in serum is helpful when paired with albumin
measured in cerebrospinal fluid (CSF) along with total IgG in serum and CSF as an aid in evaluating
multiple sclerosis and other conditions where the integrity of the blood brain barrier is reviewed. The
combination of these four analytes is referred to as CSF IgG index.
Useful For: Assessing nutritional status Aiding in the diagnosis of multiple sclerosis when used in
conjunction with serum IgG, and cerebrospinal fluid IgG and albumin concentrations
Interpretation: Hyperalbuminemia is of little diagnostic significance except in the case of

dehydration. When plasma or serum albumin values fall below 2.0 g/dL, edema is usually present.
Reference Values:
Only orderable as part of profile. For more information see: SFIG / Cerebrospinal Fluid (CSF) IgG
Index Profile, Serum and Spinal Fluid.
> or =12 months: 3500-5000 mg/dL

Clinical References: 1. Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018 2. Peters T, Jr: Serum albumin. In: Putnam
F, ed. The plasma proteins. Vol 1. 2nd ed. Academic Press; 1975
ALBSF Albumin, Spinal Fluid

68001 Clinical Information: Elevated albumin concentration in spinal fluid may serve as an indicator of the
permeability status of the blood-brain barrier. Comparison to an ALB / Albumin, Serum concentration is
recommended.
Useful For: Assessment of blood-brain barrier permeability

Interpretation: Elevated albumin concentrations may be observed in patients with a compromised
blood-brain barrier.
Reference Values:
0.0-27.0 mg/dL
Clinical References: Schliep G, Felgenhauer K: Serum-CSF protein gradients, the blood-GSF

barrier and the local immune response. J Neurol. 1978 May 18;218(2):77-96
A_CR Albumin/Creatinine Ratio

Useful For: Calculating the albumin concentration per creatinine Assessing the potential for early
onset of nephropathy in diabetic patients using random urine specimens
can tolerate it).
Reference Values:
ALBR / Albumin, Random, Urine
RALB / Albumin, Random, Urine.

the National Kidney Foundation. Am J Kidney Dis. 1995 Jan;25:107-112. doi:
nephropathy. Diabetes Care. 1997 April;20:516-519. doi: 10.2337/diacare.20.4.516 4. Miller GW,
Bruns DE, Hortin GL, et al: Current issues in measurement and reporting of urinary albumin excretion.
Clin Chem. 2009 Jan;55:1(24-38). doi: 10.1373/clinchem.2008.106567 Lamb EJ, Jones GRD: Kidney
functions tests. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:480-488 6. Sacks DB: Diabetes mellitus. In: Rifai N,
ed. In: Elsevier; 2018:1197-1199
FALBU Albuterol, Serum/Plasma

Reporting limit determined each analysis
Synonym(s): Proventil
Peak plasma levels following a 180 mcg dose via an

inhaler: 1.5 ng/mL at 13 minutes post dose.
Peak plasma levels following inhalation of a cumulative

dose of 1 mg and 4 mg: approximately 5 and 20 ng/mL,
respectively, 5 minutes post dose.
Peak plasma levels following a single 8 mg

oral-sustained release tablet:
13 ng/mL at 5.0 hours post dose.
Average steady-state peak and trough plasma

levels following a 4 mg (normal release tablet) every
6 hours for 5 days: 15 and 9.9 ng/mL, respectively.
Serum/plasma concentrations may vary significantly

depending on dose, formulation, route of
administration, device, lung function, and
user mechanics.
ALS Aldolase, Serum

606872
Clinical Information: Aldolase is necessary for glycolysis in muscle as a "rapid response" pathway
for production of adenosine triphosphate, independent of tissue oxygen. Aldolase catalyzes the conversion
of fructose 1,6-diphosphate into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, an
important reaction in the glycolytic breakdown of glucose to lactate in muscle. Aldolase is a tetramer
whose primary structure depends upon the tissue from which it was synthesized (highest expression in
liver, muscle, brain). Elevated values are found in muscle diseases, such as Duchenne muscular
dystrophy, dermatomyositis, polymyositis, and limb-girdle dystrophy. While elevated creatinine kinase
(CK) levels are more sensitive and specific for muscle disease, occasionally elevated aldolase is observed
in some patients with myositis that have normal CK values.
Useful For: Detection of muscle disease

Interpretation: Measuring serum muscle enzymes is common in the evaluation of patients with
muscle weakness or muscle myalgia. When elevated, serum muscle enzymes can help differentiate muscle
disease derived muscle weakness from a neurogenic cause. The highest levels of aldolase are found in
progressive (Duchenne) muscular dystrophy. Lesser elevations are found in dermatomyositis,
polymyositis, and limb-girdle dystrophy. In dystrophic conditions causing hyperaldolasemia, the increase
in aldolase becomes less dramatic as muscle mass decreases.
Reference Values:
<18 years: <14.5 U/L
> or =18 years: <7.7 U/L
Clinical References: 1. Bohlmeyer TJ, Wu AH, Perryman MB: Evaluation of laboratory tests as a
guide to diagnosis and therapy of myositis. Rheum Dis Clin of North Am. 1994 Nov;20(4):845-856 2.
Bohan A, Peter JB, Bowman RL, Pearson CM: Computer-assisted analysis of 153 patients with
polymyositis and dermatomyositis. Medicine (Baltimore). 1977 Jul;56(4):255-286. doi:
10.1097/00005792-197707000-00001 3. Thompson RA, Vignos PJ Jr: Serum aldolase in muscle disease.
AMA Arch Intern Med. 1959 Apr;103(4):551-564. doi: 10.1001/archinte.1959.00270040037004 4.
Ganguly A: Management of muscular dystrophy during osteoarthritis disorder: A topical phytotherapeutic
treatment protocol. Caspian J Intern Med. 2019;10(2):183-196. doi: 10.22088/cjim.10.2.183
ALDNA Aldosterone with Sodium, 24 Hour, Urine

15150 Clinical Information: Aldosterone stimulates sodium transport across cell membranes, particularly in
the distal renal tubule where sodium is exchanged for hydrogen and potassium. Secondarily, aldosterone
is important in the maintenance of blood pressure and blood volume. Aldosterone is the major
mineralocorticoid and is produced by the adrenal cortex. The renin-angiotensin system is the primary
regulator of the synthesis and secretion of aldosterone. Likewise, increased concentrations of potassium in
the plasma may directly stimulate adrenal production of the hormone. Under physiologic conditions,
pituitary adrenocorticotropic hormone can stimulate aldosterone secretion. Urinary aldosterone levels are
inversely correlated with urinary sodium excretion. Normal individuals will show a suppression of urinary
aldosterone with adequate sodium repletion. Â Primary hyperaldosteronism, which may be caused by
aldosterone-secreting adrenal adenoma/carcinomas or adrenal cortical hyperplasia, is characterized by
hypertension accompanied by increased aldosterone levels, hypernatremia, and hypokalemia. Secondary
hyperaldosteronism (eg, in response to renovascular disease, salt depletion, potassium loading, cardiac
failure with ascites, pregnancy, Bartter's syndrome) is characterized by increased aldosterone levels and
increased plasma rennin activity.
Useful For: Investigation of primary aldosteronism (eg, adrenal adenoma/carcinoma and adrenal
cortical hyperplasia) and secondary aldosteronism (eg, renovascular disease, salt depletion, potassium
loading, cardiac failure with ascites, pregnancy, Bartter syndrome) in conjunction with urine sodium
levels
Interpretation: Under normal circumstances, if the 24-hour urinary sodium excretion is greater than
200 mEq, the urinary aldosterone excretion should be less than 10 mcg/24 hours. Urinary aldosterone
excretion greater than 12 mcg/24 hours as part of an aldosterone suppression test is consistent with
hyperaldosteronism. Twenty-four hour urinary sodium excretion should exceed 200 mEq to document
adequate sodium repletion. See Renin-Aldosterone Studies in Special Instructions. Note: Advice on
stimulation or suppression tests is available from Mayo Clinic's Division of Endocrinology; call
800-533-1710.
Reference Values:
ALDOSTERONE
0-30 days: 0.7-11.0 mcg/24 hours*
1-11 months: 0.7-22.0 mcg/24 hours*
> or =1 year: 2.0-20.0 mcg/24 hours
*Loeuille GA, Racadot A, Vasseur P, Vandewalle B: Blood and urinary aldosterone levels in normal
neonates, infants and children. Pediatrie 1981;36:335-344
SODIUM
41-227 mmol/24 hours
If the 24-hour urinary sodium excretion is >200 mmol, the urinary aldosterone excretion should be <10
mcg.
Clinical References: 1. Young WF Jr: Primary aldosteronism: A common and curable form of
hypertension. Cardiol Rev. 1999;7:207-214 2. Young WF Jr: Pheochromocytoma and primary
aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am. 1977;26:801-827 3. Fredline
VF, Taylor PJ, Dodds HM, Johnson AG: A reference method for the analysis of aldosterone in blood by
high-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass
spectrometry. AnalBiochem 1997 Oct 15;252(2):308-313 4. Carey RM, Padia SH: Primary
mineralocorticoid excess disorders and hypertension. In: Jameson JL, De Groot LJ, de Kretser DM,
Giudice LC, et al: eds. Endocrinology: Adult and Pediatric. 7th ed. WB Saunders; 2016:1871-1891
ALDU Aldosterone, 24 Hour, Urine

8556 Clinical Information: Aldosterone stimulates sodium transport across cell membranes, particularly
in the distal renal tubule where sodium is exchanged for hydrogen and potassium. Secondarily,
aldosterone is important in the maintenance of blood pressure and blood volume. Aldosterone is the
major mineralocorticoid and is produced by the adrenal cortex. The renin-angiotensin system is the
primary regulator of the synthesis and secretion of aldosterone. Likewise, increased concentrations of
potassium in the plasma may directly stimulate adrenal production of the hormone. Under physiologic
conditions, pituitary adrenocorticotropic hormone can stimulate aldosterone secretion. Urinary
aldosterone levels are inversely correlated with urinary sodium excretion. Normal individuals will show
a suppression of urinary aldosterone with adequate sodium repletion. Primary hyperaldosteronism,
which may be caused by aldosterone-secreting adrenal adenoma/carcinomas or adrenal cortical
hyperplasia, is characterized by hypertension accompanied by increased aldosterone levels,
hypernatremia, and hypokalemia. Secondary hyperaldosteronism (eg, in response to renovascular
disease, salt depletion, potassium loading, cardiac failure with ascites, pregnancy, Bartter's syndrome) is
characterized by increased aldosterone levels and increased plasma rennin activity.
cortical hyperplasia) and secondary aldosteronism (renovascular disease, salt depletion, potassium
loading, cardiac failure with ascites, pregnancy, Bartter syndrome)
Interpretation: Urinary aldosterone excretion greater than 12 mcg/24 hours as part of an aldosterone
suppression test is consistent with hyperaldosteronism. See Renin-Aldosterone Studies in Special
Instructions.
Reference Values:
0-30 days: 0.7-11.0 mcg/24 hours*
31 days-11 months: 0.7-22.0 mcg/24 hours*
> or =1 year: 2.0-20.0 mcg/24 hours
aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am. 1977;26:801-827 3. Fredline
VF, Taylor PJ, Dodds HM, Johnson AG: A reference method for the analysis of aldosterone in blood by
high-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass
spectrometry. Analytical Biochemistry. 1997 Oct 15;252(2):308-313: 9344418Â 4. Carey RM, Padia SH:
Primary Mmineralocorticoid Eexcess Ddisorders and Hhypertension. In: Jameson JL, De Groot LJ, de
Kretser DM, Giudice LC, et al: eds. Endocrinology: Adult and Pediatric. 7th ed. WB Saunders; 2016:
chap 108, pp 1871-1891. e6, ISBN 9780323189071
APIVC Aldosterone, Inferior Vena Cava, Plasma

pituitary adrenocorticotropic hormone is not a major factor in regulating aldosterone secretion. See
Steroid Pathways in Special Instructions.
Useful For: Investigation using inferior vena cava specimen for: -Primary aldosteronism (eg, adrenal
adenoma/carcinoma and adrenal cortical hyperplasia) -Secondary aldosteronism (renovascular disease,
salt depletion, potassium loading, cardiac failure with ascites, pregnancy, Bartter syndrome)
Interpretation: A high ratio of plasma aldosterone (PA) in ng/dL to plasma renin activity (PRA) in
ng/mL per hour is a positive screening test result, a finding that warrants further testing. A PA:PRA ratio
of20 or greater is only interpretable with a PA of 15 ng/dL or greater and indicates probable primary
aldosteronism. Renal disease, such as unilateral renal artery stenosis, results in elevated renin and
aldosterone levels. Renal venous catheterization may be helpful. A positive test is a renal venous renin
ratio (affected/normal) above1.5. The following are available in Special Instructions: -Renin-Aldosterone
Studies -Steroid Pathways Note: Advice on stimulation or suppression tests is available from Mayo
Clinic's Division of Endocrinology and may be obtained by calling 800-533-1710.
Reference Values:
No established reference values.
hypertension. Cardiol Rev 1999;7:207-214 2. Young WF Jr: Pheochromocytoma and primary
aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997;26:801-827 3. Hurwitz S,
Cohen RJ, Williams GH: Diurnal variation of aldosterone and plasma renin activity: timing relation to
melatonin and cortisol and consistency after prolonged bed rest. J Appl Physiol 2004;96:1406-1414
AIVC Aldosterone, Inferior Vena Cava, Serum

Useful For: Investigation using inferior vena cava sample for: -Primary aldosteronism (eg, adrenal
Interpretation: A high ratio of serum aldosterone (SA) in ng/dL to plasma renin activity (PRA) in
ng/mL per hour is a positive screening test result, a finding that warrants further testing. An SA:PRA
ratio 20 or higher is only interpretable with an SA of 15 ng/dL or higher and indicates probable primary
ratio (affected/normal) greater than 1.5. See Renin-Aldosterone Studies and Steroid Pathways in Special
Instructions. Note: Advice on stimulation or suppression tests is available from Mayo Clinic's Division
of Endocrinology and may be obtained by calling 800-533-1710.
Reference Values:
APLAV Aldosterone, Left Adrenal Vein, Plasma

conditions, pituitary adrenocorticotropic hormone is not a major factor in regulating aldosterone
secretion. See Steroid Pathways in Special Instructions.
Useful For: Investigation using left adrenal vein sample for: -Primary aldosteronism (eg, adrenal
ng/mL per hour is a positive screening test result, a finding that warrants further testing. A PA:PRA
ratio of 20 or greater is only interpretable with a PA of 15 ng/dL or greater and indicates probable
primary aldosteronism. Renal disease, such as unilateral renal artery stenosis, results in elevated renin
and aldosterone levels. Renal venous catheterization may be helpful. A positive test is a renal venous
renin ratio (affected/normal) above 1.5. The following are available in Special Instructions:
-Renin-Aldosterone Studies -Steroid Pathways Note: Advice on stimulation or suppression tests is
available from Mayo Clinic's Division of Endocrinology and may be obtained by calling 800-533-1710.
Reference Values:
ALAV Aldosterone, Left Adrenal Vein, Serum

6349
Clinical Information: Aldosterone stimulates sodium transport across cell membranes, particularly in
Useful For: Investigation using left adrenal vein sample for: -Primary aldosteronism (eg, adrenal
ng/mL per hour is a positive screening test result, a finding that warrants further testing. An SA:PRA ratio
of 20 or higher is only interpretable with an SA of 15 ng/dL or higher and indicates probable primary
ratio (affected/normal) above 1.5. See Renin-Aldosterone Studies and Steroid Pathways in Special
Instructions. Note: Advice on stimulation or suppression tests is available from Mayo Clinic's Division of
Endocrinology and may be obtained by calling 800-533-1710.
Reference Values:
PALD Aldosterone, Plasma

loading, cardiac failure with ascites, pregnancy, Bartter syndrome) in plasma
ng/mL per hour, is a positive screening test result, a finding that warrants further testing. An PA/PRA
ratio greater than or equal to 20 is only interpretable with an PA greater than or equal to 15 ng/dL and
indicates probable primary aldosteronism. Renal disease, such as unilateral renal artery stenosis, results in
elevated renin and aldosterone levels. Renal venous catheterization may be helpful. A positive test is a
renal venous renin ratio (affected/normal) greater than 1.5. See Renin-Aldosterone Studies and Steroid
Pathways in Special Instructions. Note: Advice on stimulation or suppression tests is available from Mayo
Reference Values:
0-30 days: 17-154 ng/dL*
31 days-11 months: 6.5-86 ng/dL*
1-10 years:
< or =40 ng/dL (supine)*
< or =124 ng/dL (upright)*
> or =11 years: < or =21 ng/dL (a.m. peripheral vein specimen)
APRAV Aldosterone, Right Adrenal Vein, Plasma

Useful For: Investigation using right adrenal vein specimen for: -Primary aldosteronism (eg, adrenal
ng/mL per hour is a positive screening test result, a finding that warrants further testing. A PA:PRA
ratio of 20 or greater is only interpretable with a PA of 15 ng/dL or greater and indicates probable
primary aldosteronism. Renal disease, such as unilateral renal artery stenosis, results in elevated renin
and aldosterone levels. Renal venous catheterization may be helpful. A positive test is a renal venous
renin ratio (affected/normal) above 1.5. The following are available in Special Instructions:
-Renin-Aldosterone Studies -Steroid Pathways Note: Advice on stimulation or suppression tests is
available from Mayo Clinic's Division of Endocrinology and may be obtained by calling 800-533-1710.
Reference Values:
ARAV Aldosterone, Right Adrenal Vein, Serum

Useful For: Investigation using right adrenal vein sample for: -Primary aldosteronism (eg, adrenal
ng/mL per hour is a positive screening test result, a finding that warrants further testing. An SA:PRA ratio
of 20 or higher is only interpretable with an SA of 15 ng/dL or higher and indicates probable primary
ratio (affected:normal) above 1.5. See Renin-Aldosterone Studies and Steroid Pathways in Special
Instructions. Note: Advice on stimulation or suppression tests is available from Mayo Clinic's Division of
Endocrinology and may be obtained by calling 800-533-1710.
Reference Values:
ALDS Aldosterone, Serum

loading, cardiac failure with ascites, pregnancy, Bartter syndrome)
ng/mL per hour, is a positive screening test result, a finding that warrants further testing. An SA/PRA
ratio greater than or equal to 20 is only interpretable with an SA greater than or equal to 15 ng/dL and
indicates probable primary aldosteronism. Renal disease, such as unilateral renal artery stenosis, results in
elevated renin and aldosterone levels. Renal venous catheterization may be helpful. A positive test is a
renal venous renin ratio (affected/normal) greater than 1.5. See Renin-Aldosterone Studies and Steroid
Pathways in Special Instructions. Note: Advice on stimulation or suppression tests is available from Mayo
Reference Values:
0-30 days: 17-154 ng/dL*
31 days-11 months: 6.5-86 ng/dL*
1-10 years:
< or =40 ng/dL (supine)*
< or =124 ng/dL (upright)*
> or =11 years: < or =21 ng/dL (a.m. peripheral vein specimen)
For International System of Units (SI) conversion for Reference Values, see
https://www.mayocliniclabs.com/order-tests/si-unit-conversion.html
aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am. 1997;26:801-827 3. Hurwitz
S, Cohen RJ, Williams GH: Diurnal variation of aldosterone and plasma renin activity: timing relation
to melatonin and cortisol and consistency after prolonged bed rest. J Appl Physiol. 2004;96:1406-1414
4. Inoue K, Goldwater D, Allison M, Seeman T, Kestenbaum BR, Watson KE: Serum aldosterone
concentration, blood pressure, and coronary artery calcium: The Multi-Ethnic Study of Atherosclerosis.
Hypertension. 2020;76(1):113-120. doi:10.1161/HYPERTENSIONAHA.120.15006
FALPE Alfalfa (Medicago sativa) IgE

57945 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10-0.34 Equivocal/Borderline 1
0.35-0.69 Low Positive 2 0.70-3.49 Moderate Positive 3 3.50-17.49 High Positive 4 5 6 17.50-49.99
50.0-99.99 >99.99 Very High Positive Very High Positive Very High Positive
Reference Values:
<0.35 kU/L
ALP Alkaline Phosphatase, Serum

8340 Clinical Information: Alkaline phosphatase in serum consists of 4 structural genotypes:
liver-bone-kidney, intestinal, and placental types, and the variant from the germ cells. It is found in
osteoblasts, hepatocytes, leukocytes, the kidneys, spleen, placenta, prostate, and the small intestine. The
liver-bone-kidney type is particularly important. A rise in the alkaline phosphatase occurs with all forms
of cholestasis, particularly with obstructive jaundice. It is also elevated in diseases of the skeletal
system, such as Paget disease, hyperparathyroidism, rickets, and osteomalacia, as well as with fractures
and malignant tumors. A considerable rise in the alkaline phosphatase activity is sometimes seen in
children and teenagers. It is caused by increased osteoblast activity following accelerated bone growth.
Useful For: Diagnosing and monitoring treatment of liver, bone, intestinal, and parathyroid diseases
Interpretation: Increases in serum alkaline phosphatase (ALP) activity commonly originate from
either one or both of 2 sources: liver and bone. Consequently, serum ALP measurements are of
particular interest in the investigation of 2 groups of conditions: hepatobiliary disease and bone disease
associated with increased osteoblastic activity. Serum ALP was the first enzyme to be used for the
investigation of hepatic disease. The response of the liver to any form of biliary tree obstruction induces
the synthesis of ALP by hepatocytes. The newly formed coenzyme is released from the cell membrane
by the action of bile salts and enters the circulation to increase the enzyme activity in serum. Increase
tends to be more notable (greater than 4-fold the upper reference value [URV]) in extrahepatic
obstruction (eg, by stone, by cancer of the head of the pancreas) than in intrahepatic obstruction and is
greater the more complete the obstruction. Serum enzyme activities may reach 10 to 12 times the URV
and usually return to baseline on surgical removal of the obstruction. A similar increase is seen in
patients with advanced primary liver cancer or widespread secondary hepatic metastases. ALP increase
(greater than 2-fold the URV) can predict transplant-free survival rates of patients with primary biliary
cirrhosis. Liver diseases that principally affect parenchymal cells, such as infectious hepatitis, typically
show only moderately (less than 3-fold) increased or even normal serum ALP activities. Increases may
also be seen as a consequence of a reaction to drug therapy, and ALT/ALP-based criteria to discriminate
the type of liver injury in drug-induced hepatic toxicity have been recommended. Intestinal ALP
isoenzyme, an asialoglycoprotein normally cleared by the hepatic asialoglycoprotein receptors, is often
increased in patients with liver cirrhosis.
Reference Values:
Males
0-14 days: 83-248 U/L
15 days-<1 year: 122-469 U/L
1-<10 years: 142-335 U/L
10-<13 years: 129-417 U/L
13-<15 years: 116-468 U/L
15-<17 years: 82-331 U/L
17-<19 years: 55-149 U/L
> or =19 years: 40-129 U/L
Females
0-14 days: 83-248 U/L
15 days-<1 year: 122-469 U/L
1-<10 years: 142-335 U/L
10-<13 years: 129-417 U/L
13-<15 years: 57-254 U/L
15-<17 years: 50-117 U/L
> or =17 years: 35-104 U/L
Clinical References: 1. Panteghini M, Bais R: Serum enzymes. In: Rifai N, Horvath AR, Wittwer C,
eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Elsevier; 2018:404-434 2. Abicht
K, El-Samalouti V, Junge W, et al: Multicenter evaluation of new GGT and AlP reagents with new
reference standardization and determination of 37 degrees C reference intervals. Clin Chem Lab Med.
2001;39(Special Suppl):S346 3. Estey MP, Cohen AH, Colantonio DA, et al: CLSI-based transference of
the CALIPER database of pediatric reference intervals from Abbott to Beckman, Ortho, Roche and
Siemens Clinical Chemistry Assays: Direct validation using reference samples from the CALIPER cohort.
Clin Biochem. 2013;46:1197-1219 4. Lammers WJ, van Buuren HR, Hirschfield GM, et al: Levels of
alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary
cirrhosis: An international follow-up study. Gastroenterology. 2014; 147: pp. 1338-1349
ALKI Alkaline Phosphatase, Total and Isoenzymes, Serum

89503 Clinical Information: Alkaline phosphatase (ALP) is present in a number of tissues including liver,
bone, intestine, and placenta. The activity of ALP found in serum is a composite of isoenzymes from
those sites and, in some circumstances, placental or Regan isoenzymes. Serum ALP is of interest in the
diagnosis of 2 main groups of conditions: hepatobiliary disease and bone disease associated with
increased osteoblastic activity. A rise in ALP activity occurs with all forms of cholestasis, particularly
with obstructive jaundice. The response of the liver to any form of biliary tree obstruction is to synthesize
more ALP. The main site of new enzyme synthesis is the hepatocytes adjacent to the biliary canaliculi.
ALP is also elevated in disorders of the skeletal system that involve osteoblast hyperactivity and bone
remodeling, such as Paget disease, rickets, osteomalacia, fractures, and malignant tumors. Moderate
elevation of ALP may be seen in other disorders such as Hodgkin disease, congestive heart failure,
ulcerative colitis, regional enteritis, and intra-abdominal bacterial infections.
Useful For: Diagnosis and treatment of liver, bone, intestinal, and parathyroid diseases Determining
the tissue source of increased alkaline phosphatase (ALP) activity in serum Differentiating between liver
and bone sources of elevated ALP
Interpretation: Total Alkaline Phosphatase: Alkaline phosphatase (ALP) elevations tend to be more
marked (more than 3-fold) in extrahepatic biliary obstructions (eg, by stone or cancer of the head of the
pancreas) than in intrahepatic obstructions: the more complete the obstruction, the greater the elevation.
With obstruction, serum ALP activities may reach 10 to 12 times the upper limit of normal, returning to
normal upon surgical removal of the obstruction. The ALP response to cholestatic liver disease is similar
to the response of gamma-glutamyltransferase (GGT) but more blunted. If both GGT and ALP are
elevated, a liver source of the ALP is likely. Among bone diseases, the highest level of ALP activity is
encountered in Paget disease, because of the action of the osteoblastic cells as they try to rebuild bone that
is being resorbed by the uncontrolled activity of osteoclasts. Values from 10 to 25 times the upper limit of
normal are not unusual. Only moderate rises are observed in osteomalacia, while levels are generally
normal in osteoporosis. In rickets, levels 2 to 4 times normal may be observed. Primary and secondary
hyperparathyroidism are associated with slight to moderate elevations of ALP; the existence and degree of
elevation reflects the presence and extent of skeletal involvement. Very high enzyme levels are present in
patients with osteogenic bone cancer. A considerable rise in ALP is seen in children following accelerated
bone growth. ALP increases of 2 to 3 times normal may be observed in women in the third trimester of
pregnancy, although the reference interval is very wide, and levels may not exceed the upper limit of
normal in some cases. In pregnancy, the additional enzyme is of placental origin. ALP Isoenzymes: Liver
ALP isoenzyme is associated with biliary epithelium and is elevated in cholestatic processes. Various
liver diseases (primary or secondary cancer, biliary obstruction) increase the liver isoenzyme. Liver 1Â is
increased in some nonmalignant diseases (such as cholestasis, cirrhosis, viral hepatitis, and in various
biliary and hepatic pathologies). It is also increased in malignancies with hepatic metastasis, in cancer of
the lungs and digestive tract, and in lymphoma. An increase of liver 2Â may occur in cholestasis and
biliary diseases (eg, cirrhosis, viral hepatitis) and in malignancies (eg, breast, liver, lung, prostate,
digestive tract) with liver metastasis. Osteoblastic bone tumors and hyperactivity of osteoblasts involved
in bone remodeling (eg, Paget disease) increase the bone isoenzyme. Paget disease leads to a striking,
solitary elevation of bone ALP. The intestinal isoenzyme may be increased in patients with cirrhosis and
in individuals who are blood group O or B secretors. The placental (carcino-placental antigen) and Regan
isoenzyme can be elevated in cancer patients.
Reference Values:
ALKALINE PHOSPHATASE
Males
0-14 days: 83-248 U/L
15 days-<1 year: 122-469 U/L
1-<10 years: 142-335 U/L
10-<13 years: 129-417 U/L
13-<15 years: 116-468 U/L
15-<17 years: 82-331 U/L
17-<19 years: 55-149 U/L
> or =19 years: 40-129 U/L
Females
0-14 days: 83-248 U/L
15 days-<1 year: 122-469 U/L
1-<10 years: 142-335 U/L
10-<13 years: 129-417 U/L
13-<15 years: 57-254 U/L
15-<17 years: 50-117 U/L
> or =17 years: 35-104 U/L
ALKALINE PHOSPHATASE ISOENZYMES

Liver 1%
0-6 years: 5.1-49.0%
7-9 years: 3.0-45.0%
10-13 years: 2.9-46.3%
14-15 years: 7.8-48.9%
16-18 years: 14.9-50.5%
> or =19 years: 27.8-76.3%
Liver 1
0-6 years: 7.0-112.7 IU/L
7-9 years: 7.4-109.1 IU/L
10-13 years: 7.8-87.6 IU/L
14-15 years: 10.3-75.6 IU/L
16-18 years: 13.7-78.5 IU/L
> or =19 years: 16.2-70.2 IU/L
Liver 2%
0-6 years: 2.9-13.7%
7-9 years: 3.7-12.5%
10-13 years: 2.9-22.3%
14-15 years: 2.2-19.8%
16-18 years: 1.9-12.5%
> or =19 years: 0.0-8.0%
Liver 2
0-6 years: 3.0-41.5 IU/L
7-9 years: 4.0-35.6 IU/L
10-13 years: 3.3-37.8 IU/L
14-15 years: 2.2-32.1 IU/L
16-18 years: 1.4-19.7 IU/L
> or =19 years: 0.0-5.8 IU/L
Bone %
0-6 years: 41.5-82.7%
7-9 years: 39.9-85.8%
10-13 years: 31.8-91.1%
14-15 years: 30.6-85.4%
16-18 years: 38.9-72.6%
> or =19 years: 19.1-67.7%
Bone
0-6 years: 43.5-208.1 IU/L
7-9 years: 41.0-258.3 IU/L
10-13 years: 39.4-346.1 IU/L
14-15 years: 36.4-320.5 IU/L
16-18 years: 32.7-214.6 IU/L
> or =19 years: 12.1-42.7 IU/L
Intestine %
0-6 years: 0.0-18.4%
7-9 years: 0.0-18.3%
10-13 years: 0.0-11.8%
14-15 years: 0.0-8.2%
16-18 years: 0.0-8.7%
> or =19 years: 0.0-20.6%
Intestine
0-6 years: 0.0-37.7 IU/L
7-9 years: 0.0-45.6 IU/L
10-13 years: 0.0-40.0 IU/L
14-15 years: 0.0-26.4 IU/L
16-18 years: 0.0-12.7 IU/L
> or =19 years: 0.0-11.0 IU/L
Placental
Not present
Chemistry and Molecular Diagnostics 6th ed. Elsevier; 2018 2. Lowe D, Sanvictores T, John S. Alkaline
phosphatase. In: StatPearls [Internet]. StatPearls Publishing; 2021. Updated August 11, 2021. Accessed
November 10, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK459201 3. Teitelbaum JE,
Laskowski A, Barrows FP: Benign transient hyperphosphatasemia in infants and children: a prospective
cohort. J Pediatr Endocrinol Metab. 2011;24(5-6):351-353 4. Jassam NJ, Horner J, Marzo-Ortega H, et al:
Transient rise in alkaline phosphatase activity in adults. BMJ Case Rep. 2009;2009: bcr09.2009.2250 5.
Verma J, Gorard DA: Persistently elevated alkaline phosphatase. BMJ Case Reports. 2012
Aug;24;2012:bcr2012006768 6. Sharma U, Pal D, Prasad R: Alkaline phosphatase: An overview. Indian J
Clin Biochem. 2014 Jul;29(3):269-278
FABP2 Allergic Bronchopulmonary Aspergillosis Panel II

57698 Interpretation: Total IgE Age Related Reference Range 1-11 months 0-12 1 year 0-15 2 year 1-29 3
year 4-35 4 year 2-33 5 year 8-56 6 year 3-95 7 year 2-88 8 year 5-71 9 year 3-88 10 year 7-110 11-14
year 7-111 15-19 year 6-96 20-30 year 4-59 31-50 year 5-79 51-80 year 3-48 Aspergillus fumigatus IgE
Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10-0.34 Equivocal 1 0.35-0.69 Low Positive 2
0.70-3.4 Moderate Positive 3 3.5-17.4 High Positive 4 17.5-49.9 Very High Positive 5 50.0-99.9 Very
High Positive 6 >= 100 Very High Positive Aspergillus fumigatus IgG mcg/mL of IgG Lower Limit of
Quantitation 2.0 Upper Limit of Quantitation 200
Reference Values:
Immunoglobulin E (IgE)
Age Related Reference Range
1-11 months 0-12
1 year 0-15
2 year 1-29
3 year 4-35
4 year 2-33
5 year 8-56
6 year 3-95
7 year 2-88
8 year 5-71
9 year 3-88
10 year 7-110
11-14 year 7-111
15-19 year 6-96
20-30 year 4-59
31-50 year 5-79
51-80 year 3-48
Aspergillus fumigatus IgE <0.35 kU/L

Aspergillus fumigatus IgG <46 mcg/mL
A. fumigatus Mix Gel Diffusion Negative
The gel diffusion method was used to test this patientÃ¢â‚¬â„¢s serum for the presence of
precipitating antibodies (IgG) to the antigens indicated. These antibodies are serological markers for
exposure and immunological sensitization. The clinical significance varies, depending on the history
and symptoms. This test was developed and its performance characteristics determined by Viracor
Eurofins. It has not been cleared or approved by the FDA.
Patients with allergic bronchopulmonary aspergillosis (ABPA) are expected to have the following
serological features:
1) A high total IgE of >500 IU/mL, unless patient is receiving corticosteroids.

2) An elevated Aspergillus-specific IgE of class 4 or higher.
3) Positive for Aspergillus-specific IgG.
ALLOI Allo-isoleucine, Blood Spot

88888 Clinical Information: Maple-syrup urine disease (MSUD) is an inborn error of metabolism caused
by the deficiency of the branched-chain-ketoacid dehydrogenase (BCKDH) complex. The BCKDH
complex is involved in the metabolism of the branched-chain amino acids (BCAA): isoleucine (Ile),
leucine (Leu), and valine (Val). Classic MSUD presents in the neonate with feeding intolerance, failure
to thrive, vomiting, lethargy, and maple-syrup odor to urine and cerumen. If untreated, it progresses to
irreversible intellectual disability, hyperactivity, failure to thrive, seizures, coma, cerebral edema, and
possibly death. MSUD is a panethnic condition but is most prevalent in the Old Order Mennonite
community in Lancaster, Pennsylvania with an incidence there of 1 in760 live births. The incidence of
MSUD is approximately 1 in 185,000 live births in the general population. Newborn screening includes
the measurement of BCAA (Leu, Ile, and Val), which are elevated in MSUD. However, unaffected
infants receiving total parenteral nutrition frequently have increased levels of BCAA, a situation that
often triggers unnecessary follow-up investigations. Abnormal concentrations of allo-isoleucine
(Allo-Ile) are pathognomonic for MSUD. The determination of Allo-Ile (second-tier testing) in the same
newborn screening specimens that reveals elevated BCAA allows for positive identification of patients
with MSUD and differentiation from BCAA elevations due to dietary artifacts, reducing the occurrence
of false-positive newborn screening results. Treatment of MSUD aims to normalize the concentration of
BCAA by dietary restriction of these amino acids. BCAA are essential amino acids, which require
frequent adjustment of the dietary treatment. Dietary monitoring is accomplished by regular
determination of BCAA and Allo-Ile concentrations.
Useful For: Evaluation of newborn screening specimens that test positive for branched-chain amino
acids elevations Follow-up of patients with maple-syrup urine disease
Interpretation: Allo-isoleucine is nearly undetectable in individuals not affected by maple-syrup urine

disease (MSUD). Accordingly, its presence is diagnostic for MSUD, and its absence is sufficient to
rule-out MSUD.
Reference Values:
Allo-isoleucine: <2 nmol/mL
Leucine: 35-215 nmol/mL
Isoleucine: 13-130 nmol/mL
Valine: 51-325 nmol/mL
An interpretive report will also be provided.
Clinical References: 1. Chace DH, Kalas TA, Naylor EW: Use of tandem mass spectrometry for
multianalyte screening of dried blood specimens from newborns. Clin Chem. 2003
Nov;49(11):1797-1817. doi: 10.1373/clinchem.2003.022178 2. Simon E, Fingerhut R, Baumkotter J,
Konstantopoulou V, Ratschmann R, Wendel U: Maple syrup urine disease: Favorable effect of early
diagnosis by newborn screening on the neonatal course of the disease. J Inherit Metab Dis. 2006
Aug;29(4):532-537. doi: 10.1007/s10545-006-0315-y 3. Morton DH, Strauss KA, Robinson DL,
Puffenberger EG, Kelley RI: Diagnosis and treatment of maple syrup disease: a study of 36 patients.
Pediatrics. 2002 Jun;109(6):999-1008. doi: 10.1542/peds.109.6.999 4. Strauss KA, Puffenberger EG,
Carson VJ: Maple syrup urine disease. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews
[Internet]. University of Washington, Seattle; 2006. Updated April 23, 2020. Accessed December 16,
2020. Available at www.ncbi.nlm.nih.gov/books/NBK1319/
FALFG Almond Food IgG

57519 Interpretation:
Reference Values:
Reference ranges have not been established for food-specific IgG tests. The clinical utility of
food-specific IgG tests has not been established. These tests can be used in special clinical situations to
select foods for evaluation by diet elimination and challenge in patients who have food-related
complaints. It should be recognized that the presence of food-specific IgG alone cannot be taken as
evidence of food allergy and only indicates immunologic sensitization by the food allergen in question.
This test should only be ordered by physicians who recognize the limitations of the test.
ALM Almond, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to almonds Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
ALPS Alpha Beta Double-Negative T Cells for Autoimmune

82449 Lymphoproliferative Syndrome, Blood
Clinical Information: Autoimmune lymphoproliferative syndrome (ALPS) (also known as
Canale-Smith syndrome) is a complex clinical disorder of dysregulated lymphocyte homeostasis that is
characterized by lymphoproliferative disease, autoimmune cytopenias, splenomegaly, and
lymphadenopathy with an increased susceptibility to malignancy.(1) Typically, ALPS is diagnosed by
childhood or young adulthood. Genetic defects in the apoptosis (programmed cell death) pathway have
been determined for most cases of ALPS. Apoptosis plays a role in normal immune homeostasis by
limiting lymphocyte accumulation and autoimmune reactivity. The interaction of the surface receptor
CD95 (FAS) and its ligand (CD95L; FASL) triggers the apoptotic pathway in lymphocytes. Germline
variants in CD95 (FAS) are the most common cause (60-75%) of ALPS(2), followed by somatic
mutations in CD95 (FAS). Variants in CD95L (FASL), CASP10, and others are rare causes. Currently
up to 20% of patients do not have an identifiable genetic variant (ALPS-U). The following molecular
ALPS classification has been established: Revised ALPS classification Previous classification
Molecular/genetic defect in apoptosis ALPS-FAS Type Ia CD95 (FAS) variants(1,2) ALPS-sFAS
Somatic CD95 (FAS) mutations (1,2) ALPS-FASL Type Ib Heterozygous CD95L (FASLG)
variants(1,2) ALPS-FASL Type Ic Homozygous CD95L (FASLG) variants(1,2) ALPS-CASP10 Type
II CASP10 variants(1,2) ALPS-U Type III Unknown(1,3) Patients with ALPS have an increase in a
normally rare population of T cells (typically <1%) that are alpha beta T-cell receptor (TCR)-positive,
as well as negative for both CD4 and CD8 coreceptors (double-negative T cells: DNT).(1) The alpha
beta TCR+DNT cells from ALPS patients also express an unusual B-cell-specific CD45R isoform,
called B220.(4,5) B220 expression on alpha beta TCR+DNT cells has been demonstrated to be a
sensitive and specific marker for ALPS and is associated with FAS mutations.(4) Several other diseases
can present with an ALPS-like phenotype, including other inborn errors of immunity, like CTLA4 and
LRBA deficiency, and gain-of function variants in STAT3 and CARD11 genes(2,3), as well as
independent conditions like Evans syndrome (a combination of autoimmune hemolytic anemia and
autoimmune thrombocytopenic purpura), Rosai-Dorfman disease (massive painless cervical
lymphadenopathy that may be accompanied by leukocytosis, elevated erythrocyte sedimentation rate,
and hypergammaglobulinemia), and nodular lymphocyte-predominant Hodgkin disease, among others
(1,2,3). B220 expression on double negative T cells has also been described in large granular
lymphocyte leukemias.(5)
Useful For: Diagnosing autoimmune lymphoproliferative syndrome, primarily in patients younger than
45 years of age
Interpretation: The presence of increased circulating T cells (CD3+) that are negative for CD4 and
CD8 (double-negative T cells: DNT) and positive for the alpha/beta T-cell receptor (TCR) is required for
the diagnosis of autoimmune lymphoproliferative syndrome (ALPS). The laboratory finding of increased
alpha beta TCR+DNT cells is consistent with ALPS only with the appropriate clinical picture
(nonmalignant lymphadenopathy, splenomegaly, and autoimmune cytopenias). Conversely, there are
other immunological disorders, including common variable immunodeficiency (CVID), which have
subsets for patients with this clinical picture, but no increase in alpha beta TCR+DNT cells. If the percent
of the absolute count of either the alpha beta TCR+DNT cells or alpha beta TCR+DNT B220+ cells is
abnormal, additional testing is indicated. All abnormal alpha beta TCR+DNT cell results should be
confirmed (for ALPS) with additional testing for defective in vitro lymphocyte apoptosis, followed by
confirmatory genetic testing for FAS variants; call 800-533-1710 for test information.
Reference Values:
Alpha beta TCR+DNT cells
2-18 years: <2% CD3 T cells
19-70+ years: <3% CD3 T cells
Reference values have not been established for patients that are younger than 24 months of age.
Alpha beta TCR+DNT cells

2-18 years: <35 cells/mcL
19-70+ years: <35 cells/mcL
Alpha beta TCR+DNT B220+ cells

2-18 years: <0.4% CD3 T cells
19-70+ years: <0.3% CD3 T cells
Alpha beta TCR+DNT B220+ cells

2-18 years: <7 cells/mcL
19-70+ years: <6 cells/mcL
TCR = T-cell receptor

DNT = Double negative T cell
Clinical References: 1. Oliveira JB, Bleesing JJ, Dianzani U, et al: Revised diagnostic criteria and
classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH
International Workshop. Blood. 2010 Oct 7;116(14):e35-40 2. Consonni F, Gambineri E, Favre C: ALPS,
FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies. Ann Hematol. 2022
Mar;101(3):469-484. doi: 10.1007/s00277-022-04761-7 3. Lopez-Nevado M, Gonzalez-Granado LI,
Ruiz-Garcia R, et al: Primary immune regulatory disorders with an autoimmune lymphoproliferative
syndrome-like phenotype: Immunologic evaluation, early diagnosis and management. Front Immunol.
2021 Aug 10;12:671755. Published 2021 Aug 10. doi:10.3389/fimmu.2021.671755 4. Bleesing JJ, Brown
MR, Dale JK, et al: TCR alpha beta+ CD4-CD8-T-cells in humans with the autoimmune
lymphoproliferative syndrome express a novel CD45 isoform that is analogous to urine B220 and
represents a marker of altered O-glycan biosynthesis. Clin Immunol. 2001 Sep;100(3):314-324 5.
Bleesing JJH, Janik JE, Fleisher TA: Common expression of an unusual CD45 isoform on T-cells from
patients with large granular lymphocyte leukemia and autoimmune lymphoproliferative syndrome. Br J
Haematol. 2003 Jan;120(1):93-96
ALDEF Alpha Defensin, Lateral Flow Assay, Synovial Fluid

607710 Clinical Information: Diagnosis of prosthetic joint infections (PJI) may be challenging in certain
clinical scenarios. Multiple societies have defined criteria for establishing the presence of a PJI,
including results from laboratory tests, clinical findings, and tissue histopathology. The challenge,
however, is that results of these tests are frequently not available at the time of or after surgery. As an
alternative, determining the cell count and differential on synovial fluid are frequently used biomarkers
for PJI, however there is a lack of consensus on the optimal thresholds to use for a PJI diagnosis.
Additionally, cell count and differential results require clinician interpretation as laboratories do not
report abnormal levels correlating with PJI. Alpha defensins are antimicrobial peptides released by
activated neutrophils in response to infection and served as part of the host-defense innate immune
system with broad antimicrobial activity against gram-positive and gram-negative bacteria,
mycobacteria, fungi, and viruses. The presence of alpha defensins in synovial fluid may therefore be
used by clinicians as a marker of PJI.
Useful For: Detection of alpha defensins 1-3, human host response proteins, in synovial fluid of
adults with a total joint replacement who are being evaluated for revision surgery This test is not
intended to be used to determine timing for reimplantation in 2-stage procedures.
Interpretation: Negative:Â No alpha defensin detected in synovial fluid, suggesting absence of

prosthetic joint infection. Positive:Â Alpha defensin in synovial fluid detected suggesting presence of
prosthetic joint infection. Additional microbiologic studies (eg, culture, molecular detection) are
recommended.
Reference Values:
Negative
Clinical References: Bonanzinga T, Ferrari MC, Tanzi G, et al: The role of alpha defensin in
prosthetic join infection (PJI) diagnosis: a literature review. EFFORT Open Rev 2019;4:10-13
AFSH Alpha Follicle Stimulating Hormone Immunostain, Technical

Clinical Information: Follicle stimulating hormone (FSH) alpha subunit is a component common
to all glycoprotein hormones produced by the anterior pituitary (luteinizing hormone [LH],
thyroid-stimulating hormone [TSH], and FSH). Glycoprotein hormone-producing cells (approximately
30% of the total cell population) in normal pituitary stain in a cytoplasmic pattern.
Immunohistochemical detection of alpha-FSH may be useful in the classification of pituitary adenomas.
Useful For: May aid in the classification of pituitary adenomas

Interpretation: This test does not include pathologist interpretation, only technical performance of
the stain. If interpretation is required, order PATHC / Pathology Consultation for a full diagnostic
evaluation or second opinion of the case. Â The positive and negative controls are verified as showing
upon request, call 855-516-8404. Â Interpretation of this test should be performed in the context of the
Clinical References: 1. Hamid Z, Mrak RE, Ijaz MT, Faas FH: Sensitivity and specificity of
immunohistochemistry in pituitary adenomas. The Endocrinologist. 2009;19(1):38-43 2. Osamura RY,
Kajiya H, Takei M, et al: Pathology of the human pituitary adenomas. Histochem Cell Biol.
2008;130(3):495-507 3. Osamura RY, Watanabe K: Immunohistochemical studies of human FSH
producing pituitary adenomas. Virchows Archiv A. 1988;413(1):61-68 4. Pawlikowski M, Pisarek H,
Kubiak R, Jaranowska M, Stepien H: Immunohistochemical detection of FSH receptors in pituitary
adenomas and adrenal tumors. Folia Histochem Cytobiol. 2012;50(3):325-330
WASEQ Alpha Globin Gene Sequencing, Varies

61362 Clinical Information: Alpha-globin gene sequencing detects alpha-globin variants and nondeletional
alpha-thalassemia variants. Alpha thalassemia is the most common monogenic condition in the world. It is
estimated that up to 5% of the world's population carries at least one alpha-thalassemia variant and, in the
United States, approximately 30% of African Americans are thought to carry an alpha-thalassemia
variant. Alpha-thalassemia variations are most common in individuals of Southeastern Asian, African,
Mediterranean, Indian, and Middle Eastern descent, but they can be found in persons from any ethnic
group. Four alpha-globin genes are normally present, 2 copies on each chromosome 16.
Alpha-thalassemia variants result in decreased alpha-globin chain production. In general, alpha
thalassemia is characterized by hypochromic, microcytic anemia and varies clinically from asymptomatic
(alpha-thalassemia silent carrier and alpha-thalassemia trait) to lethal hemolytic anemia (hemoglobin [Hb]
Barts hydrops fetalis). Large deletions of the alpha-globin genes account for approximately 90% of
alpha-thalassemia alterations, and these variations will not be detected by alpha-globin gene sequencing.
Other variants, such as point alterations or small deletions within the alpha-globin genes, account for most
of the remaining 10% of alpha-thalassemia variations. These nondeletional subtypes can be detected by
alpha-globin gene sequencing. The most common nondeletional alpha-thalassemia variant is Hb Constant
Spring. The majority of alpha-globin chain variants are clinically and hematologically benign however,
some cause erythrocytosis and chronic hemolytic anemia. Hemoglobin electrophoresis may not be able to
confirm their identity. In these instances, alpha-globin gene sequencing can be useful.
Useful For: Diagnosing nondeletional alpha thalassemia Testing for nondeletional alpha thalassemia in
a symptomatic individual Follow-up testing to an abnormal hemoglobin electrophoresis that identified an
alpha-globin chain variant
Interpretation: An interpretive report will be provided.

Reference Values:
Clinical References: 1. Harteveld CL, Higgs DR: Alpha-thalassemia. Orphanet J Rare Dis.
2010;5:13 2. Hoyer JD, Hoffman DR: The Thalassemia and hemoglobinopathy syndromes. In:
McClatchey, KD, ed. Clinical Laboratory Medicine. 2nd ed. Lippincott Williams and Wilkins.
2002;866-895 3. Farashi S, Harteveld CL: Molecular basis of a-thalassemia. Blood Cells Mol Dis. 2018
May;70:43-53. doi: 10.1016/j.bcmd.2017.09.004 4. Henderson SJ, Timbs AT, McCarthy J, et al: Ten
years of routine a- and B-globin gene sequencing in UK hemoglobinopathy referrals reveals 60 novel
mutations. Hemoglobin. 2016;40(2):75-84. doi: 10.3109/03630269.2015.1113990
FALG Alpha Lactalbumin IgG

Reference Values:
ASYN Alpha Synuclein Immunostain, Technical Component Only

70635
Clinical Information: Alpha synuclein is a member of a family of cytoplasmic proteins found
predominantly in the presynaptic nerve terminal of the brain. Synucleins are thought to be involved in
neuronal plasticity, synaptic function, and neurodegenerative disease. Alpha-synuclein is abundant in
Lewy bodies in sporadic Parkinson disease and dementia with Lewy bodies. It is a major component of
amyloid plaques in Alzheimer disease.
Useful For: Identification of alpha synuclein in neurogenerative disorders

and will be performed as necessary at the discretion of the Mayo pathologist. Â The positive and
negative controls are verified as showing appropriate immunoreactivity and documentation is retained at
Mayo Clinic Rochester. If a control tissue is not included on the slide, a scanned image of the relevant
quality control tissue is available upon request. Contact 855-516-8404. Â Interpretation of this test
should be performed in the context of the patient's clinical history and other diagnostic tests by a
qualified pathologist.
Clinical References: 1. Jellinger KA: Formation and development of Lewy pathology: a critical
update. J Neurol 2009 Aug;256 Suppl 3:270-279 2. Kotzbauer PT, Trojanowsk JQ, Lee VM: Lewy
body pathology in Alzheimer's disease. J Mol Neurosci 2001 Oct;17(2):225-232 3. Spillantini MG,
Goedert M: The alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple
system atrophy. Y Acad Sci 2000;920:16-27 4. Baba M, Nakajo S, Tu PH, et al: Aggregation of
alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J
Pathol 1998 (152):879-884 5. McKeith IG, Galasko D, Kosaka K, et al: Consensus guidelines for the
clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on
DLB international workshop. Neurology 1996 Nov;47(5):1113-1124
FA1GP Alpha-1-Acid Glycoprotein

Adults: 39 Ã¢â‚¬â€œ 115 mg/dL
A1AFS Alpha-1-Antitrypsin Clearance, Feces and Serum

604982 Clinical Information: Alpha-1-antitrypsin (AAT) is a 54kDa glycoprotein that is resistant to
degradation by digestive enzymes and is, therefore, used as an endogenous marker for the presence of
blood proteins in the intestinal tract. AAT clearance is reliable for measuring protein loss distal to the
pylorus. A serum sample is required to interpret results as a serum deficiency of AAT would make the
AAT fecal excretion lower and could invalidate the test utility. Gastrointestinal protein enteropathy has
been associated with regional enteritis, sprue, Whipple intestinal lipodystrophy, gastric carcinoma,
allergic gastroenteropathy, intestinal lymphangiectasia, constrictive pericarditis, congenital
hypogammaglobulinemia, and iron deficiency anemia associated with intolerance to cow's milk.
Increased fecal excretion of AAT can be found in small and large intestine disease and is applicable to
adult and children.
Useful For: Diagnosing protein-losing enteropathies

Interpretation: Elevated alpha-1-antitrypsin (AAT) clearance suggests excessive gastrointestinal
protein loss. The positive predictive value of the test has been found to be 97.7% and the negative
predictive value is 75%. Patients with protein-losing enteropathies generally have AAT clearance values
greater than 50 mL/24 hours and AAT fecal concentrations above 100 mg/dL. Borderline elevations
above the normal range are equivocal for protein-losing enteropathies.
Reference Values:
CLEARANCE:
< or =27 mL/24 hours
FECAL ALPHA-1-ANTRYPSIN CONCENTRATION:

< or =54 mg/dL
SERUM ALPHA-1-ANTRYPSIN CONCENTRATION:

100-190 mg/dL
Clinical References: 1. Florent C, L'Hirondel C, Desmazures C, Aymes C, Bernier JJ: Intestinal

clearance of alpha 1-antitrypsin. A sensitive method for the detection of protein losing enteropathy.
Gastroenterology. 1981 Oct;81(4):777-780 2. Crossley JR, Elliott RB: Simple method for diagnosing
protein-losing enteropathies. Br Med J. 1977 Feb 12;1(6058):428-429 3. Perrault J, Markowitz H:
Protein-losing gastroenteropathy and the intestinal clearance of serum alpha-1-antitrypsin. Mayo Clin
Proc. 1984 Apr;59(4):278-279 4. Schmidt PN, Blirup-Jensen S, Svendsen PJ, Wandall JH:
Characterization and quantification of plasma proteins excreted in faeces from healthy humans. Scand J
Clin Lab Invest. 1995 Feb;55(1):35-45 5. Davidson NO: Intestinal lipid absorption. In: Yamada T, Alpers
DH, Kaplowitz N, eds. Textbook of Gastroenterology. JB Lippincott; 2003:413 6. Rybolt AH, Bennett
RG, Laughon BE, Thomas DR, Greenough WB III, Bartlett JG: Protein-losing enteropathy associated
with Clostridium difficile infection. Lancet. 1989 Jun 17;1(8651):1353-1355 7. Molina JF, Brown RF,
Gedalia A, Espinoza LR: Protein losing enteropathy as the initial manifestation of childhood systemic
lupus erythematosus. J Rheumatol. 1996 Jul;23(7):1269-1271 8. Umar SB, DiBaise JK: Protein-losing
enteropathy: case illustrations and clinical review. Am J Gastroenterol. 2010 Jan;105(1):43-49 9. Levitt
DG, Levitt MD: Protein losing enteropathy: comprehensive review of the mechanistic association with
clinical and subclinical disease states. Clin Exp Gastroenterol. 2017 Jul;10:147-168 10. Murray FR,
Morell B, Biedermann L, Schreiner P: Protein-losing enteropathy as precursor of inflammatory bowel
disease: A review of the literature. BMJ Case Rep. 2021 Jan 11;14(1):e238802
AATRP Alpha-1-Antitrypsin Immunostain, Technical Component Only

70350 Clinical Information: Alpha-1-antitrypsin (AAT) is a plasma protein synthesized in the liver and is
present in serum and tissue fluids where it acts as an inhibitor of proteases, especially elastase. AAT
deficiency is associated with development of emphysema and liver disease. In liver disease, abnormal
accumulation of AAT is seen as cytoplasmic globules in hepatocytes.
Useful For: Identification of abnormal accumulation of alpha-1-antitrypsin

control tissue is available upon request, call 855-516-8404. Interpretation of this test should be performed
in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Callea F, Fevery J, Massi G, Lievens C, de Groote J, Desmet VJ:

Alpha-1-antitrypsin (AAT) and its stimulation in the liver of PiMZ phenotype individuals. A
"recruitment-secretory block" ("R-SB") phenomenon. Liver. 1984:4(5):325-337 2. Lam M, Torbenson M,
Yeh MM, Vivekanandan P, Ferrell L: HFE mutations in alpha-1-antitrypsin deficiency: an examination of
cirrhotic explants. Mod Pathol. 2010;23:637-643 3. Theaker JM, Fleming KA: Alpha-1-antitrypsin and
the liver: a routine immunohistological screen. J Clin Pathol. 1986;39(1):58-62
A1APP Alpha-1-Antitrypsin Phenotype, Serum

26953 Clinical Information: Alpha-1-antitrypsin (A1A) is the most abundant serum protease inhibitor and
inhibits trypsin and elastin, as well as several other proteases. The release of proteolytic enzymes from
plasma onto organ surfaces and into tissue spaces results in tissue damage unless inhibitors are present.
Congenital deficiency of A1A is associated with the development of emphysema at an unusually early age
and with an increased incidence of neonatal hepatitis, usually progressing to cirrhosis. Most normal
individuals have the M phenotype (M, M1, or M2). Over 99% of M phenotypes are genetically MM. In
the absence of family studies, the phenotype (M) and quantitative level can be used to infer the genotype
(MM). The most common alleles associated with a quantitative deficiency are Z and S. See
Alpha-1-Antitrypsin-A Comprehensive Testing Algorithm in Special Instructions.
Useful For: Identification of homozygous and heterozygous phenotypes of the alpha-1-antitrypsin

deficiency
Interpretation: There are greater than 40 alpha-1-antitrypsin (A1A) phenotypes (most of these are
associated with normal quantitative levels of protein). The most common normal phenotype is M (M,
M1, or M2), and greater than 90% of Caucasians are genetically homozygous M (MM). A1A deficiency
is usually associated with the Z phenotype (homozygous ZZ), but SS and SZ are also associated with
decreased A1A levels.
Reference Values:
ALPHA-1-ANTITRYPSIN
100-190 mg/dL
ALPHA-1-ANTITRYPSIN PHENOTYPE
The interpretive report will identify the alleles present. For rare alleles, the report will indicate whether
or not they have been associated with reduced quantitative levels of alpha-1-antitrypsin.
Clinical References: 1. Morse JO: Alpha-1-antitrypsin deficiency. N Engl J Med

1978;299:1045-1048;1099-1105 2. Donato LJ, Jenkins SM, Smith C, et al: Reference and interpretive
ranges for alpha(1)-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin
Pathol 2012 Sep;138(3):398-405
A1ALC Alpha-1-Antitrypsin Proteotype S/Z, LC-MS/MS, Serum

61767 Clinical Information: Alpha-1-antitrypsin (A1A) is a protein that inhibits the enzyme neutrophil
elastase. It is predominantly synthesized in the liver and secreted into the bloodstream. The inhibition
function is especially important in the lungs because it protects against excess tissue degradation. Tissue
degradation due to A1A deficiency is associated with an increased risk for early onset panlobular
emphysema, which initially affects the lung bases (as opposed to smoking-related emphysema, which
presents with upper-lung field emphysema). Patients may become symptomatic in their 30s and 40s.
The most frequent symptoms reported in a National Institute of Health study of 1129 patients with
severe deficiency (mean age 46 years) included cough (42%), wheezing (65%), and dyspnea with
exertion (84%). Many patients were misdiagnosed as having asthma. It is estimated that approximately
one-sixth of all lung transplants are for A1A deficiency. Liver disease can also occur, particularly in
children; it occurs much less commonly than emphysema in adults. A1A deficiency is a relatively
common disorder in those of Northern European ancestry. The diagnosis of A1A deficiency is initially
made by quantitation of protein levels in serum followed by determination of specific allelic variants by
isoelectric focusing (IEF). While there are many different alleles in this gene, only 3 are common. The 3
major alleles include: M (full functioning, normal allele), S (associated with reduced levels of protein),
and Z (disease-causing variant associated with liver disease and premature emphysema). The S and Z
alleles account for the majority of the abnormal alleles detected in affected patients. As a codominant
disorder, both alleles are expressed. An individual of SZ or S-null genotype may have a small increased
risk for emphysema (but not liver disease) due to slightly reduced protein levels. On the other hand, an
individual with the ZZ genotype is at greater risk for early onset liver disease and premature
emphysema. Smoking appears to hasten development of emphysema by 10 to 15 years. These
individuals should be monitored closely for lung and liver function. Historically, IEF has been the
primary method for characterizing variants, although in some cases, the interpretation is difficult and
prone to error. Serum quantitation is helpful in establishing a diagnosis but can be influenced by other
factors. A proteomic method using trypsin-digested sera can detect the mutated peptides of the S and Z
alleles but can miss disease alleles other than the S and Z alleles. This test combines all of these
methods to provide a comprehensive result.
Useful For: Identification of homozygous and heterozygous S and Z proteotypes of

alpha-1-antitrypsin deficiency
Interpretation: For each of the possible alpha-1-antitrypsin (A1A) genotypes there is an expected
range for the total serum level of A1A. However, a number of factors can influence either the A1A serum
level or the A1A proteotype results, including acute illness (A1A is an acute-phase reactant), protein
replacement therapy, the presence of other rare variants, or the presence of rare DNA alterations (ie,
polymorphisms). When the serum level differs from what is expected for that proteotype (ie, discordant),
additional studies are performed to ensure the most appropriate interpretation of test results. Additional
follow-up may include A1A phenotyping by isoelectric focusing, obtaining additional clinical
information, and DNA sequencing. See Alpha-1-Antitrypsin Testing Result Table.
Reference Values:
ALPHA-1-ANTITRYPSIN:
100-190 mg/dL
ALPHA-1-ANTITRYPSIN PROTEOTYPE:
Negative for S and Z phenotype (Non S Non Z)
Clinical References: 1. Stoller JK, Aboussouan LS: Alpha-1-antitrypsin deficiency. Lancet. 2005
Jun 25-Jul 1;365(9478):2225-2236 2. McElvaney NG, Stoller JK, Buist AS, et al: Baseline characteristics
of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency.
Alpha 1-Antitrypsin Deficiency Registry Study Group. Chest. 1997 Feb;111(2):394-403 3. Murray JD,
Willrich MA, Krowka et al: Liquid chromatography-tandem mass spectrometry based alpha1-antitypsin
(AAT) testing, Am J Clin Clin Pathol. 2021 Mar 15;155(4):547-552
A1AF Alpha-1-Antitrypsin, Random, Feces

182 Clinical Information: Alpha-1-antitrypsin (AAT) is a 54kDa glycoprotein that is resistant to
degradation by digestive enzymes and is, therefore, used as an endogenous marker for the presence of
blood proteins in the intestinal tract. AAT clearance is reliable for measuring protein loss distal to the
pylorus. A serum sample is required to interpret results as a serum deficiency of AAT) would make the
AAT fecal excretion lower and could invalidate the test utility. Gastrointestinal protein enteropathy has
been associated with regional enteritis, sprue, Whipple intestinal lipodystrophy, gastric carcinoma,
allergic gastroenteropathy, intestinal lymphangiectasia, constrictive pericarditis, congenital
hypogammaglobulinemia, and iron deficiency anemia associated with intolerance to cow's milk. Increased
fecal excretion of AAT can be found in small and large intestine disease and is applicable to adults and
children.
Useful For: Diagnosing protein-losing enteropathies, especially when used in conjunction with serum
alpha-1-antitrypsin (AAT) levels as a part of AAT clearance studies
Interpretation: Patients with protein-losing enteropathies generally have alpha-1-antitrypsin fecal

concentrations over 100 mg/dL. Borderline elevations above the normal range are equivocal for
protein-losing enteropathies.
Reference Values:
< or =54 mg/dL
Clinical References: 1. Florent C, L'Hirondel C, Desmazures C, Aymes C, Bernier JJ: Intestinal

clearance of alpha 1-antitrypsin. A sensitive method for the detection of protein losing enteropathy.
Gastroenterology. 1981 Oct;81(4):777-780 2. Crossley JR, Elliott RB: Simple method for diagnosing
protein-losing enteropathies. Br Med J. 1977 Feb 12;1(6058):428-429 3. Perrault J, Markowitz H:
Protein-losing gastroenteropathy and the intestinal clearance of serum alpha-1-antitrypsin. Mayo Clin
Proc. 1984 Apr;59(4):278-279 4. Levitt DG, Levitt MD: Protein losing enteropathy: comprehensive
review of the mechanistic association with clinical and subclinical disease states. Clin Exp Gastroenterol.
2017 Jul;10:147-168 5. Murray FR, Morell B, Biedermann L, Schreiner P: Protein-losing enteropathy as
precursor of inflammatory bowel disease: A review of the literature. BMJ Case Rep. 2021 Jan
11;14(1):e238802
AAT Alpha-1-Antitrypsin, Serum
8161 Clinical Information: Alpha-1-antitrypsin (A1A) is the most abundant serum protease inhibitor
and inhibits trypsin and elastin, as well as several other proteases. The release of proteolytic enzymes
from plasma onto organ surfaces and into tissue spaces results in tissue damage unless inhibitors are
present. Congenital deficiency of A1A is associated with the development of emphysema at an
unusually early age and with an increased incidence of neonatal hepatitis, usually progressing to
cirrhosis. See Alpha-1-Antitrypsin-A Comprehensive Testing Algorithm in Special Instructions.
Useful For: Workup of individuals with suspected disorders such as familial chronic obstructive lung
disease Diagnosis of alpha-1-antitrypsin deficiency
Interpretation: Patients with serum levels less than 70 mg/dL may have a homozygous deficiency
and are at risk for early lung disease. Alpha-1-antitrypsin proteotyping should be done to confirm the
presence of homozygous deficiency alleles. If clinically indicated, patients with serum levels less than
125 mg/dL should be proteotyped in order to identify heterozygous individuals. Heterozygotes do not
appear to be at increased risk for early emphysema.
Reference Values:
100-190 mg/dL
Clinical References: 1. Kanakoudi F, Drossou V, Tzimouli V, et al: Serum concentrations of 10

acute-phase proteins in healthy term and pre-term infants from birth to age 6 months. Clin Chem.
1995;41:605-608 2. Morse JO: Alpha-1-antitrypsin deficiency. N Engl J Med. 1978;299:1045-1048,
1099-1105 3. Cox DW: Alpha-1-antitrypsin deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D,
eds. The Metabolic and Molecular Basis of Inherited Disease. Vol 3. 7th ed. McGraw-Hill Book
Company; 1995:4125-4158
A124 Alpha-1-Microglobulin, 24 Hour, Urine.

610363 Clinical Information: Alpha-1-microglobulin is a low-molecular-weight protein of 26 kDa and a
member of the lipocalin protein superfamily.(1) It is synthesized in the liver, freely filtered by
glomeruli, and reabsorbed by renal proximal tubules cells where it is catabolized.(1) Due to extensive
tubular reabsorption, under normal conditions very little filtered alpha-1-microglobulin appears in the
final excreted urine. Therefore, an increase in the urinary concentration of alpha-1-microglobulin
indicates proximal tubule injury and/or impaired proximal tubular function. Elevated excretion rates can
indicate tubular damage associated with renal tubulointerstitial nephritis or tubular toxicity from heavy
metal or nephrotoxic drug exposure. Glomerulonephropathies and renal vasculopathies also are often
associated with coexisting tubular injury and so may result in elevated excretion. Elevated
alpha-1-microglobulin in patients with urinary tract infections may indicate renal involvement
(pyelonephritis). Measurement of urinary excretion of retinol-binding protein, another
low-molecular-weight protein, is an alternative to the measurement of alpha-1-microglobulin. To date,
there are no convincing studies to indicate that one test has better clinical utility than the other. Urinary
excretion of alpha-1-microglobulin can be determined from either a 24-hour collection or from a
random urine collection. The 24-hour collection is traditionally considered the gold standard. For
random or spot collections, the concentration of alpha-1-microglobulin is divided by the urinary
creatinine concentration. This corrected value adjusts alpha-1-microglobulin for variabilities in urine
concentration.
Useful For: Assessment of renal tubular injury or dysfunction using 24-hour urine collections
Screening for tubular abnormalities Detecting chronic asymptomatic renal tubular dysfunction(2)
Interpretation: Alpha-1-microglobulin above the reference values may be indicative of a proximal

tubular dysfunction.
Reference Values:
> or =18 years: <23 mg/24 hours
Reference values have not been established for patients who are less than 18 years of age.
Clinical References: 1. Akerstrom B, Logdberg L, Berggard T, Osmark P, Lindqvist A:

Alpha(1)-microglobulin: a yellow-brown lipocalin. Biochim Biophys Acta. 2000 Oct
18;1482(1-2):172-184 2. Yu H, Yanagisawa Y, Forbes M, Cooper EH, Crockson RA, MacLennan RC:
Alpha-1-microglobulin: an indicator protein for renal tubular function. J Clin Pathol. 1983
Mar;36(3):253-259 3. Hjorth L, Helin I, Grubb A: Age-related reference limits for urine levels of
albumin, orosomucoid, immunoglobulin G, and protein HC in children. Scand J Clin Lab Invest. 2000
Feb;60(1):65-73 4. Pagana K, Pagana T, Papana T, eds: Mosbyâ€™s Diagnostic and Laboratory Test
Reference. Mosby; 2020:632
RA1U Alpha-1-Microglobulin, Random, Urine

610364 Clinical Information: Alpha-1-microglobulin is a low-molecular-weight protein of 26 kDa and a
member of the lipocalin protein superfamily.(1) It is synthesized in the liver, freely filtered by glomeruli,
and reabsorbed by renal proximal tubules cells where it is catabolized.(1) Due to extensive tubular
reabsorption, under normal conditions very little filtered alpha-1-microglobulin appears in the final
excreted urine. Therefore, an increase in the urinary concentration of alpha-1-microglobulin indicates
proximal tubule injury and/or impaired proximal tubular function. Elevated excretion rates can indicate
tubular damage associated with renal tubulointerstitial nephritis or tubular toxicity from heavy metal or
nephrotoxic drug exposure. Glomerulonephropathies and renal vasculopathies also are often associated
with coexisting tubular injury and so may result in elevated urinary alpha-1-microglobulin excretion.
Elevated alpha-1-microglobulin in patients with urinary tract infections may indicate renal involvement
(pyelonephritis). Measurement of urinary excretion of retinol-binding protein, another
low-molecular-weight protein, is an alternative to the measurement of alpha-1-microglobulin. To date,
there are no convincing studies to indicate that one test has better clinical utility than the other. Urinary
excretion of alpha-1-microglobulin can be determined from either a 24-hour collection or from a random
urine collection. The 24-hour collection is traditionally considered the gold standard. For random or spot
collections, the concentration of alpha-1-microglobulin is divided by the urinary creatinine concentration.
This corrected value adjusts alpha-1-microglobulin for variabilities in urine concentration.
Useful For: Assessment of renal tubular injury or dysfunction using random urine specimens
Screening for tubular abnormalities Detecting chronic asymptomatic renal tubular dysfunction (2)
Interpretation: Alpha-1-microglobulin above the reference values may indicate a proximal tubular
dysfunction. As suggested in the literature, 7 mg/g creatinine is an upper reference limit for pediatric
patients of 1 month to 15 years of age.(3)
Reference Values:
> or =18 years: <35 mg/g creatinine
Clinical References: 1. Akerstrom B, Logdberg L, Berggard T, Osmark P, Lindqvist A:

Alpha(1)-microglobulin: a yellow-brown lipocalin. Biochim Biophys Acta. 2000 Oct
18;1482(1-2):172-184 2. Yu H, Yanagisawa Y, Forbes M, Cooper EH, Crockson RA, MacLennan RC:
Alpha-1-microglobulin: an indicator protein for renal tubular function. J Clin Pathol. 1983
Mar;36(3):253-259 3. Hjorth L, Helin I, Grubb A: Age-related reference limits for urine levels of
albumin, orosomucoid, immunoglobulin G, and protein HC in children. Scand J Clin Lab Invest. 2000
Feb;60(1):65-73 4. Pagana K, Pagana T, Papana T, eds: Mosbyâ€™s Diagnostic and Laboratory Test
Reference. Mosby; 2020:632
A2PI Alpha-2 Plasmin Inhibitor, Plasma

602169 Clinical Information: Alpha-2 plasmin inhibitor (antiplasmin) is synthesized in the liver with a
biological half-life of approximately 3 days. It inactivates plasmin, the primary fibrinolytic enzyme
responsible for remodeling the fibrin thrombus, and binds fibrin, together with factor XIIIa, making the
clot more difficult to lyse. Absence of alpha-2 plasmin inhibitor results in uncontrolled plasmin-mediated
breakdown of the fibrin clot and is associated with increased risk of bleeding.
Useful For: Diagnosing congenital alpha-2 plasmin inhibitor deficiencies (rare) Providing a more
complete assessment of disseminated intravascular coagulation, intravascular coagulation and
fibrinolysis, or hyperfibrinolysis (primary fibrinolysis), when measured in conjunction with fibrinogen,
fibrin D-dimer, fibrin degradation products, soluble fibrin monomer complex, and plasminogen
Evaluating liver disease Evaluating the effects of fibrinolytic or antifibrinolytic therapy
Interpretation: Patients with congenital homozygous deficiency (with levels of <10%) are clinically
affected (bleeding). Heterozygotes having levels of 30% to 60% of mean normal activity are usually
asymptomatic. Lower than normal levels may be suggestive of consumption due to activation of
plasminogen and its inhibition by alpha-2 plasmin inhibitor. The clinical significance of high levels of
alpha-2 plasmin inhibitor is unknown.
Reference Values:
Adults: 80-140%
Normal, full-term, and premature infants may have mildly decreased levels (> or =50%) which reach
adult levels < or = 90 days postnatal.*
*See Pediatric Hemostasis References section in Coagulation Guidelines for Specimen Handling and
Processing.
Clinical References: 1. Lijnen HR, Collen D: Congenital and acquired deficiencies of components
of the fibrinolytic system and their relation to bleeding or thrombosis. Blood Coagul Fibrinolysis.
1989;3:67-77 2. Francis RB Jr: Clinical disorders of fibrinolysis: A critical review. Blut. 1989
Jul;59(1):1-14 3. Aoki N: Hemostasis associated with abnormalities of fibrinolysis. Blood Rev. 1989
Mar;3(1):11-17 4. Singh S, Saleem S, Reed GL: Alpha2-antiplasmin: The devil you donâ€™t know in
cerebrovascular and cardiovascular disease. Front Cardiovasc Med. 2020 Dec 23;7:608899
A2M Alpha-2-Macroglobulin, Serum

9270 Clinical Information: Alpha-2-macroglobulin is a protease inhibitor and is one of the largest
plasma proteins. It transports hormones and enzymes, exhibits effector and inhibitor functions in the
development of the lymphatic system, and inhibits components of the complement system and
hemostasis system. Increased levels of alpha-2-macroglobulin are found in nephrotic syndrome when
other lower molecular weight proteins are lost, and alpha-2-macroglobulin is retained because of its
large size. In patients with liver cirrhosis and diabetes, the levels are found to be elevated. Patients with
acute pancreatitis exhibit low serum concentrations, which correlate with the severity of the disease. In
hyperfibrinolytic states, after major surgery, in septicemia, and severe hepatic insufficiency, the
measured levels of alpha-2-macroglobulin are often low. Acute myocardial infarction patients with low
alpha-2-macroglobulin have been reported to have a significantly better prognosis with regard to the
greater than a year survival time.
Useful For: Evaluation of patients with nephrotic syndrome and pancreatitis

Interpretation: Values are elevated in the nephrotic syndrome in proportion to the severity of
protein loss (lower molecular weight). Values are low in proteolytic diseases such as pancreatitis.
Reference Values:
< or =18 years: 178-495 mg/dL
>18 years: 100-280 mg/dL
Clinical References: 1. McMahon MJ, Bowen M, Mayer AD, Cooper EH: Relation of
alpha-2-macroglobulin and other antiproteases to the clinical features of acute pancreatitis. Am J Surg.
1984 Jan;147(1):164-170. doi: 10.1016/0002-9610(84)90052-7 2. Haines AP, Howarth D, North WR, et
al: Haemostatic variables and the outcome of myocardial infarction. Thromb Haemost.
1983;50(4):800-803 3. Hofmann W, Schmidt D, Guder WG, Edel HH: Differentiation of hematuria by
quantitative determination of urinary marker proteins. Klin Wochenschr. 1991 Jan 22;69(2):68-75. doi:
10.1007/BF01666819 4. Solerte SB, Adamo S, Viola C, et al: Acute-phase protein reactants pattern and
alpha 2 macroglobulin in diabetes mellitus. Pathophysiological aspects in diabetic microangiopathy.
RIC Clin Lab. 1984;14(3):575-579. doi: 10.1007/BF02904891 5. Silverman LM, Christenson RH,
Grant GH: Basic chemistry of amino acids and proteins. In: Tietz, NW ed. Clinical Guide to Laboratory
Tests. 2nd ed. WB Saunders Comp; 1990:380-381 6. Rifai N, Horvath AR, Wittwer CT, eds: Tietz
Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018
AAMY Alpha-Amylase, IgE, Serum

immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for
clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of
Useful For: Establishing the diagnosis of an allergy Defining the allergen responsible for eliciting
signs and symptoms Identifying allergens: -Responsible for allergic disease and/or anaphylactic episode
-To confirm sensitization prior to beginning immunotherapy -To investigate the specificity of allergic
reactions to insect venom allergens, drugs, or chemical allergens

responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the
concentration of IgE antibodies expressed as a class score or kU/L.
Reference Values:
0 Negative

apply to all ages.
ALFP Alpha-Fetoprotein (AFP) Immunostain, Technical Component

70353 Only
Clinical Information: Alpha-fetoprotein (AFP) is an oncofetal antigen normally expressed in fetal
liver, but not present in normal adult tissues. AFP can be expressed in yolk sac tumors and in
hepatocellular carcinomas.
Useful For: Aiding in the identification of yolk sac tumors and hepatocellular carcinoma
interpretation is performed). If diagnostic consultation by a pathologist is required order PATHC /
Pathology Consultation. The positive and negative controls are verified as showing appropriate
pathologist.
Clinical References: 1. Melms JC, Thummalapalli R, Shaw K, et al: Alpha-fetoprotein (AFP) as

tumor marker in a patient with urothelial cancer with exceptional response to anti-PD-1 therapy and an
escape lesion mimic. J Immunother Cancer. 2018 Sep 12;6(1):89. doi: 10.1186/s40425-018-0394-y 2.
Suzuki A, Koide N, Kitazawa M, et al: Gastric composite tumor of alpha fetoprotein-producing
carcinoma/hepatoid adenocarcinoma and endocrine carcinoma with reference to cellular phenotypes.
Patholog Res Int 2012;2012:1-8 3. Tsung SH: The Characteristics of Immunoreactivity of
Alpha-fetoprotein Producing Gastric Cancer. Cancer and Clinical Oncology 2013;2(1):73-79
L3AFP Alpha-Fetoprotein (AFP) L3% and Total, Hepatocellular

88878 Carcinoma Tumor Marker, Serum
Clinical Information: Worldwide, hepatocellular carcinoma is the third leading cause of death
from cancer.(1) While hepatocellular carcinoma can be treated effectively in its early stages, most
patients are not diagnosed until they are symptomatic and at higher grades and stages, which are less
responsive to therapies. Alpha-fetoprotein (AFP) is the standard serum tumor marker utilized in the
evaluation of suspected hepatocellular carcinoma. However, increased serum concentrations of AFP
might be found in chronic hepatitis and liver cirrhosis as well as in other tumor types (eg, germ cell
tumors),(2) decreasing the specificity of AFP testing for hepatocellular carcinoma. Furthermore, AFP is
not expressed at high levels in all hepatocellular carcinoma patients, resulting in decreased sensitivity,
especially in potentially curable small tumors. AFP is differentially glycosylated in several hepatic
diseases. For example, uridine diphosphate (UDP)-alpha-(1->6)-fucosyltransferase is differentially
expressed in hepatocytes following malignant transformation.(3) This enzyme incorporates fucose
residues on the carbohydrate chains of AFP. Different glycosylated forms of AFP can be recognized
following electrophoresis by reaction with different carbohydrate-binding plant lectins. The fucosylated
form of serum AFP, which is most closely associated with hepatocellular carcinoma, is recognized by a
lectin from the common lentil (Lens culinaris). This is designated as AFP-L3 (third electrophoretic form
of lentil lectin-reactive AFP). AFP-L3 is most useful in the differential diagnosis of individuals with
total serum AFP of 200 ng/mL or below, which may result from a variety of benign pathologies such as
chronic liver diseases. AFP-L3 should be utilized as an adjunct to high-resolution ultrasound for
surveillance of individuals at significant risk for developing hepatic lesions.
Useful For: Distinguishing between hepatocellular carcinoma and chronic liver disease Monitoring
individuals with hepatic cirrhosis from any etiology for progression to hepatocellular carcinoma
Surveillance for development of hepatocellular carcinoma in individuals with a positive family history
of hepatic cancer Surveillance for development of hepatocellular carcinoma in individuals within
specific ethnic and gender groups who do not have hepatic cirrhosis, but have a confirmed diagnosis of
chronic infection by hepatitis B acquired early in life including: -African males above the age of 20
-Asian males above the age of 40 -Asian females above the age of 50
Interpretation: Alpha-fetoprotein (AFP)-L3 results of 10% or above are associated with a 7-fold
increased risk of developing hepatocellular carcinoma. Patients with AFP-L3 at this level should be
monitored more intensely for evidence of hepatocellular carcinoma according to current practice
guidelines. A total serum AFP above 200 ng/mL is highly suggestive of a diagnosis of hepatocellular
carcinoma. In patients with liver disease, a total serum AFP at this level is near 100% predictive of
hepatocellular carcinoma. With decreasing total AFP levels, there is an increased likelihood that chronic
liver disease, rather than hepatocellular carcinoma, is responsible for the AFP elevation. AFP
concentrations over 100,000 ng/mL have been reported in normal newborns, and the values rapidly
decline in the first 6 years of life.
Reference Values:
TOTAL AFP:
<4.7 ng/mL
%L3:
<10%
Clinical References: 1. Kawai K, Kojima T, Miyanaga N, et al: Lectin-reactive alpha-fetoprotein as

a marker for testicular tumor activity. Int J Urol 2005 Mar;12(3):284-289 2. Noda K, Miyoshi E, Kitada
T, et al: The enzymatic basis for the conversion of nonfucosylated to fucosylated alpha-fetoprotein by
acyclic retinoid treatment in human hepatoma cells: Activation of alpha 1-6 fucosyltransferase. Tumor
Biol 2002 Jul-Aug;23(4):202-211 3. Leerapun A, Suravarapu S, Bida JP, et al: The utility of serum
AFP-L3 in the diagnosis of hepatocellular carcinoma: Evaluation in a U.S. referral population. Clin
Gastroenterol Hepatol 2007 Mar;5(3):394-402 4. Chaiteerakij R, Addissie BD, Roberts LR: Update on
biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2015 Feb;13(2):237-245. doi:
10.1016/j.cgh.2013.10.038 5. Johnson P, Pirrie S, Cox T, et al: The detection of hepatocellular carcinoma
using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol
Biomarkers Prev 2014 Jan;23(1):144-153. doi: 10.1158/1055-9965.EPI-13-0870 6. Yang JD, Addissie
BD, Mara KC, et al: GALAD Score for Hepatocellular Carcinoma Detection in Comparison with Liver
Ultrasound and Proposal of GALADUS Score. Cancer Epidemiol Biomarkers Prev 2019
Mar;28(3):531-538. doi: 10.1158/1055-9965
AFP Alpha-Fetoprotein (AFP) Tumor Marker, Serum

8162 Clinical Information: Alpha-fetoprotein (AFP) is a glycoprotein that is produced in early fetal life by
the liver and by a variety of tumors including hepatocellular carcinoma, hepatoblastoma, and
nonseminomatous germ cell tumors of the ovary and testis (eg, yolk sac and embryonal carcinoma). Most
studies report elevated AFP concentrations in approximately 70% of patients with hepatocellular
carcinoma. Elevated AFP concentrations are found in 50% to 70% of patients with nonseminomatous
testicular tumors.(1) AFP is elevated during pregnancy. Persistence of AFP in the mother following birth
is a rare hereditary condition.(2) Neonates have markedly elevated AFP levels (>100,000 ng/mL) that
rapidly fall to below 100 ng/mL by 150 days and gradually return to normal over their first year.(2)
Concentrations of AFP above the reference range also have been found in the serum of patients with
benign liver disease (eg, viral hepatitis, cirrhosis), gastrointestinal tract tumors, and along with
carcinoembryonic antigen, in ataxia telangiectasia. The biological half-life of AFP is approximately 5
days.
Useful For: Follow-up management of patients undergoing cancer therapy, especially for testicular and
ovarian tumors and for hepatocellular carcinoma Often used in conjunction with human chorionic
gonadotropin.(2) This test is not recommended as a screening procedure for cancer detection in the
general population. This test is not intended for the detection of neural tube defects. This test is not useful
for patients with pure seminoma or dysgerminoma.
Interpretation: Alpha-fetoprotein (AFP) levels may be elevated in association with a variety of

malignancies or benign diseases. Failure of the AFP value to return to normal by approximately one
month after surgery suggests the presence of residual tumor. Elevation of AFP after remission suggests
tumor recurrence; however, tumors originally producing AFP may recur without an increase in AFP.
Reference Values:
<8.4 ng/mL
Reference values are for nonpregnant subjects only; fetal production of alpha-fetoprotein elevates values
in pregnant women.
Range for newborns is not available, but concentrations over 100,000 ng/mL have been reported in
normal newborns, and the values rapidly decline in the first 6 months of life.(See literature reference: Ped
Res 1981;15:50-52) For further interpretive information, see Alpha-Fetoprotein (AFP)
Serum markers are not specific for malignancy, and values may vary by method.
Clinical References: 1. Sturgeon CM, Duffy MJ, Stenman UH, et al: National Academy of
Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular,
prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008 Dec; 54(12):e11-79 2. Blohm ME,
Vesterling-Horner D, Calaminus G, et al: Alpha-1-fetoprotein (AFP) reference values in infants up to 2
years of age. Pediatr Hematol Onco. 1998 Mar-April;15(2):135-142 3. Milose JC, Filson CP, Weizer
AZ, et al: Role of biochemical markers in testicular cancer: diagnosis, staging, and surveillance. Open
Access J Urol. 2011 Dec 30;4:1-8 4. Schefer H, Mattmann S, Joss RA: Hereditary persistence of
alpha-fetoprotein. Case report and review of the literature. Ann Oncol. 1998 June;9(6):667-672
AFPPT Alpha-Fetoprotein (AFP), Peritoneal Fluid

61534 Clinical Information: Malignancy accounts for approximately 7% of cases of ascites formation.
Malignant disease can cause ascites by various mechanisms including: peritoneal carcinomatosis (53%),
massive liver metastasis causing portal hypertension (13%), peritoneal carcinomatosis plus massive
liver metastasis (13%), hepatocellular carcinoma plus cirrhosis (7%), and chylous ascites due to
lymphoma (7%). The evaluation and diagnosis of malignancy-related ascites is based on the patient
clinical history, ascites fluid analysis, and imaging tests. The overall sensitivity of cytology for the
detection of malignancy-related ascites ranges from 58% to 75%. Cytology examination is most
successful in patients with ascites related to peritoneal carcinomatosis as viable malignant cells are
exfoliated into the ascitic fluid. However, only approximately 53% of patients with malignancy-related
ascites have peritoneal carcinomatosis. Patients with other causes of malignancy-related ascites almost
always have a negative cytology. Alpha-fetoprotein (AFP) measurement in serum is used in the
management of patients with hepatocellular carcinoma (HCC). Measurement of AFP in ascites fluid
might be useful, when used in conjunction with cytology, in patients with a history of HCC and in
whom a cause of peritoneal fluid accumulation is uncertain.
Useful For: An adjunct to cytology to differentiate between malignancy-related ascites and benign
causes of ascites formation
Interpretation: A peritoneal fluid alpha-fetoprotein (AFP) concentration >6.0 ng/mL is suspicious

but not diagnostic of ascites related to hepatocellular carcinoma (HCC). This clinical decision limit
cutoff yielded a sensitivity of 58%, specificity of 96% in a study of 137 patients presenting with ascites.
AFP concentrations were significantly higher in ascites caused by HCC. Ascites caused by malignancies
other than HCC routinely had AFP concentrations <6.0 ng/mL. Therefore, negative results should be
interpreted with caution.
Reference Values:
Clinical References: Sari R, Yildirim B, Sevinc A, et al: The importance of serum and ascites
fluid alpha-fetoprotein, carcinoembryonic antigen, CA 19-9, and CA 15-3 levels in differential
diagnosis of ascites etiology. Hepatogastroenterology 2001 Nov-Dec;48(42):1616-1621
MAFP1 Alpha-Fetoprotein (AFP), Single Marker Screen, Maternal,

113382 Serum
Clinical Information: Alpha-fetoprotein (AFP) is a fetal protein that is initially produced in the
fetal yolk sac and liver. A small amount is produced by the gastrointestinal tract. By the end of the first
trimester, nearly all of the AFP is produced by the fetal liver. The concentration of AFP peaks in fetal
serum between 10 to 13 weeks. Fetal AFP diffuses across the placental barrier into the maternal
circulation. A small amount also is transported from the amniotic cavity. The AFP concentration in
maternal serum rises throughout pregnancy, from the nonpregnancy level of 0.2 ng/mL to about 250
ng/mL at 32 weeks gestation. If the fetus has an open neural tube defect (NTD), AFP is thought to leak
directly into the amniotic fluid causing unexpectedly high concentrations of AFP. Subsequently, the
AFP reaches the maternal circulation, producing elevated serum levels. Other fetal abnormalities such
as omphalocele, gastroschisis, congenital kidney disease, esophageal atresia, and other fetal distress
situations (eg, threatened abortion and fetal demise) also may result in maternal serum AFP elevations.
Increased maternal serum AFP concentrations also may be seen in multiple pregnancies and in
unaffected singleton pregnancies in which the gestational age has been underestimated. Lower maternal
serum AFP concentrations have been associated with an increased risk for genetic conditions such as
trisomy 21 (Down syndrome) and trisomy 18 (Edwards syndrome). Risks for these syndrome disorders
are only provided with the use of multiple marker screening (QUAD1 / Quad Screen [Second
Trimester] Maternal, Serum). Measurement of maternal serum AFP values is a standard tool used in
obstetrical care to identify pregnancies that may have an increased risk for NTD. The screen is
performed by measuring AFP in maternal serum and comparing this value to the median AFP value in
an unaffected population to obtain a multiple of the median (MoM). The laboratory has established a
MoM cutoff of 2.5, which classifies each screen as either screen-positive or screen-negative. A
screen-positive result indicates that the value obtained exceeds the established cutoff. A positive screen
does not provide a diagnosis but indicates that further evaluation should be considered.
Useful For: Prenatal screening for open neural tube defect

Interpretation: Neural tube defects: A screen-negative result indicates that the calculated
alpha-fetoprotein (AFP) multiple of the median (MoM) falls below the established cutoff of 2.50 MoM. A
negative screen does not guarantee the absence of neural tube defects (NTD). A screen-positive result
indicates that the calculated AFP MoM is 2.50 or greater and may indicate an increased risk for open
NTD. The actual risk depends on the level of AFP and the individual's pretest risk of having a child with
NTD based on family history, geographical location, maternal conditions such as diabetes and epilepsy,
and use of folate prior to conception. A screen-positive result does not infer a definitive diagnosis of a
NTD but indicates that further evaluation should be considered. Approximately 80% of pregnancies
affected with an open NTD have elevated AFP MoM values greater than 2.50. Follow up: Upon receiving
maternal serum screening results, all information used in the risk calculation should be reviewed for
accuracy (ie, weight, diabetic status, gestational dating). If any information is incorrect the laboratory
should be contacted for a recalculation of the estimated risks. Screen-negative results typically do not
warrant further evaluation. Ultrasound is recommended to confirm dates for NTD screen-positive results.
If ultrasound yields new dates that differ by at least 7 days, a recalculation should be considered. If dates
are confirmed, high-resolution ultrasound and amniocentesis (including amniotic fluid AFP and
acetylcholinesterase measurements for NTD) are typically offered.
Reference Values:
NEURAL TUBE DEFECTS
An alpha-fetoprotein (AFP) multiple of the median (MoM) <2.5 is reported as screen negative.
AFP MoM > or =2.5 (singleton and twin pregnancies) are reported as screen positive.
Clinical References: 1. Christensen RL, Rea MR, Kessler G, et al: Implementation of a screening
program for diagnosing open neural tube defects: selection, evaluation, and utilization of
alpha-fetoprotein methodology. Clin Chem. 1986;32:1812-1817 2. American College of Obstetricians and
Gynecologists: Practice Bulletin No. 163: Screening for Fetal Aneuploidy. Obstet Gynecol. 2016
May;127(5):e123-137 3. Zhang J, Lambert-Messerlian G, Palomaki GE, Canick JA: Impact of smoking
on maternal serum markers and prenatal screening in the first and second trimesters. Prenat Diagn. 2011
Jun;31(6):583-588 4. Yarbrough ML, Stout M, Gronowski AM: Pregnancy and its disorders. In: Rifai N,
Elsevier; 2018:1655-1696
AFPSF Alpha-Fetoprotein (AFP), Spinal Fluid

8876 Clinical Information: Alpha-fetoprotein (AFP) is an oncofetal glycoprotein, homologous with
albumin that is produced both in early fetal life and in tumors arising from midline embryonic structures.
AFP is synthesized in the yolk sac, liver, and gastrointestinal track of the fetus. In adults, the liver
synthesizes AFP. AFP is not normally expressed in the central nervous system (CNS). AFP
concentrations are increased in hepatomas and hepatocellular and colon carcinomas, as well as in
germ-cell tumors arising from the ovaries and nonseminomatous germ-cell tumors of the testes and
testicular teratocarcinomas. Based on histologic components and differentiation, CNS germ cell tumors
(GCT) are classified as either germinomatous or nongerminomatous germ cell tumors (NGGCT). NGGCT
include embryonal carcinomas, yolk sac tumors, choriocarcinomas, and mixed tumors. Teratomas
(including teratomas of testicular origin) are sometimes considered to be NGGCT. Germinomas comprise
two-thirds of the CNS GCT, whereas NGGCT account for the other third. However, CNS GCT are rare,
comprising only 1% to 2% of all primary CNS neoplasms. The presence of germinomas in the CNS, CNS
involvement in metastatic cancer, and meningeal carcinomatosis may result in increased concentrations of
AFP (and/or betaâ€“human chorionic gonadotropin: hCG) in cerebrospinal fluid (CSF). In some patients
with intracranial or intraspinal tumors, containing trophoblasts, regardless if it is primary or metastatic,
AFP secreted by trophoblasts can diffuse into the CSF. Following treatment, AFP elevation in CSF is a
potential marker of tumor recurrence. Increased concentrations of AFP in CSF are more indicative of sac
tumors/yolk sac components in mixed GCT. High concentrations of hCG in CSF support the presence of
choriocarcinomas/choriocarcinomatous components in mixed GCT. If a germ cell tumor is suspected, the
measurement of CSF and serum AFP and hCG may be considered. The secretion of these tumor markers
in the CSF is pathognomonic for NGGCT.
Useful For: An adjunct in the diagnosis of central nervous system (CNS) germinomas and meningeal
carcinomatosis Evaluating the presence of germ-cell tumors in the CNS, in conjunction with
cerebrospinal fluid (CSF) beta-human chorionic gonadotropin measurement A supplement to CSF
cytologic analysis
Interpretation: Alpha-fetoprotein (AFP) concentrations that exceed the upper end of normal are
consistent with the presence of central nervous system (CNS) germinoma.Â The presence of
germinomas in the CNS, CNS involvement in metastatic cancer, and meningeal carcinomatosis may
result in increased cerebrospinal fluid AFP concentrations in approximately 20% of germinomas.
Reference Values:
<1.5 ng/mL
Values for alpha-fetoprotein in cerebrospinal fluid have not been formally established for newborns
and infants. The available literature indicates that by 2 months of age, levels comparable to adults
should be reached.(Ann Clin Biochem 2005;42:24-29)
Clinical References: 1. Jubran RF, Finlay J: Central nervous system germ cell tumors:
controversies in diagnosis and treatment. Oncology. 2005 May;19(6):705-711 2. Seregni E, Massimino
M, Nerini Molteni S, et al: Serum and cerebrospinal fluid human chorionic gonadotropin (hCG) and
alpha-fetoprotein (AFP) in intracranial germ cell tumors. Int J Biol Markers. 2002
Apr-Jun;17(2):112-118 3. Hu M, Guan H, Lau CC,et al:. An update on the clinical diagnostic value of
beta-hCG and alpha FP for intracranial germ cell tumors. Eur J Med Res. 2016 Mar 12;21:10. doi:
10.1186/s40001-016-0204-2 4. Shi Q, Tian C, Pu C, Yu S, Huang X. CSF and serum AFP in patients
without gestational or neoplastic AFP-secretion. Scand J Clin Lab Invest. 2012 Dec;72(8):619-22. doi:
10.3109/00365513.2012.725865 5. Coakley J, Kellie SJ: Interpretation of alpha-fetoprotein
concentrations in cerebrospinal fluid of infants. Ann Clin Biochem. 2005 Jan;42:24-29 6. Shajani-Yi Z,
Martin IW, Brunelle AA, Cervinski MA: Method validation of human chorionic gonadotropin and
alpha-fetoprotein in cerebrospinal fluid: Aiding the diagnosis of intracranial germ cell tumors. J Appl
Lab Med. 2017 Jul 1;2(1):65-75. doi: 10.1373/jalm.2016.022822
AFPA Alpha-Fetoprotein, Amniotic Fluid

9950 Clinical Information: Alpha-fetoprotein (AFP) is a single polypeptide chain glycoprotein with a
molecular weight of approximately 70,000 Da. Synthesis of AFP occurs primarily in the liver and yolk
sac of the fetus. It is secreted in fetal serum, reaching a peak at approximately 13 weeks gestation, after
which it rapidly declines until about 22 weeks gestation and then gradually declines until term. Transfer
of AFP into maternal circulation is accomplished primarily through diffusion across the placenta.
Maternal serum AFP levels rise from the normal non-pregnancy level of 0.20 ng/mL to about 250
ng/mL at 32 weeks gestation. If the fetus has an open neural tube defect, AFP is thought to leak directly
into the amniotic fluid causing unexpectedly high concentrations of AFP. Other fetal abnormalities such
as omphalocele, gastroschisis, congenital renal disease, and esophageal atresia; and other fetal distress
situations such as threatened abortion, prematurity, and fetal demise, may also show AFP elevations.
Decreased amniotic fluid AFP values may be seen when gestational age has been overestimated.
Useful For: Screening for open neural tube defects or other fetal abnormalities Follow-up testing for
patients with elevated serum alpha-fetoprotein results or in conjunction with cytogenetic testing
Interpretation: A diagnostic alpha-fetoprotein (AFP) cutoff level of 2.0 multiples of median (MoM),
followed by acetylcholinesterase (AChE) confirmatory testing on positive results, is capable of detecting
96% of open spina bifida cases with a false-positive rate of only 0.06% in nonblood-stained specimens.
AChE analysis is an essential confirmatory test for all amniotic fluid specimens with positive AFP results.
Normal amniotic fluid does not contain AChE, unless contributed by the fetus as a result of open
communication between fetal central nervous system (eg, open neural tube defects), or to a lesser degree,
fetal circulation. All amniotic fluid specimens testing positive for AFP will have the AChE test
performed. False-positive AChE may occur from a bloody tap, which may cause both elevated AFP and
AChE levels.
Reference Values:
< or =2.0 multiples of median (MoM)
Clinical References: 1. Assessing the Quality of Systems for Alpha-Fetoprotein (AFP) Assays Used
in Prenatal Screening and Diagnosis of Open Neural Tube Defects: Approved Guideline. NCCLS
I/LA17-A Vol 17. No 5. April 1997 2. Cuckle H: Prenatal screening using maternal markers. J Clin Med.
2014 May 9;3(2):504-520. doi:10.3390/jcm3020504 3. Bernard JP, Cuckle HS, Bernard MA, Brochet C,
Salomon LJ, Ville Y: Combined screening for open spina bifida at 11-13 weeks using fetal biparietal
diameter and maternal serum markers. Am J Obstet Gynecol. 2013 Sep;209(3):223.e1-5
FUCW Alpha-Fucosidase, Leukocytes

8814 Clinical Information: Fucosidosis is an autosomal recessive lysosomal storage disorder caused by
reduced or absent alpha-L-fucosidase enzyme activity. This enzyme is involved in degrading
asparagine-linked, fucose-containing complex molecules (oligosaccharides and glycoasparagines) present
in cells. Reduced or absent activity of this enzyme results in the abnormal accumulation of these
molecules in the tissues and body fluids. Severe and mild subgroups of fucosidosis, designated types I and
II, have been described, although recent data suggests individual patients may represent a continuum
within a wide spectrum of severity. The more severe type is characterized by infantile onset, rapid
psychomotor regression, and severe neurologic deterioration. Additionally, dysostosis multiplex and
elevated sweat sodium chloride are frequent findings. Death typically occurs within the first decade of
life. Those with the milder phenotype express comparatively mild psychomotor and neurologic
regression, radiologic signs of dysostosis multiplex, and skin lesions (angiokeratoma corporis diffusum).
Normal sweat salinity, the presence of the skin lesions, and survival into adulthood most readily
distinguish milder from more severe phenotypes. Fucosidosis is an autosomal recessive condition
resulting from two biallelic pathogenic variants in the FUCA1 gene. Although the disorder is panethnic,
the majority of reported patients with fucosidosis have been from Italy and southwestern United States.
To date, about 100 cases have been reported worldwide. An initial diagnostic workup includes a urine
screening assay for several oligosaccharidosis (OLIGU / Oligosaccharide Screen, Random, Urine). If the
screening assay is suggestive of fucosidosis, enzyme analysis of alpha-L-fucosidase can confirm the
diagnosis.
Useful For: Detection of fucosidosis This test is not useful for establishing carrier status for
fucosidosis.
Interpretation: Values below 0.32 nmol/min/mg protein are consistent with a diagnosis of fucosidosis.
Reference Values:
> or =0.32 nmol/min/mg protein
Clinical References: 1. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders. In: Sarafoglou K,
Hoffmann GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. McGraw-Hill
Medical Division; 2009:747-748 2. Thomas GH: Disorders of glycoprotein degradation:
Alpha-mannosidosis, beta-mannosidosis, fucosidosis, and sialidosis. In: Valle DL, Antonarakis S,
Ballabio A, Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited
Disease. McGraw-Hill; 2019. Accessed February 17, 2022. Available at:
https://ommbid.mhmedical.com/content.aspx?sectionid=225545029 3. Stepien KM, Ciara E,
Jezela-Stanek A. Fucosidosis-clinical manifestation, long-term outcomes, and genetic profile-review and
case series. Genes (Basel). 2020 Nov 22;11(11):1383. doi: 10.3390/genes11111383
AGABS Alpha-Galactosidase, Blood Spot

89407 Clinical Information: Fabry disease is an X-linked lysosomal storage disorder resulting from
deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the subsequent deposition of
glycosylsphingolipids in tissues throughout the body, in particular, the kidney, heart, and brain. Variants
within the GLA gene cause Fabry disease with severity and symptom onset dependent on the amount of
residual enzyme activity. The classic form of Fabry disease occurs in male patients who have less than
1% alpha-Gal A activity. Symptoms usually appear in childhood or adolescence and can include
acroparesthesias (burning pain in the extremities), gastrointestinal issues, multiple angiokeratomas,
reduced or absent sweating, corneal opacity, and proteinuria. In addition, progressive renal involvement
leading to kidney failure (formerly end-stage renal disease) typically occurs in adulthood, followed by
cardiovascular and cerebrovascular disease. The estimated incidence varies from 1 in 3000 infants
detected via newborn screening to 1 in 10,000 male patients diagnosed after onset of symptoms.
Measurement of alpha-Gal A in blood spots, leukocytes (AGAW / Alpha-Galactosidase, Leukocytes),
or serum (AGAS / Alpha-Galactosidase, Serum) can reliably diagnose classic or variant Fabry disease
in males. Male patients with residual alpha-Gal A activity greater than 1% may present with 1 of 3
variant forms of Fabry disease with onset of symptoms later in life: a kidney variant associated with
kidney failure but without the pain or skin lesions; a cardiac variant typically presenting in the sixth to
eighth decade with left ventricular hypertrophy, cardiomyopathy and arrhythmia, and proteinuria, but
without kidney failure; and a cerebrovascular variant presenting as stroke or transient ischemic attack.
The variant forms of Fabry disease may be underdiagnosed. Molecular genetic analysis of the GLA
gene (FABRZ / Fabry Disease, Full Gene Analysis, Varies) allows for confirmation of a diagnosis of
classic of variant Fabry disease in affected male patients with reduced alpha-Gal A activity. Female
patients who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to
severely affected. Measurement of alpha-Gal A activity is not generally useful for identifying carriers of
Fabry disease, as many of these individuals will have normal levels. Therefore, molecular genetic
analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis, Varies) is recommended as the
most appropriate diagnostic test to detect asymptomatic or symptomatic female carriers. The biomarkers
globotriaosylsphingosine (LGB3S / Globotriaosylsphingosine, Serum) and ceramide trihexosides
(CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine) may be elevated in patients with Fabry
disease and can also be used in follow up of absent or reduced alpha-Gal A activity in both male and
female patients. Unless irreversible damage has already occurred, treatment with enzyme replacement
therapy has led to significant clinical improvement in affected individuals. In addition, some (adult)
patients may be candidates for an oral chaperone therapy. For this reason, early diagnosis and treatment
are desirable, and in a few US states early detection of Fabry disease through newborn screening has
been implemented. Molecular genetic testing is the recommended diagnostic test for female patients
Useful For: Diagnosis of Fabry disease in male patients using blood spot specimens Verifying
abnormal serum alpha-galactosidase results in male patients with a clinical presentation suggestive of
Fabry disease Follow-up to an abnormal newborn screen for Fabry disease This test is not useful for
patients undergoing a workup for a meat or meat-derived product allergy.
Interpretation: In male patients, results less than 1.2 nmol/mL/hour in properly submitted
specimens are consistent with Fabry disease. Normal results (> or =1.2 nmol/mL/hour) are not
consistent with Fabry disease. In female patients, normal results (> or =2.8 nmol/mL/hour) in properly
submitted specimens are typically not consistent with carrier status for Fabry disease; however, enzyme
analysis, in general, is not sufficiently sensitive to detect all carriers. Because a carrier range has not
been established in females, molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full
Gene Analysis, Varies) should be considered when alpha-galactosidase A activity is less than 2.9
nmol/mL/hour, or if clinically indicated. Pseudodeficiency results in low measured alpha-galactosidase
A activity but is not consistent with Fabry disease; FABRZ / Fabry Disease, Full Gene Analysis, Varies
should be performed to resolve the clinical question. See Fabry Disease Diagnostic Testing Algorithm
Reference Values:
Males: > or =1.2 nmol/mL/hour
Females: > or =2.8 nmol/mL/hour
Clinical References: 1. Desnick RJ, Ioannou YA, Eng CM: Alpha-galactosidase A deficiency:
Fabry disease. In: Valle D, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online
Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed January 5, 2022.
Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225546984 2. Matern D, Gavrilov
D, Oglesbee D, et al: Newborn screening for lysosomal storage disorders. Semin Perinatol. 2015
Apr;39(3):206-216 3. Mehta A, Hughes DA: Fabry Disease. In: Pagon RA, Adam MP, Ardinger HH, et
al: eds. GeneReviews [Internet]. University of Washington, Seattle; 2002. Updated January 5, 2017.
Accessed January 05, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1292/ 4. Laney DA, Bennett
RL, Clarke V, et al: Fabry disease practice guidelines: recommendations of the National Society of
Genetic Counselors. J Genet Couns. 2013 Oct;22(5):555-564
AGAW Alpha-Galactosidase, Leukocytes

glycosylsphingolipids in tissues throughout the body, in particular in the kidney, heart, and brain. Variants
within the GLA gene cause Fabry disease and more than 630 genetic alterations have been identified.
Severity and onset of symptoms are dependent on the amount of residual enzyme activity. The classic
form of Fabry disease occurs in male patients who have less than 1% alpha-Gal A activity. Symptoms
usually appear in childhood or adolescence and can include acroparesthesias (burning pain in the
extremities), gastrointestinal issues, multiple angiokeratomas, reduced or absent sweating, corneal
opacity, and proteinuria. In addition, progressive kidney involvement leading to end-stage kidney disease
(ESRD) typically occurs in adulthood, followed by cardiovascular and cerebrovascular disease. The
estimated incidence varies from 1 in 3000 infants detected via newborn screening to 1 in 10,000 male
patients diagnosed after onset of symptoms. Male patients with residual alpha-Gal A activity greater than
1% may present with 1 of 3 variant forms of Fabry disease with onset of symptoms later in life: a kidney
variant associated with ESRD but without the pain or skin lesions; a cardiac variant typically presenting in
the 6th to 8th decade with left ventricular hypertrophy, cardiomyopathy and arrhythmia, and proteinuria,
but without ESRD; and a cerebrovascular variant presenting as stroke or transient ischemic attack. The
variant forms of Fabry disease may be underdiagnosed. Female patients who are carriers of Fabry disease
can have clinical presentations ranging from asymptomatic to severely affected. Measurement of
alpha-Gal A activity is not generally useful for identifying carriers of Fabry disease, as many of these
individuals will have normal levels. Therefore, molecular genetic analysis of the GLA gene (FABRZ /
Fabry Disease, Full Gene Analysis, Varies) is recommended to detect carriers. Unless irreversible damage
has already occurred, treatment with enzyme replacement therapy has led to significant clinical
improvement in affected individuals. In addition, some adult patients may be candidates for an oral
chaperone therapy. For this reason, early diagnosis and treatment are desirable and, in a few US states,
early detection of Fabry disease through newborn screening has been implemented. Absent or reduced
alpha-Gal A in blood spots (AGABS / Alpha-Galactosidase, Blood Spot), leukocytes (this test), or serum
(AGAS / Alpha-Galactosidase, Serum) can indicate a diagnosis of classic or variant Fabry disease. The
biomarkers globotriaosylsphingosine (LGBWB / Globotriaosylsphingosine, Blood) and ceramide
trihexosides (CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine) may be elevated in patients
with Fabry disease and may aid in the diagnostic evaluation of female patients. Molecular sequence
analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis, Varies) allows for detection of
the disease-causing variant in both male and female patients.
Useful For: Diagnosis of Fabry disease in male patients Verifying abnormal serum alpha-galactosidase
results in male patients with a clinical presentation suggestive of Fabry disease This test is not useful for
patients undergoing a work-up for a meat or meat-derived product allergy.
Interpretation: Values below the reference range are consistent with a diagnosis Fabry Disease.
When abnormal results are detected, a detailed interpretation is given, including an overview of the
results and of their significance, a correlation to available clinical information, elements of differential
diagnosis, recommendations for additional biochemical testing and in vitro, confirmatory studies
(enzyme assay, molecular analysis), name and phone number of key contacts who may provide these
studies, and a phone number to reach one of the laboratory directors in case the referring physician has
additional questions.
Reference Values:
Note: Results from this assay do not reflect carrier status because of individual variation of
alpha-galactosidase enzyme levels.
Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed March 3, 2022.
Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225546984 2. De Schoenmakere
G, Poppe B, Wuyts B, et al: Two-tier approach for the detection of alpha-galactosidase A deficiency in
kidney transplant recipients. Nephrol Dial Transplant. 2008 Dec;23(12):4044-4048. doi:
10.1093/ndt/gfn370 3. Mehta A, Hughes DA: Fabry disease. In: Adam MP, Ardinger HH, Pagon RA, et
Accessed March 3, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1292/ 4. Laney DA, Bennett
RL, Clarke V, et al: Fabry disease practice guidelines: recommendations of the National Society of
Genetic Counselors. J Genet Couns. 2013 Oct;22(5):555-564. doi: 10.1007/s10897-013-9613-3 5.
Laney DA, Peck DS, Atherton AM, et al: Fabry disease in infancy and early childhood: a systematic
literature review. Genet Med. 2015 May;17(5):323-330. doi: 10.1038/gim.2014.120
AGAS Alpha-Galactosidase, Serum

glycosylsphingolipids in tissues throughout the body; in particular, in the kidney, heart, and brain.
Variants within the GLA gene cause Fabry disease and more than 630 variants have been identified.
Severity and onset of symptoms are dependent on the amount of residual enzyme activity. The classic
form of Fabry disease occurs in male patients who have less than 1% alpha-Gal A activity. Symptoms
usually appear in childhood or adolescence and can include acroparesthesias (burning pain in the
extremities), gastrointestinal issues, multiple angiokeratomas, reduced or absent sweating, corneal
opacity, and proteinuria. In addition, progressive renal involvement leading to kidney failure, also called
end-stage renal (kidney) disease (ESRD), typically occurs in adulthood, followed by cardiovascular and
cerebrovascular disease. The estimated incidence varies from 1 in 3000 infants detected via newborn
screening to 1 in 10,000 males diagnosed after onset of symptoms. Male patients with residual
alpha-Gal A activity greater than 1% may present with 1 of 3 variant forms of Fabry disease with onset
of symptoms later in life: a renal variant associated with ESRD but without the pain or skin lesions; a
cardiac variant typically presenting in the sixth to eighth decade with left ventricular hypertrophy,
cardiomyopathy and arrhythmia, and proteinuria, but without ESRD; and a cerebrovascular variant
presenting as stroke or transient ischemic attack. The variant forms of Fabry disease may be
underdiagnosed. Female patients who are carriers of Fabry disease can have clinical presentations
ranging from asymptomatic to severely affected. Measurement of alpha-Gal A activity is not generally
useful for identifying carriers of Fabry disease, as many of these individuals have normal levels of
alpha-Gal A. Therefore, molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full
Gene Analysis, Varies) is recommended to detect carriers. Unless irreversible damage has already
occurred, treatment with enzyme replacement therapy has led to significant clinical improvement in
affected individuals. In addition, some (adult) patients may be candidates for oral chaperone therapy.
For this reason, early diagnosis and treatment are desirable, and in a few US states, early detection of
Fabry disease through newborn screening has been implemented. Absent or reduced alpha-Gal A in
blood spots (AGABS / Alpha-Galactosidase, Blood Spot), leukocytes (AGAW / Alpha-Galactosidase,
Leukocytes), or serum (AGAS / Alpha-Galactosidase, Serum) can indicate a diagnosis of classic or
variant Fabry disease. Molecular sequence analysis of the GLA gene (FABRZ / Fabry Disease, Full
Gene Analysis, Varies) allows for detection of the disease-causing variant in both male and female
patients. The biomarkers globotriaosylsphingosine (LGB3S / Globotriosylsphingosine, Serum) and
ceremide trihexosides (CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine) are typically
elevated in symptomatic patients with Fabry disease and may aid in the diagnostic evaluation of female
patients and individuals with a variant of uncertain significance in GLA. See Fabry Disease Testing
Algorithm and Fabry Disease: Newborn Screen-Positive Follow-up
Useful For: Diagnosis of Fabry disease in male patients Preferred screening test (serum) for Fabry
disease This test is not useful for patients undergoing a work up for a meat or meat-derived product
allergy.
Interpretation: Deficiency (<0.016 U/L) of alpha-galactosidase in properly submitted specimens is

diagnostic for Fabry disease in male patients. If concerned about specimen integrity, recheck using
leukocyte testing (AGAW / Alpha-Galactosidase, Leukocytes).
Reference Values:
0.074-0.457 U/L
Note: Results from this assay are not useful for female carrier determination. Carriers usually have levels
in the normal range.
Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed February 18, 2022.
Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225546984 2. De Schoenmakere G,
Poppe B, Wuyts B, et al: Two-tier approach for the detection of alpha-galactosidase A deficiency in
kidney transplant recipients. Nephrol Dial Transplant. 2008 Dec;23(12):4044-4048. doi:
10.1093/ndt/gfn370 3. Mehta A, Hughes DA: Fabry Disease. In: Pagon RA, Adam MP, Ardinger HH, et
Accessed February 18, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1292/ 4. Laney DA, Bennett
RL, Clarke V, et al: Fabry disease practice guidelines: Recommendations of the National Society of
Genetic Counselors. J Genet Couns. 2013 Oct;22(5):555-564. doi: 10.1007/s10897-013-9613-3 5. Laney
DA, Peck DS, Atherton AM, et al: Fabry disease in infancy and early childhood: a systematic literature
review. Genet Med. 2015 May;17(5)323-330. doi: 10.1038/gim.2014.120 6. Ferreira S, Auray-Blais C,
Boutin M, et et al: Variations in the GLA gene correlate with globotriaosylceramide and
globotriaosylsphingosine analog levels in urine and plasma. Clin Chim Acta. 2015 Jul 20;447:96-104. doi:
10.1016/j.cca.2015.06.003 7. Nowak A, Beuschlein F, Sivasubramaniam V, et al: Lyso-Gb3 associates
with adverse long-term outcome in patients with Fabry disease. J Med Genet. 2022 Mar;59(3):287-293.
doi: 10.1136/jmedgenet-2020-107338
ATHL Alpha-Globin Gene Analysis

Only orderable as part of a profile. For more information see ATHAL / Alpha-Globin Gene Analysis.
ATHAL Alpha-Globin Gene Analysis, Varies

35346 Clinical Information: The thalassemias are a group of inherited conditions characterized by
decreased synthesis of one or more of the globin chains, resulting in an imbalance in the relative amounts
of the alpha and beta chains. The excess normal chains precipitate in the cell, damaging the membrane
and leading to premature red blood cell destruction. Additionally, the defect in hemoglobin synthesis
produces a hypochromic, microcytic anemia. The frequency of thalassemia is due to the protective
advantage against malaria that it gives carriers. Consequently, thalassemias are prevalent in populations
from equatorial regions in the world where malaria is endemic. Alpha-thalassemia is caused by decreased
synthesis of alpha-globin chains. Four alpha-globin genes are normally present (2 on each chromosome
16). One, 2, 3, or 4 alpha-globin genes may be deleted or, less commonly, contain variants. Deletions
account for approximately 90% of disease-causing alleles in alpha thalassemia. Phenotypically, these
deletions result in 4 categories of disease expression: -Deletion of 1 alpha-chain: Silent carrier state, with
a normal phenotype -Deletion of 2 alpha-chains: Alpha-thalassemia trait (alpha-1 thalassemia), with mild
hematologic changes but no major clinical difficulties -Deletion of 3 alpha-chains: Hemoglobin H disease,
which is extremely variable but usually includes anemia due to hemolysis, jaundice, and
hepatosplenomegaly -Deletion of all 4 alpha-chains: Hemoglobin Bart, with hydrops fetalis and almost
invariably in utero demise Less frequently, alpha-thalassemia results from single point alterations, such as
hemoglobin Constant Spring Â (HBA2: c.427T >C). Note: these point alterations are not detected by this
assay. Alpha-thalassemia occurs in all ethnic groups but is especially common in individuals of Southeast
Asian and African ancestry. It is also frequent in individuals of Mediterranean ancestry. The carrier
frequency is estimated to be 1 in 20 for Southeast Asians, 1 in 30 for African Americans, and 1 in 30 to 1
in 50 for individuals of Mediterranean ancestry. Both deletional and nondeletional (caused by point
alterations) forms of alpha-thalassemia are found in individuals with Mediterranean ancestry. Deletions in
cis (deletions on the same chromosome) are rare in African or Mediterranean populations but are
prevalent in Asian populations. Couples in which both partners carry deletions in cis are at risk of having
a child with the fatal hemoglobin Bart hydrops fetalis syndrome.
Useful For: Diagnosis of alpha-thalassemia Prenatal diagnosis of deletional alpha-thalassemia

Carrier screening for individuals from high-risk populations for alpha-thalassemia This test is not useful
for diagnosis or confirmation of beta-thalassemia or hemoglobinopathies.

Reference Values:
Clinical References: 1. Harteveld CL, Voskamp A, Phylipsen M, et al: Nine unknown

rearrangements in 16p13.3 and 11p15.4 causing alpha- and beta-thalassaemia characterized by high
resolution multiplex ligation-dependent probe amplification. J Med Genet. 2005 Dec;42(12):922-931.
doi: 10.1136/jmg.2005.033597 2. Harteveld CL, Higgs DR: Alpha-thalassemia. Orphanet J Rare Dis.
2010 May;5:13. doi: 10.1186/1750-1172-5-13 3. Bunn HF, Forget BG: Hemoglobin: Molecular,
Genetic and Clinical Aspects. 2nd ed. WB Saunders Company; 1986 4. Weatherall DJ, Higgs DR,
Clegg JB, Hill AS, Nicholls R: Heterogeneity and origins of the alpha-thalassemias. Birth Defects Origi
Artic Ser. 1987;23(5A):3-14
WASQR Alpha-Globin Gene Sequencing, Blood

47958 Clinical Information: Alpha-globin gene sequencing detects alpha-globin variants and
nondeletional alpha-thalassemia variants. Alpha thalassemia is the most common monogenic condition
in the world. It is estimated that up to 5% of the world's population carries at least one
alpha-thalassemia variant and, in the United States, approximately 30% of African Americans are
thought to carry an alpha thalassemia variant. Alpha thalassemia variants are most common in
individuals of Southeastern Asian, African, Mediterranean, Indian, and Middle Eastern descent, but they
can be found in persons from any ethnic group. Four alpha-globin genes are normally present, 2 copies
on each chromosome 16. Alpha-thalassemia variants result in decreased alpha-globin chain production.
In general, alpha thalassemia is characterized by hypochromic, microcytic anemia and varies clinically
from asymptomatic (alpha-thalassemia silent carrier and alpha-thalassemia trait) to lethal hemolytic
anemia (hemoglobin [Hb] Barts hydrops fetalis). Large deletions of the alpha-globin genes account for
approximately 90% of alpha-thalassemia alterations, and these will not be detected by alpha-globin gene
sequencing. Other alterations, such as point alterations or small deletions within the alpha-globin genes,
account for most of the remaining 10% of alpha-thalassemia variants. These nondeletional subtypes can
be detected by alpha-globin gene sequencing. The most common nondeletional alpha-thalassemia
variant is Hb Constant Spring. The majority of alpha-globin chain variants are clinically and
hematologically benign; however, some cause erythrocytosis and chronic hemolytic anemia.
Hemoglobin electrophoresis may not be able to confirm their identity. In these instances, alpha-globin
gene sequencing can be useful.
Useful For: Testing for nondeletional alpha thalassemia in a symptomatic individual Follow-up testing
to an abnormal hemoglobin electrophoresis that identified an alpha-globin chain variant Evaluating for
nondeletional alpha thalassemias in an algorithmic process for: -HAEV1 / Hemolytic Anemia Evaluation,
Blood -HBEL1 / Hemoglobin Electrophoresis Evaluation, Blood -MEV1 / Methemoglobinemia
Evaluation, Blood -REVE1 / Erythrocytosis Evaluation, Whole Blood THEV1 / Thalassemia and
Hemoglobinopathy Evaluation, Blood and Serum
Interpretation: A summary interpretation will be provided as a part of the HAEV1 / Hemolytic

Anemia Evaluation, Blood; HBEL1 / Hemoglobin Electrophoresis Evaluation, Blood; MEV1 /
Methemoglobinemia Evaluation, Blood; REVE1 / Erythrocytosis Evaluation, Whole Blood; THEV1 /
Thalassemia and Hemoglobinopathy Evaluation, Blood and Serum.
Reference Values:
-HBEL1 / Hemoglobin Electrophoresis Evaluation, Blood
-MEV1 / Methemoglobinemia Evaluation, Blood
-REVE1 / Erythrocytosis Evaluation, Whole Blood
-THEV1 / Thalassemia and Hemoglobinopathy Evaluation, Blood and Serum
Clinical References: 1. Harteveld CL, Higgs DR: Alpha-thalassemia. Orphanet J Rare Dis.
2010;5:13 2. Hoyer JD, Hoffman DR: The Thalassemia and hemoglobinopathy syndromes. In:
McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Lippincott Williams and Wilkins;
2002:866-895 3. Farashi S, Harteveld CL: Molecular basis of a-thalassemia. Blood Cells Mol Dis. 2018
May;70:43-53. doi: 10.1016/j.bcmd.2017.09.004 4. Henderson SJ, Timbs AT, McCarthy J, ed al: Ten
years of routine a- and B-globin gene sequencing in UK hemoglobinopathy referrals reveals 60 novel
mutations. Hemoglobin. 2016;40(2):75-84. doi: 10.3109/03630269.2015.1113990
IDUAW Alpha-L-Iduronidase, Leukocytes

606276 Clinical Information: The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders
caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate,
heparan sulfate, keratan sulfate, or chondroitin sulfate, also known as glycosaminoglycans (GAG) or
mucopolysaccharides. Accumulation of GAG in lysosomes interferes with normal functioning of cells,
tissues, and organs. There are 11 known disorders that involve the accumulation of GAG. MPS disorders
involve multiple organ systems and are characterized by coarse facial features, cardiac abnormalities,
organomegaly, intellectual disabilities, short stature, and skeletal abnormalities. Mucopolysaccharidosis I
(MPS I) is an autosomal recessive disorder caused by reduced or absent activity of the enzyme
alpha-L-iduronidase due to variants in the IDUA gene. Deficiency of alpha-L-iduronidase can result in a
wide range of phenotypes categorized into 3 syndromes: Hurler syndrome (MPS IH), Scheie syndrome
(MPS IS), and Hurler-Scheie syndrome (MPS IH/S). Because these syndromes cannot be distinguished
biochemically, they are also referred to as MPS I and attenuated MPS I. Clinical features and severity of
symptoms of MPS I are variable, ranging from severe disease to an attenuated form that generally
presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse
facies, progressive dysostosis multiplex, hepatosplenomegaly, corneal clouding, hearing loss, intellectual
disabilities or learning difficulties, and cardiac valvular disease. The incidence of MPS I is approximately
1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme
replacement therapy. Individuals with MPS I typically demonstrate elevated levels of the GAG dermatan
sulfate and heparan sulfate (see MPSSC / Mucopolysaccharides Screen, Random, Urine; MPSWB /
Mucopolysaccharides, Blood). Reduced or absent activity of alpha L-iduronidase can confirm a diagnosis
of MPS I; however, enzymatic testing is not reliable for carrier detection. Molecular sequence analysis of
the IDUA gene allows for detection of a disease-causing variant in affected individuals and subsequent
carrier detection in relatives (see MPS1Z / Hurler Syndrome, Full Gene Analysis, Varies). To date, a clear
genotype-phenotype correlation has not been established.
Useful For: Diagnosis of mucopolysaccharidosis I, Hurler, Scheie, and Hurler-Scheie syndromes in

leukocytes This test is not useful for determining carrier status.
Interpretation: Results below 2.06 nmol/hour/mg protein in properly submitted specimens are
consistent with alpha-L-iduronidase deficiency (mucopolysaccharidosis I). Further differentiation
between Hurler, Scheie, and Hurler-Scheie syndromes is dependent upon the clinical findings. Normal
results (> or =2.06 nmol/hour/mg protein) are not consistent with alpha-L-iduronidase deficiency.
Reference Values:
Clinical References: 1. Neufeld EF, Muenzer J: The mucopolysaccharidoses. In: Valle D,

Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases
of Inherited Disease. McGraw-Hill; 2019. Accessed March 23, 2022. Available at
https://ommbid.mhmedical.com/content.aspx?sectionid=225544161 2. Clark LA, Atherton AM, Burton
BK, et al: Mucopolysaccharidosis type I newborn screening: Best practices for diagnosis and
management. J Pediatr. 2017 Mar;182:363-370 3. Martins AM, Dualibi AP, Norato D, et al: Guidelines
for the management of mucopolysaccharidosis type I. J Pediatr. 2009 Oct:155(4 Suppl):S32-S46 4.
Enns GM, Steiner RD, Cowan TM: Lysosomal disorders: mucopolysaccharidoses. In: Sarafoglou K,
Hoffmann GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. McGraw-Hill,
Medical Publishing Division; 2009:721-730 5. Clarke LA: Mucopolysaccharidosis type I. In: Adam
MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle;
2002. Updated February 25, 2021. Accessed March 23, 2022. Available at
www.ncbi.nlm.nih.gov/books/NBK1162/ 6. Elliott S, Buroker N, Cournoyer JJ, et al: Pilot study of
newborn screening for six lysosomal storage diseases using tandem mass spectrometry. Mol Genet
Metab. 2016 Aug;118(4):304-309
ALFA Alpha-Lactalbumin, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to alpha-lactalbumin Defining the allergen

and/or anaphylactic episode -To confirm sensitization prior to beginning immunotherapy -To
investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens

Reference Values:
0 Negative

apply to all ages.
Clinical References: Homburger HA, Hamilton RG: Allergic diseases. In: McPherson RA, Pincus
MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier;
2017:1057-1070
MANN Alpha-Mannosidase, Leukocytes

62511 Clinical Information: Alpha-mannosidosis is an autosomal recessive lysosomal storage disorder
caused by reduced or absent acid alpha-mannosidase enzyme activity. This enzyme is involved in
glycoprotein catabolism, with absent or reduced activity resulting in the accumulation of undigested
mannose-containing complex oligosaccharides in the lysosomes, disrupting the normal functioning of
cells. Clinical features and severity of symptoms are widely variable within alpha-mannosidosis but, in
general, the disorder is characterized by skeletal abnormalities, immune deficiency, hearing impairment,
and intellectual disability. Three clinical subtypes of the disorder have been described and vary with
respect to age of onset and clinical presentation. Type 1 is generally classified by a mild presentation and
slow progression with onset after 10 years of age and absence of skeletal abnormalities. Type 2 is
generally a more moderate form with slow progression and onset prior to 10 years of age with skeletal
abnormalities and myopathy. Type 3 is the most severe form with onset in early infancy, skeletal
abnormalities such as dysostosis multiplex, and severe central nervous system involvement. Although
treatment is mostly supportive and aimed at preventing complications, hematopoietic stem cell transplant
has been reported to be a feasible therapeutic option. The incidence of alpha-mannosidosis is estimated at
1 in 500,000 live births. An initial diagnostic workup may include a screening assay for several
oligosaccharides in urine, OLIGU / Oligosaccharide Screen, Random, Urine. If the urine oligosaccharide
screening assay is suggestive of alpha-mannosidosis, enzyme analysis of acid alpha-mannosidase can
confirm the diagnosis. Molecular analysis of the MAN2B1 gene allows for detection of a disease-causing
variant in affected individuals and subsequent carrier detection in relatives (see CGPH / Custom Gene
Panel, Hereditary, Next-Generation Sequencing; specify MAN2B1 gene list ID: IEMCP-MUMNLV).
Useful For: Diagnosis of alpha-mannosidosis This test is not useful for establishing carrier status for
alpha-mannosidosis.
Interpretation: Values below 0.54 nmol/min/mg protein are consistent with a diagnosis of
alpha-mannosidosis.
Reference Values:
> or =0.54 nmol/min/mg protein
Clinical References: 1. Malm D, Nilssen O: Alpha-mannosidosis. In: Adam MP, Ardinger HH,
Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle. 2001. Updated July 18,
2019. Accessed February 18, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1396/ 2. Thomas GH:
Disorders of glycoprotein degradation: alpha-mannosidosis, beta-mannosidosis, fucosidosis, and
sialidosis. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA eds. The Online Metabolic
and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed February 18, 2022. Available at
https://ommbid.mhmedical.com/content.aspx?sectionid=225545029 3. Mynarek M, Tolar J, Albert MH,
et al: Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow
Transplant. 2012 Mar;47(3):352-359. doi: 10.1038/bmt.2011.99 4. Guffon N, Tylki-Szymanska AT,
Borgwardt L, et al: Recognition of alpha-mannosidosis in paediatric and adult patients: Presentation of a
diagnostic algorithm from an international working group. Mol Genet Metab. 2019 Apr;126(4):470.474.
doi: 10.1016/j.ymgme.2019.01.024
ANAS Alpha-N-Acetylglucosaminidase, Serum
8782 Clinical Information: The mucopolysaccharidoses (MPS) are a group of disorders caused by a
deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan
sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans: GAG). Accumulation of GAG in
lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical
features observed in MPS disorders. Sanfilippo syndrome (MPS type III) is an autosomal recessive
MPS with 4 recognized types (A-D). Each type is caused by a deficiency in 1 of 4 enzymes involved in
the degradation of heparan sulfate resulting in its intra- and extra-cellular accumulation. Though
biochemically different, the clinical presentation of all types is indistinguishable. Sanfilippo syndrome
is characterized by severe central nervous system degeneration, but other symptoms seen in MPS, such
as coarse facial features and skeletal involvement, tend to be milder. It is important to note the
variability in severity for MPSIII. In some patients, only moderate intellectual disability can be
observed even at the end of the third decade of life. However, onset of clinical features usually occurs
between 2 and 6 years in a child who previously appeared normal. The presenting symptoms are most
commonly developmental delay and severe behavioral problems. Severe neurologic degeneration occurs
in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive
skills. Death generally occurs by age 20, although individuals with an attenuated phenotype may have a
longer life expectancy and remain functional into their third and fourth decades. Sanfilippo syndrome
type B is due to a deficiency of the enzyme N-acetyl-alpha-D-glucosaminidase (alpha-hexosaminidase),
caused by variants in the NAGLU gene. Affected individuals demonstrate elevations of heparan sulfate
in blood and urine (MPSBS / Mucopolysaccharidosis, Blood Spot and MPSQU / Mucopolysaccharides
Quantitative, Random, Urine). Diagnostic sequencing and deletion/duplication studies of the NAGLU
gene (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify NAGLU
Gene List ID: IEMCP-KG2Q99) is available for patients with an enzyme deficiency. Elevations in
serum of alpha-N-acetylglucosaminidase and other hydrolases may be seen in patients with
mucolipidosis II/III (I-cell disease).(1) I-cell disease is an autosomal recessive lysosomal storage
disorder resulting in impaired transport and phosphorylation of newly synthesized lysosomal proteins to
the lysosome due to deficiency of N-acetylglucosamine 1-phosphotransferase (GlcNAc). Characteristic
clinical features include short stature, skeletal and cardiac abnormalities, and developmental delay.
Measurement of alpha-N-acetylglucosaminidase activity is not the preferred diagnostic test for I-cell
disease but may be included in the testing strategy.
Useful For: Diagnosis of Sanfilippo syndrome type B (mucopolysaccharidoses type IIIB) This test is
not suitable for carrier detection.
Interpretation: Deficiency of alpha-N-acetylglucosaminidase is diagnostic for Sanfilippo syndrome

type B.
Reference Values:
0.09-0.58 U/L
Clinical References: 1. Braulke T, Raas-Rothschild A, Kornfeld S: I-cell disease and

pseudo-Hurler polydystrophy: Disorders of lysosomal enzyme phosphorylation and localization. In:
Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds: The Online Metabolic and
Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed May 24, 2021. Available at
https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225544648 2. Joanna
Jakobkiewicz-Banecka, Magdalena Gabig-Ciminska, Anna Kloska, et al. Glycosaminoglycans and
mucopolysaccharidosis type III. Frontiers in Bioscience-Landmark. 2016 Jun. 21; 1393-1409. 3.
Neufeld EF, Muenzer J: The mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, et al; eds.
The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed May 24, 2021.
Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225544161&bookid=2709 4.
Valstar MJ, Bruggenwirth HT, Olmer R, et al: Mucopolysaccharidosis type IIIB may predominantly
present with an attenuated clinical phenotype. J Inherit Metab Dis. 2010 Dec;33(6):759-767. doi:
10.1007/s10545-010-9199-y 5. Beneto N, Vilageliu L, Grinberg D, Canals I: Sanfilippo syndrome:
Molecular basis, disease models and therapeutic approaches. Int J Mol Sci. 2020 Oct;21(21):7819. doi:
10.3390/ijms21217819
APGH Alpha-Subunit Pituitary Tumor Marker, Serum
9003 Clinical Information: The 3 human pituitary glycoprotein hormones: luteinizing hormone (LH),
follicle-stimulating hormone (FSH), thyrotropin (TSH), and the placenta-derived chorionic gonadotropin
(hCG), are closely related tropic hormones. They signal through G-protein-coupled receptors, regulating
the hormonal activity of their respective endocrine target tissues. Each is composed of an alpha- and a
beta-subunit, coupled by strong noncovalent bonds. The alpha-subunits of all 4 hormones are essentially
identical (92 amino acids; molecular weight [MW] of the "naked" protein:10,205 Da), being transcribed
from the same gene and showing only variability in glycosylation (MW of the glycosylated
proteins:13,000-18,000 Da). The alpha-subunits are essential for receptor transactivation. By contrast, all
the different beta-subunits are transcribed from separate genes, show less homology, and convey the
receptor specificity of the dimeric hormones. Under physiological conditions, alpha- and beta-chain
synthesis and secretions are tightly coupled, and only small amounts of monomeric subunits are secreted.
However, under certain conditions, coordinated production of intact glycoprotein hormones may be
disturbed and disproportionate quantities of free alpha-subunits are secreted. In particular, some pituitary
adenomas may overproduce alpha subunits. Although most commonly associated with gonadotroph- or
thyrotroph-derived tumors, alpha-subunit secretion has also been observed in corticotroph, lactotroph, and
somatotroph pituitary adenomas. Overall, depending on cell type and tumor size, 5% to 30% of pituitary
adenomas will produce sufficient free alpha-subunits to result in elevated serum levels, which usually fall
with successful treatment. Stimulation testing with hypothalamic releasing factors (eg, gonadotropin
releasing hormone: GnRH or thyrotropin-releasing hormone: TRH) may result in further elevations,
disproportionate to those seen in individuals without tumors. Measurement of free alpha-subunit after
GnRH-stimulation testing can also be useful in the differential diagnosis of constitutional delay of puberty
(CDP) versus hypogonadotrophic hypogonadism (HH). CDP is a benign, often familial, condition in
which puberty onset is significantly delayed, but eventually occurs and then proceeds normally. By
contrast, HH represents a disease state characterized by lack of gonadotropin production. Its causes are
varied, including hypothalamic and pituitary inflammatory or neoplastic disorders, a range of specific
genetic abnormalities, as well as unknown causes. In children, HH results in complete failure to enter
puberty without medical intervention. In children with CDP, in normal pubertal children, in normal adults
and, to a lesser degree, in normal prepubertal children, GnRH administration results in increased serum
LH, FSH, and alpha-subunit levels. This response is greatly attenuated in patients with HH, particularly
with regard to the post-GnRH rise in alpha-subunit concentrations.
Useful For: Adjunct in the diagnosis of pituitary tumors As part of the follow-up of treated pituitary
tumor patients Differential diagnosis of thyrotropin-secreting pituitary tumor versus thyroid hormone
resistance Differential diagnosis of constitutional delay of puberty versus hypogonadotrophic
hypogonadism
Interpretation: In the case of pituitary adenomas that do not produce significant amounts of intact
tropic hormones, diagnostic differentiation between sellar- and tumors of non-pituitary origin (eg,
meningiomas or craniopharyngiomas) can be difficult. In addition, if such nonsecreting adenomas are
very small, they can be difficult to distinguish from physiological pituitary enlargements. In a proportion
of these cases, free alpha-subunit may be elevated, aiding in diagnosis. Overall, 5% to 30% of pituitary
adenomas produce measurable elevation in serum free alpha-subunit concentrations. There is also
evidence that an exuberant free alpha-subunit response to thyrotropin-releasing hormone (TRH)
administration may occur in some pituitary adenoma patients that do not have elevated baseline free
alpha-subunit levels. A more than 2-fold increase in free alpha-subunit serum concentrations at 30 to 60
minutes following intravenous administration of 500 mcg of TRH is generally considered abnormal, but
some investigators consider any increase of serum free alpha-subunit that exceeds the reference range as
abnormal. TRH testing is not performed in the laboratory but in specialized clinical testing units under the
supervision of a physician. In pituitary tumors patients with pre-treatment elevations of serum free
alpha-subunit, successful treatment is associated with a reduction of serum free alpha-subunit levels.
Failure to lower levels into the normal reference range may indicate incomplete cure, and secondary rises
in serum free alpha-subunit levels can indicate tumor recurrence. Small thyrotropin (TSH)-secreting
pituitary tumors are difficult to distinguish from thyroid hormone resistance. Both types of patients may
appear clinically euthyroid or mildly hyperthyroid and may have mild-to-modest elevations in peripheral
thyroid hormone levels along with inappropriately (for the thyroid hormone level) detectable TSH, or
mildly-to-modestly elevated TSH. Elevated serum free alpha-subunit levels in such patients suggest a
TSH secreting tumor, but genetic variant screening of the thyroid hormone receptor gene may be
necessary for a definitive diagnosis. Constitutional delay of puberty (CDP) is a benign, often familial
condition in which puberty onset is significantly delayed but eventually occurs and then proceeds
normally. By contrast, hypogonadotrophic hypogonadism (HH) represents a disease state characterized by
lack of gonadotropin production. Its causes are varied, ranging from idiopathic over specific genetic
abnormalities to hypothalamic and pituitary inflammatory or neoplastic disorders. In children, it results in
complete failure to enter puberty without medical intervention. CDP and HH can be extremely difficult to
distinguish from each other. Intravenous administration of 100 mcg gonadotropin releasing hormone
(GnRH) results in much more substantial rise in free alpha-subunit levels in CDP patients, compared with
HH patients. A greater than 6-fold rise at 30 or 60 minutes post-injection is seen in more than 75% of
patients with CDP, while a less than 2-fold rise appears diagnostic of HH. Increments between 2- and
6-fold are nondiagnostic. GnRH testing is not performed in the laboratory but in specialized clinical
testing units under the supervision of a physician.
Reference Values:
PEDIATRIC
< or =5 days: < or =50 ng/mL
6 days-12 weeks: < or =10 ng/mL
3 months-17 years: < or =1.2 ng/mL
Tanner II-IV*: < or =1.2 ng/mL
ADULTS
Males: < or =0.5 ng/mL
Premenopausal females: < or =1.2 ng/mL
Postmenopausal females: < or =1.8 ng/mL
Pediatric and adult reference values based on Mayo studies.
*Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for boys at a median age of
11.5 (+/-2) years and for girls at a median age of 10.5 (+/-2) years. There is evidence that it may occur
up to 1 year earlier in obese girls and in African American girls. For boys, there is no proven
relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages
is variable. Tanner stage V (adult) should be reached by age 18.
Clinical References: 1. Preissner CM, Klee GG, Scheithauer BW, Abboud CF: Free alpha subunit
of the pituitary glycoprotein hormones. Measurement in serum and tissue of patients with pituitary
tumors. Am J Clin Pathol. 1990 Oct;94(4):417-421 2. Samejima N, Yamada S, Takada K, et al: Serum
alpha-subunit levels in patients with pituitary adenomas. Clin Endocrinol. 2001 Apr:54(4):479-484 3.
Mainieri AS, Elnecave RH: Usefulness of the free alpha-subunit to diagnose hypogonadotropic
hypogonadism. Clin Endocrionol. 2003 Sep;59(3):307-313 4. Socin HV, Chanson P, Delemer B, et al:
The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients.
Eur J Endocrinol. 2003 Apr;148(4):433-442 5. Solarski M, Rotondo F, Syro LV, Cusimano MD,
Kovacs K: Alpha subunit in clinically non-functioning pituitary adenomas: An immunohistochemical
study. Pathol Res Pract. 2017 Sep;213(9):1130-1133
ABCRS Alpha/Beta Crystallin IHC, Technical Component Only

70636 Clinical Information: Alpha-beta crystallin is a lens protein and a member of the superfamily of
small heat shock proteins. It is expressed in a variety of tissues such as skeletal muscle, cardiac muscle,
smooth muscle, renal tubular epithelium, Schwann cells, glial cells, thyroid epithelium, colonic
epithelium, and stratified squamous epithelium. It is also found in ubiquitinated intermediate filament
inclusion bodies, such as Lewy bodies (neurofilaments), Rosenthal fibers (glial filaments), and Mallory
bodies (cytokeratins) present in certain disease states.
Useful For: Characterization of neuroectodermal tumors

and will be performed as necessary at the discretion of the Mayo pathologist. The positive and negative
controls are verified as showing appropriate immunoreactivity and documentation is retained at Mayo
Clinic Rochester. If a control tissue is not included on the slide, a scanned image of the relevant quality
pathologist.
Clinical References: 1. Romi F, Helgeland G, Gilhus NE: Heat-shock proteins in clinical neurology.
Eur Neurol 2011;66(2):65-69 2. Fort PE, Lampi KJ: New focus on alpha-crystallins in retinal
neurodegenerative diseases. Exp Eye Res 2011 Feb;92(2):98-103 3. Pinder SE, Balsitis M, Ellis IO, et al:
The expression of alpha B-crystallin in epithelial tumours: a useful tumour marker? J Pathol 1994
Nov;174(3):209-215 4. Leach IH, Tsang ML, Church RJ, Lowe J: Alpha-B crystallin in the normal
human myocardium and cardiac conducting system. J Pathol 1994 Jul;173(3):255-260 5. Lowe J,
McDermott H, Pike I, et al: alpha B crystallin expression in non-lenticular tissues and selective presence
in ubiquitinated inclusion bodies in human disease. J Pathol 1992 Jan;166(1):61-68 6. Iwaki T,
Wisniewski T, Iwaki A, et al: Accumulation of alpha B-crystallin in central nervous system glia and
neurons in pathologic conditions. Am J Pathol 1992 Feb;140(2):345-356
ALPRT Alport (Collagen IV Alpha 5 and Alpha 2) Immunofluorescent

70593 Stain, Renal Biopsy
Clinical Information: Alport syndrome is a hereditary disease of basement membrane collagen type
IV. Variants in collagen IV alpha genes cause characteristic abnormal immunofluorescence staining
patterns within the glomerular basement membrane. Alport syndrome is characterized by hematuria,
proteinuria, progressive kidney failure, and high-tone sensorineural hearing loss.
Useful For: Assisting in the diagnosis of hereditary nephritis (Alport syndrome)

Interpretation: This test, (when not accompanied by a pathology consultation request) will be reported
as: 1) Normal pattern 2) Consistent with X-linked hereditary nephritis 3) Consistent with autosomal
hereditary nephritis If additional interpretation or analysis is needed, request PATHC / Pathology
Consultation along with this test and send the corresponding renal pathology light microscopy and
immunofluorescence (IF) slides (or IF images on a CD), electron microscopy images (prints or CD), and
the pathology report.
Reference Values:
Clinical References: 1. Kagawa M, Kishiro Y, Naito I, et al: Epitope-defined monoclonal antibodies

against type-IV collagen for diagnosis of Alport's syndrome. Nephrol Dial Transplant. 1997
Jun;12(6):1238-1241 2. Hashimura Y, Nozu K, Nakanishi K, et al: Milder clinical aspects of X-linked
Alport syndrome in men positive for the collagen IV alpha 5 chain. Kidney Int. 2014;85(5):1208-1213 3.
Kamiyoshi N, Nozu K, Fu XJ, et al: Genetic, clinical, and pathologic backgrounds of patients with
autosomal dominant Alport syndrome. Clin J Am Soc Nephrol. 2016 Aug 8;11(8):1441-1449 4. Said SM,
Fidler ME, Valeri AM, et al: Negative staining for COL4A5 correlates with worse prognosis and more
severe ultrastructural alterations in males with Alport syndrome. Kidney Int Rep. 2016; Sep 29;2(1):44-52
FALPX Alprazolam (Xanax)

5 Ã¢â‚¬â€œ 25 ng/mL
Reporting Limit: 2.0 ng/mL

ALTN Alternaria tenuis, IgE, Serum
Useful For: Establishing a diagnosis of an allergy to Alternaria tenuis Defining the allergen

Reference Values:
0 Negative

apply to all ages.
AH50 Alternative Complement Pathway, Functional, Serum

88676 Clinical Information: Complement proteins are components of the innate immune system. There
are 3 pathways to complement activation: 1. The classical pathway 2. The alternative (or properdin)
pathway 3. The lectin (or mannose-binding lectin, MBL) pathway The total complement (CH50) assay
(COM / Complement, Total, Serum) assesses the classical complement pathway including early
components that activate the pathway in response to immune complexes (C1q, C2 and C4), as well as
the terminal complement components (C3, C5, C6, C7, C8, C9) involved in the formation of the
membrane attack complex (MAC). The CH50 assay will be abnormal if there are specific hereditary or
acquired C1-C9 complement component deficiencies or if there is consumption of complement due to
immune (or autoimmune) complexes. This assay is a screening test for complement abnormalities in the
alternative pathway. The alternative complement (AH50) pathway shares C3 and C5-C9 components
but has unique early complement components designated factors D, B, and properdin, as well as control
proteins factor H and factor I. This pathway can be activated by spontaneous hydrolysis of C3 or by
microbial polysaccharides and does not require immune complex formation. Patients with disseminated
infections with pyogenic bacteria in the presence of a normal CH50 may have a decreased AH50 due to
hereditary or acquired deficiencies of the alternative pathway. Patients with deficiencies in the
alternative pathway factors (D, B, properdin, H, and I) or late complement components (C3, C5-C9) are
highly susceptible to recurrent Neisserial meningitis. The use of the CH50 and AH50 assays allow
identification of the specific pathway abnormality. Functional testing for complement pathways activity
is indicated in the study of complement components deficiency, where testing serves as a first-tier
screening, or in the study of complement dysregulation. Complement dysregulation is a general
grouping of complement conditions where there is loss of control of the complement cascade with
over-activation. In several cases, the complement system will attack the host and the over-activation of
the complement cascade may cause disease. Over-activation of the alternative pathway usually presents
with renal function impairment, in rare conditions such as atypical hemolytic uremic syndrome and C3
glomerulopathies (dense deposit disease and C3 glomerulonephritis). The use of complement inhibitor
therapies such as eculizumab and ravulizumab will result in the blocking of C5. C5 is necessary for the
AH50 test to progress until the formation of the MAC. Hence, in the presence of eculizumab or
ravulizumab, AH50 results will be decreased or undetectable.
Useful For: Investigation of suspected alternative pathway complement deficiency, atypical hemolytic
uremic syndrome, C3 glomerulonephritis, dense-deposit disease
Interpretation: Absent complement alternative pathway (AH50) in the presence of a normal total
hemolytic complement (CH50) suggests an alternative pathway component deficiency. Normal AH50
with absent CH50 suggests an early (C1, C2, C4) classic pathway deficiency. Absent AH50 and CH50
suggests a late (C3, C5, C6, C7, C8, C9) component deficiency or complement consumption. Absent
AH50 and CH50 in the presence of a normal C3 and C4 suggests a late (C5, C6, C7, C8, C9) component
deficiency. Normal CH50 and AH50 in the presence of recurrent infection and continued suspicion of
complement deficiency, suggest testing for lectin pathway function.
Reference Values:
> or =46% normal
Clinical References: 1. Frank MM: Medical intelligence current concepts: complement in the
pathophysiology of human disease. N Engl J Med. 1987;316:1525-1530. doi:
10.1056/NEJM198706113162407 2. Thurman JM, Holers VM: Brief reviews: the central role of the
alternative complement pathway in human disease. J Immunol. 2006;176:1305-1310. doi:
10.4049/jimmunol.176.3.1305 3. Frank MM: Complement deficiencies. Pediatr Clin North Am.
2000;47(6):1339-1354. doi: 10.1016/s0031-3955(05)70274-1 4. Go RS, Winters JL, Leung N, et al:
Thrombotic microangiopathy care pathway: A consensus statement for the Mayo Clinic Complement
Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin
Proc. 2016;91(9):1189-1211. doi: 10.1016/j.mayocp.2016.05.015 5. Willrich MAV, Andreguetto BD,
Sridharan M, et al: The impact of eculizumab on routine complement assays. J Immunol Methods.
2018;460:63-71. doi: 10.1016/j.jim.2018.06.010
ALU Aluminum, 24 Hour, Urine

8828 Clinical Information: Under normal physiologic conditions, the usual daily dietary intake of
aluminum (5-10 mg) is completely eliminated. Excretion is accomplished by avid filtration of aluminum
from the blood by the glomeruli of the kidney. Patients in kidney failure lose the ability to clear aluminum
and are candidates for aluminum toxicity. Many factors increase the incidence of aluminum toxicity in
patients with kidney failure: -Aluminum-laden dialysis water can expose dialysis patients to aluminum.
-Aluminum-laden albumin can expose patients to an aluminum burden they cannot eliminate. -The
dialysis process is not highly effective at eliminating aluminum. -Aluminum-based phosphate binder gels
are administered orally to minimize phosphate accumulation; a small fraction of this aluminum may be
absorbed and accumulated. If it is not removed by kidney filtration, aluminum accumulates in the blood
where it binds to proteins such as albumin and is rapidly distributed through the body. Aluminum
overload leads to accumulation of aluminum at 2 sites: brain and bone. Brain deposition has been
implicated as a cause of dialysis dementia. In bone, aluminum replaces calcium at the mineralization
front, disrupting normal osteoid formation. Urine aluminum concentrations are likely to be increased
above the reference range in patients with metallic joint prosthesis. Prosthetic devices produced by
Zimmer Company and Johnson and Johnson typically are made of aluminum, vanadium, and titanium.
This list of products is incomplete, and these products change occasionally; see prosthesis product
information for each device for composition details.
Useful For: Monitoring aluminum exposure Preferred matrix for assessment of exposure in patients
with normal kidney function since rapidly filtered by kidneys Monitoring metallic prosthetic implant
wear This test is not an acceptable substitute for serum aluminum measurements and is not
recommended for routine aluminum screening.
Interpretation: Daily excretion greater than 10 mcg/24 hours indicates exposure to excessive
amounts of aluminum. In kidney failure, the ability of the kidney to excrete aluminum decreases, while
the exposure to aluminum increases (aluminum-laden dialysis water, aluminum-laden albumin, and
aluminum-laden phosphate binders). Patients receiving chelation therapy with desferrioxamine (for
iron- or aluminum-overload states) also excrete considerably more aluminum in their urine than normal.
Prosthesis wear is known to result in increased circulating concentration of metal ions.(1) Modest
increase (10-20 mcg/24 hours) in urine aluminum concentration is likely to be associated with a
prosthetic device in good condition. Urine concentrations above 50 mcg/ 24 hours in a patient with an
aluminum-based implant and not undergoing dialysis, suggests significant prosthesis wear. Increased
urine trace element concentrations in the absence of corroborating clinical information do not
independently predict prosthesis wear or failure.
Reference Values:
0-17 years: not established
> or =18 years: <13 mcg/24 hours
Clinical References: 1. Liu TK, Liu SH, Chang CH, Yang RS: Concentration of metal elements in
the blood and urine in the patients with cementless total knee arthroplasty. Tohoku J Exp Med.
1998;185:253-262 2. O'Shea S, Johnson DW: Review article: Addressing risk factors in chronic kidney
disease mineral and bone disorder: Can we influence patient-level outcomes? Nephrology.
2009;14:416-427 3. Meyer-Baron M, Schuper M, Knapp G, van Thriel C: Occupational aluminum
exposure: Evidence in support of its neurobehavioral impact. NeuroToxicology. 2007;28:1068-1078
4.Strathmann FG, Blum LM: Toxic elements In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz
Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:888-924 5. US
Department of Health and Human Services, Agency for Toxic Substances and Disease Registry.
Toxicological Profile for Aluminum. HHS; 2006. Accessed July 20, 2021. Available at
www.atsdr.cdc.gov/toxprofiles/tp22.pdf 6. Willhite CC, Karyakina NA, Yokel RA, et al: Systematic
review of potential health risks posed by pharmaceutical, occupational and consumer exposures to
metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide, and its soluble salts. Crit
Rev Toxicol. 2014;44 Suppl 4(Suppl 4):1-80. doi: 10.3109/10408444.2014.934439
AL Aluminum, Serum
from the blood by the glomeruli of the kidney. Patients in kidney failure lose the ability to clear
aluminum and are candidates for aluminum toxicity. Many factors increase the incidence of aluminum
toxicity in patients with kidney failure: -Aluminum-laden dialysis water can expose dialysis patients to
aluminum. -Aluminum-laden albumin can expose patients to an aluminum burden they cannot
eliminate. -The dialysis process is not highly effective at eliminating aluminum. -Aluminum-based
phosphate binder gels are administered orally to minimize phosphate accumulation; a small fraction of
this aluminum may be absorbed and accumulated. If it is not removed by kidney filtration, aluminum
accumulates in the blood where it binds to proteins such as albumin and is rapidly distributed through
the body. Aluminum overload leads to accumulation of aluminum at 2 sites: brain and bone. Brain
deposition has been implicated as a cause of dialysis dementia. In bone, aluminum replaces calcium at
the mineralization front, disrupting normal osteoid formation. Deposition of aluminum in bone also
interrupts normal calcium exchange. The calcium in bone becomes unavailable for resorption back into
blood under the physiologic control of parathyroid hormone (PTH) and results in secondary
hyperparathyroidism. While PTH is typically quite elevated in kidney failure, 2 different processes may
occur: 1) High-turnover bone disease associated with high PTH (>150 pg/mL) and relatively low
aluminum (<20 ng/mL) 2) Low-turnover bone disease with lower PTH (<50 pg/mL) and high aluminum
(>60 ng/mL). Low-turnover bone disease indicates aluminum intoxication. Serum aluminum
concentrations are likely to be increased above the reference range in patients with metallic joint
prosthesis. Prosthetic devices produced by Zimmer Company and Johnson and Johnson typically are
made of aluminum, vanadium, and titanium. Prosthetic devices produced by Depuy Company, Dow
Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside, typically are
made of chromium, cobalt, and molybdenum. This list of products is incomplete, and these products
change occasionally; see prosthesis product information for each device for composition details.
Useful For: Preferred monitoring for aluminum toxicity in patients undergoing dialysis Preferred test
for routine aluminum screening Monitoring metallic prosthetic implant wear
Interpretation: Patients in kidney failure not receiving dialysis therapy invariably have serum
aluminum levels above the 60 ng/mL range. McCarthy(1) and Hernandez(2) describe a biochemical
profile that is characteristic of aluminum overload disease in dialysis patients: -Patients in kidney failure
with no signs or symptoms of osteomalacia or encephalopathy usually had serum aluminum below 20
ng/mL and parathyroid hormone (PTH) concentrations above 150 pg/mL, which is typical of secondary
hyperparathyroidism. -Patients with signs and symptoms of osteomalacia or encephalopathy had serum
aluminum above 60 ng/mL and PTH concentrations below 50 pg/mL (PTH above the reference range, but
low for secondary hyperparathyroidism). -Patients who had serum aluminum above 60 ng/mL and below
100 ng/mL were identified as candidates for later onset of aluminum-overload disease that required
aggressive efforts to reduce their daily aluminum exposure. This was done by switching them from
aluminum-containing phosphate binders to calcium-containing phosphate binders, by ensuring that their
dialysis water had less than 10 ng/mL of aluminum, and ensuring the albumin used during postdialysis
therapy was aluminum free. Prosthesis wear is known to result in increased circulating concentration of
metal ions.(3) Modest increase (6-10 ng/mL) in serum aluminum concentration is likely to be associated
with a prosthetic device in good condition. Serum concentrations above 10 ng/mL in a patient with an
aluminum-based implant not undergoing dialysis suggest significant prosthesis wear. Increased serum
trace element concentrations in the absence of corroborating clinical information do not independently
predict prosthesis wear or failure.
Reference Values:
<7 ng/mL
<60 ng/mL (dialysis patients)
Clinical References: 1. McCarthy JT, Milliner DS, Kurtz SB, et al: Interpretation of serum
aluminum values in dialysis patients. Am J Clin Pathol. 1986;86:629-636 2. Hernandez JD, Wesseling K,
Salusky IB: Role of parathyroid hormone and therapy with active vitamin D sterols in renal
osteodystrophy. Semin Dial. 2005;18:290-295 3. Liu TK, Liu SH, Chang CH, Yang RS: Concentration of
metal elements in the blood and urine in the patients with cementless total knee arthroplasty. Tohoku J
Exp Med. 1998;185:253-262 4. Schwarz C, Sulzbacher R, Oberbauer R: Diagnosis of renal
osteodystrophy. Eur J Clin Invest. 2006;36:13-22 5. Sharma AK, Toussaint ND, Pickering J, et al:
Assessing the utility of testing aluminum levels in dialysis patients. Hemodial Int. 2015
Apr;19(2):256-262 doi: 10.1111/hdi.12231 6. Riihimaki V, Aitio A: Occupational exposure to aluminum
and its biomonitoring in perspective. Crit Rev Toxicol. 2012 Nov;42(10):827-853
doi:10.3109/10408444.2012.725027 7. Strathmann FG, Blum LM: Toxic elements In: Rifai N, Horwath
AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier;
2018:888-924 8. US Department of Health and Human Services, Agency for Toxic Substances and
Disease Registry. Toxicological Profile for Aluminum. HHS; 2006. Accessed July 20, 2021. Available at
metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide, and its soluble salts. Crit Rev
Toxicol. 2014;44 Suppl 4(Suppl 4):1-80. doi: 10.3109/10408444.2014.934439
ALUCR Aluminum/Creatinine Ratio, Random, Urine

from the blood by the glomeruli of the kidney. Patients in kidney failure lose the ability to clear
aluminum and are candidates for aluminum toxicity. Many factors increase the incidence of aluminum
toxicity in patients with kidney failure: -Aluminum-laden dialysis water can expose dialysis patients to
aluminum. -Aluminum-laden albumin can expose patients to an aluminum burden they cannot
eliminate. -The dialysis process is not highly effective at eliminating aluminum. -Aluminum-based
phosphate binder gels are administered orally to minimize phosphate accumulation; a small fraction of
this aluminum may be absorbed and accumulated. If it is not removed by kidney filtration, aluminum
accumulates in the blood where it binds to proteins such as albumin and is rapidly distributed through
the body. Aluminum overload leads to accumulation of aluminum at 2 sites: brain and bone. Brain
deposition has been implicated as a cause of dialysis dementia. In bone, aluminum replaces calcium at
the mineralization front, disrupting normal osteoid formation. Urine aluminum concentrations are likely
to be increased above the reference range in patients with metallic joint prosthesis. Prosthetic devices
produced by Zimmer Company and Johnson and Johnson typically are made of aluminum, vanadium,
and titanium. This list of products is incomplete, and these products change occasionally; see prosthesis
product information for each device for composition details.
Useful For: Monitoring aluminum exposure when a 24-hour urine cannot be collected Monitoring
metallic prosthetic implant wear when a 24-hour urine cannot be collected This test is not an acceptable
substitute for serum aluminum measurements and is not recommended for routine aluminum screening.
Interpretation: Daily excretion more than 10 mcg/24 hours indicates exposure to aluminum.
Prosthesis wear is known to result in increased circulating concentration of metal ions.(1) Modest
increase (10-20 mcg/24 hours) in urine aluminum concentration is likely to be associated with a
prosthetic device in good condition. Urine concentrations more than 50 mcg/24 hours in a patient with
an aluminum-based implant, not undergoing dialysis, suggest significant prosthesis wear. Increased
independently predict prosthesis wear or failure. In kidney failure, the ability of the kidney to excrete
aluminum decreases, while the exposure to aluminum increases (aluminum-laden dialysis water,
aluminum-laden albumin, and aluminum-laden phosphate binders). Patients receiving chelation therapy
with desferrioxamine (for iron- or aluminum-overload states) also excrete considerably more aluminum
in their urine than normal.
Reference Values:
ALCU:
> or =18 years: <14 mcg/g Creatinine
CRETR:
16-326 mg/dL
Reference values have not been established for patients less than 18 years of age.
4.Strathmann FG, Blum LM: Toxic elements In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz
Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:888-924 5. US
Toxicological Profile for Aluminum. HHS; 2006. Accessed July 20, 2021. Available at
metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide, and its soluble salts. Crit
Rev Toxicol. 2014;44 Suppl 4(Suppl 4):1-80. doi: 10.3109/10408444.2014.934439
ALCU Aluminum/Creatinine Ratio, Urine

from the blood by the glomeruli of the kidney. Patients in kidney failure lose the ability to clear aluminum
and are candidates for aluminum toxicity. Many factors increase the incidence of aluminum toxicity in
patients with kidney failure: -Aluminum-laden dialysis water can expose dialysis patients to aluminum.
-Aluminum-laden albumin can expose patients to an aluminum burden they cannot eliminate. -The
dialysis process is not highly effective at eliminating aluminum. -Aluminum-based phosphate binder gels
are administered orally to minimize phosphate accumulation; a small fraction of this aluminum may be
absorbed and accumulated. If it is not removed by kidney filtration, aluminum accumulates in the blood
where it binds to proteins such as albumin and is rapidly distributed through the body. Aluminum
overload leads to accumulation of aluminum at 2 sites: brain and bone. Brain deposition has been
implicated as a cause of dialysis dementia. In bone, aluminum replaces calcium at the mineralization
front, disrupting normal osteoid formation. Urine aluminum concentrations are likely to be increased
above the reference range in patients with metallic joint prosthesis. Prosthetic devices produced by
Useful For: Measurement of aluminum concentration as a part of aluminum exposure

Interpretation: Daily excretion more than 10 mcg/24 hours indicates exposure to aluminum.
Prosthesis wear is known to result in increased circulating concentration of metal ions.(1) Modest increase
(10-20 mcg/24 hours) in urine aluminum concentration is likely to be associated with a prosthetic device
in good condition. Urine concentrations more than 50 mcg/24 hours in a patient with an aluminum-based
implant, not undergoing dialysis, suggest significant prosthesis wear. Increased urine trace element
concentrations in the absence of corroborating clinical information do not independently predict
prosthesis wear or failure. In kidney failure, the ability of the kidney to excrete aluminum decreases, while
the exposure to aluminum increases (aluminum-laden dialysis water, aluminum-laden albumin, and
aluminum-laden phosphate binders). Patients receiving chelation therapy with desferrioxamine (for iron-
or aluminum-overload states) also excrete considerably more aluminum in their urine than normal.
Reference Values:
Only orderable as part of a profile. For more information see ALUCR / Aluminum/Creatinine Ratio,
Random, Urine.
Not applicable
4.Strathmann FG, Blum LM: Toxic elements In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook
of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:888-924 5. US Department of
Health and Human Services, Agency for Toxic Substances and Disease Registry. Toxicological Profile for
Aluminum. HHS; 2006. Accessed July 20, 2021. Available at www.atsdr.cdc.gov/toxprofiles/tp22.pdf 6.
Willhite CC, Karyakina NA, Yokel RA, et al: Systematic review of potential health risks posed by
pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum
oxides, aluminum hydroxide, and its soluble salts. Crit Rev Toxicol. 2014;44 Suppl 4(Suppl 4):1-80. doi:
10.3109/10408444.2014.934439
FOXOF Alveolar Rhabdomyosarcoma (ARMS), 13q14 (FOXO1 or
35281 FKHR) Rearrangement, FISH, Tissue
Clinical Information: Rhabdomyosarcomas are a heterogeneous group of malignant tumors
showing skeletal muscle differentiation. They can be divided into 3 subtypes: alveolar, embryonal, and
pleomorphic. The rarer alveolar rhabdomyosarcomas (ARMS) are seen in older children, are more
likely to occur in limbs, and are associated with higher stage disease and an unfavorable prognosis. The
alveolar form consists of 2 variants; classic and solid. The classic form is characterized by small round
cells with dark hyperchromatic nuclei containing distinct nucleoli, held together by strands of
intercellular collagen, thereby creating a cellular architecture resembling the alveolar spaces of the
lungs. The solid form is characterized by a similar cellular morphology but without the formation of
alveolar spaces. ARMS are also members of the small round cell tumor group that includes synovial
sarcoma, lymphoma, Wilms tumor, Ewing sarcoma, and desmoplastic small round cell tumor. Most
cases of ARMS (75%) are associated with a t(2;13)(q35;q14), where a chimeric gene is formed from the
rearrangement of the PAX3 gene on chromosome 2 and the FOXO1(FKHR) gene on chromosome 13.
A small subset of ARMS patients (10%) are associated with a variant translocation, t(1;13)(q36;q14),
involving the PAX7 gene of chromosome 1 and the FOXO1 gene. Detection of these transcripts by
RT-PCR (ARMS / Alveolar Rhabdomyosarcoma by Reverse Transcriptase PCR [RT-PCR]), which
allows specific identification of the t(2;13) and t(1;13), has greatly facilitated the diagnosis of ARMS
tumors. FISH analysis (using the FOXO1 probe) adds the ability to detect variant FOXO1
rearrangements not detectible by PCR, and will often yield results when the quality of the available
RNA is poor or the PCR results are equivocal.
Useful For: Supporting the diagnosis of alveolar rhabdomyosarcomas (ARMS) when used in
conjunction with an anatomic pathology consultation Aiding in the diagnosis of ARMS when reverse
transcriptase-PCR results are equivocal or do not support the clinical picture
the normal cutoff for the FOXO1 FISH probe. A positive result suggests rearrangement of the FOXO1
gene region at 13q14 and is consistent with a subset of alveolar rhabdomyosarcomas (ARMS). A
negative result suggests FOXO1 gene rearrangement is not present, but does not exclude the diagnosis
of alveolar rhabdomyosarcomas (ARMS).
Reference Values:
Clinical References: 1. Fletcher CDM, Unni K, Mertens F: World Health Organization

Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. IARC: Lyon
2002, pp 150-152 2. Galili N, Davis RJ, Fredericks WJ, et al: Fusion of a fork head domain gene to
PAX3 in the solid tumor alveolar rhabdomyosarcoma. Nat Genet 1993 Nov;5(3):230-235 3. Nishio J,
Althof PA, Bailey JM, et al: Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to
diagnosis of alveolar rhabdomyosarcoma. Lab Invest 2006 Jun;86(6):547-556 4. Ladanyi M. Bridge JA:
Contribution of molecular genetic data to the classification of sarcomas. Hum Pathol 2000
May;31(5):532-538 5. Lae ME, Roche PC, Jin L, et al: Desmoplastic small round cell tumor: a
clinicopathologic, immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol 2002
Jul;26(7):823-835 6. Barr FG: Gene fusions involving PAX and FOX family members in alveolar
rhabdomyosarcoma. Oncogene 2001 Sep 10;20(40):5736-5746
TFE3F Alveolar Soft Part Sarcoma (ASPS)/Renal Cell Carcinoma

35319 (RCC), Xp11.23 (TFE3), FISH, Tissue
Clinical Information: Alveolar soft-part sarcoma (ASPS) is a rare malignant tumor typically
occurring in patients in their 20s to 30s within the muscle and deep tissues of the extremities. ASPS is
slow growing and refractory to chemotherapy with a propensity to metastasize. Prolonged survival is
possible even with metastasis, although the long-term disease-related mortality rate is high. ASPS is
characterized by a translocation that results in fusion of TFE3 on chromosome Xp11.2 with ASPSCR1
(also called ASPL or RCC17) on chromosome 17q25.3. Both balanced and unbalanced forms (loss of
the derivative X chromosome) of the translocation have been observed. Another tumor, a rare subset of
papillary renal cell carcinoma (RCC) with a distinctive pathologic morphology, has rearrangements of
TFE3 with ASPSCR1 or other fusion partner genes. This tumor predominantly affects children and
young adults, presents at an advanced stage but with an indolent clinical course, and is a distinct entity
in the World Health Organization classification. Typically a balanced form of the translocation is
present in the RCC variant. An assay to detect rearrangement of TFE3 is useful to resolve diagnostic
uncertainty in these tumor types, as immunohistochemistry for TFE3 is not reliable.
Useful For: An aid in the diagnosis of alveolar soft-part sarcoma or renal cell carcinoma variant when
used in conjunction with an anatomic pathology consultation
Interpretation: A neoplastic clone is detected when the percent of nuclei with the abnormality exceeds
the established normal cutoff for the TFE3 probe set. A positive result of TFE3 rearrangement is
consistent with a diagnosis of alveolar soft-part sarcoma (ASPS) or renal cell carcinoma (RCC) variant. A
negative result suggests that TFE3 is not rearranged, but does not exclude the diagnosis of ASPS or RCC
variant.
Reference Values:
Clinical References: 1. Zhong M, De Angelo P, Osborne L, et al: Dual-color break-apart FISH

assay on paraffin-embedded tissues as an adjunct to diagnosis of Xp11 translocation renal cell carcinoma
and alveolar soft part sarcoma. Am J Surg Pathol 2010;34(6):757-766 2. Ladanyi M, Lui MY, Antonescu
CR, et al: The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription
factor gene to ASPL, a novel gene at 17q25. Oncogene 2001;20:48-57 3. Ross H, Argani P: Xp11
translocation renal cell carcinoma. Pathology 2010;42(4):369-373
ADEVL Alzheimer Disease Evaluation, Spinal Fluid

607273 Clinical Information: Currently the diagnosis of probable Alzheimer disease (AD) is made based on
clinical symptoms, largely by the exclusion of other causes of dementia, with postmortem evidence of AD
pathology required to confirm the diagnosis. Two common neuropathologic features found in the brain of
patients with AD dementia are the presence of plaques composed of beta-amyloid (Abeta) peptides and
intracellular neurofibrillary tangles containing hyperphosphorylated Tau (tubulin-associated unit)
proteins. These 2 groups of molecules are the most established biomarkers of the disease used in clinical
and research practice. Positron emission tomography (PET) imaging using US Food and Drug
Administration approved amyloid radiotracer to visualize the presence of amyloid lesions in the cerebral
cortex is available in some specialized centers. Measuring Abeta peptides and Tau proteins in
cerebrospinal fluid (CSF) is being proposed as an alternative/adjunct to imaging studies to assess AD
pathology. Recently the use of these biomarkers has been included in the new consensus research
diagnostic criteria for AD, mild cognitive impairment (MCI), and preclinical AD, proposed by the
National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework. The CSF
assays included in this evaluation are beta-amyloid (1-42; Abeta42), total-Tau (t-Tau), and
phosphorylated-Tau (p-Tau181). Abeta42 is approximately 4 kDa protein of 42 amino acids that is formed
following proteolytic cleavage of a transmembrane protein known as amyloid precursor protein (APP).
Due to its hydrophobic nature, Abeta42 has the propensity to form aggregates and oligomers. Oligomers
form fibrils that accumulate into amyloid plaques. These pathological changes in Abeta42 are reflected by
the decrease in the CSF concentrations of Abeta42 and/or by the increase in the brain uptake of specific
tracers during beta-amyloid PET. Tau is present as six isoforms in human brain tissue. These isoforms are
generated by alternative splicing of the pre-mRNA. The t-Tau assay measures all these isoforms. The
most common post-translational modification of Tau proteins is phosphorylation. During
neurodegeneration, abnormal phosphorylation leads to the formation of intracellular neurofibrillary
tangles composed of the Tau protein that has undergone hyper-phosphorylation and developed aggregates
of hyper-phosphorylated Tau proteins called p-Tau. The p-Tau assay detects phosphorylated Tau at
threonine 181 (p-Tau181). Pathological changes associated with AD are reflected by an increase in the
CSF concentrations of t-Tau and p-Tau. Increases in CSF t-Tau reflect the intensity of the neuronal and
axonal damage and degeneration and is associated with a faster progression from MCI to AD. Increases in
CSF p-Tau concentrations are also associated with a faster progression from MCI to AD with more rapid
cognitive decline in AD patients and in mild AD dementia cases. The Alzheimer's Association has
developed an appropriate use criterion in order to guide safe and optimal use of CSF testing for AD
pathology detection in the diagnostic process. The use of CSF biomarker testing may be indicated for the
following patient groups: 1) Patients with subjective cognitive decline who are considered to be at
increased risk for AD 2) Patients with MCI that is persistent, progressing, and unexplained 3) Patients
with symptoms that suggest possible AD 4) MCI or dementia with an onset at an early age (less than 65)
5) Patients meeting core clinical criteria for probable AD with typical age of onset 6) Patients whose
dominant symptom is a change in behavior (eg, Capgras syndrome, paranoid delusions, unexplained
delirium, combative symptoms, and depression) and where AD diagnosis is being considered. Ultimately,
the decision to initiate CSF testing for the evaluation of suspected AD is also based on the clinical
judgment of expert providers and the patient's individual presentation.
Useful For: Assessment of adults with cognitive impairment being evaluated for Alzheimer disease
(AD) and other causes of cognitive impairment These assays should not be used to predict the
development of dementia or other neurologic conditions or to monitor response to therapies.
Interpretation: A beta-amyloid (1-42; Abeta42) result greater than 1026 pg/mL is consistent with a
negative amyloid positron emission tomography (PET) scan. A negative amyloid PET scan indicates the
presence of no or sparse neuritic plaques and is inconsistent with a neuropathological diagnosis of
Alzheimer disease (AD). An Abeta42 result greater than 1026 pg/mL is associated with a reduced
likelihood that a patient's cognitive impairment is due to AD. Total Tau (t-Tau) and phosphorylated Tau
(p-Tau181) cerebrospinal fluid (CSF) concentrations increase approximately 2 to 3-times as much in
patients with mild-moderate AD as compared to age-matched controls. A t-Tau and/or p-Tau181
concentration of less than or equal to 238 pg/mL and less than or equal to 21.7 pg/mL, respectively,
reduces the likelihood that a patient's cognitive impairment is due to AD. The use of p-Tau181/Abeta42
ratio provides better concordance with amyloid PET scan when compared to Abeta42, p-Tau181, and
t-Tau individually. A cut-off of 0.023 provides optimal balance between NPA (negative % agreement)
and PPA (positive % agreement) when compared to amyloid PET results. A p-Tau181/Abeta42 ratio of
less than or equal to 0.023 has a 92% NPA with normal amyloid PET. A ratio greater than 0.023 has a
92% PPA with abnormal amyloid PET. High CSF t-Tau protein concentrations are found in other
neurodegenerative diseases such as prion disease or Creutzfeldt-Jakob disease (CJD). In this situation,
an elevated t-Tau concentration and an increased t-Tau to p-Tau ratio has a very high specificity for
differential diagnoses of CJD. Abnormal (+)/normal (-) Individual comments for AD reporting values
Abeta42 (-) phospho Tau (-) total Tau (-) Normal concentrations of Abeta42, phospho-Tau, and
total-Tau concentrations are present in CSF. These results are not consistent with the presence of
pathological changes associated with Alzheimer disease. Abeta42 (+) phospho-Tau (-) total-Tau (-)
Abnormal Abeta42 concentrations are present in CSF. Phospho-Tau and total-Tau concentrations are
normal. These results may be consistent with Alzheimer related pathologic change. Abeta42 (+)
phospho-Tau (+) total-Tau (-) Abnormal Abeta42 and phospho-Tau concentrations are present in CSF.
The total-Tau concentration is normal. These results are consistent with the presence of Alzheimer
disease. Abeta42 (+) phospho Tau (+) total Tau (+) Abnormal Abeta42, phospho-Tau and total-Tau
concentrations are present in CSF. These results are consistent with the presence of Alzheimer disease.
Abeta42 (+) phospho Tau (-) total Tau (+) Abnormal Abeta42, and total-Tau concentrations are present
in CSF. The phospho-Tau concentration is normal. These results may be consistent with Alzheimer
related pathologic change. Abeta42 (-) phospho-Tau (+) total-Tau (-) Abnormal phospho-Tau
concentrations are present in CSF. Abeta42 and total-Tau concentrations are normal. These results are
not consistent with the presence of pathological changes associated with Alzheimer disease. Abeta42 (-)
phospho tau (-) total-Tau (+) Abnormal total-Tau concentrations are present in CSF. The Abeta42 and
phospho-Tau concentrations are normal. These results are not consistent with the presence of
pathological changes associated with Alzheimer disease. Abeta42 (-) phospho-Tau (+) total-Tau (+)
Abnormal phospho-Tau and total-Tau concentrations are present in CSF. The Abeta42 concentration is
normal. These results are not consistent with the presence of pathological changes associated with
Alzheimer disease. This table and interpretations are based on the National Institute on Aging and
Alzheimer's Association research framework diagnostic recommendations.(1)
Reference Values:
Beta-amyloid (1-42) (Abeta42): >1026 pg/mL
Total-Tau: < or =238 pg/mL
Phosphorylated-Tau 181: < or =21.7 pg/mL
p-Tau/Abeta42: < or =0.023
Clinical References: 1. Jack CR Jr, Bennett DA, Blennow K, et al: NIA-AA Research Framework:
Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562 2.
Lifke V, Kollmorgen G, Manuilova E, et al: Elecsys Total-Tau and Phospho-Tau (181P) CSF assays:
Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in
human cerebrospinal fluid. Clin Biochem. 2019 Oct;72:30-38 3. Willemse EAJ, van Maurik IS, Tijms
BM, et al: Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease
biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project. Alzheimers Dement
(Amst). 2018 Sep 12;10:563-572 4. Hansson O, Seibyl J, Stomrud E et al: CSF biomarkers of Alzheimer's
disease concord with amyloid-beta PET and predict clinical progression: A study of fully automated
immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018 Nov;14(11):1470-1481 5.
Schindler SE, Gray JD, Gordon BA, et al: Cerebrospinal fluid biomarkers measured by Elecsys assays
compared to amyloid imaging. Alzheimers Dement. 2018 Nov;14(11):1460-1469 6. Shaw LM, Arias J,
Blennow K, et al: Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the
diagnosis of Alzheimer's disease. Alzheimers Dement. 2018; 14(11):1505-1521 7. Hansson O, Batrla R,
Brix B, et al: The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for
routine clinical measurements of amyloid beta and tau. Alzheimers Dement. 2021 Sep;17(9):1575-1582.
doi: 10.1002/alz.12316
FAMAN Amantadine (Symmetrel)

Units: ng/mL
Therapeutic range has not been established.
Expected steady state amantadine concentrations in patients receiving recommended daily dosages:
200-1000 ng/mL
Toxicity reported at greater than 2000 ng/mL
PAMIK Amikacin, Peak, Serum

37032 Clinical Information: Amikacin is an aminoglycoside used to treat severe blood infections by
susceptible strains of gram-negative bacteria. Aminoglycosides induce bacterial death by irreversibly
binding bacterial ribosomes to inhibit protein synthesis. Amikacin is minimally absorbed from the
gastrointestinal tract, and thus can been used orally to reduce intestinal flora. Peak serum concentrations
are seen 30 minutes after intravenous infusion, or 60 minutes after intramuscular administration. Serum
half-lives in patients with normal renal function are generally 2 to 3 hours. Excretion of aminoglycosides
is principally renal, and all aminoglycosides may accumulate in the kidney at 50 to 100 times the serum
concentration. Toxicity can present as dizziness, vertigo, or, if severe, ataxia and a Meniere disease-like
syndrome. Auditory toxicity may be manifested by simple tinnitus or any degree of hearing loss, which
may be temporary or permanent, and can extend to total irreversible deafness. Nephrotoxicity is most
frequently manifested by transient proteinuria or azotemia, which may occasionally be severe.
Aminoglycosides also are associated with variable degrees of neuromuscular blockade leading to apnea.
Useful For: Monitoring adequacy of serum concentration during amikacin therapy

Interpretation: For conventional (nonpulse) dosing protocols, clinical effects may not be achieved if
the peak serum concentration is <20.0 mcg/mL. Toxicity may occur if the peak serum concentration is
maintained >35.0 mcg/mL for a prolonged period of time.
Reference Values:
Peak: 20.0-35.0 mcg/mL Toxic peak: >40.0 mcg/mL
Clinical References: 1. Wilson JW, Estes LL: Mayo Clinic Antimicrobial Therapy Quick Guide,
2008 2. Hammett-Stabler CA, Johns T: Laboratory guidelines for monitoring of antimicrobial drugs.
national academy of clinical biochemistry. Clin Chem 1998 May;44(5):1129-1140 3. Gonzalez LS III,
Spencer JP: Aminoglcosides: a practical review. Am Fam Physician 1998 Nov 15;58(8):1811-1820
RAMIK Amikacin, Random, Serum

half-lives in patients with normal renal function are generally 2 to 3 hours. Excretion of
aminoglycosides is principally renal, and all aminoglycosides may accumulate in the kidney at 50 to
100 times the serum concentration. Toxicity can present as dizziness, vertigo, or, if severe, ataxia and a
Meniere disease-like syndrome. Auditory toxicity may be manifested by simple tinnitus or any degree
of hearing loss, which may be temporary or permanent, and can extend to total irreversible deafness.
Nephrotoxicity is most frequently manifested by transient proteinuria or azotemia, which may
occasionally be severe. Aminoglycosides also are associated with variable degrees of neuromuscular
blockade leading to apnea.
Useful For: Monitoring adequacy of blood concentration during amikacin therapy

Interpretation: For conventional (nonpulse) dosing protocols, clinical effects may not be achieved if
the peak serum concentration is <20.0 mcg/mL. Toxicity may occur if, for prolonged periods of time,
peak serum concentrations are maintained >35.0 mcg/mL, or trough concentrations are maintained at
>10.0 mcg/mL.
Reference Values:
Peak: 20.0-35.0 mcg/mL
Toxic peak: >40.0 mcg/mL
Trough: <8.0 mcg/mL
Toxic trough:>10.0 mcg/mL
2008 2. Hammett-Stabler CA, Johns T: Laboratory Guidelines for Monitoring of Antimicrobial Drugs.
National Academy of Clinical Biochemistry. Clin Chem. 1998 May;44(5):1129-1140 3. Gonzalez LS
III, Spencer JP: Aminoglcosides: a practical review. Am Fam Physician 1998 Nov 15;58(8):1811-1820
TAMIK Amikacin, Trough, Serum

half-lives in patients with normal renal function are 2 to 3 hours. Excretion of aminoglycosides is
principally renal, and all aminoglycosides may accumulate in the kidney at 50 to 100 times the serum
concentration. Toxicity can present as dizziness, vertigo, or, if severe, ataxia and a Meniere disease-like
syndrome. Auditory toxicity may be manifested by simple tinnitus or any degree of hearing loss, which
may be temporary or permanent, and can extend to total irreversible deafness. Nephrotoxicity is most
frequently manifested by transient proteinuria or azotemia, which may occasionally be severe.
Aminoglycosides also are associated with variable degrees of neuromuscular blockade leading to apnea.
Useful For: Monitoring adequate clearance of amikacin near the end of a dosing cycle
Interpretation: For conventional (nonpulse) dosing protocols, trough concentrations should fall to
<8.0 mcg/mL. Toxicity may occur if the trough serum concentration is maintained >10.0 mcg/mL for
prolonged periods of time.
Reference Values:
Trough: <8.0 mcg/mL
Toxic trough: >10.0 mcg/mL
2008 2. Hammett-Stabler CA, Johns T: Laboratory guidelines for monitoring of antimicrobial drugs.
National Academy of Clinical Biochemistry.. Clin Chem 1998 May;44(5):1129-1140 3. Gonzalez LS III,
Spencer JP: Aminoglcosides: a practical review. Am Fam Physician 1998 Nov 15;58(8):1811-1820
AAMSD Amino Acids, Maple Syrup Urine Disease Panel, Plasma

60200 Clinical Information: Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by
the deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex. The BCKDH
complex is involved in the metabolism of the branched-chain amino acids (BCAA): isoleucine, leucine,
and valine. MSUD can be divided into 5 phenotypes: classic, intermediate, intermittent,
thiamine-responsive, and dihydrolipoyl dehydrogenase (E3)-deficient, depending on the clinical
presentation and response to thiamin administration. Classic MSUD, the most common and most severe
form, presents in the neonate with feeding intolerance, failure to thrive, vomiting, lethargy, and maple
syrup odor to urine and cerumen. If untreated, it progresses to irreversible intellectual diabilities,
hyperactivity, failure to thrive, seizures, coma, cerebral edema, and possibly death. Age of onset for
individuals with variant forms of MSUD is variable and some have initial symptoms as early as 2 years of
age. Symptoms include poor growth and feeding, irritability, and developmental delays. These patients
can also experience severe metabolic intoxication and encephalopathy during periods of sufficient
catabolic stress. MSUD is a panethnic condition but is most prevalent in the Old Order Mennonite
community in Lancaster, Pennsylvania with an incidence thereof 1:760 live births. The incidence of
MSUD is approximately 1:185,000 live births in the general population. Treatment of MSUD aims to
normalize the concentration of BCAA by dietary restriction of these amino acids. Because BCAA belong
to the essential amino acids, the dietary treatment requires frequent adjustment, which is accomplished by
regular determination of BCAA and allo-isoleucine concentrations. Orthotopic liver transplantation has
been used with success and is an effective therapy for MSUD.
Useful For: Follow-up of patients with maple syrup urine disease Monitoring of dietary compliance for
patients with maple syrup urine disease
Interpretation: The quantitative results of isoleucine, leucine, valine, and allo-isoleucine with
age-dependent reference values are reported without added interpretation. When applicable, reports of
abnormal results may contain an interpretation based on available clinical interpretation.
Reference Values:
ISOLEUCINE
< or =23 months: 31-105 nmol/mL
2-17 years: 30-111 nmol/mL
> or =18 years: 36-107 nmol/mL
LEUCINE
VALINE
ALLO-ISOLEUCINE
< or =23 months: <2 nmol/mL
2-17 years: <3 nmol/mL
> or =18 years: <5 nmol/mL
Clinical References: 1. Chuang DT, Shih VE, Max Wynn RR. Maple syrup urine disease
(Branched-chain ketoaciduria). In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA.
eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Accessed
April 18, 2022. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225084607 2.
Frazier DM, Allgeier C, Horner C, et al: Nutrition management guideline for maple syrup urine disease:
an evidence- and consensus-based approach. Mol Genet Metab. 2014 Jul;112(3)210-217. doi:
10.1016/j.ymgme.2014.05.006 3. Strauss KA, Puffenberger EG, Morton DH: Maple syrup urine
disease. In: RA Pagon, MP Adam, HH Ardinger, et al, eds. GeneReviews[Internet]. University of
Washington, Seattle; 2006. Updated April 23, 2020. Accessed April 18, 2022. Available at
www.ncbi.nlm.nih.gov/books/NBK1319 4. Diaz VM, Camarena C, de la Vega A, et al: Liver
transplantation for classical maple syrup urine disease: Long-term follow-up. J Pediatr Gastroenterol
Nutr. 2014 Nov;59(5):636-639. doi: 10.1097/MPG.0000000000000469
AAQP Amino Acids, Quantitative, Plasma

9265 Clinical Information: Amino acids are the basic structural units that comprise proteins and are
found throughout the body. Many inborn errors of amino acid metabolism, such as phenylketonuria and
tyrosinemia, have been identified. Amino acid disorders can manifest at any age, but most become
evident in infancy or early childhood. These disorders result in the accumulation or the deficiency of 1
or more amino acids in biological fluids, which leads to the clinical signs and symptoms of the
particular amino acid disorder. The clinical presentation is dependent upon the specific amino acid
disorder. In general, affected patients may experience failure to thrive, neurologic symptoms, digestive
problems, dermatologic findings, and physical and cognitive delays. If not diagnosed and treated
promptly, amino acid disorders can result in intellectual disability and possibly death. Treatment for
amino acid disorders includes very specific dietary modifications. Nonessential amino acids are
synthesized by the body, while essential amino acids are not and must be obtained through an
individual's diet. Therapeutic diets are coordinated and closely monitored by a dietician or physician.
They are structured to provide the necessary balance of amino acids with particular attention to essential
amino acids and those that accumulate in a particular disorder. Patients must pay close attention to the
protein content in their diet and generally need to supplement with medical formulas and foods. Dietary
compliance is monitored by periodic analysis of plasma amino acids. In addition, plasma amino acid
analysis may have clinical importance in the evaluation of several acquired conditions including
endocrine disorders, liver diseases, muscle diseases, neoplastic diseases, neurological disorders,
nutritional disturbances, kidney failure, and burns.
Useful For: Evaluation of patients with possible inborn errors of metabolism using plasma specimens
May aid in evaluation of endocrine disorders, liver diseases, muscle diseases, neoplastic diseases,
neurological disorders, nutritional disturbances, renal failure, and burns
Interpretation: When no significant abnormalities are detected, a simple descriptive interpretation is

provided. When abnormal results are detected, a detailed interpretation is given, including an overview
of the results and their significance, a correlation to available clinical information, elements of
differential diagnosis, recommendations for additional biochemical testing, and in vitro confirmatory
Reference Values:
Amino acids Age groups
2-17 years > or =18 years
Phosphoserine (PSer)
Phosphoethanolamine (PEtN)
Taurine (Tau) 37-177 38-153 42-156
Asparagine (Asn) 25-91 29-87 37-92
Serine (Ser) 69-271 71-208 63-187
Hydroxyproline (Hyp) 8-61 7-35 4-29
Glycine (Gly) 111-426 149-417 126-490
Glutamine (Gln) 316-1,020 329-976 371-957
Aspartic Acid (Asp) 2-20
Ethanolamine (EtN)
Histidine (His) 10-116 12-132 39-123
Threonine (Thr) 47-237 58-195 85-231
Citrulline (Cit) 9-38 11-45 17-46
Sarcosine (Sar)
b-Alanine (bAla)
Alanine (Ala) 139-474 144-557 200-579
Glutamic Acid (Glu) 31-202 22-131 13-113
1-Methylhistidine (1MHis)
3-Methylhistidine (3MHis) 2-9
Argininosuccinic Acid (Asa)
Carnosine (Car)
Anserine (Ans)
Homocitruline (Hcit) Â
Arginine (Arg) 29-134 31-132 32-120
a-Aminoadipic Acid (Aad)
g-Amino-n-butyric Acid (GABA)
b-Aminoisobutyric Acid (bAib)
a-Amino-n-butyric Acid (Abu) 7-28 7-31 9-37
Hydroxylysine (Hyl)
Proline (Pro) 85-303 80-357 97-368
Ornithine (Orn) 20-130 22-97 38-130
Cystathionine (Cth)
Cystine (Cys) 2-32 2-36 3-95
Lysine (Lys) 49-204 59-240 103-255
Methionine (Met) 11-35 11-37 4-44
Valine (Val) 83-300 106-320 136-309
Tyrosine (Tyr) 26-115 31-106 31-90
Isoleucine (IIe) 31-105 30-111 36-107
Leucine (Leu) 48-175 51-196 68-183
Phenylalanine (Phe) 28-80 30-95 35-80
Tryptophan (Trp) 17-75 23-80 29-77
Alloisoleucine (Allolle) All results reported in nmol/mL
Clinical References: 1. Part 8: Amino Acids. In: Valle DL, Antonarakis S, Ballabio A, Beaudet
AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill,
2019. Accessed April 18, 2022 Available at
https://ommbid.mhmedical.com/book.aspx?bookID=2709#225069340 2. Duran M: Amino acids. In:
Blau N, Duran M, Gibson KM. Laboratory Guide to the Methods in Biochemical Genetics.
Springer-Verlag; 2008:53-89
AAPD Amino Acids, Quantitative, Random, Urine

found throughout the body. Many inborn errors of amino acid metabolism that affect amino acid
transport or metabolism have been identified, such as phenylketonuria and tyrosinemia. Amino acid
disorders can manifest at any age, but most become evident in infancy or early childhood. These
disorders result in the accumulation or the deficiency of 1 or more amino acids in biological fluids,
which leads to the clinical signs and symptoms of the particular amino acid disorder. The clinical
presentation is dependent upon the specific amino acid disorder. In general, affected patients may
experience failure to thrive, neurologic symptoms, digestive problems, dermatologic findings, and
physical and cognitive delays. If not diagnosed and treated promptly, amino acid disorders can result in
intellectual disabilities and possibly death. In addition, amino acid analysis may have clinical
importance in the evaluation of several acquired conditions including endocrine disorders, liver
diseases, muscle diseases, neoplastic diseases, neurological disorders, nutritional disturbances, kidney
failure, and burns. General elevations in urine amino acid levels, called aminoaciduria, can be seen in
disorders with amino acid transport defects such as lysinuric protein intolerance and Hartnup disease, as
well as in conditions with renal tubular dysfunction including Lowe syndrome and Dent disease.
Useful For: Evaluating patients with possible inborn errors of metabolism using random urine
specimens May aid in evaluation of endocrine disorders, liver diseases, muscle diseases, neoplastic
diseases, neurological disorders, nutritional disturbances, renal failure, and burns

provided. When abnormal results are detected, a detailed interpretation is given, including an overview
of the results and of their significance, a correlation to available clinical information, elements of
differential diagnosis, recommendations for additional biochemical testing and in vitro confirmatory
Reference Values:
Amino Acid Age groups
< or =12 13-35 3-6 years 7-8 years 9-17 years > or =18
months months years
Phosphoserine PSer
Phosphoethanolamine PEtN 15-341 33-342 19-164 12-118
Taurine Tau 37-8300 64-3255 76-3519 50-2051 57-2235 24-1531
Asparagine Asn 25-1000 62-884 28-412 38-396 22-283 25-238
Serine Ser 18-4483 284-1959 179-1285 153-765 105-846 97-540
Hydroxyproline Hyp
Glycine Gly 362-18614 627-6914 412-5705 449-4492 316-4249 229-2989
Glutamine Gln 139-2985 263-2979 152-1325 164-1125 188-1365 93-686
Aspartic Acid Asp
Ethanolamine EtN 282-3782 256-947 193-643 137-564 158-596 95-471
Histidine His 145-3833 427-3398 230-2635 268-2147 134-1983 81-1128
Threonine Thr 25-1217 55-763 30-554 25-456 37-418 31-278
Citrulline Cit
Sarcosine Sar
Beta-Alanine bAla
Alanine Ala 93-3007 101-1500 64-1299 44-814 51-696 56-518
Glutamic Acid Glu 12-128
1-Methylhistidine 1MHis 17-419 18-1629 10-1476 19-1435 12-1549 23-1339

3-Methylhistidine 3MHis 88-350 86-330 56-316 77-260 47-262 70-246
Argininosuccinic Acid Asa
Carnosine Car 27-1021 16-616 18-319
Anserine Ans
Homocitrulline Hcit 11-158
Arginine Arg 10-560 20-395 14-240
Alpha-aminoadipic Acid Aad 10-275 15-324 10-135
Gamma Amino-n-butyric GABA

Acid
Beta-aminoisobutyric bAib 18-3137 15-1039 24-511 11-286

Acid
Alpha-amino-n-butyric Abu
Acid
Hydroxylysine Hyl
Proline Pro 28-2029
Ornithine Orn
Cystathionine Cth
Cystine Cys 12-504 11-133 10-98
Lysine Lys 19-1988 25-743 14-307 17-276 10-240 15-271
Methionine Met
Valine Val 11-211 11-211 16-91 11-61
Tyrosine Tyr 39-685 38-479 23-254 22-245 12-208 15-115
Isoleucine Ile
Leucine Leu 15-167 12-100 13-73
Phenylalanine Phe 14-280 34-254 20-150 21-106 11-111 13-70
Tryptophan Trp 14-315 14-315 10-303 10-303 15-229 18-114
Allo-isoleucine AlloIle All results
reported as
nmol/mg
creatinine.
Clinical References: Part 8: Amino Acids. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL,
Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill,
2019. Accessed April 18, 2022 Available at
https://ommbid.mhmedical.com/book.aspx?bookID=2709#225069340 2. Camargo SMR, Bockenhauer
D, Kleta R: Aminoacidurias: Clinical and molecular aspects. Kidney Int. 2008 Apr;73(8):918-925. doi:
10.1038/sj.ki.5002790 3. Duran M: Amino acids. In: Blau N, Duran M, Gibson KM. Laboratory Guide
to the Methods in Biochemical Genetics. Springer-Verlag; 2008:53-89
AACSF Amino Acids, Quantitative, Spinal Fluid

found throughout the body. Many inborn errors of amino acid metabolism that affect amino acid
transport and metabolism have been identified. Amino acid disorders can manifest at any age, but most
become evident in infancy or early childhood. These disorders result in the accumulation or deficiency
of 1 or more amino acids in biological fluids, which leads to the clinical signs and symptoms of the
particular amino acid disorder. The clinical presentation is dependent upon the specific amino acid
disorder. In general, affected patients may experience failure to thrive, neurologic symptoms, digestive
problems, dermatologic findings, and physical and cognitive delays. If not diagnosed and treated
promptly, amino acid disorders can result in intellectual diabilities and death. Cerebrospinal fluid (CSF)
specimens are highly informative for a subset of these conditions, such as nonketotic hyperglycinemia
and serine biosynthesis defects. CSF specimens are most informative when a plasma specimen is drawn
at the same time and the ratio of the amino acid concentrations in CSF to plasma is calculated.
Useful For: Evaluating patients with possible inborn errors of amino acid metabolism, in particular
nonketotic hyperglycinemia (glycine encephalopathy) and serine biosynthesis defects, especially when
used in conjunction with concomitantly collected plasma specimens

provided. When abnormal results are detected, a detailed interpretation is provided. This interpretation
includes an overview of the results and their significance, a correlation to available clinical information,
elements of differential diagnosis, recommendations for additional biochemical testing and in vitro
confirmatory studies (enzyme assay, molecular analysis), name and phone number of key contacts who
may provide these studies, and the telephone number to reach one of the laboratory directors in case the
referring physician has additional questions.
Reference Values:
< or =31 days 32 days-23 months 2-18 years > or =19 years
Phosphoserine (PSer)
Phosphoethanolamine (PEtN)
Taurine (Tau) 8-48
Asparagine (Asn) 8-34 5-16 5-20
Serine (Ser) 44-136 26-71 21-51 19-40
Hydroxyproline (Hyp)
Glycine (Gly) 5-115
Glutamine (Gln) 467-1832 301-1128 326-1092 380-1348
Aspartic Acid (Asp)
Ethanolamine (EtN) 11-193 7-155 7-153 7-153
Histidine (His) 11-70 9-28 9-21 9-28
Threonine (Thr) 32-143 11-77 14-38 23-57
Citrulline (Cit)
Sarcosine (Sar)
Beta-alanine (bAla)
Alanine (Ala) 24-124 16-53 12-34 19-60
Glutamic Acid (Glu)
Argininosuccinic Acid (Asa)
Carnosine (Car)
Anserine (Ans)
Homocitrulline (Hcit)
Arginine (Arg) 5-39 11-35 11-27 11-32
Alpha-aminoadipic Acid (Aad)
Gamma-amino-n-butyric Acid
(GABA)
Beta-aminoisobutyric Acid (bAib)
Alpha-amino-n-butyric Acid (Abu)
Hydroxylysine (Hyl)
Proline (Pro)
Ornithine (Orn)
Cystathionine (Cth)
Cystine (Cys)
Lysine (Lys) 11-63 9-33 10-25 13-42

Methionine (Met)
Valine (Val) 14-61 9-28 8-20 11-40
Tyrosine (Tyr) 8-83 5-24 5-17
Isoleucine (Ile)
Leucine (Leu) 12-41 6-21 7-16 7-29
Phenylalanine (Phe) 7-40 5-18 7-21
Tryptophan (Trp)
Allo-isoleucine (AlloIle) All results reported

in nmol/mL
Clinical References: 1. Rinaldo P, Hahn S, Matern D: Inborn errors of amino acid, organic acid,
and fatty acid metabolism. In: Burtis CA, Ashwood ER, Bruns DE. Tietz Textbook of Clinical
Chemistry and Molecular Diagnosis. 4th ed. WB Saunders Company; 2005:2207-2247 2. Van Hove J,
Coughlin C II, Scharer G: Glycine Encephalopathy. In: Adam MP, Ardinger HH, Pagon RA, et al:
GeneReviews[Internet]. 2002 Updated May 23, 2019. Accessed April 27, 2022. Available at
www.ncbi.nlm.nih.gov/books/NBK1357/ 3. El-Hattab AW: Serine biosynthesis and transport defects.
Mol Genet Metab 2016 Jul;118(3):153-159. doi: 10.1016/j.ymgme.2016.04.010 4. Duran M: Amino
acids. In: Blau N, Duran M, Gibson KM. Laboratory Guide to the Methods in Biochemical Genetics..
Springer-Verlag; 2008:53-89
AAUCD Amino Acids, Urea Cycle Disorders Panel, Plasma

60202 Clinical Information: Urea cycle disorders (UCD) are a group of inherited disorders of nitrogen
detoxification that result when any of the enzymes in the urea cycle (carbamoylphosphate synthetase I
[CPS I], ornithine transcarbamylase [OTC], argininosuccinic acid synthetase, argininosuccinic acid
lyase, arginase, or the cofactor producer, N-acetyl glutamate synthetase [NAGS]), have deficient or
reduced activity. The role of the urea cycle is to metabolize and clear waste nitrogen, and defects in any
of the steps of the pathway can result in an accumulation of ammonia, which can be toxic to the nervous
system. The urea cycle is also responsible for endogenous production of the amino acids citrulline,
ornithine, and arginine. Infants with a complete urea cycle enzyme deficiency typically appear normal at
birth but present in the neonatal period as ammonia levels rise with lethargy, seizures, hyper- or
hypoventilation, and ultimately coma or death. Individuals with partial enzyme deficiency may present
later in life, typically following an acute illness or other stressors. Symptoms may be less severe and
may present with episodes of psychosis, lethargy, cyclical vomiting, and behavioral abnormalities.
Patients with impaired ornithine metabolism due to ornithine aminotransferase deficiency may present
with childhood onset myopia progressing to vision loss in the 4th to 6th decades of life. Patients may or
may not have accompanying hyperammonemia but display marked elevations in plasma ornithine. All
of the UCD are inherited as autosomal recessive disorders, with the exception of OTC deficiency, which
is X-linked. UCD may be suspected with elevated ammonia, normal anion gap, and a normal glucose.
Plasma amino acids can be used to aid in the diagnosis of UCD and may aid in monitoring treatment
effectiveness. Measurement of urinary orotic acid, enzyme activity (CPS I, OTC, or NAGS), and
molecular genetic testing can help to distinguish the conditions and allows for diagnostic confirmation.
Acute treatment for UCD consists of dialysis and administration of nitrogen scavenger drugs to reduce
ammonia concentration. Chronic management typically involves restriction of dietary protein with
essential amino acid supplementation. More recently, orthotopic liver transplantation has been used with
success in treating some patients.
Useful For: Differential diagnosis and follow-up of patients with urea cycle disorders
Interpretation: The quantitative results of glutamine, ornithine, citrulline, arginine, and
argininosuccinic acid with age-dependent reference values are reported without added interpretation.
When applicable, reports of abnormal results may contain an interpretation based on available clinical
interpretation.
Reference Values:
GLUTAMINE
ORNITHINE
CITRULLINE
ARGININE
ARGININOSUCCINIC ACID
<2 nmol/mL
Reference value applies to all ages.
Clinical References: 1. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Valle DL, Antonarakis
S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited
Disease. McGraw Hill; 2019. Accessed April 18, 2022.
https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225084071 2. Haberle J, Burlina
A, Chakrapani A, et al: Suggested guidelines for diagnosis and management of urea cycle disorders: First
revision. OJ Inherit Metab Dis. 2019 Nov;42(6):1192-1230. doi: 10.1002/jimd.12100 3. Valle D, Simell
O. The Hyperornithinemias. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The
Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Accessed April 18,
2022. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225083672 4. Foshci FG,
Morelli MC, Savini S, et al: Urea cycle disorders: A case report of a successful liver transplant and a
literature review. World J Gastroenterol. 2015 Apr 7;21(13):4063-4068. doi: 10.3748/wjg.v21.i13.4063 5.
Ah Mew N, Simpson KL, Gropman AL, et al: Urea Cycle Disorders Overview. In: Adam MP, Ardinger
HH, Pagon RA, et al. GeneReviews[Internet]. University of Washington, Seattle; 2003. Updated June 22,
2017. Accessed May 28, 2019. Available at https://www.ncbi.nlm.nih.gov/books/NBK1217/
AIHL Aminoglycoside-Induced Hearing Loss, Targeted Variant

609784 Testing, Droplet Digital PCR, Varies
Clinical Information: Aminoglycosides (tobramycin, streptomycin, and gentamicin, etc) are a group
of broad-spectrum antibiotics commonly prescribed for infections caused by Gram-negative bacteria. In
the United States alone, approximately 4 million courses of aminoglycosides are administered each year
with approximately 2% to 5% of patients treated developing clinically significant hearing loss.
Mitochondrial gene RNR1 (MT-RNR1) variants m.1555A>G and m.1494C>T are the most common
variants associated with aminoglycoside-induced ototoxicity. Hearing loss associated with
aminoglycoside exposure can occur even after a single dose and may be bilateral, irreversible, and often
severe to profound. Avoidance of aminoglycoside antibiotics reduces the risk of developing hearing loss
for individuals carrying one of these 2 variants. The severity and onset of hearing loss in individuals with
the associated pathogenic mitochondrial variants range from profound congenital deafness to mild to
moderate late-onset hearing loss. Evidence demonstrates that this variance can often be explained by
variant load in an individual. In contrast to variants in nuclear genes, which are present in either 0, 1, or 2
copies, mitochondrial variants can be present in any fraction of the total organelles, a phenomenon known
as heteroplasmy. Penetrance of hearing loss without exposure to aminoglycosides is thought to be a
function of the degree of heteroplasmy, with a correlation between higher fraction of altered mitochondria
and higher penetrance. Hearing loss is believed to be 100% penetrant in homoplasmic individuals who
receive aminoglycoside antibiotics.
Useful For: Identification of individuals who may be at risk for aminoglycoside-induced hearing loss
(AIHL) Establishing a diagnosis of late-onset sensorineural hearing loss associated with aminoglycoside
exposure Identifying mitochondrial variants associated with AIHL, allowing for predictive testing of

Reference Values:
Clinical References: 1. Gao Z, Chen Y, Guan MX: Mitochondrial DNA mutations associated with
aminoglycoside induced ototoxicity. J Otol. 2017 Mar;12(1):1-8 2. Krause KM, Serio AW, Kane TR,
Connolly LE: Aminoglycosides: An overview. Cold Spring Harb Perspect Med. 2016 Jun 1;6(6):a027029
3. Qian Y, Guan MX: Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the
deafness-associated mutation. Antimicrob Agents Chemother. 2009 Nov;53(11):4612-4618 4. Usami S,
Nishio S: Nonsyndromic hearing loss and deafness, mitochondrial. In: Adam MP, Ardinger HH, Pagon
RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2004. Updated June 14, 2018.
Accessed March 15, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1422/
FALAU Aminolevulinic Acid (ALA), Urine

Procedure Units Ref Interval
Creatinine, Urine-mg/dL mg/dL
Creatinine, Urine-mg/day mg/d
Age Male Female
3-8 years 140-700 140-700

9-12 years 300-1300 300-1300
13-17 years 500-2300 400-1600
18-50 years 1000-2500 700-1600
51-80 years 800-2100 500-1400
81 years and older 600-2000 400-1300
Aminolevulinic Acid umol/L umol/L 0-35
Aminolevulinic Acid umol/day umol/d 0-60
ALADW Aminolevulinic Acid Dehydratase, Washed Erythrocytes

31895 Clinical Information: Porphyrias are a group of inherited disorders resulting from enzyme defects
in the heme biosynthetic pathway. A defect in the second enzyme of this pathway causes
5-aminolevulinic acid (ALA) dehydratase (ALAD) deficiency porphyria (ADP). A marked deficiency
of ALAD causes the accumulation and subsequent urinary excretion of large amounts of ALA. Urinary
porphobilinogen (PBG) remains essentially normal, which rules out other forms of acute porphyria.
ADP is an autosomal recessive acute hepatic porphyria that produces neurologic symptoms similar to
those seen in acute intermittent porphyria. Symptoms include acute abdominal pain, peripheral
neuropathy, nausea, vomiting, constipation, and diarrhea. Respiratory impairment, seizures, and
psychosis are possible during an acute period. ADP is extremely rare with only 7 cases described in the
literature since 1979. The workup of patients with a suspected porphyria is most effective when
following a stepwise approach. See Porphyria (Acute) Testing Algorithm in Special Instructions or call
800-533-1710 to discuss testing strategies.
Useful For: Confirmation of a diagnosis of aminolevulinic acid dehydratase deficiency porphyria

using washed erythrocyte specimens This test is not useful for detecting lead intoxication.
Interpretation: Abnormal results are reported with a detailed interpretation including an overview of
the results and their significance, a correlation to available clinical information provided with the
specimen, differential diagnosis, and recommendations for additional testing when indicated and
available.
Reference Values:
Reference ranges have not been established for patients who are <16 years of age.
> or =4.0 nmol/L/sec

3.5-3.9 nmol/L/sec (indeterminate)
<3.5 nmol/L/sec (diminished)
Clinical References: 1. Tortorelli S, Kloke K, Raymond K: Chapter 15: Disorders of porphyrin

metabolism. In Biochemical and Molecular Basis of Pediatric Disease. Fourth edition. Edited by DJ
Dietzen, MJ Bennett, ECC Wong. AACC Press, 2010, pp 307-324 2. Nuttall KL, Klee GG: Analytes of
hemoglobin metabolism - porphyrins, iron, and bilirubin. In Tietz Textbook of Clinical Chemistry. Fifth
edition. Edited by CA Burtis, ER Ashwood. WB Saunders Company, 2001, pp 584-607 3. Anderson KE,
Sassa S, Bishop DF, Desnick RJ: Disorders of Heme Biosynthesis: X-Linked Sideroblastic Anemia and
the Porphyrias In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL
Beaudet, B Vogelstein, et al. McGraw-Hill, Accessed August 9, 2017 Available at
http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62638866
ALAD Aminolevulinic Acid Dehydratase, Whole Blood

88924 Clinical Information: Porphyrias are a group of inherited disorders resulting from enzyme defects in
the heme biosynthetic pathway. A defect in the second enzyme of this pathway causes 5-aminolevulinic
acid (ALA) dehydratase (ALAD) deficiency porphyria (ADP). A marked deficiency of ALAD causes the
accumulation and subsequent urinary excretion of large amounts of ALA. Urinary porphobilinogen (PBG)
remains essentially normal, which rules out other forms of acute porphyria. ADP is an autosomal
recessive acute hepatic porphyria that produces neurologic symptoms similar to those seen in acute
intermittent porphyria. Symptoms include acute abdominal pain, peripheral neuropathy, nausea, vomiting,
constipation, and diarrhea. Respiratory impairment, seizures, and psychosis are possible during an acute
period. ADP is extremely rare with only 7 cases described in the literature since 1979. The workup of
patients with a suspected porphyria is most effective when following a stepwise approach. See Porphyria
(Acute) Testing Algorithm in Special Instructions or call 800-533-1710 to discuss testing strategies.
Useful For: Preferred confirmation test for the diagnosis of aminolevulinic acid dehydratase deficiency
porphyria This test is not useful for detecting lead intoxication.
available.
Reference Values:
Reference ranges have not been established for patients who are <16 years of age.
> or =4.0 nmol/L/sec

3.5-3.9 nmol/L/sec (indeterminate)
<3.5 nmol/L/sec (diminished)
Clinical References: 1. Tortorelli S, Kloke K, Raymond K: Chapter 15: Disorders of porphyrin

metabolism. In Biochemical and Molecular Basis of Pediatric Disease. Fourth edition. Edited by DJ
Dietzen, MJ Bennett, ECC Wong. AACC Press 2010, pp 307-324 2. Nuttall KL, Klee GG: Analytes of
hemoglobin metabolism-porphyrins, iron, and bilirubin. In Tietz Textbook of Clinical Chemistry. Fifth
edition. Edited by CA Burtis, ER Ashwood. WB Saunders Company, 2001, pp 584-607 3. Anderson KE,
Sassa S, Bishop DF, Desnick RJ: Disorders of Heme Biosynthesis: X-Linked Sideroblastic Anemia and
the Porphyrias In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL
Beaudet, B Vogelstein, et al. McGraw-Hill, Accessed August 9, 2017 Available at
http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62638866
ALAUR Aminolevulinic Acid, Urine

61547 Clinical Information: The porphyrias are a group of inherited disorders resulting from enzyme
defects in the heme biosynthetic pathway. Depending on the specific enzyme involved, various porphyrins
and their precursors accumulate in different specimen types. The patterns of porphyrin accumulation in
erythrocytes and plasma and excretion of the heme precursors in urine and feces allow for the detection
and differentiation of the porphyrias. See The Heme Biosynthetic Pathway in Special Instruction for more
information. The porphyrias are typically classified as erythropoietic or hepatic based upon the primary
site of the enzyme defect. In addition, hepatic porphyrias can be further classified as chronic or acute,
based on their clinical presentation. The primary acute hepatic porphyrias: aminolevulinic acid
dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), hereditary coproporphyria
(HCP), and variegate porphyria (VP), are associated with neurovisceral symptoms that typically onset
during puberty or later. Common symptoms include severe abdominal pain, peripheral neuropathy, and
psychiatric symptoms. A broad range of medications (including barbiturates and sulfa drugs), alcohol,
infection, starvation, heavy metals, and hormonal changes may precipitate crises. Photosensitivity is not
associated with AIP, but may be present in HCP and VP. The excretion of aminolevulinic acid (ALA) can
be increased due to one of the inherited acute porphyrias or due to secondary inhibition of ALA
dehydratase. Among the secondary causes, acute lead intoxication results in the greatest increases of
aminolevulinic aciduria. Less significant elevations are seen in chronic lead intoxication, tyrosinemia type
I, alcoholism, and pregnancy. The following algorithms are available in Special Instructions or call
800-533-1710 to discuss testing strategies: -Porphyria (Acute) Testing Algorithm -Porphyria (Cutaneous)
Testing Algorithm
Useful For: Assistance in the differential diagnosis of the acute hepatic porphyrias
Interpretation: Abnormal results are reported with a detailed interpretation that may include an
overview of the results and their significance, a correlation to available clinical information provided
with the specimen, differential diagnosis, recommendations for additional testing when indicated and
available, and a phone number to reach one of the laboratory directors in case the referring physician
Reference Values:
<1 year: < or =10 nmol/mL
1-17 years: < or =20 nmol/mL
> or =18 years: < or =15 nmol/mL
Clinical References: 1. Tortorelli S, Kloke K, Raymond K: Disorders of porphyrin metabolism.

In: Dietzen DJ, Bennett MJ, Wong ECC, eds. Biochemical and Molecular Basis of Pediatric Disease.
4th ed. AACC Press; 2010:chap 15. 2. Anderson KE, Sassa S, Bishop DF, Desnick RJ: Disorders of
heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: Valle DL, Antonarakis S,
Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited
Disease. McGraw-Hill; 2019. Accessed September 04, 2020. Available at
https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225540906 3. Nuttall KL, Klee
GG: Analytes of hemoglobin metabolism-porphyrins, iron, and bilirubin. In: Burtis CA, Ashwood ER,
eds. Tietz Textbook of Clinical Chemistry. 5th ed. WB Saunders Company; 2001:584-607
AMIO Amiodarone, Serum

9247 Clinical Information: Amiodarone is an antiarrhythmic agent used to treat life-threatening
arrhythmias; it is typically categorized as a Class III drug (antiarrhythmic agents that are potassium
channel blockers) but shows several mechanisms of action. The US Food and Drug Administration
approved the use of amiodarone for recurrent ventricular fibrillation and recurrent hemodynamically
unstable ventricular tachycardia only after demonstrating lack of response to other antiarrhythmics, but
more recent studies have shown amiodarone to be the antiarrhythmic agent of choice for many
situations, including atrial fibrillation.(1) Amiodarone can be administered orally or intravenously for
cardiac rhythm control. It is approximately 95% protein bound in blood, with a volume of distribution
of 60 L/kg. Amiodarone elimination is quite prolonged, with a half-life of 26-107 days for oral, chronic
dosing. Cytochrome P450 (CYP) 3A4 converts amiodarone to its equally active metabolite,
N-desethylamiodarone (DEA), which displays very similar pharmacokinetics and serum concentrations
compared with the parent drug.(2) Current therapeutic ranges are based solely on amiodarone, but most
individuals will have roughly equivalent concentrations of DEA at steady state.(3) Numerous side
effects have been associated with amiodarone. The most common adverse effect is disruption of thyroid
function (hypo- or hyperthyroidism) due to amiodarone's structural similarity to thyroid hormones.
Neurological and gastrointestinal toxicities are concentration-dependent, whereas thyroid dysfunction,
pulmonary fibrosis, and hepatotoxicity are more loosely linked to drug concentration. There is
significant potential for drug interactions involving amiodarone, including several other cardioactive
drugs (eg, digoxin, verapamil, class I antiarrhythmics [sodium channel blockers]), warfarin, statins, and
CYP3A4 substrates.
Useful For: Monitoring amiodarone therapy, especially when amiodarone is coadministered with other
drugs that may interact Evaluation of possible amiodarone toxicity Assessment of patient compliance
Interpretation: Clinical effects generally require serum concentrations above 0.5 mcg/mL. Increased
risk of toxicity is associated with amiodarone concentrations above 2.5 mcg/mL. Although therapeutic
and toxic ranges are based only on the parent drug, the active metabolite N-desethylamiodarone should be
present in similar concentrations to amiodarone.
Reference Values:
AMIODARONE
Trough Value
0.5-2.0 mcg/mL: Therapeutic concentration
>2.5 mcg/mL: Toxic concentration
DESETHYLAMIODARONE:
No therapeutic range established for desethylamiodarone; activity and serum concentration are similar to
parent drug.
Clinical References: 1. Goldschlager N, Epstein AE, Naccarelli GV, et al: A practical guide for
clinicians who treat patients with amiodarone: 2007. Heart Rhythm. 2007 Sep;4(9):1250-1259 2. Klotz U:
Antiarrhythmics: elimination and dosage considerations in hepatic impairment. Clin Pharmacokinet.
2007;46(12):985-996 3. Campbell TJ, Williams KM: Therapeutic drug monitoring: antiarrhythmic drugs.
Br J Clin Pharmacol. 2001;52 Suppl1(Suppl 1):21S-34S 4. Rifai N, Horwath AR, Wittwer CT: In: Tietz
AMTRP Amitriptyline and Nortriptyline, Serum

63506 Clinical Information: Amitriptyline is a tricyclic antidepressant that is metabolized to nortriptyline,
which has similar pharmacologic activity. The relative blood levels of amitriptyline and nortriptyline are
highly variable among patients. Amitriptyline is the drug of choice in treatment of depression when the
side effect of mild sedation is desirable. Nortriptyline is used when its stimulatory side effect is
considered to be of clinical advantage. Nortriptyline is unique among the antidepressants in that its blood
level exhibits the classical therapeutic window effect; blood concentrations above or below the therapeutic
window correlate with poor clinical response. Thus, therapeutic monitoring to ensure that the blood level
is within the therapeutic window is critical to accomplish successful treatment with this drug.
Amitriptyline displays major cardiac toxicity when the combined serum level of amitriptyline and
nortriptyline is above 500 ng/mL, characterized by QRS widening, which leads to ventricular tachycardia
and asystole. In some patients, toxicity may manifest at lower concentrations. Like amitriptyline,
nortriptyline can cause major cardiac toxicity when the concentration is above 500 ng/mL, characterized
by QRS widening, which leads to ventricular tachycardia and asystole. In some patients, toxicity may
manifest at lower concentrations.
Useful For: Monitoring amitriptyline and nortriptyline serum concentrations during therapy Evaluating
potential amitriptyline and nortriptyline toxicity The test may also be useful to evaluate patient
compliance
Interpretation: Most individuals display optimal response to amitriptyline when combined serum
levels of amitriptyline and nortriptyline are between 80 and 200 ng/mL. Risk of toxicity is increased with
combined levels are above 500 ng/mL. Most individuals display optimal response to nortriptyline with
serum levels between 70 and 170 ng/mL. Risk of toxicity is increased with nortriptyline levels above 500
ng/mL. Some individuals may respond well outside of these ranges or may display toxicity within the
therapeutic range, thus, interpretation should include clinical evaluation. Therapeutic ranges are based on
specimens collected at trough (ie, immediately before the next dose).
Reference Values:
AMITRIPTYLINE AND NORTRIPTYLINE
Total therapeutic concentration: 80-200 ng/mL
NORTRIPTYLINE ONLY
Therapeutic concentration: 70-170 ng/mL
Note: Therapeutic ranges are for specimens drawn at trough (ie, immediately before next scheduled
dose). Levels may be elevated in non-trough specimens.
Clinical References: 1. Wille SM, Cooreman SG, Neels HM, Lambert WE: Relevant issues in the
monitoring and the toxicology of antidepressants. Crit Rev Clin Lab Sci. 2008;45(1):25-89 2.
Thanacoody HK, Thomas SHL: Antidepressant poisoning. Clin Med (Lond). 2003
Mar-Apr;3(2):114-118 3. Hiemke C, Baumann P, Bergemann N, et al: AGNP Consensus Guidelines for
Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry. 2011
Sep;44(6):195-235 4. Burtis CA, Ashwood ER, Bruns DE, eds. Tietz Textbook of Clinical Chemistry
and Molecular Diagnostics. 5th ed. Elsevier; 2012
NH3V Ammonia, Plasma

35130 Clinical Information: Ammonia is a waste product of protein catabolism; it is potentially toxic to
the central nervous system. Increased plasma ammonia may be indicative of hepatic encephalopathy,
hepatic coma in terminal stages of liver cirrhosis, hepatic failure, acute and subacute liver necrosis, and
Reye's syndrome. Hyperammonemia may also be found with increasing dietary protein intake. The
major cause of hyperammonemia in infants includes inherited deficiencies of urea cycle enzymes,
inherited metabolic disorders of organic acids and the dibasic amino acids lysine and ornithine, and
severe liver disease.
Useful For: Assisting in the diagnosis of hepatic coma Investigating and monitoring treatment for
inborn errors of metabolism Evaluating patients with advanced liver disease
Interpretation: Plasma ammonia concentrations do not correlate well with the degree of hepatic
encephalopathy. Elevated ammonia concentration may also be found with increased dietary protein
intake. Plasma ammonia concentrations in newborns younger than one week are elevated compared to
adults. Values less than or equal to 82 mcmol/L have been observed.(1)
Reference Values:
< or =30 mcmol/L
Clinical References: 1. Madigan T, Block DR, Carey WA, et al: Proposed plasma ammonia
reference intervals in a reference group of hospitalized term and preterm neonates. J App Lab Med.
2020 Mar 1;5(2):363-369 2. Rosenberg W: Liver disease. In: Rifai N, Horvath AR, Wittwer CT, eds.
Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:1348-1397
AMMO Ammonium, 24 Hour, Urine

606643 Clinical Information: The kidney regulates acid excretion and systemic acid base balance.
Changing the amount of ammonium in the urine is one important way the kidneys accomplish this task.
Thus, measuring the urine ammonium level can provide understanding of the cause of an acid base
disturbance in individual patients.(1-3) The urine ammonium level can also provide a lot of information
about the daily acid production in a given patient. Since most of an individual's acid load comes from
ingested protein, the urine ammonium is a good indicator of dietary protein intake. Urine ammonium
measurements can be particularly helpful for the diagnosis and treatment of kidney stone patients: -High
urine ammonium and low urinary pH suggest ongoing gastrointestinal losses. Such patients are at risk of
uric acid and calcium oxalate stones. -Low urine ammonium and high urine pH suggest renal tubular
acidosis. Such patients are at risk of calcium phosphate stones. -Patients with calcium oxalate and
calcium phosphate stones are often treated with citrate to raise the urine citrate (a natural inhibitor of
calcium oxalate and calcium phosphate crystal growth). However, citrate is metabolized to bicarbonate
(a base), which can increase the urine pH. If the urine pH gets too high, the risk of calcium phosphate
stones may have unintentionally been increased. Monitoring the urine ammonium concentration is one
way to titrate the citrate dose and avoid this problem. A good starting citrate dose is about one-half of
the urine ammonium excretion (in mEq of each). One can monitor the effect of this dose on urine
ammonium, citrate, and pH values, and adjust the citrate dose based upon the response. A fall in urine
ammonium should indicate whether the current citrate is enough to partially (but not completely)
counteract the daily acid load of that given patient.(4)
Useful For: Diagnosis of the cause of acidosis Diagnosis and treatment of kidney stones
Interpretation: If a patient has acidosis and the amount of ammonium in the urine is low, this is
suggestive of a renal tubular acidosis. If the amount of ammonium is high, this suggests that the kidneys
are working normally and that there are other losses of bicarbonate in the body. Typically this implies
gastrointestinal losses.
Reference Values:
15-56 mmol/24 hour
Reference values have not been established for patients <18 years and >77 years of age.
Reference values apply to 24 hour collections.
Clinical References: 1. Peonides A, Levin B, Young W: The renal excretion of hydrogen ions in
infants and children. Arch Dis Child. 1965 Feb;40(209):33-39 2. Kamel KS, Briceno LF, Sanchez MI, et
al: A new classification for renal defects in net acid excretion. Am J Kidney Dis. 1997 Jan;29(1):136-146
3. Madison LL, Seldin DW: Ammonia excretion and renal enzymatic adaptation in human subjects, as
disclosed by administration of precursor amino acids. J Clin Invest .1958 Nov;37(11):1615-1627 4. Coe
FL, Evan A, Worcester E: Pathophysiology-based treatment of idiopathic calcium kidney stones. Clin J
Am Soc Nephrol. 2011 Aug;6(8):2083-2092
RAMCN Ammonium, Random, Urine

Only orderable as part of a profile. For more information see SSATR / Supersaturation Profile, Pediatric,
Random, Urine.
RAMBO Ammonium, Random, Urine

606709 Clinical Information: The kidney regulates acid excretion and systemic acid base balance. Changing
the amount of ammonium in the urine is one important way the kidneys accomplish this task. Thus,
measuring the urine ammonium level can provide understanding of the cause of an acid base disturbance
in individual patients.(1-3) The urine ammonium level can also provide a lot of information about the
daily acid production in a given patient. Since most of an individual's acid load comes from ingested
protein, the urine ammonium is a good indicator of dietary protein intake. Urine ammonium
measurements can be particularly helpful for the diagnosis and treatment of kidney stone patients: -High
urine ammonium and low urinary pH suggests ongoing gastrointestinal losses. Such patients are at risk of
uric acid and calcium oxalate stones. -Low urine ammonium and high urine pH suggests renal tubular
acidosis. Such patients are at risk of calcium phosphate stones. -Patients with calcium oxalate and calcium
phosphate stones are often treated with citrate to raise the urine citrate (a natural inhibitor of calcium
oxalate and calcium phosphate crystal growth). However, citrate is metabolized to bicarbonate (a base),
which can increase the urine pH. If the urine pH gets too high, the risk of calcium phosphate stones may
have unintentionally been increased. Monitoring the urine ammonium concentration is one way to titrate
the citrate dose and avoid this problem. A good starting citrate dose is about one-half of the urine
ammonium excretion (in mEq of each). One can monitor the effect of this dose on urine ammonium,
citrate, and pH values, and adjust the citrate dose based upon the response. A fall in urine ammonium
should indicate whether the current citrate is enough to partially (but not completely) counteract the daily
acid load of that given patient.(4)
Useful For: Diagnosis of the cause of acidosis using random urine specimens Diagnosis and
treatment of kidney stones
Interpretation: If a patient has acidosis and the amount of ammonium in the urine is low, this is
suggestive of a renal tubular acidosis. If the amount of ammonium is high, this suggests that the kidneys
are working normally and that there are other losses of bicarbonate in the body. Typically this implies
gastrointestinal losses.
Reference Values:
Random: 3-65 mmol/L
No reference values established for <18 years and >77 years of age.
Clinical References: 1. Peonides A, Levin B, Young W: The renal excretion of hydrogen ions in
infants and children. Arch Dis Child. 1965 Feb;40(209):33-39 2. Kamel KS, Briceno LF, Sanchez MI,
et al: A new classification for renal defects in net acid excretion. Am J Kidney Dis. 1997
Jan;29(1):136-146 3. Madison LL, Seldin DW: Ammonia excretion and renal enzymatic adaptation in
human subjects, as disclosed by administration of precursor amino acids. J Clin Invest 1958.
Nov;37(11):1615-1627 4. Coe FL, Evan A, Worcester E: Pathophysiology-Based Treatment of
Idiopathic Calcium Kidney Stones. Clin J Am Soc Nephrol. 2011 Aug;6(8):2083-2092
AMOBS Amobarbital, Serum

8325 Clinical Information: Amobarbital is an intermediate-acting barbiturate with hypnotic properties
used in short-term treatment of insomnia and to reduce anxiety and provide sedation
preoperatively.(1,2) Amobarbital is administered by intravenous infusion or intramuscular injection.
The duration of its hypnotic effect is about 6 to 8 hours. The drug distributes throughout the body, with
a volume of distribution of 0.9 to 1.4 L/kg, and about 59% of a dose is bound to plasma proteins.
Metabolism takes place in the liver primarily via hepatic microsomal enzymes. Its half-life is about 15
to 40 hours (mean: 25 hours). Excretion occurs mainly in the urine.(2,3)
Useful For: Monitoring amobarbital therapy

Interpretation: Amobarbital concentrations above 10 mcg/mL have been associated with toxicity.
Reference Values:
Therapeutic concentration: 1.0-5.0 mcg/mL
Toxic concentration: >10.0 mcg/mL
Clinical References: 1. Mihic SJ, Mayfield J, Harris RA: Hypnotics and sedatives. In: Brunton
LL, Hilal-Dandan R, Knollmann BC, eds. Goodman and Gilman's The Pharmacological Basis of
Therapeutics. 13th ed. McGraw-Hill Education; 2017 2. Milone MC, Shaw LM: Therapeutic drugs and
their management. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:800-831 3. Baselt RC: Disposition of Toxic Drugs and
Chemicals in Man. 10th ed. Biomedical Publications; 2014:2211 4. Langman LJ, Bechtel LK, Meier
BM, Holstege C: Clinical toxicology. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of
Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887
FAMOX Amoxapine (Asendin) and 8-Hydroxyamoxapine

Amoxapine No reference range provided ng/mL
8-Hydroxyamoxapine No reference range provided ng/mL
Combined Total 200 Ã¢â‚¬â€œ 400 ng/mL
AMOXY Amoxicillin, IgE, Serum

82663
Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are
Useful For: Establishing a diagnosis of an allergy to amoxicillin Defining the allergen responsible for
eliciting signs and symptoms Identifying allergens: -Responsible for allergic disease and/or anaphylactic
episode -To confirm sensitization prior to beginning immunotherapy -To investigate the specificity of
allergic reactions to insect venom allergens, drugs, or chemical allergens

Reference Values:
0 Negative

apply to all ages.
FAMP Amphetamine, Serum or Plasma

Reference Range: 10 Ã¢â‚¬â€œ 100 ng/mL
AMPMX Amphetamine-Type Stimulants Confirmation, Chain of Custody,

62712 Meconium
Clinical Information: Several stimulants and hallucinogens chemically related to phenylethylamine
are referred to collectively as the amphetamine-type stimulants (amphetamines). Generally, this refers to
the prescription and illicit amphetamines including amphetamine; methamphetamine;
3,4-methylenedioxymethamphetamine ( MDMA, Ecstasy); 3,4-methylenedioxyamphetamine (MDA); and
3,4-methylenedioxyethylamphetamine (MDEA).(1) Methamphetamine has become a drug of choice
among stimulant abusers because of its availability and ease to synthesize. The metabolism of
amphetamine consists of hydroxylation and deamination followed by conjugation with glucuronic acid.
Methamphetamine is metabolized to amphetamine; both should be present in urine after
methamphetamine use. Both MDMA and MDEA are metabolized to MDA.(1) The disposition of drug in
meconium, the first fecal material passed by the neonate, is not well understood. The proposed
either by direct deposition from bile or through swallowing of amniotic fluid.(2) The first evidence of
meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation, and slowly
moves to the colon by the 16th week of gestation.(3) Therefore, the presence of drugs in meconium has
been proposed to be indicative of in utero drug exposure up to 5 months before birth, a longer historical
measure than is possible by urinalysis.(2) Intrauterine drug exposure to amphetamines has been associated
with maternal abruption, prematurity, and decreased growth parameters such as low-birth weight.(4)
Some intrauterine amphetamine-exposed infants may develop hypertonia, tremors, and poor feeding and
abnormal sleep patterns.(5) Chain of custody is a record of the disposition of a specimen to document who
collected it, who handled it, and who performed the analysis. When a specimen is submitted in this
manner, analysis will be performed in such a way that it will withstand regular court scrutiny.
required whenever the results of testing could be used in a court of law. Its purpose is to protect the
rights of the individual contributing the specimen by demonstrating that it was under the control of
personnel involved with testing the specimen at all times; this control implies that the opportunity for
specimen tampering would be limited. Since the evidence of illicit drug use during pregnancy can be
cause for separating the baby from the mother, a complete chain of custody ensures that the test results
are appropriate for legal proceedings.
Interpretation: The presence of any of the following: amphetamine; methamphetamine;

3,4-methylenedioxyamphetamine; 3,4-methylenedioxymethamphetamine; or
3,4-methylenedioxyethylamphetamine at more than 20 ng/g is indicative of in utero exposure up to 5
months before birth.
Reference Values:
Negative
Positives are reported with a quantitative liquid chromatography-tandem mass spectrometry
(LC-MS/MS) result.
Cutoff concentrations for LC-MS/MS testing:
Amphetamine: 20 ng/g
Methamphetamine: 20 ng/g
3,4-Methylenedioxyamphetamine: 20 ng/g
3,4-Methylenedioxyethylamphetamine: 20 ng/g
3,4-Methylenedioxymethamphetamine: 20 ng/g
Clinical References: 1. Baselt RC, ed: Disposition of Toxic Drugs and Chemical in Man.
Biochemical Publications; 2008:83-86; 947-952; 993-999 2. Ostrea EM Jr, Brady MJ, Parks PM,
Asensio DC, Naluz: Drug screening of meconium in infants of drug-dependent mothers: an alternative
to urine testing. J Pediatr. 1989;115:474-477 3. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG:
Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv.
2005;60:45-56 4. Kwong TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug
testing. National Academy of Clinical Biochemistry. Clin Chem. 1997;43:235-242 5. Dixon SD: Effects
of transplacental exposure to cocaine and methamphetamine on the neonate. West J Med.
1989;150:436-442 6. Langman LJ Bechtel LK, Meier BM, Holstege C: Clinical toxicology. In: Rifai N,
ed. Elsevier; 2018:832-887
AMPHM Amphetamine-Type Stimulants Confirmation, Meconium

84371 Clinical Information: Several stimulants and hallucinogens chemically related to
phenylethylamine are referred to collectively as the amphetamine-type stimulants (amphetamines).
Generally, this refers to the prescription and illicit amphetamines including amphetamine;
methamphetamine; 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy);
3,4-methylenedioxyamphetamine (MDA); and 3,4-methylenedioxyethylamphetamine (MDEA).(1)
Methamphetamine has become a drug of choice among stimulant abusers because of its availability and
ease to synthesize. The metabolism of amphetamine consists of hydroxylation and deamination
followed by conjugation with glucuronic acid. Methamphetamine is metabolized to amphetamine; both
should be present in urine after methamphetamine use. Both MDMA and MDEA are metabolized to
MDA.(1) The disposition of drug in meconium is not well understood. The proposed mechanism is that
the fetus excretes drug into bile and amniotic fluid. Drug accumulates in meconium either by direct
deposit from bile or through swallowing of amniotic fluid.(2) The first evidence of meconium in the
fetal intestine appears at approximately the tenth to twelfth week of gestation, and slowly moves into
the colon by the sixteenth week of gestation.(3) Therefore, the presence of drugs in meconium has been
proposed to be indicative of in utero drug exposure during the final 4 to 5 months of pregnancy, a longer
historical measure than is possible by urinalysis.(2) Intrauterine drug exposure to amphetamines has
been associated with maternal abruption, prematurity, and decreased growth parameters such as
low-birth weight.(4) Some intrauterine amphetamine-exposed infants may develop hypertonia, tremors,
and poor feeding and abnormal sleep patterns.(5)
Useful For: Detection of in utero exposure to amphetamine-type stimulants up to 5 months before birth
Interpretation: The presence of any of the following: amphetamine; methamphetamine;
3,4-methylenedioxyamphetamine; 3,4-methylenedioxymethamphetamine; or
3,4-methylenedioxyethylamphetamine at greater than 20 ng/g is indicative of in utero exposure up to 5
months before birth.
Reference Values:
Negative
(LC-MS/MS) result.

Amphetamine: 20 ng/g
Methamphetamine: 20 ng/g
3,4-Methylenedioxyamphetamine: 20 ng/g
3,4-Methylenedioxyethylamphetamine: 20 ng/g
3,4-Methylenedioxymethamphetamine: 20 ng/g
Clinical References: 1. Baselt RC, ed: Disposition of Toxic Drugs and Chemical in Man.
Biochemical Publications; 2008:83-86; 947-952; 993-999 2. Ostrea EM Jr, Brady MJ, Parks PM, Asensio
DC, Naluz: Drug screening of meconium in infants of drug-dependent mothers: an alternative to urine
testing. J Pediatr. 1989;115:474-477 3. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium
passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv. 2005;60:45-56 4.
Kwong TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National
Academy of Clinical Biochemistry. Clin Chem. 1997;43:235-242 5. Dixon SD: Effects of transplacental
exposure to cocaine and methamphetamine on the neonate. West J Med. 1989;150:436-442
FASCC Amphetamines Analysis, Serum

Reference Range:
Amphetamines: Cutoff: 50
Confirmation Threshold: 10 mg/mL
AMPHX Amphetamines Confirmation, Chain of Custody, Random, Urine

62711 Clinical Information: Amphetamines are sympathomimetic amines that stimulate central nervous
system activity and, in part, suppress the appetite. Phentermine, amphetamine, and methamphetamine are
prescription drugs for weight loss. All of the other amphetamines are Class I (distribution prohibited)
compounds. In addition to their medical use as anorectic drugs, they are used in the treatment of
narcolepsy, attention-deficit disorder/attention-deficit hyperactivity disorder, and minimal brain
dysfunction. Because of their stimulant effects, the drugs are commonly sold illicitly and abused.
Physiological symptoms associated with very high amounts of ingested amphetamine or
methamphetamine include elevated blood pressure, dilated pupils, hyperthermia, convulsions, and acute
amphetamine psychosis. Chain-of-custody is a record of the disposition of a specimen to document each
individual who collected, handled, and performed the analysis. When a specimen is submitted in this
Useful For: Confirming drug exposure involving amphetamines such as amphetamine and
methamphetamine, phentermine, methylenedioxymethamphetamine (MDMA),
methylenedioxyethylamphetamine (MDEA), and methylenedioxyamphetamine (MDA) Providing
chain-of-custody for when the results of testing could be used in a court of law. Its purpose is to protect
the rights of the individual contributing the specimen by demonstrating that it was under the control of
specimen tampering would be limited.
Interpretation: The presence of amphetamines in urine at concentrations greater than 500 ng/mL is
a strong indicator that the patient has used these drugs within the past 3 days. This test will produce
true-positive results for urine specimens collected from patients who are administered Adderall and
Benzedrine (contain amphetamine); Desoxyn and Vicks Inhaler (contain methamphetamine); Selegiline
(metabolized to methamphetamine and amphetamine); and clobenzorex, famprofazone, fenethylline,
fenproporex, and mefenorex, which are amphetamine pro-drugs.
Reference Values:
Negative
IMMUNOASSAY SCREEN: <500 ng/mL
Liquid chromatography-tandem mass spectrometry:

Amphetamine: <25 ng/mL
Methamphetamine: <25 ng/mL
Phentermine: <25 ng/mL
Methylenedioxyamphetamine: <25 ng/mL
Methylenedioxymethamphetamine: <25 ng/mL
Pseudoephedrine/ephedrine: <25 ng/mL reported as negative
Clinical References: 1. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man. 10th ed.
Biomedical Publications; 2014 2. Langman LJ et al: Clinical toxicology. In: Rifai N, Horvath AR,
Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier;
2018:832-887 3. Principles of Forensic Toxicology. 2nd ed. AACC Press; 2003:385
AMPHU Amphetamines Confirmation, Random, Urine

8257 Clinical Information: Amphetamines are sympathomimetic amines that stimulate the central
nervous system activity and, in part, suppress the appetite. Phentermine, amphetamine, and
methamphetamine are prescription drugs for weight loss. All of the other amphetamines are Class I
(distribution prohibited) compounds. In addition to their medical use as anorectic drugs, they are used in
the treatment of narcolepsy, attention-deficit disorder/attention-deficit hyperactivity disorder and
minimal brain dysfunction. Because of their stimulant effects, the drugs are commonly sold illicitly and
abused. Physiological symptoms associated with very high amounts of ingested amphetamine or
amphetamine psychosis.
Useful For: Confirming drug exposure involving amphetamines such as amphetamine and
methamphetamine, phentermine, methylenedioxyamphetamine (MDA),
methylenedioxymethamphetamine (MDMA), and methylenedioxyethylamphetamine (MDEA)
Interpretation: The presence of amphetamines in urine at concentrations greater than 500 ng/mL is a
strong indicator that the patient has used one of these drugs within the past 3 days. Methamphetamine has
a half-life of 9 to 24 hours and is metabolized by hepatic demethylation to amphetamines. Consequently, a
sample containing methamphetamine usually also contains amphetamine. Amphetamine has a half-life of
4 to 24 hours. Amphetamine is not metabolized to methamphetamine; absence of methamphetamine in the
presence of amphetamine indicates the primary drug of abuse is amphetamine.
3,4-Methylenedioxymethamphetamine (Ecstasy, MDMA) is metabolized to
3,4-methylenedioxyamphetamine (MDA). The detection interval in urine for amphetamine type
stimulants is typically to 3 to 5 days after last ingestion. This test will produce true-positive results for
urine specimens collected from patients who are administered Adderall and Benzedrine (contain
amphetamine); Desoxyn and Vicks Inhaler (contain methamphetamine); Selegiline, and famprofazone
(metabolized to methamphetamine and amphetamine); and clobenzorex, fenproporex, and mefenorex,
which are metabolized to amphetamine.
Reference Values:
Negative
Cutoff concentrations by liquid chromatography-tandem mass spectrometry:

Amphetamine: <25 ng/mL
Methamphetamine: <25 ng/mL
Phentermine: <25 ng/mL
Methylenedioxyamphetamine: <25 ng/mL
Methylenedioxymethamphetamine: <25 ng/mL
Pseudoephedrine/ephedrine: <25 ng/mL reported as negative
Biomedical Publications; 2014 2. Langman LJ Bechtel LK, Meier BM, Holstege C: Clinical toxicology.
Diagnostics. 6th ed. Elsevier; 2018:832-887
FCDU5 Amphetamines, Umbilical Cord Tissue

Units: ng/g
AMP Ampicillin, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to ampicillin Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
AMBF Amylase, Body Fluid

606595 Clinical Information: Pleural fluid: Amylase-rich pleural effusions are commonly associated with
pancreatitis, esophageal rupture, malignancy, pneumonia, and liver cirrhosis.(1) Pleural fluid amylase
measurement is not routinely indicated though may help to narrow the differential due to these causes.
Results should be interpreted in conjunction with serum measurement usually as a ratio of pleural fluid
to serum amylase. The ratio of pleural fluid to serum amylase in effusions caused by pancreatic disease
is much higher (mean + or - SD = 18 + or - 6.3) versus non-pancreatic disease (4.8 + or - 1.3) (P =
0.003).(2) Isoform analysis revealed that pancreatic amylase is diagnostic of pancreatitis-related pleural
effusions, whereas salivary amylase isoforms are more often associated with esophageal rupture and
malignancy.(3) Peritoneal fluid: The digestive enzymes amylase and lipase can be measured in the
identification of pancreatic fluid in the peritoneal cavity. Concentrations are expected to be elevated and
at least several-fold times higher in fluid of pancreatic origin compared to simultaneous concentrations
in serum.(4) In contrast, amylase concentration in ascites of non-pancreatic origin was approximately
half the plasma value.(5) Drain fluid: Amylase might be measured in a drain fluid to aid in the
identification of internal pancreatic fistulas due to chronic pancreatitis or formation of a fistula after
surgery.(6,7) Comparison to serum concentrations is recommended with elevations several-fold higher
than blood being suggestive of the presence of pancreatic fluid in the drained cavity.
Useful For: Evaluation of patients with a pathological accumulation of fluid to determine whether
pancreatic inflammation, pancreatic fistula, or esophageal rupture may be contributing Aiding in the
diagnosis of pancreatitis
Interpretation: Peritoneal and drain fluid amylase activity in non-pancreatic peritoneal fluid is often
less than or equal to the serum amylase activity. Ascites associated with pancreatitis typically has
amylase activity at least 5-fold greater than serum.(1) Normal pleural fluid amylase activity is typically
less than the upper limit of normal serum amylase and has a ratio of pleural fluid amylase to serum
amylase ratio less than 1.0.(3) All Other Fluids: Body fluid amylase activity may become elevated due
to the presence of pancreatitis, esophageal rupture, or amylase producing neoplasms. Results should be
interpreted in conjunction with serum amylase and other clinical findings.
Reference Values:
Clinical References: 1. Burgess LJ: Biochemical analysis of pleural, peritoneal and pericardial
effusions. Clin Chim Acta. 2004;343:61-84 2. Joseph J, Viney S, Beck P, et al: A prospective study of
amylase-rich pleural effusions with special reference to amylase isoenzyme analysis. Chest.
1992;102:1455-1459 3. Sahn SA: Getting the most from pleural fluid analysis. Respirology.
2012;17:270-277 4. Robert JH, Meyer P, Rohner A: Can serum and peritoneal amylase and lipase
determinations help in the early prognosis of acute pancreatitis? Ann Surg. 1986;203:163-168 5. Runyon
BA: Amylase levels in ascitic fluid. J Clin Gastroenterol. 1987;9:172-174 6. Lipsett PA, Cameron JL:
Internal pancreatic fistula. Am J Surg. 1992;163:216-220 7. Kaman L, Behera A, Singh R, et al: Internal
pancreatic fistulas with pancreatic ascites and pancreatic pleural effusions: recognition and management.
ANZ J Surg. 2001;71:221-225 8. Nandakumar V, Dolan C, Baumann NA, Block DR: Effect of pH on the
quantification of body fluid analytes for clinical diagnostic testing. Am J Clin Path. 2019 Oct;152(S1):
S10-S11
AMISO Amylase, Isoenzymes, Serum

604930 Clinical Information: The amylase enzymes are a group of hydrolases that degrade complex
carbohydrates (starches) into simple sugars. The pancreas and salivary glands have amylase
concentrations that are orders of magnitude greater than any other tissue. These two amylase isoenzymes,
pancreatic and salivary, are present in serum. Pancreatic and salivary amylase isoenzymes can be
measured in serum at both physiologic concentrations (within the age-specific reference interval), and
elevated concentrations indicate hyperamylasemia. Hyperamylasemia can result from either increased rate
of release of amylase into blood or decreased metabolic clearance of the enzyme (ie, macroamylase).
Routine amylase laboratory tests measure total amylase activity in serum and do not differentiate between
amylase isoenzymes. Differentiation of amylase isoenzymes is useful in cases where amylase elevations
are not thought to be from a pancreatic source. Pancreatic amylase may be elevated due to pancreatitis as
well as other conditions in which pancreatic amylase is released (eg, cannulation of the pancreatic duct) or
absorbed (eg, loss of bowel integrity) into the blood. Serum pancreatic amylase should always be
interpreted in a context of total amylase to determine the relative contribution of salivary and pancreatic
isoenzymes. Hyperamylasemia due to salivary amylase may occur when salivary gland disease is present.
Salivary amylasemia may also be observed in conditions where there is no clinical evidence of salivary
gland disease such as chronic alcoholism, postoperative states, lactic acidosis, anorexia nervosa or
bulimia, and malignant neoplasms that secrete amylase.
Useful For: Ruling out salivary amylase as the cause of elevated serum amylase
Interpretation: Increased concentrations of total amylase activity in conjunction with increased
concentration of specific amylase isoenzymes may aid in differentiating the source of amylase (pancreatic
versus salivary).
Reference Values:
AMYLASE, TOTAL
0-30 days: < or =6 U/L
31-182 days: 1-17 U/L
183-365 days: 6-44 U/L
1-3 years: 8-79 U/L
4-17 years: 21-110 U/L
> or =18 years: 28-100 U/L
AMYLASE, PANCREATIC
0-<24 months: < or =20 U/L
2-<18 years: 9-35 U/L
> or =18 years: 13-53 U/L
AMYLASE, SALIVARY
0-<18 years: Not established
> or =18 years: <87 U/L
Clinical References: 1. Panteghini M: Laboratory evaluation of pancreatic diseases. Biochimica

Clinica. 2010;34(1):19-25 2. Rifai N, Horvath AR, Wittwer CT: Tietz Fundamentals of Clinical
Chemistry and Molecular Diagnostics. 8th ed. Elsevier; 2018 3. Pieper-Bigelow C, Strocchi A, Levitt
MD: Where does serum amylase come from and where does it go? Gastroenterol Clin North Am. 1990
Dec;19(4):793-810 4. Azzopardi E, Lloyd C, Teixeira SR, Conlan RS, Whitaker IS: Clinical
applications of amylase: Novel perspectives. Surgery. 2016 Jul;160(1):26-37
AMLPC Amylase, Pancreatic Cyst Fluid

60078 Clinical Information: Amylases are a group of hydrolases that degrade complex carbohydrates into
fragments. Amylase is produced by the exocrine pancreas and the salivary glands to aid in the digestion
of starch. It is also produced by the small intestine mucosa, ovaries, placenta, liver, and fallopian tubes.
Measurement of amylase in pancreatic cyst fluid is often used in conjunction with tumor markers,
carcinoembryonic antigen and CA19-9, as an aid in the differential diagnosis of pancreatic cysts lesions.
Amylase seems to be particularly helpful in excluding pancreatic pseudocysts. A number of studies
have demonstrated that amylase levels are typically very high, usually in the thousands in pseudocysts,
therefore, low amylase values virtually excludes pseudocysts. Based on the evidence available, the
American College of Gastroenterology (ACG) practice guidelines for the Diagnosis and Management of
Neoplastic Pancreatic Cysts suggest that an amylase cutoff value of 250 U/L is useful to exclude
pseudocysts.
Useful For: Aiding in distinguishing between pseudocysts and other types of pancreatic cysts, when
used in conjunction with imaging studies, cytology, and other pancreatic cyst fluid tumor markers
Interpretation: A pancreatic cyst fluid amylase concentration of less than 250 U/L indicates a low
risk of a pseudocyst and is more consistent with cystic neoplasms such as mucinous cystic neoplasms
(MCN), intraductal papillary mucinous neoplasm (IPMN), serous cystadenomas, cystic neuroendocrine
tumor, and mucinous cystadenocarcinoma. High pancreatic cyst fluid amylase values are nonspecific
and occur both in pseudocysts and some mucin-producing cystic neoplasms including MCN, IPMN, and
mucinous cystadenocarcinoma. In-house studies to verify this cutoff value showed that 94% (66/70) of
pseudocysts had a value of greater or equal to 250 U/L. Cysts with amylase levels of less than 250 U/L
included 69% of adenocarcinomas, 31% of intraductal papillary mucinous neoplasia, 55% of mucinous
cystadenomas, 64% serous cystadenomas, and 6% of pseudocysts. Therefore, using a cutoff of less than
250 U/L to exclude a pseudocyst has 94% sensitivity and 42% specificity.
Reference Values:
Clinical References: 1. Snozek CL, Mascarenhas RC, O'Kane DJ: Use of cyst fluid CEA,
CA19-9, and amylase for evaluation of pancreatic lesions. Clin Biochem. 2009;42:1585-1588 2. van der
Waaij LA, van Dullemen HM, Porte RJ: Cyst fluid analysis in the differential diagnosis of pancreatic
cystic lesions: a pooled analysis. Gastrointest Endosc. 2005;62:383-389 3.Â Elta GH, Enestvedt BK:
ACG clinical guideline for the diagnosis and management of pancreatic cysts. Am J Gasroenterol.
2018;113:464-479 4. Brugge WR: Diagnosis and management of cystic lesions of the pancreas. J
Gastrointest Oncol. 2015;6(4):375-388. doi:10.3978/j.issn.2078-6891.2015.057
AMS Amylase, Total, Serum

8352 Clinical Information: The amylase enzymes are a group of hydrolases that degrade complex
carbohydrates into fragments. Amylase is produced primarily by the exocrine pancreas where the
enzyme is synthesized by the acinar cells and then secreted into the intestinal tract by way of the
pancreatic duct system. Amylases also are produced by the salivary glands, small intestine mucosa,
ovaries, placenta, liver, and fallopian tubes. Pancreatic and salivary isoenzymes are found in serum.
Useful For: Diagnosis and management of pancreatitis Evaluation of pancreatic function
Interpretation: In acute pancreatitis, a transient rise in serum amylase activity occurs within 2 to 12
hours of onset; levels return to normal by the third or fourth day. A 4- to 6-fold elevation of amylase
activity above the reference limit is usual with the maximal levels obtained in 12 to 72 hours. However, a
significant number of subjects show lesser elevations and sometimes none. The magnitude of the
elevation of serum enzyme activity is not related to the severity of pancreatic involvement. Normalization
is not necessarily a sign of resolution. In acute pancreatitis associated with hyperlipidemia, serum amylase
activity may be spuriously normal; the amylasemia may be unmasked either by serial dilution of the
serum or ultracentrifugation. A significant amount of serum amylase is excreted in the urine and,
therefore, elevation of serum activity is reflected in the rise of urinary amylase activity. Urine amylase, as
compared to serum amylase, appears to be more frequently elevated, reaches higher levels, and persists
for longer periods. However, the receiver operator curves (ROC) of various serum and urine amylase
assays demonstrated that all urine assays had poorer diagnostic utility than all serum assays. In quiescent
chronic pancreatitis, both serum and urine activities are usually subnormal. Because it is produced by
several organs, amylase is not a specific indicator of pancreatic function. Elevated levels also may be seen
in a number of nonpancreatic disease processes including mumps, salivary duct obstruction, ectopic
pregnancy, and intestinal obstruction/infarction.
Reference Values:
0-30 days: 0-6 U/L
31-182 days: 1-17 U/L
183-365 days: 6-44 U/L
1-3 years: 8-79 U/L
4-17 years: 21-110 U/L
> or =18 years: 28-100 U/L
Clinical References: 1. Soldin SJ: Pediatric Reference Ranges. 2nd ed AACC Press; 1997 2. Rifai
N, Horvath AR, Wittwer CT, eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th
ed. Elsevier; 2018 3. Swaroop VS, Chari ST, Clain JE: Acute pancreatitis. JAMA. 2004;291:2865-2868 4.
Azzopardi E, Lloyd C, Teixeira SR, Conlan, RS, Whitaker, IS: Clinical applications of amylase: Novel
perspectives. Surgery. 2016;160(1):26-37
AAH Amyloid A (Hepatic) Immunostain, Technical Component Only

70349 Clinical Information: Amyloid A (AA), also called serum amyloid A (SAA), is an acute-phase
protein. In the liver, AA is expressed on hepatocytes, although expression has been observed in
adipocytes. AA can be used with a panel of immunohistochemical markers (beta-catenin, liver fatty acid
binding protein, C-reactive protein, and glutamine synthetase) to distinguish hepatic adenoma from focal
nodular hyperplasia and non-neoplastic liver. AA, along with C-reactive protein is overexpressed in
inflammatory (type 3) hepatic adenoma and is not detectable in normal liver or in other adenoma types.
Useful For: Classification of hepatic adenomas

pathologist.
Clinical References: 1. van Aalten SM, Verheij J, Terkivatan T, et al: Validation of a liver adenoma
classification system in a tertiary referral centre: implications for clinical practice. J Hepatol
2011;55(1):120-125 2. Bioulac-Sage P, Cubel G, Balabaud C, et al: Revisiting the pathology of resected
benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis
2011;31(1):91-103 3. Bioulac-Sage P, Rebouissou S, Thomas C, et al: Hepatocellular adenoma subtype
classification using molecular markers and immunohistochemistry. Hepatology 2007;46(3):740-748
AMYA Amyloid A (SAA) Immunostain, Technical Component Only
70548 Clinical Information: Immunohistochemical staining for amyloid A (SAA) produces diffuse,
extracellular staining in positive tissues and colocalizes with Congo Red apple-green birefringence.
SAA-type amyloid is associated with chronic inflammatory conditions, such as tuberculosis and
rheumatoid arthritis. Immunohistochemical classification of amyloid has been largely replaced by
subtyping using tandem mass spectrometry analysis on formalin-fixed paraffin-embedded specimens,
due to its superior sensitivity and specificity.
Useful For: Identification and classification of amyloid subtypes in tissue

Clinical References: 1. Jang B, Koh Y, Seo JW: Immunohistochemical Classification of Amyloid

Deposits in Surgical Pathology. Basic and Applied Pathology 2009;2:1-8 2. Leung N, Nasr SH, Sethi S:
How I Treat Amyloidosis: The Importance of Accurate Diagnosis and Amyloid Typing. Blood.
2012;120(16):3206-3213 3. Sen S, Sarsik B, Nazan O, et al: Problems in Diagnosis of NonAA Renal
Amyloidosis. Turkish Journal of Pathology 2010;26(1):14-24 4. Schonland SO, Hegenbart U, Bochtler
T, et al: Immunohistochemistry in the Classification of Systemic Forms of Amyloidosis: A Systematic
Investigation of 117 patients. Blood. 2012;119(2):488-493
FABP Amyloid Beta-Protein

91408 Clinical Information: Amyloid B-Protein is a peptide that ranges in size from 28-43 amino acids.
Most fragments have the same biological activity as the whole molecule. Amyloid B-Protein causes
vascular and cerebral plaque formation. Insoluble fibrils of Amyloid B-Protein accumulate in adrenal
blood vessels and un neutritic plaques. Occurrence of plaques are present in normal brain but in a much
less dense degree as in Alzheimer's disease patients. Amyloid B-Protein is also found in elevated levels
in patients with Down's Syndrome. Substance P has been found to counteract the effects of Amyloid
B-Protein.
Reference Values:
Adult Reference Range(s):
20-80 pg/ml
AMYPI Amyloid P (SAP) Immunostain, Technical Component Only

70549 Clinical Information: Amyloid P (SAP) is a serum protein that is generally incorporated into the
extracellular deposits of all amyloid types. Immunohistochemical staining for SAP produces diffuse,
extracellular staining in positive tissues, and colocalizes with Congo Red apple-green birefringence. All
types of amyloid should be positive for SAP. Immunohistochemical classification of amyloid has been
largely replaced by subtyping using tandem mass spectrometry analysis on formalin-fixed
paraffin-embedded specimens, due to its superior sensitivity and specificity.
Useful For: Identification of amyloid deposits in tissue

Clinical References: 1. Jang B, Koh Y, Seo JW: Immunohistochemical classification of amyloid

deposits in surgical pathology. Basic and Applied Pathology 2009;2:1-8 2. Schonland SO, Hegenbart U,
Bochtler T, et al: Immunohistochemistry in the classification of systemic forms of amyloidosis: a
systematic investigation of 117 patients. Blood 2012;119(2):488-493 3. Stewart CR, Haw A 3rd, Lopez R,
et al: Serum amyloid P colocalizes with apolipoproteins in human atheroma: functional implications. J
Lipid Res 2007;48:2162-2171
APPI Amyloid Precursor Protein (APP) Immunostain, Technical

Clinical Information: Amyloid precursor protein (APP) is present in Alzheimer disease-associated
plaques, large pyramidal cells as well as smaller neurons, astrocytes, and microglia. Histologic features of
Alzheimer disease include the presence of abundant neurofibrillary, tangles, neuropil threads, and neuritic
("senile") plaques. The main component of senile plaque amyloid is a 39- to 42-amino acid segment
referred to as beta amyloid, which is derived from APP.
Useful For: Aids in the identification of amyloid precursor protein present in Alzheimer disease
pathologist.
Clinical References: 1. Ahlgren S, Li GL, Olsson Y: Accumulation of beta-amyloid precursor

protein and ubiquitin in axons after spinal cord trauma in humans: immunohistochemical observations on
autopsy material. Acta Neuropathol 1996;92(1):49-55 2. Craggs LJ, Yamamoto Y, Ihara M, et al: White
matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL). Neuropathol Appl Neurobiol 2014;40:591-602
3. Dermaut B, Kumar-Singh S, De Jonghe C, et al: Cerebral amyloid angiopathy is a pathogenic lesion in
Alzheimer's disease due to a novel presenilin 1 mutation. Brain 2001;124:2383-2392 4. Reichard RR,
White CL 3rd, Hogan RN, et al: Beta-amyloid precursor protein immunohistochemistry in the evaluation
of pediatric traumatic optic nerve injury. Ophthalmology 2004;111(4):822-827 5. Sawaguchi T, Franco P,
Kadhim H, et al: Investigation into the correlation in SIDS victims between Alzheimer precursor protein
A4 in the brainstem and sleep apnea. 2004;10:161-166
AMPIP Amyloid Protein Identification, Paraffin, Mass Spectrometry

70356 Clinical Information: Amyloidosis is a group of hereditary and acquired diseases that are unified by
extracellular tissue deposition of misfolded proteins resulting in end organ damage. Amyloidosis can be a
systemic or localized disease. Although many cases of amyloidosis are hereditary, most are acquired as
the result of an underlying monoclonal B-cell/plasma cell malignancy, as a phenomenon of aging, or as
the result of long-standing chronic inflammation. Specific amyloid-related diseases are therefore
associated with specific amyloid proteins. These include kappa or lambda immunoglobulin light chains
(AL amyloid), transthyretin (ATTR amyloid), serum amyloid A (SAA amyloid), and other uncommon
subtypes. Because treatment of amyloidosis patients differs radically for the different amyloid subtypes, it
is critically important to accurately identify the proteins that constitute the amyloid deposits. The basic
diagnosis of amyloidosis is typically achieved by Congo red staining of paraffin-embedded tissue biopsy
specimens obtained from diverse anatomic sites and demonstrating Congo red-positive, apple-green
birefringent, amyloid deposits in the tissues. The next step is to definitively subtype the amyloid deposits.
This test fulfills that need. It relies on laser microdissection of Congo red-positive amyloid deposits
followed by analysis by liquid chromatography-tandem mass spectrometry to accurately determine the
identity of the proteins that constitute the amyloid.
Useful For: Definitive identification of amyloid proteins

Interpretation: An interpretation will be provided.
Clinical References: 1. Theis JD, Dasari S, Vrana JA, et al: Shotgun-proteomics-based clinical
testing for diagnosis and classification of amyloidosis. J Mass Spectrom. 2013;48(10):1067-1077 2.
Said SM, Sethi S, Valeri AM, et al: Renal amyloidosis: origin and clinicopathologic correlations of 474
recent cases. Clin J Am Soc Nephrol. 2013 Sep;8(9):1515-1523 3. Dasari S, Theis JD, Vrana JA, et al.
Amyloid typing by mass spectrometry in clinical practice: a comprehensive review of 16,175 samples.
Mayo Clin Proc. 2020;95(9):1852-1864. doi:10.1016/j.mayocp.2020.06.029 4. Klein CJ, Vrana JA,
Theis JD, et al: Amyloid neuropathy type is distinguished by mass spectrometric based proteomic
analysis of nerve tissue. Arch Neurol. 2011:68(2):195-199 5. Vrana JA, Gamez JD, Madden BJ, et al:
Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis
in clinical biopsy specimens. Blood. 2009;114(24):4957-4959
TTRX Amyloidosis, Transthyretin-Associated Familial, Reflex, Blood

83674 Clinical Information: The amyloidoses are a group of diseases that result from the abnormal
deposition of amyloid in various tissues of the body. They have been classified into 3 major types:
primary, secondary, and hereditary. The most common form of amyloidosis (AL) is a disease of the
bone marrow called primary systemic AL (immunoglobulin light chain). Secondary AL usually occurs
in tandem with chronic infectious or inflammatory diseases, such as rheumatoid arthritis, tuberculosis,
or osteomyelitis. Familial or hereditary AL is the least common form. Determining the specific type of
AL is imperative in order to provide both an accurate prognosis and appropriate therapies. Familial or
hereditary transthyretin AL is an autosomal dominant disorder caused by variants in the transthyretin
gene (TTR). The resulting amino acid substitutions lead to a relatively unstable, amyloidogenic
transthyretin (TTR) protein. Most individuals begin to exhibit clinical symptoms between the third and
seventh decades of life. Affected individuals may present with a variety of symptoms including
sensorimotor and autonomic neuropathy, vitreous opacities, cardiomyopathy, nephropathy, and
gastrointestinal dysfunction. TTR-associated AL is progressive over a course of 5 to 15 years and
usually ends in death from cardiac or kidney failure or malnutrition. Orthotopic liver transplantation is a
treatment option for some patients who are diagnosed in early stages of the disease. Other treatment
options include the use of TTR tetramer stabilizer medications and gene-silencing therapies (RNA
interference/RNAi) recently approved for use in several countries including the United States. Mayo
Clinic Laboratories recommends a testing strategy that includes both protein analysis by mass
spectrometry (MS) and TTR gene analysis by DNA sequencing for patients in whom TTR-associated
familial AL is suspected. The structure of TTR protein in plasma is first determined by MS. The
presence of a disease-causing variant in the TTR gene leads to conformational changes in the TTR
protein. This ultimately disrupts the stability of the mature TTR protein tetramer, leading to increased
amounts of pro-amyloidogenic TTR monomers in the plasma of affected individuals. MS technology is
able to identify the mass difference between wildtype TTR and variant TTR protein. Only the
transthyretin (also known as prealbumin) is analyzed for amino acid substitutions. Other proteins
involved in other less common forms of familial amyloidosis are not examined. If no alterations are
detected, gene analysis will not be performed unless requested by the provider (ie, when the diagnosis is
still strongly suspected; to rule out the possibility of a false-negative by MS). In all cases demonstrating
a structural change by MS, DNA sequence analysis will be performed on the TTR gene to identify and
characterize the observed alteration (disease-causing or benign variant). More than 90 variants that
cause TTR-associated familial AL have now been identified within the TTR gene. Most of the variants
described to date are single base pair changes that result in an amino acid substitution. Some of these
variants correlate with the clinical presentation of AL. For predictive testing in cases where a familial
variant is known, testing for the specific variant by DNA sequence analysis (FMTT / Familial Mutation,
Targeted Testing, Varies) is recommended. These assays do not detect alterations associated with
non-TTR forms of familial AL. Therefore, it is important to first test an affected family member to
determine if TTR is involved and to document a specific alteration in the family before testing at-risk
individuals.
Useful For: Diagnosis of adult individuals suspected of having transthyretin-associated familial

amyloidosis
Interpretation: The presence of a structural change in transthyretin (TTR) is suggestive of a gene

variant that requires confirmation by DNA sequence analysis. A negative result by mass spectrometry
does not rule out a TTR variant. Mass spectrometric (MS) results are falsely negative if the amino acid
substitution does not produce a measurable mass shift for the transthyretin variant. Approximately 90% of
the TTR variants are positive by MS (see Cautions). After identification of the variant at the DNA level,
predictive testing for at-risk family members can be performed by molecular analysis (FMTT / Familial
Mutation, Targeted Testing, Varies).
Reference Values:
Clinical References: 1. Sekijima Y: Hereditary transthyretin amyloidosis. In: Adam MP, Ardinger
HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2001. Updated
June 17, 2021 Accessed January 5, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1194/ 2.
Finsterer J, Iglseder S, Wanschitz J, et al: Hereditary transthyretin-related amyloidosis. Acta Neurol
Scand. 2019 Feb;139(2):92-105 3. Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum,
molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015
Sep;86(9):1036-1043. doi: 10.1136/jnnp-2014-308724
ANAID Anaerobe Ident (Bill Only)

ISAN Anaerobe Identification by Sequencing (Bill Only)

BATTA Anaerobe Suscep Battery (Bill Only)

SANA Anaerobe Suscep per Agent (Bill Only)

ATPCO Anal ThinPrep Cytology with Human Papillomavirus (HPV)
614402 Co-Test, Varies
Clinical Information: Persistent infection with human papillomavirus (HPV) can cause anal
cancer, with approximately 90% of all anal cancers being associated with HPV infection. HPV is a
small, nonenveloped, double-stranded DNA virus, with a genome of approximately 8000 nucleotides.
There are more than 118 different types of HPV and approximately 40 different HPVs that can infect
the human anogenital mucosa. However, data suggest that 14 of these types (HPV types 16, 18, 31, 33,
35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high-risk (HR) for the development of cervical
and anal cancer and precursor lesions. Furthermore, HPV types 16 and 18 have been regarded as the
genotypes most closely associated with progression to cancer. HPV-16 is the most carcinogenic and is
associated with approximately 60% of all HPV-related cancers, while HPV-18 accounts for
approximately 10% to 15% of HPV-related cancers.(1-3) Sexually transmitted infection with HPV is
extremely common, with estimates of up to 75% of all women being exposed to HPV at some point.
However, almost all infected patients will mount an effective immune response and clear the infection
within 2 years without any long-term health consequences. DNA testing by real-time polymerase chain
reaction (PCR) is a noninvasive method for determining the presence of anal HPV infection. Proper
implementation of DNA testing for HPV may: 1. Increase the sensitivity of anal cancer detection 2.
Reduce the need for unnecessary biopsy and treatment Recently, data suggest that individual genotyping
for HPV types 16 and 18 can assist in determining appropriate follow-up testing and triaging of patients
who are at risk for cervical cancer and may be useful in cases of possible anal cancer. Detection of
HRHPV DNA, especially genotypes 16 and 18, may assist in triaging patients and determining
appropriate management strategies.
Useful For: Detection of malignant and premalignant changes Detection of high-risk (HR) genotypes
associated with the development of anal cancer Individual genotyping of human papillomavirus
(HPV)-16 and HPV-18, if present May aid in triaging men and women with positive HR-HPV but
negative anal Pap smear results The cobas HPV test is not recommended for evaluation of suspected
sexual abuse.
Interpretation: Cytology: Suspicious or atypical results need further confirmation: clinical

observation, repeat cytology, or perhaps appropriate biopsy. Positive results should be confirmed by
histologic examination of tissue before definitive therapy is instituted. Human papillomavirus: A
positive result indicates the presence of human papillomavirus (HPV) DNA due to 1 or more of the
following genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. A negative result
indicates the absence of HPV DNA of the targeted genotypes. Management of abnormal results requires
consideration of baseline risk of anal cancer and prior anal cytology and HPV results. For patients with
an anal Pap test result showing atypical squamous cells of undetermined significance (ASC-US) and
who are positive for high-risk (HR) HPV, consider referral for anoscopy, if clinically indicated. For men
and women with a negative anal Pap test result but who are positive for HPV-16 or HPV-18, consider
referral for anoscopy, if clinically indicated. For men and women with a negative anal Pap smear,
positive-HR-HPV test result, but who are negative for HPV-16 and HPV-18, consider repeat testing by
both cytology and HR-HPV in 12 months.
Reference Values:
ThinPrep ANAL SWAB
Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy.
HUMAN PAPILLOMAVIRUS (HPV)

Negative for HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68
Clinical References: 1. Swanson AA, Hartley C, Long ME, et al: Evaluation of high-risk human
papillomavirus testing and anal cytology to detect high-grade anal intraepithelial neoplasia. J Am Soc
Cytopathol. 2021 Jul-Aug;10(4):406-413. doi: 10.1016/j.jasc.2021.03.007 2. Libera SD, et al. 2019.
Human papillomavirus and anal cancer: Prevalence, genotype distribution, and prognosis aspects from
Midwestern region of Brazil. J Oncol. Sep 18; 2019:6018269 3. Wieland U, and Kreuter A: Anal cancer
risk: HPV-based cervical screening programmes. Lancet Infect Dis. 2019 Aug:19(8):799-800
ANAP Anaplasma phagocytophilum (Human Granulocytic
81157 Ehrlichiosis) Antibody, Serum
Clinical Information: Anaplasma phagocytophilum, an intracellular rickettsia-like bacterium,
preferentially infects granulocytes and forms inclusion bodies, referred to as morulae. A phagocytophilum
is transmitted by Ixodes species ticks, which also transmit Borrelia burgdorferi and Babesia species.
Infection with A phagocytophilum is also referred to as human granulocytic anaplasmosis (HGA) and
symptoms in otherwise healthy individuals are often mild and nonspecific, including fever, myalgia,
arthralgia, and nausea. Clues to the diagnosis of anaplasmosis in a patient with an acute febrile illness
after tick exposure include laboratory findings of leukopenia or thrombocytopenia and elevated liver
enzymes. HGA is most prevalent in the upper Midwest and in other areas of the United States that are
endemic for Lyme disease.
Useful For: As an adjunct in the diagnosis of human granulocytic ehrlichiosis Seroepidemiological

surveys of the prevalence of the infection in certain populations
Interpretation: A positive result of an immunofluorescence assay (IFA) test (titer > or =1:64) suggests
current or previous infection with human granulocytic ehrlichiosis. In general, the higher the titer, the
more likely it is that the patient has an active infection. Seroconversion may also be demonstrated by a
significant increase in IFA titers. During the acute phase of the infection, serologic tests are often
nonreactive, polymerase chain reaction (PCR) testing is available to aid in the diagnosis of these cases
(see EHRL / Ehrlichia/Anaplasma, Molecular Detection, PCR, Blood).
Reference Values:
<1:64
Clinical References: Center for Disease Control and Prevention (CDC): Tick-borne diseases of the
United States: A Reference Manual for Health Care Providers. 5th ed. CDC; 2018
ALKLC Anaplastic Lymphoma Kinase for Lung Cancer,

615713 Immunohistochemistry
Clinical Information: A subset of anaplastic large-cell lymphomas overexpresses anaplastic
lymphoma kinase (ALK-1) protein, resulting from a translocation involving the ALK1 gene. The
abnormal ALK-1 expression can be in a nuclear or cytoplasmic distribution. Overexpression of ALK-1
protein is also useful for targeted therapy in lung adenocarcinoma and in the diagnosis of inflammatory
myofibroblastic tumor. In normal tissue ALK-1 is negative.
Useful For: Identification of anaplastic lymphoma kinase overexpression Diagnosis of inflammatory

myofibroblastic tumor, anaplastic large-cell lymphoma, and for targeted therapy of lung adenocarcinoma
Interpretation: This test, when not accompanied by a pathology consultation request, will be
answered as either positive or negative. If additional interpretation or analysis is needed, request PATHC /
Pathology Consultation along with this test.
Clinical References: 1. Hutarew G, Hauser-Kronberger C, Strasser F, Llenos IC, Dietze O:

Immunohistochemistry as a screening tool for ALK rearrangement in NSCLC: evaluation of five different
ALK antibody clones and ALK FISH. Histopathology. 2014 Sept;65(3):398-407 2. Stein H, Foss H,
Durkop H, et al: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and
clinical features. Blood. 2000 Dec;96(12):3681-3695 3. Yi ES, Boland JM, Maleszewski JJ, et al:
Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score
algorithm for FISH. J Thorac Oncol. 2011 Mar;6(3):459-465
ALK Anaplastic Lymphoma Kinase Immunostain, Technical

70354
Component Only
Clinical Information: A subset of anaplastic large-cell lymphomas shows overexpression of
anaplastic lymphoma kinase (ALK-1) protein, resulting from a translocation involving the ALK1 gene.
The abnormal ALK-1 expression can be in a nuclear or cytoplasmic distribution. Overexpression of
ALK-1 protein is also useful in the diagnosis of lung adenocarcinoma and inflammatory
myofibroblastic tumor. In normal tissue ALK-1 is negative.
Useful For: Identification of anaplastic lymphoma kinase overexpression Diagnosis of lung

adenocarcinoma and inflammatory myofibroblastic tumor
appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the
relevant quality control tissue is available upon request, call 855-516-8404. Interpretation of this test
Clinical References: 1. Hutarew G, Hauser-Kronberger C, Strasser F, Llenos IC, Dietze O:

Immunohistochemistry as a screening tool for ALK rearrangement in NSCLC: evaluation of five
different ALK antibody clones and ALK FISH. Histopathology. 2014;65:398-407 2. Stein H, Foss H,
Durkop H, et al: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and
clinical features. Blood. 2000;96(12):3681-3695 3. Yi ES, Boland JM, Maleszewski JJ, et al:
Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score
algorithm for FISH. J Thorac Oncol. 2011;6(3):459-465
ANPAT Anatomic Pathology Consultation, Wet Tissue

70318 Clinical Information: Mayo Clinic Rochester is staffed by pathologists whose expertise and special
interests cover the entirety of Pathology, from surgical pathology with all of its respective subspecialty
areas, to Hematopathology, Renal Pathology, and Dermatopathology. Consultation services are
provided for difficult diagnostic problems. Consultation cases may be sent by a referring pathologist
and directed to one of the pathologists who is an expert in the given area or directed more broadly to the
subspecialty group. Cases are frequently shared and sometimes transferred between the pathologists, as
deemed appropriate for the type of case or diagnostic problem encountered. Emphasis is placed on
prompt and accurate results. Materials received are reviewed in conjunction with the clinical history
provided, laboratory findings, radiographic findings (if applicable), and sending pathologist's report or
letter. If additional special stains or studies are needed, the results are included in the final interpretive
report. In some cases, electron microscopy and other special procedures are utilized as required. A
variety of ancillary studies are available (eg, cytochemistry, immunohistochemistry,
immunofluorescence, electron microscopy, mass spectrometry, cytogenetics, and molecular genetics) to
aid in establishing a diagnosis. These ancillary studies are often expensive and labor intensive and are
most efficiently utilized and interpreted in the context of the morphologic features. The goal is to
provide the highest possible level of diagnostic consultative service, while trying to balance optimal
patient care with a cost-conscious approach to solving difficult diagnostic problems.
Useful For: Obtaining a rapid, expert opinion on unprocessed specimens referred by the pathologist
This test is not useful for suspected hematologic disorders.
Interpretation: Results of the consultation are reported in a formal pathology report, which includes
a description of ancillary test results (if applicable) and an interpretive comment. When the case is
completed, results may be communicated by a phone call. The formal pathology report is faxed.
Reference Values:
The laboratory will provide a pathology consultation.
ANCH Anchovy, IgE, Serum
Useful For: Establishing the diagnosis of an allergy to anchovy Defining the allergen responsible for
eliciting signs and symptoms Identifying allergens: - Responsible for allergic disease and/or anaphylactic
episode - To confirm sensitization prior to beginning immunotherapy - To investigate the specificity of
allergic reactions to insect venom allergens, drugs, or chemical allergens Testing for IgE antibodies is not
useful in patients previously treated with immunotherapy to determine if residual clinical sensitivity
exists, or in patients in whom the medical management does not depend upon identification of allergen
specificity.

Reference Values:
0 Negative

apply to all ages.
Clinical References: Homburger HA: Chapter 53: Allergic diseases. In Clinical Diagnosis and
Management by Laboratory Methods. 21st edition. Edited by RA McPherson, MR Pincus. WB Saunders
Company, New York, 2007, Part VI, pp 961-971
AREC Androgen Receptor Immunostain, Technical Component Only

70358 Clinical Information: Androgen receptor binds testosterone and 5 alpha-dihydrotestosterone and
mediates the biologic action of these sex hormones. It is normally expressed in a wide variety of tissues,
including the epithelium and stromal cells of the prostate, endometrium, ovary, and breast. Cells of
meningiomas and the pituitary gland may also be positive.
Useful For: Identification of tumors that express androgen receptor

Interpretation: This test does not include pathologist interpretation, only technical performance of the
stain. If interpretation is required, order PATHC / Pathology Consultation for a full diagnostic evaluation
or second opinion of the case. Â The positive and negative controls are verified as showing appropriate
immunoreactivity and documentation is retained at Mayo Clinic Rochester. If a control tissue is not
included on the slide, a scanned image of the relevant quality control tissue is available upon request, call
855-516-8404. Â Interpretation of this test should be performed in the context of the patient's clinical
history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Chen C, Yuan JP, Wei W, et al: Subtype classification for prediction of
prognosis of breast cancer from a biomarker panel: correlations and indications. Int J Nanomedicine.
2014;9:1039-1048 2. Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A: Androgen
receptor status of lymph node metastases from prostate cancer. Prostate. 1996;28:129-135 3. Park S,
Koo J, Park HS, et al: Expression of androgen receptors in primary breast cancer. Ann Oncol.
2010;21:488-492
FAGES Androstanediol Glucuronide (Endocrine Sciences)

Age Range
Prepubertal Children Not Established
Adult Males 112-1046 ng/dL
Adult Females 11-249 ng/dL Occasionally, normal females with no

evidence of hirsutism may have levels well beyond the
normal range.
ANST Androstenedione, Serum

9709 Clinical Information: Androstenedione is secreted predominately by the adrenal gland and
production is at least partly controlled by adrenocorticotropic hormone (ACTH). It is also produced
ACTH-independent in the testes and ovaries from adrenal-secreted dehydroepiandrosterone sulfate
(DHEA-S). Androstenedione is a crucial sex-steroid precursor. It lies at the convergence of the 2
biosynthetic pathways that lead from the progestins to the sex-steroids, being derived either via:
-C3-dehydrogenation of dehydroepiandrosterone (DHEA) -Catalyzed by 3-beta-hydroxysteroid
dehydrogenase-2 (adrenals and gonads) -17,20-lyase (CYP17A1)-mediated side-chain cleavage of
17-alpha-hydroxyprogesterone (OHPG) Androstenedione production during life mimics the pattern of
other androgen precursors. Fetal serum concentrations increase throughout embryonal development and
peak near birth at approximately young adult levels. Levels then fall rapidly during the first year of life
to low prepubertal values. With the onset of adrenarche, androstenedione rises gradually, a process that
accelerates with the onset of puberty, reaching adult levels around age 18. Adrenarche is a poorly
understood phenomenon peculiar to higher primates that is characterized by a gradual rise in adrenal
androgen production. It precedes puberty, but is not causally linked to it. Early adrenarche is not
associated with early puberty, or with any reduction in final height, or overt androgenization, and is
generally regarded as a benign condition not requiring intervention. However, girls with early
adrenarche may be at increased risk of polycystic ovarian syndrome as adults, and some boys may
develop early penile enlargement. Elevated androstenedione levels can cause symptoms or signs of
hyperandrogenism in women. Men are usually asymptomatic, but through peripheral conversion of
androgens to estrogens can occasionally experience mild symptoms of estrogen excess, such as
gynecomastia. Most mild-to-moderate elevations in androstenedione are idiopathic. However,
pronounced elevations of androstenedione may be indicative of androgen-producing adrenal or gonadal
tumors. In children, adrenal and gonadal tumors are uncommon, but many forms of congenital adrenal
hyperplasia can increase serum androstenedione concentrations. Diagnosis always requires
measurement of other androgen precursors (eg, OHPG, 17-alpha-hydroxypregnenolone, and DHEA-S)
and cortisol, in addition to androstenedione. See Steroid Pathways in Special Instructions.
Useful For: Diagnosis and differential diagnosis of hyperandrogenism (in conjunction with
measurements of other sex-steroids). An initial workup in adults might also include total and
bioavailable testosterone (TTBS / Testosterone, Total and Bioavailable, Serum) measurements.
Depending on results, this may be supplemented with measurements of sex hormone-binding globulin
(SHBG / Sex Hormone Binding Globulin [SHBG], Serum) and other androgenic steroids (eg,
dehydroepiandrosterone sulfate [DHEA-S]). Diagnosis of congenital adrenal hyperplasia (CAH), in
conjunction with measurement of other androgenic precursors, particularly,
17-alpha-hydroxyprogesterone (OHPG) (OHPG / 17-Hydroxyprogesterone, Serum), 17
alpha-hydroxypregnenolone, DHEA-S (DHES / Dehydroepiandrosterone Sulfate [DHEA-S], Serum),
and cortisol (CORT / Cortisol, Serum). Monitoring CAH treatment, in conjunction with testosterone
(TTST / Testosterone, Total, Serum), OHPG (OHPG / 17-Hydroxyprogesterone, Serum), DHEA-S
(DHES / Dehydroepiandrosterone Sulfate [DHEA-S], Serum), and DHEA (DHEA_ /
Dehydroepiandrosterone [DHEA], Serum). Diagnosis of premature adrenarche, in conjunction with
gonadotropins (FSH / Follicle-Stimulating Hormone [FSH], Serum; LH / Luteinizing Hormone [LH],
Serum) and other adrenal and gonadal sex-steroids and their precursors (TTBS / Testosterone, Total and
Bioavailable, Serum or TGRP / Testosterone, Total and Free, Serum; EEST / Estradiol, Serum; DHES /
Dehydroepiandrosterone Sulfate [DHEA-S], Serum; DHEA_ / Dehydroepiandrosterone [DHEA],
Serum; SHBG / Sex Hormone Binding Globulin [SHBG], Serum; OHPG / 17-Hydroxyprogesterone,
Serum).
Interpretation: Elevated androstenedione levels indicate increased adrenal or gonadal androgen

production. Mild elevations in adults are usually idiopathic, or related to conditions such as polycystic
ovarian syndrome (PCOS) in women, or use of androstenedione supplements in men and women.
However, levels greater than or equal to 500 ng/dL can suggest the presence of an androgen-secreting
adrenal, or less commonly, a gonadal, tumor. Androstenedione levels are elevated in more than 90% of
patients with benign androgen-producing adrenal tumors, usually well above 500 ng/dL. Most
androgen-secreting adrenal carcinomas also exhibit elevated androstenedione levels, but more typically
show relatively larger elevations in 17-alpha-hydroxyprogesterone (OHPG) and dehydroepiandrosterone
sulfate (DHEA-S) than in androstenedione, as they have often lost the ability to produce downstream
androgens. Most androgen-secreting gonadal tumors also overproduce androstenedione, but often to lesser
degrees than adrenal tumors. They also overproduce testosterone. In men and in women with high
baseline androgen levels (eg, PCOS), the respective elevations of androstenedione and testosterone may
not be high enough to allow unequivocal diagnosis of androgen-producing gonadal tumors. In these cases,
an elevation of the usual ratio of testosterone to androstenedione of 1, to a ratio of >1.5, is a strong
indicator of neoplastic androgen production. Diagnosis and differential diagnosis of congenital adrenal
hyperplasia (CAH) always requires the measurement of several steroids. Patients with CAH due to
21-hydroxylase gene (CYP21A2) mutations the most common cause of CAH (>90% of cases), usually
have very high levels of androstenedione, often 5- to 10-fold elevations. OHPG levels are usually even
higher, while cortisol levels are low or undetectable. All 3 analytes should be tested. In the much less
common CYP11A1 mutation, androstenedione levels are elevated to a similar extend as in CYP21A2
mutation, and cortisol is also low, but OHPG is only mildly, if at all, elevated. Also less common, 3 beta
HSD-2 deficiency is characterized by low cortisol and substantial elevations in DHEA-S and 17-
alpha-hydroxypregnenolone, while androstenedione is either low, normal, or, rarely, very mildly elevated
(as a consequence of peripheral tissue androstenedione production by 3 beta HSD-1). In the very rare
STAR (steroidogenic acute regulatory protein) deficiency, all steroid hormone levels are low and
cholesterol is elevated. In the also very rare 17-alpha-hydroxylase deficiency, androstenedione, all other
androgen-precursors (17-alpha-hydroxypregnenolone, OHPG, DHEA-S), androgens (testosterone,
estrone, estradiol), and cortisol are low, while production of mineral corticoid and their precursors, in
particular progesterone, 11-deoxycorticosterone, corticosterone, and 18-hydroxycorticosterone, are
increased. The goal of CAH treatment is normalization of cortisol levels and, ideally, also of sex-steroid
levels. Traditionally, OHPG and urinary pregnanetriol or total ketosteroid excretion are measured to guide
treatment, but these tests correlate only modestly with androgen levels. Therefore, androstenedione and
testosterone should also be measured and used for treatment modifications. Normal prepubertal levels
may be difficult to achieve, but if testosterone levels are within the reference range, androstenedione
levels up to 100 ng/dL are usually regarded as acceptable. Girls below the age of 7 to 8 and boys before
age 8 to 9 who present with early development of pubic hair or, in boys, penile enlargement, may be
suffering from either premature adrenarche or premature puberty, or both. Measurement of DHEA-S,
DHEA, and androstenedione, alongside determination of sensitive estradiol, total and bioavailable or free
testosterone, sex hormone binding globulin (SHBG), and luteinizing hormone/follicle-stimulating
hormone levels will allow correct diagnosis in most cases. In premature adrenarche, only the adrenal
androgens, chiefly DHEA-S, and to a lesser degree, androstenedione, will be above prepubertal levels,
whereas early puberty will also show a fall in SHBG levels and variable elevations of gonadotropins and
gonadal sex-steroids above the prepuberty reference range. See Steroid Pathways in Special Instructions.
Reference Values:
Tanner Stages Age (Years) Reference Range (ng/dL)
Stage I (prepubertal)
Stage II 9.8-14.5 31-65
Stage III 10.7-15.4 50-100
Stage IV 11.8-16.2 48-140
Stage V 12.8-17.3 65-210 Females*
Stage II 9.2-13.7 42-100
Stage III 10.0-14.4 80-190
Stage IV 10.7-15.6 77-225
Stage V 11.8-18.6 80-240 *Source: Androstenedione. In Pediatric Reference Ranges. Fourth

edition. Edited by SJ Soldin, C Brugnara, EC Wong. Washington, DC,
AACC Press, 2003, pp 32-34 ADULTS Males: 40-150 ng/dL Females:
30-200 ng/dL For SI unit Reference Values, see

hyperplasia. Eur J Pediatr 1980;133:259-267 2. Sciarra F, Tosti-Croce C, Toscano V:
Androgen-secreting adrenal tumors. Minerva Endocrinol 1995;20:63-68 3. Young WF Jr: Management
approaches to adrenal incidentalomas-a view from Rochester, Minnesota. Endocrinol Metab Clin North
Am 2000;29:159-185 4. Ibanez L, DiMartino-Nardi J, Potau N, Saenger P: Premature
adrenarche-normal variant or forerunner of adult disease? Endocr Rev 2000;21:671-696 5.
Collett-Solberg P: Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice,
part I. Clin Pediatr 2001;40:1-16 6. Allolio B, Arlt W: DHEA treatment: myth or reality? Trends
Endocrinol Metab 2002;13:288-294
MASF Angiosarcoma, MYC (8q24) Amplification, FISH, Tissue

35859 Clinical Information: Postradiation cutaneous angiosarcoma is a malignancy associated with very
poor outcome and is consequently treated aggressively. Conversely, atypical vascular lesions are also
associated with radiation therapy but are considered to be benign and do not require aggressive
management. Therefore, the differentiation of these neoplasms is of considerable clinical importance.
Postradiation cutaneous angiosarcomas are characterized by high-level amplification of MYC, whereas
reactive and benign vascular lesions do not show amplification of MYC. Similar diagnostic difficulties
arise in the setting of primary cutaneous vascular lesions. A subset of primary cutaneous angiosarcomas
also shows high-level MYC amplification, which can be useful in the differentiation from benign
primary cutaneous vascular lesions.
Useful For: Identifying MYC amplification to aid in the differentiation of cutaneous angiosarcomas
from atypical vascular lesions after radiotherapy An aid in the diagnosis of primary cutaneous
angiosarcoma
Interpretation: The MYC locus is reported as amplified when the MYC:D8Z2 ratio of 2.0 or greater
and demonstrates 6 or more copies of the MYC locus. A lesion with a MYC:D8Z2 ratio less than 2.0 or
showing a ratio of 2.0 or greater with less than 6 copies of MYC is considered to lack amplification of
the MYC locus.
Reference Values:
Clinical References: 1. Mentzel T, Schildhaus H, Palmedo G, et al: Postradiation cutaneous

angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to
atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical
and molecular analysis of 66 cases. Mod Pathol. 2012;25:75-85 2. Manner J, Radlwimmer B,
Hohenberger P, et al: MYC high level gene amplification is a distinctive feature of angiosarcomas after
irradiation or chronic lymphedema. Am J Pathol. 2010;176(1):34-39
FACEC Angiotensin Converting Enzyme, CSF

57824 Useful For: Support diagnosis of neurosarcoidosis. May be used to evaluate treatment response.
Reference Values:
0.0-2.5 U/L
ACE Angiotensin Converting Enzyme, Serum

603622 Clinical Information: Angiotensin converting enzyme (ACE) is integral to the renin-angiotensin
system (RAS), which maintains blood pressure by regulation of fluid volume and vascular tension. Its
peptidase action on the decapeptide angiotensinogen I results in the hydrolysis of a terminal histidyl
leucine dipeptide and the formation of the octapeptide angiotensin II, a potent vasoconstrictor that
increases blood pressure. ACE activity is increased in sarcoidosis, a systemic granulomatous disease that
commonly affects the lungs. In sarcoidosis, ACE is thought to be produced by epithelioid cells and
macrophages of the granuloma. ACE activity reflects the severity of sarcoidosis: 68% positivity in those
with stage I sarcoidosis, 86% in stage II sarcoidosis, and 91% in stage III sarcoidosis. Other conditions
such as Gaucher disease, leprosy, untreated hyperthyroidism, psoriasis, premature infants with respiratory
distress syndrome, adults with amyloidosis, and histoplasmosis have been associated with increased
serum ACE activity.
Useful For: Evaluation of patients with suspected sarcoidosis

Interpretation: An elevation in the level of serum angiotensin converting enzyme (ACE), along with
radiographic evidence of infiltrates or adenopathy and organ biopsies showing noncaseating epithelial
granulomas is suggestive of a diagnosis of sarcoidosis. Normal, healthy children and infants are known to
have ACE activity levels greater than the adult reference interval.
Reference Values:
> or =18 years: 16-85 U/L
0-17 years: Angiotensin converting enzyme activity may be 20-50% higher in healthy children compared
to healthy adults.
Clinical References: 1. Liebermann J: Elevation of serum angiotensin-converting-enzyme (ACE)

level in sarcoidosis. Am J Med. 1975;59:365-372 2. Rodriguez GE, Shin BC, Abernathy RS, Kendig EL
Jr: Serum angiotensin-converting enzyme activity in normal children and in those with sarcoidosis. J
Pediatr. 1981;99:68-72 3. Personal observations from a Mayo pediatric normal range study using a
manual method (Hana) 4. Maguire GA, Price CP: A continuous monitoring spectrophotometric method
for the measurement of angiotensin-converting enzyme in human serum. Ann Clin Biochem.
1985;22:204-210 5. Allen DW, Rajagopal V: Other adjunctive drugs for coronary intervention:
beta-blockers, calcium-channel blockers, and angiotensin-converting enzyme inhibitors. In: Tropol EJ,
Teirstein P, eds. Textbook of Interventional Cardiology. 8th ed. Elsevier; 2020:214-222
FANGI Angiotensin I, Plasma
90429 Clinical Information: Angiotensin I is a ten amino acid peptide formed by Renin cleavage of
Angiotensinogen (Renin Substrate). Angiotensin I has little biological activity except that high levels
can stimulate Catecholamine production. It is metabolized to its biologically active byproduct
Angiotensin II by Angiotensin Converting Enzyme (ACE). The formation of Angiotensin I is controlled
by negative feedback of Angiotensin II and II on Renin release and by Aldosterone concentration.
Levels of Angiotensin I are increased in many types of hypertension. Angiotensin I levels are used to
determine Renin activity. Angiotensin I is excreted directly into the urine.
Reference Values:
Up to 25 pg/mL
ANISP Anisakis, Parasite, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to the Anisakis parasite Defining the allergen

Reference Values:
0 Negative

apply to all ages.
ANSE Anise, IgE, Serum
Useful For: Establishing the diagnosis of an allergy to anise Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed.Â Elsevier;
2017:1057-1070
FANSE Annatto Seed (Bixa orellana) IgE

57520 Interpretation: Class IgE (kU/L) Comment 0 <0.35 Below Detection 1 0.35 -0.69 Low Positive 2
0.70 - 3.49 Moderate Positive 3 3.50 Ã¢â‚¬â€œ 17.49 Positive 4 17.50 Ã¢â‚¬â€œ 49.99 Strong Positive 5
50.00 Ã¢â‚¬â€œ 99.99 Very Strong Positive 6 >99.99 Very Strong Positive
Reference Values:
<0.35 kU/L
ANNEX Annexin-1 Immunostain, Technical Component Only

70355 Clinical Information: Annexin-1 (A1) was identified by gene expression profiling studies of hairy
cell leukemia. In the appropriate context, positivity for annexin A1 favors a diagnosis of hairy cell
leukemia. Normal granulocytes and precursors also express annexin A1, serving as a positive internal
control in bone marrow specimens.
Useful For: Classification of leukemias

pathologist.
Clinical References: Falini B, Tiacci E, Liso A, et al: Simple diagnostic assay for hairy cell
leukaemia by immunocytochemical detection of annexin A1 (ANXA1). Lancet 2004 Jun
5;363(9424):1869-1870
FABAA Anti-bestrophin Autoantibodies

A final report will be provided.
FACN1 Anti-cN-1A (NT5c1A) IBM

75620 Clinical Information: Anti-cN-1A autoantibodies in idiopathic inflammatory myopathy (IIM)
patients appear to be disease-specific for sporadic Inclusion Body Myositis (sIBM) and are rarely
detected in other autoimmune conditions. Anti-cN-1A autoantibodies have a moderate sensitivity, but
their high specificity for sIBM may be helpful in the diagnosis of this infrequent and
difficult-to-diagnose myopathy. This assay can augment and accelerate the suspected diagnosis of sIBM
using sera where muscle biopsy is delayed and/or unfeasible.
Reference Values:
Reference Range: <20
Interpretation:
Negative: <20 units
Weak Positive: 20 - 39 units
Moderate Positive: 40 - 80 units
Strong Positive: >80 units
ADNAS Anti-DNase B Titer, Serum

80204 Clinical Information: A number of bacterial antigens have been identified in cultures of group A
streptococci. These extracellular products are primarily enzymatic proteins and include streptolysin O,
streptokinase, hyaluronidase, deoxyribonucleases (DNases A, B, C, and D), and nicotinamide adenine
nucleotidase. Infections by the group A streptococci are unique because they can be followed by serious
nonpurulent complications of rheumatic fever and glomerulonephritis. Recent information suggests that
rheumatic fever is associated with infection by certain rheumatogenic serotypes (M1, M3, M5, M6,
M18, and M19), while glomerulonephritis follows infection by nephritogenic serotypes (M2, M12,
M49, M57, M59, and M60). Glomerulonephritis and rheumatic fever occur following the infection,
after a period of latency following the infection, during which the patient is asymptomatic. The latency
period for glomerulonephritis is approximately 10 days, and the latency period for rheumatic fever is 20
days.
Useful For: Demonstration of acute or recent streptococcal infection using anti-DNase B titer
Interpretation: Elevated values are consistent with an antecedent infection by group A streptococci.
Although the antistreptolysin O (ASO) test is quite reliable, performing the anti-DNase is justified for 2
primary reasons. First, the ASO response is not universal. Elevated ASO titers are found in the sera of
about 85% of individuals with rheumatic fever; ASO titers remain normal in about 15% of individuals
with the disease. The same holds true for other streptococcal antibody tests: a significant portion of
individuals with normal antibody titers for 1 test will have elevated antibody titers for another test. Thus,
the percentage of false-negative results can be reduced by performing 2 or more antibody tests. Second,
skin infections, in contrast to throat infections, are associated with a poor ASO response. Patients with
acute glomerulonephritis following skin infection (post-impetigo) have an attenuated immune response to
streptolysin O. For such patients, performance of an alternative streptococcal antibody test, such as this
assay, is recommended.
Reference Values:
<5 years: < or =250 U/mL
5-17 years < or =375 U/mL
> or =18 years: < or =300 U/mL
Clinical References: 1. Ayoub EM, Harden E: Immune response to streptococcal antigens:

diagnostic methods. In: Rose NR, de Marco EC, Folds JD, et al, eds. Manual of Clinical and Laboratory
Immunology. 5th ed. ASM Press; 1997 2. Anti-DNase B. Testing .com. Updated June 28, 2021. Accessed
February 11, 2022. Available at www.testing.com/tests/anti-dnase-b/
FAEAB Anti-Enterocyte Antibodies

IgG: Negative
IgA: Negative
IgM: Negative
FIGA Anti-IgA
57552 Clinical Information: For the evaluation of patients with recurrent infection for the possibility of IgA
deficiency (IgAD). Patients with IgA deficiency may develop antibodies against IgA that make them
susceptible to adverse reactions to blood products including intravenous immunoglobulin.
Reference Values:
<99 U/mL
Patients with IgG antibodies against IgA may suffer from anaphylactoid reactions when given IVIG that
contains small quantities of IgA. In one study (Clinical Immunology 2007; 122:156) five out of eight
patients with IgG anti-IgA antibodies developed anaphylactoid reactions when IVIG was administered.
Clinical References: Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency

(SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000; 120:225-231. -
Burrows D, Cooper MD: IgA Deficiency. Adv Immunol 1997; 65:245-276. - Aghamohammadi A,
Mohammadi J, Parvaneh N, Rezael N, Moin M, Espanol T. and Hammarstrom L. Progression of Selective
IgA Deficiency to Common Variable Immunodeficiency. Int Arch Allergy Immunol 2008;147:87-92.
Horn J, Thon V, Bartonkova D, Salzer U, warnatz K, Schlesier M, Peter H, and Grimbacher B. Anti-IgA
antibodies in Common Variable Immunodeficiency (CVID): Diagnostic workup and therapeutic strategy.
Clin Immunol 2007;122:156-162.
FANTI Anti-IgE
Normal
This ELISA measures IgG antibodies specific for IgE. A result of normal indicates that the level of
IgG anti-IgE antibodies is similar to that seen in a population of healthy individuals. A result of elevated
indicates an increased level of IgG anti-IgE antibodies compared to healthy individuals. These
autoantibodies have been implicated as a causative agent in autoimmune chronic urticaria and atopic
dermatitis.
FAMDA Anti-MDA-5 Ab (CADM-140)

75622 Clinical Information: Anti-MDA5 antibodies are present in 7-35% of adult DM. Clinical features
consist of absent or mild muscle symptoms (CADM), rapidly progressive ILD, specific mucocutaneous
features of skin ulcerations and papules, oral ulcerations and arthritis.
Reference Values:
Interpretation:
Negative: <20 units
Weak Positive: 20-39 units
Moderate Positive: 40-80 units
FFMI2 Anti-Mi-2 Ab
75591 Clinical Information: Anti-Mi-2 antibodies are found in 10-20% of adult dermatomyositis (DM)
and <10% of JDM. They are associated with classic DM features: mild to moderate weakness with
shawl rash, heliotrope rash, V-sign, Gottronâ€™ s papules and have good response to therapy, with
lower incidence of cancer compared to Mi-2 negative DM.
Reference Values:
Negative
FANIC Anti-Nuclear Antibodies by Indirect Fluorescent Antibody

75635 (IFA), Cerebrospinal Fluid
Useful For: ANA are commonly found in a variety of autoimmune diseases. Antibody frequency
increases with age in apparently healthy people. ANA patterns on Hep-2 slides provide only general
clues about particles (chromatin, nucleosomes and spliceosomes). ANA patterns (other than centromere
pattern) are not reliably correlated with the presence of specific antibodies and must be further
evaluated by EIA using individual ENA antigens.
Reference Values:
ANA by IFA, CSF: Negative
ANA Pattern: No Pattern
FFANA Anti-Nuclear Antibodies, Synovial Fluid

75593 Useful For: ANA are commonly found in a variety of autoimmune diseases. Antibody frequency
increases with age in apparently healthy people. ANA patterns on Hep-2 slides provide only general
clues about particles (chromatin, nucleosomes, and spliceosomes). ANA patterns (other than centromere
pattern) are not reliably correlated with the presence of specific antibodies and must be further
evaluated by EIA using individual ENA antigens.
Reference Values:
ANA Titer: <1:10
ANA Pattern: No Pattern
FCLNE Anti-Phosphatidylcholine Ab
Anti-Phosphatidylcholine IgA: <12.0 U/mL
Anti-Phosphatidylcholine IgG: <12.0 U/mL
Anti-Phosphatidylcholine IgM: <12.0 U/mL
Reference Range applies to Antiphosphatidylcholine IgA, IgG & IgM:

Normal <12.0
Equivocal 12.0 Ã¢â‚¬â€œ 18.0
Elevated >18.0
FPHET Anti-Phosphatidylethanolamine Panel

Anti-Phosphatidylethanolamine IgA
<12.0 U/mL
Anti-Phosphatidylethanolamine IgG
<12.0 U/mL
Anti-Phosphatidylethanolamine IgM
<12.0 U/mL
Reference Range applies to Antiphosphatidylethanolamine IgA, IgG, & IgM

Normal: <12.0
Equivocal: 12.0 Ã¢â‚¬â€œ 18.0
Elevated: >18.0
FAPMA Anti-PM/Scl-100 Ab
75623 Clinical Information: The anti-PM/Scl-100 antibody is associated with younger age, calcinosis and
has lower rates of gastrointestinal symptoms, ILD and pulmonary hypertension. There is also evidence of
a possibly better survival compared to the presence of either anti-PM/Scl-75 or anti-Scl-70 antibodies.
Reference Values:
Interpretation:
Negative: <20 units
FARWB Anti-retinal autoantibodies follow up, WB
A final report will be attached in MayoAccess.
FAS1A Anti-SAE1 Ab, IgG

75634 Clinical Information: Anti-SAE 1 IgG autoantibody can be used to assist in the diagnoses and
characterization of a subset of dermatomyositis (DM). It is highly specific for DM (>95%) and is
present in 5-8% of the European DM population. Initial disease onset may consist of mild myopathic
features with severe skin involvement; however, extensive myalgia and muscle disease with weakness
can appear as the disease progresses. It is associated with dysphagia and systemic symptoms (i.e. fevers,
weight loss, increased inflammatory markers). In one cohort, an association with ILD and cancer had
been found.
Reference Values:
Interpretation:
Negative: <20 units
FFRFT Anti-Synthetase Profile

75624 Clinical Information: This Anti-Synthetase Profile is comprised of Anti-Jo-1 Ab, Anti-PL-7 Ab,
Anti-PL-12 Ab, Anti-EJ Ab and Anti-OJ Ab. Anti-synthetase syndrome is an autoimmune disease
characterized by interstitial lung disease (ILD), non-erosive arthritis, myositis, Raynaudâ€™s
phenomenon, unexplained fever and/or mechanicâ€™s hands.
Reference Values:
Anti-PL-7 Ab, Anti-PL-12 Ab, Anti-EJ Ab, Anti-OJ Ab:
Reference Range: Negative
Interpretation for:
Anti-Jo-1 Ab:
Negative: <20 units
FATHO Anti-Th/To Ab
75619 Clinical Information: The Th/To antibodies are present in 10-19% of patients with limited SSc, in
11% of patients with diffuse cutaneous SSc, and in 3% of patients with primary Raynaud's disease.
Anti-Th/To antibody has been shown to be highly specific for patients with SSc.
Reference Values:
Negative
FAT1G Anti-TIF-1gamma Antibody

75632 Clinical Information: Anti-TIF-1(P155) antibodies are present in 15-38% of adult DM and 20-30%
in JDM. Highly associated with malignancy which is found in 50-75% of positive adult patients; 89%
specificity and 78% sensitivity for diagnosing cancer associated DM; no cancer association in children.
Reference Values:
Â
Interpretation:
Negative: <20 units
Weak Positive: 20 - 39 units
Moderate Positive: 40 - 80 units
FAU3R Anti-U3 RNP Antibodies (Fibrillarin)

75631 Clinical Information: The U3-RNP (Fibrillarin) particle is thought to participate in the first step of
preribosomal RNA processing. Anti-U3 RNP antibodies have been shown to be highly specific for
patients with SSc. Anti-Fibrillarin (U3 RNP) antibodies are highly specific for diffuse SSc with a
sensitivity of 4-10%. They are associated with isolated pulmonary arterial hypertension, myositis, renal
and cardiac manifestations of SSc. 15% of IIM, mostly found in scleroderma/myositis overlap. Found in
4-10% of Diffuse SSc, <2% in Limited SSc, associated with isolated PAH, myositis, cardiac and renal
involvement. More prevalent in African-Americans.
Reference Values:
Negative
ABIDR Antibody Identification, Blood and Serum

113389 Clinical Information: After exposure to foreign red blood cells (RBC) via transfusion or pregnancy,
some people form antibodies that are capable of the destruction of transfused RBC or of fetal RBC in
utero. It is important to identify the antibody specificity in order to assess the antibody's capability of
causing clinical harm and, if necessary, to avoid the antigen on transfused RBC. Autoantibodies react
against the patient's own RBC as well as the majority of cells tested. Autoantibodies can be clinically
benign or can hemolyze the patient's own RBC, such as in cold agglutinin disease or autoimmune
hemolytic anemia.
Useful For: Assessing positive pretransfusion antibody screens, transfusion reactions, hemolytic
disease of the newborn, and autoimmune hemolytic anemias This test is not useful for monitoring the
efficacy of Rh-immune globulin administration. This test is not useful for identifying antibodies detected
only at 4 degrees C or only after extended room temperature incubation.
Interpretation: Specificity of alloantibodies will be stated. The patient's red blood cells will be typed
for absence of the corresponding antigens or as an aid to identification in complex cases. A consultation
service is offered, at no charge, regarding the clinical relevance of red cell antibodies.
Reference Values:
Negative,
If positive, antibodies will be identified and corresponding special red cell antigen typing on
patientâ€™s red blood cells will be performed.Â
AABB; 2017
ABYSR Antibody Screen with Reflexed Antibody Identification, Blood

113387 Clinical Information: Transfusion and pregnancy are the primary means of sensitization to red cell
antigens. In a given population, 2% to 4% of the general population possess irregular red cell
alloantibodies. Such antibodies may cause hemolytic disease of the newborn or hemolysis of transfused
donor red blood cells.
Useful For: Detection of allo- or autoantibodies directed against red blood cell antigens in the
settings of pretransfusion testing Evaluation of transfusion reactions Evaluation of hemolytic anemia
Interpretation: A positive result (antibody detected) necessitates antibody identification to establish

the specificity and clinical significance of the antibody detected. Alloantibodies detected on pregnant
Mayo Clinic-Rochester patients will be evaluated for the allo-antibody titer. If antibody reacts strongly,
the titre test will be performed. Negative results indicate no antibody was detected.
Reference Values:
Negative
If positive, antibody identification will be performed.
Clinical References: Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds: Technical Manual.
19th ed. AABB; 2017
ABTIR Antibody Titer, Blood and Serum

113390 Clinical Information: Some maternal IgG alloantibodies to red blood cell antigens will cross the
placenta and cause hemolysis of antigen-positive fetal red blood cells. The resulting fetal anemia and
hyperbilirubinemia can be harmful or possibly fatal to the newborn.
Useful For: Monitoring antibody levels during pregnancy to help assess the risk of hemolytic disease
of the newborn This test is not useful for monitoring the efficacy of Rh-immune globulin
administration.
Interpretation: The specificity of the maternal alloantibody will be stated. The titer result is the
reciprocal of the highest dilution at which macroscopic agglutination (1+) is observed. If the antibody
problem identified is not relevant in hemolytic disease of the newborn or if titrations are not helpful, the
titer will be canceled and will be replaced by ABIDR / Antibody Identification, Blood and Serum. A
consultation service is offered, at no charge, regarding the clinical relevance of red blood cell
antibodies.
Reference Values:
Negative,
If positive, result will be reported as the reciprocal of the highest dilution at with macroscopic
agglutination (1+) is observed.
AABB; 2017
ENAE Antibody to Extractable Nuclear Antigen Evaluation, Serum

89035 Clinical Information: SSA, SSB, SM, and RNP are extractable nuclear antigens (ENA) that occur
in patients with several different connective tissue diseases. Scl 70 (topoisomerase 1) is a 100-kD
nuclear and nucleolar enzyme. Scl 70 antibodies are considered to be specific for scleroderma (systemic
sclerosis) and are found in up to 60% of patients with this connective tissue disease. Scl 70 antibodies
are more common in patients with extensive cutaneous involvement and interstitial pulmonary fibrosis,
and are considered a poor prognostic sign.(1) JO1 is a member of the amino acyl-tRNA synthetase
family of enzymes found in all nucleated cells and a marker for the disease polymyositis. For more
information, see individual unit codes.
Useful For: Evaluating patients with signs and symptoms of a connective tissue disease in whom the
test for antinuclear antibodies is positive Testing is not useful in patients without demonstrable
antinuclear antibodies.
Interpretation: A positive result is consistent with a connective tissue disease. For more
information, see individual unit codes.
Reference Values:
SS-A/Ro ANTIBODIES, IgG
<1.0 U (negative)
> or =1.0 U (positive)
SS-B/La ANTIBODIES, IgG

<1.0 U (negative)
Sm ANTIBODIES, IgG
<1.0 U (negative)
RNP ANTIBODIES, IgG

<1.0 U (negative)
Scl 70 ANTIBODIES, IgG

<1.0 U (negative)
Jo 1 ANTIBODIES, IgG
<1.0 U (negative)
Clinical References: 1. Homburger H, Larsen S: Detection of specific antibodies. In Clinical

Immunology: Principles and Practice. First edition. Edited by R Rich, T Fleisher, B Schwartz, et al. St.
Louis, Mosby-Year Book, Inc, 1996, pp 2096-2109 2. Targoff I: Autoantibodies in polymyositis. Rheum
Dis Clin North Am 1992;18:455
FADDS Antidepressant Drug Screen, Qualitative

Antidepressant screen includes the analysis for:
Amytriptyline, Clomipramine and Desmethylclomipramine, Cyclobenzaprine, Desipramine, Doxepin
and Desmethyldoxepin, Fluoxetine and Norfluoxetine, Imipramine, Maprotiline, Nortriptyline,
Paroxetine, Protriptyline, Sertraline and Desmethylsertraline, Trimipramine.
FASQN Antidepressant Drug Screen, Ur, Quantitative

Antidepressant screen includes the analysis for: amitriptyline, clomipramine and desmethylclomipramine,
cyclobenzaprine, desipramine, doxepin and desmethldoxepin, fluoxetine and norfluoxetine, imipramine,
maprotiline, nortriptyline, paroxetine, protriptyline, sertraline and desmethylsertraline, trimipramine.
MMLYP Antimicrobial Susceptibility Panel, Yeast, Varies

81602
Clinical Information: Candida species are the fourth leading cause of nosocomial infections and
are frequent causes of community-acquired infections. Antifungal susceptibility testing may aid in the
management of patients with invasive infections due to Candida species or patients who appear to be
experiencing therapeutic failure. The Clinical Laboratory Standards Institute has approved the use of a
broth microdilution method for determining the susceptibility of Candida species.
Useful For: Determining in vitro quantitative antifungal susceptibility (minimum inhibitory

concentration) of non-fastidious yeast As an aid in the management of certain circumstances, such as:
-Refractory oropharyngeal infections due to Candida species in patients who appear to be experiencing
therapeutic failure with standard agents at standard doses -Invasive infections due to Candida species
when the utility of azole antifungal agents is uncertain (eg, when the infection is due to a non-Candida
albicans organism)
Interpretation: The Clinical and Laboratory Standards Institute method, breakpoints, and
interpretive criteria are used.
Reference Values:
Results reported in mcg/mL
Clinical References: Pappas PG, Kauffman CA, Andes DR, et al: Clinical Practice Guideline for
the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin
Infect Dis. 2016 Feb 15;62(4):e1-e50
MMLRG Antimicrobial Susceptibility, Acid-Fast Bacilli, Rapidly

81601 Growing, Varies
Clinical Information: There are more than 100 species of rapidly growing mycobacteria and many
are significant human pathogens (eg, Mycobacterium abscessus, Mycobacterium chelonae,
Mycobacterium fortuitum). Rapidly growing mycobacteria cause a variety of infections including
pulmonary infections, skin and soft tissue infections, and disseminated disease. Antimicrobial
susceptibility testing of clinically significant rapidly growing mycobacteria is important to help guide
patient care. Antimicrobials tested in this assay are amikacin, cefoxitin, ciprofloxacin, clarithromycin,
clofazimine, doxycycline, imipenem, linezolid, moxifloxacin, tigecycline, tobramycin, and
trimethoprim/sulfamethoxazole.
Useful For: Determination of susceptibility of rapidly growing mycobacteria to the antimicrobial

agents on the test panel
Interpretation: Results are reported as the minimum inhibitory concentration in micrograms/mL.

Interpretive criteria (susceptible, intermediate, or resistant) are reported according the Clinical and
Laboratory Standards Institute (CLSI) guidelines.
Reference Values:
Antimicrobial Susceptible (mcg/mL) Intermediate (mcg/mL) Resistant (mcg/mL)
Amikacin < or =16 32 > or =64
Cefoxitin < or =16 32-64 > or =128
Ciprofloxacin < or =1 2 > or =4
Clarithromycin < or =2 4 > or =8
Clofazimine No interpretations available
Doxycycline < or =1 2-4 > or =8
Imipenem < or =4 8-16 > or =32
Linezolid < or =8 16 > or =32
Moxifloxacin < or =1 2 > or =4
Tigecycline No interpretations available
Tobramycin < or =2 4 > or =8
Trimethoprim/Sulfamethoxazole < or =2/38 - > or =4/76
Clinical References: 1. Brown-Elliott BA and Pilley JV. Rapidly growing mycobacteria.

Microbiol Spectr. 2017;5:1-19 2. Apiwattankul N, Flynn PM, Hayden RT, Adderson EE. Infections
caused by rapidly growing mycobacteria spp in children and adolescents with cancer. J Pediatric Infect
Dis Soc. 2015 Jun;4(2):104-113 3. Kasperbauer SH, De Groote MA. The treatment of rapidly growing
mycobacterial infections. Clin Chest Med. 2015 Mar;36(1):67-78
MMLSG Antimicrobial Susceptibility, Acid-Fast Bacilli, Slowly Growing,

34805 Varies
Clinical Information: The slowly growing nontuberculous mycobacteria are associated with a variety
of infections including pulmonary, extra-pulmonary, and disseminated disease. Â Slowly growing
mycobacteria differ from the rapidly growing mycobacteria and Mycobacterium tuberculosis complex by
their growth rates, metabolic properties, and antimicrobial susceptibility profiles. The antimicrobial
susceptibility profile of an organism within this group varies depending on the species and is performed
according to the Clinical and Laboratory Standards Institute (CLSI) guideline for slowly growing
mycobacteria.(1, 2) The antimicrobials listed below are included on the routine panel. Those marked with
an "X" are routinely reported. Organism Antimicrobial agent Amikacin Clarithromycin Clofazimine
Ciprofloxacin Doxycycline Linezolid Minocycline Moxifloxacin Rifabutin Rifampin Streptomycin
Trimethoprim-sulfamethoxazole Mycobacterium avium complex X X X X X Other slowly growing
nontuberculous Mycobacterium species X X X X X X X X X X X Â The extremely fastidious slowly
growing mycobacteria (Mycobacterium genavense and Mycobacterium haemophilum) will not be tested.
Mycobacterium malmoense can be difficult to grow in the test medium so some isolates may not be
amenable to testing. Mycobacterium xenopi requires incubation at a higher temperature and may require
extended incubation times. Mycobacterium gordonae is frequently encountered in the environment and in
clinical laboratories but is almost always considered nonpathogenic; therefore, antimicrobial susceptibility
testing for M gordonae is performed by specific request only.
Useful For: Determination of resistance of slowly growing mycobacteria to antimicrobial agents

Interpretation: Results are reported as the minimum inhibitory concentration in micrograms/mL.
Reference Values:
Interpretive criteria for Mycobacterium avium-intracellulare complex
Antimicrobial agent Minimum inhibitory concentration (MIC, mcg/mL) for each interpretation
S I R
Amikacin (IV) < or =16 32 > or =64
Amikacin (liposomal, inhaled) < or =64 - > or =128
Interpretative criteria for Â Mycobacterium kansasii and other slowly growing mycobacteria
Antimicrobial agent MIC (mcg/mL) for each interpretation
S I R
Amikacin < or =16 32 > or =64
Ciprofloxacin < or =1 2 > or =4
Doxycycline < or =1 2-4 > or =8
Minocycline < or =1 2-4 > or =8
Rifabutin < or =2 - > or =4
Rifampin < or =1 - > or =2
Trimethoprim/ Sulfamethoxazole < or =2/38 - > or =4/76
Clinical References: 1. CLSI: Susceptibility Testing of Mycobacteria, Nocardia spp., and Other
Aerobic Actinomycetes. 3rd ed. CLSI standard M24. Clinical and Laboratory Standards Institute; 2018 2.
CLSI: Performance Standards for Susceptibility Testing of Mycobacteria, Nocardia spp., and Other
Aerobic Actinomycetes. 1st ed. CLSI supplement M62. Clinical and Laboratory Standards Institute; 2018
3. Caulfield AJ, Richter E, Brown-Elliott BA, et al: Mycobacterium: laboratory characteristics of slowly
growing mycobacteria other than Mycobacterium tuberculosis. In: Carroll KC, Pfaller MA, Landry ML, et
al. eds. Manual of Clinical Microbiology. 12th ed. ASM Press; 2019:595-611 4. Philley JV, Griffith DE.
Treatment of slowly growing mycobacteria. Clin Chest Med. 2015 Mar;36(1):79-90. doi:
10.1016/j.ccm.2014.10.005 5. Daley CL, Laccarino JM, Lange C, et al: Treatment of nontuberculous
mycobacterial pulmonary disease: An official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. Clin
Infect Dis. 2020 Aug 14;71(4):905-913. doi: 10.1093/cid/ciaa1125
ZMMLS Antimicrobial Susceptibility, Aerobic Bacteria, Varies

8073 Clinical Information: Antimicrobial susceptibility testing (AST) determines the minimal inhibitory
concentration (MIC) of antimicrobial agents. The MIC is a measurement of the activity of an
antimicrobial agent against an organism. It is defined as the lowest concentration of an antimicrobial
agent that inhibits growth of the microorganism. Clinical breakpoints are derived from a number of data
including: -The pharmacokinetics/pharmacodynamics of an antimicrobial agent -The MIC distribution
of a large number of isolates -Clinical outcome data for a patient population treated with the
antimicrobial of interest AST should be performed on pure culture isolates of pathogenic bacteria (or
those potentially pathogenic in special situations) grown from specimens that have been appropriately
collected so as not to confuse clinically significant isolates with normal or contaminating microbiota.
Susceptibility testing is indicated for any organism that contributes to an infectious process warranting
antimicrobial chemotherapy if its susceptibility cannot be reliably predicted from the organism's
identity. The MIC obtained during AST is helpful in indicating the concentration of antimicrobial agent
required at the site of infection necessary to inhibit the infecting organism. For each
organism-antimicrobial agent combination, the Clinical and Laboratory Standards Institute and/or the
European Committee on Antimicrobial Susceptibility Testing provides interpretive criteria for
determining whether the MIC should be interpreted as susceptible, susceptible dose dependent,
intermediate, nonsusceptible, resistant, or epidemiological cutoff value if applicable.
Useful For: Determining the in vitro susceptibility of aerobic bacteria involved in human infections
Interpretation: A "susceptible" category result and a low minimum inhibitory concentration value
indicate in vitro susceptibility of the organism to the antimicrobial tested. Refer to Reference Values for
interpretation of various antimicrobial susceptibility interpretive categories (ie, susceptible,
susceptible-dose dependent, intermediate, nonsusceptible, resistant, or epidemiological cutoff value).
Reference Values:
Susceptibility results are reported as minimal inhibitory concentration (MIC) in mcg/mL Breakpoints
(also known as "clinical breakpoints") are used to categorize an organism as susceptible,
susceptible-dose dependent, intermediate, resistant, or nonsusceptible according to breakpoint setting
organizations, either the Clinical and Laboratory Standards Institute (CLSI) or the European Committee
on Antimicrobial Susceptibility Testing (EUCAST), as applicable.
In some instances, an interpretive category cannot be provided based on available data and the
following comment will be included: "There are no established interpretive guidelines for agents
reported without interpretations."
Clinical and Laboratory Standards Institute (CLSI) Interpretive Category Definitions:

Susceptible:
A category defined by a breakpoint that implies that isolates with an MIC at or below or a zone
diameter at or above the susceptible breakpoint are inhibited by the usually achievable concentrations of
antimicrobial agent when the dosage recommended to treat the site of infection is used, resulting in
likely clinical efficacy.
Susceptible-Dose Dependent:
A category defined by a breakpoint that implies that susceptibility of an isolate depends on the dosing
regimen that is used in the patient. To achieve levels that are likely to be clinically effective against
isolates for which the susceptibility testing results (either MICs or zone diameters) are in the
susceptible-dose dependent (SDD) category, it is necessary to use a dosing regimen (ie, higher doses,
more frequent doses, or both) that results in higher drug exposure than that achieved with the dose that
was used to establish the susceptible breakpoint. Consideration should be given to the maximum
literature-supported dosage regimens, because higher exposure gives the highest probability of adequate
coverage of a SDD isolate. The drug label should be consulted for recommended doses and adjustment
for organ function.
Intermediate:
A category defined by a breakpoint that includes isolates with MICs or zone diameters within the
intermediate range that approach usually attainable blood and tissue levels and/or for which response
rates may be lower than for susceptible isolates.
Note: The intermediate category implies clinical efficacy in body sites where the drugs are
physiologically concentrated or when a higher than normal dosage of a drug can be used. This category
also includes a buffer zone, which should prevent small, uncontrolled, technical factors from causing
major discrepancies in interpretations, especially for drugs with narrow pharmacotoxicity margins.
Resistant:
A category defined by a breakpoint that implies that isolates with an MIC at or above or a zone
diameter at or below the resistant breakpoint are not inhibited by the usually achievable concentrations
of the agent with normal dosage schedules and/or that demonstrate MICs or zone diameters that fall in
the range in which specific microbial resistance mechanisms are likely, and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Nonsusceptible:
A category used for isolates for which only a susceptible breakpoint is designated because of the
absence or rare occurrence of resistant strains. Isolates for which the antimicrobial agent MICs are
above or the zone diameters are below the value indicated for the susceptible breakpoint should be
reported as nonsusceptible.
Note: An isolate that is interpreted as nonsusceptible does not necessarily mean that the isolate has a
resistance mechanism. It is possible that isolates with MICs above the susceptible breakpoint that lack
resistance mechanisms may be encountered within the wild-type distribution after the time the
susceptible-only breakpoint was set.
Epidemiological Cutoff Value:

The MIC that separates microbial populations into those with and without phenotypically detectable
resistance (non-wild-type or wild-type, respectively). The epidemiological cutoff value (ECV) defines
the highest MIC for the wild type population of isolates. ECVs are based on in vitro data only, using
MIC distributions. ECVs are not clinical breakpoints, and the clinical relevance of ECVs for a particular
patient has not yet been identified or approved by CLSI or any regulatory agency.
When an ECV is reported, an interpretive category is not assigned, and the following comment will be
included: "This MIC is consistent with the Epidemiological Cutoff Value (ECV) observed in isolates
(WITH / WITHOUT) acquired resistance; however, correlation with treatment outcome is unknown."
-Wild-type (WT) â€“ an interpretive category defined by an ECV that describes the microbial
population with no phenotypically detectable mechanisms of resistance or reduced susceptibility for an
antimicrobial agent being evaluated.
-Non-wild-type (NWT) â€“ an interpretive category defined by an ECV that describes the microbial
population with phenotypically detectable mechanisms of resistance or reduced susceptibility for the
Note: MIC values for which ECVâ€™s are defined are not to be interpreted or reported as susceptible,
intermediate or resistant but rather as WT or NWT. The ECVâ€™s should not be used as clinical
breakpoints.(Clinical and Laboratory Standards Institute [CLSI]. Performance Standards for
Antimicrobial Susceptibility Testing. 31st ed. CLSI supplement M100. CLSI; 2021:4-6, 268-269)
European Committee on Antimicrobial Susceptibility Testing (EUCAST) Interpretive Category

Definitions:
S - Susceptible, standard dosing regimen: A microorganism is categorized as "Susceptible, standard
dosing regimen", when there is a high likelihood of therapeutic success using a standard dosing regimen
of the agent
I - Susceptible, increased exposure*: A microorganism is categorized as "Susceptible, Increased

exposure*" when there is a high likelihood of therapeutic success because exposure to the agent is
increased by adjusting the dosing regimen or by its concentration at the site of infection.
R - Resistant: A microorganism is categorized as "Resistant" when there is a high likelihood of

therapeutic failure even when there is increased exposure*.
*Exposure is a function of how the mode of administration, dose, dosing interval, infusion time, as
well as distribution and excretion of the antimicrobial agent will influence the infecting organism at the
site of infection.
(The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for

interpretation of MICs and zone diameters. v11.0, 2021. Available at www.eucast.org.)
Clinical References: 1. Jorgensen JH, Ferraro MJ: Antimicrobial susceptibility testing: a review of
general principles and contemporary practices. Clin Infect Dis. 2009 Dec 1;49(11):1749-1755 2. Jenkins
SG, Schuetz AN: Current concepts in laboratory testing to guide antimicrobial therapy. Mayo Clin Proc.
2012 Mar;87(3):290-308 3. Procop GW, Church DL, Hall GS, et al: Antimicrobial susceptibility testing.
In: Koneman's Color Atlas and Textbook of Diagnostic Microbiology. 7th ed. Wolters Kluwer Health;
2017:1074-1171
MMLSA Antimicrobial Susceptibility, Anaerobic Bacteria, Minimal

56031 Inhibitory Concentration, Varies
Clinical Information: Anaerobic bacteria are the greatest component of the human body's normal
bacterial flora. Anaerobes colonize the skin, oral cavity, and genitourinary and lower gastrointestinal
tracts and generally do not cause infection. Their presence is important for vitamin and other nutrient
absorption and in preventing infection with pathogenic bacteria. When usual skin and mucosal barriers
are compromised, in an anaerobic environment, these bacteria can behave as pathogens. Typical
anaerobic infections include periodontitis, abdominal or pelvic abscesses, endometritis, pelvic
inflammatory disease, aspiration pneumonia, empyema and lung abscesses, sinusitis, brain abscesses,
gas gangrene, and other soft tissue infections. Anaerobes grow aggressively in the body under anaerobic
conditions and may possess a variety of virulence factors including capsules and extracellular enzymes.
They also can develop resistance to antimicrobials by producing beta-lactamase and other modifying
enzymes and by alterations in membrane permeability and structure of penicillin-binding proteins.
Susceptibility testing results are useful to clinicians because anaerobic bacteria are a significant cause of
human infection, and they are often resistant to commonly used antimicrobials. Bacteroides and
Parabacteroides species produce beta-lactamases. Ertapenem, metronidazole, and clindamycin are
generally effective agents although resistance to clindamycin, and occasionally ertapenem, is increasing.
The minimal inhibitory concentration obtained during antimicrobial susceptibility testing is helpful in
indicating the concentration of antimicrobial agent required at the site of infection necessary to inhibit
the infecting organism. For each organism-antimicrobial agent combination, the Clinical and Laboratory
Standards Institute and/or the European Committee on Antimicrobial Susceptibility Testing provides
interpretive criteria for determining whether the MIC should be interpreted as susceptible, susceptible
dose dependent, intermediate, nonsusceptible, resistant, or epidemiological cutoff value.
Useful For: Determining the in vitro susceptibility on isolates of anaerobic bacteria involved in human
infections Directing antimicrobial therapy for anaerobic infections
Interpretation: A "susceptible" category result and a low minimum inhibitory concentration value
indicate in vitro susceptibility of the organism to the antimicrobial tested. For interpretation of various
antimicrobial susceptibility interpretive categories (ie, susceptible, intermediate, resistant, or
epidemiological cutoff value), see Reference Values.
Reference Values:
(also known as "clinical breakpoints") are used to categorize an organism as susceptible, susceptible-dose
dependent, intermediate, resistant or nonsusceptible according to breakpoint setting organizations, either
the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial
Susceptibility Testing (EUCAST), as applicable.
In some instances, an interpretive category cannot be provided based on available data and the following
comment will be included: "There are no established interpretive guidelines for agents reported without
interpretations."

Susceptible:
A category defined by a breakpoint that implies that isolates with an MIC at or below or a zone diameter
at or above the susceptible breakpoint are inhibited by the usually achievable concentrations of
antimicrobial agent when the dosage recommended to treat the site of infection is used, resulting in likely
clinical efficacy.
literature-supported dosage regimens because higher exposure gives the highest probability of adequate
coverage of a SDD isolate. The drug label should be consulted for recommended doses and adjustment for
organ function.
Intermediate:
intermediate range that approach usually attainable blood and tissue levels and/or for which response rates
may be lower than for susceptible isolates.
Resistant:
A category defined by a breakpoint that implies that isolates with an MIC at or above or a zone diameter
at or below the resistant breakpoint are not inhibited by the usually achievable concentrations of the agent
with normal dosage schedules and/or that demonstrate MICs or zone diameters that fall in the range in
which specific microbial resistance mechanisms are likely, and clinical efficacy of the agent against the
isolate has not been reliably shown in treatment studies.
Nonsusceptible:
A category used for isolates for which only a susceptible breakpoint is designated because of the absence
or rare occurrence of resistant strains. Isolates for which the antimicrobial agent MICs are above or the
zone diameters are below the value indicated for the susceptible breakpoint should be reported as
nonsusceptible.

resistance (non-wild-type or wild-type, respectively). The epidemiological cutoff value (ECV) defines the
highest MIC for the wild type population of isolates. ECVs are based on in vitro data only, using MIC
distributions. ECVs are not clinical breakpoints, and the clinical relevance of ECVs for a particular patient
has not yet been identified or approved by CLSI or any regulatory agency.
included:
This MIC is consistent with the Epidemiological Cutoff Value (ECV) observed in isolates (WITH /
WITHOUT) acquired resistance; however, correlation with treatment outcome is unknown.
-Wild-type (WT): an interpretive category defined by an ECV that describes the microbial population
with no phenotypically detectable mechanisms of resistance or reduced susceptibility for an antimicrobial
agent being evaluated.
-Non-wild-type (NWT): an interpretive category defined by an ECV that describes the microbial
Note: MIC values for which ECV's are defined are not to be interpreted or reported as susceptible,
intermediate, or resistant but rather as WT or NWT. The ECV's should not be used as clinical

Definitions:
of the agent


*Exposure is a function of how the mode of administration, dose, dosing interval, infusion time, as well
as distribution and excretion of the antimicrobial agent will influence the infecting organism at the site of
infection.
(The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation
of MICs and zone diameters. Version 11.0, 2021. Available at www.eucast.org.)
Clinical References: 1. Rosenblatt JE, Brook I: Clinical relevance of susceptibility testing of

anaerobic bacteria. Clin Infect Dis. 1993 Jun;16(Suppl 4):S446-S448 2. Jenkins SG, Schuetz AN:
Current concepts in laboratory testing to guide antimicrobial therapy. Mayo Clin Proc. 2012
Mar;87(3):290-308 3. Schuetz AN, Carpenter DE: Susceptibility test methods: anaerobic bacteria. In:
Carroll KC, Pfaller MA, eds. Manual of Clinical Microbiology. 12th ed. ASM Press; 2019:1377-1397 4.
Jenkins SG, Schuetz AN: Current concepts in laboratory testing to guide antimicrobial therapy. Mayo
Clin Proc. 2012 Mar;87(3):290-308
MMLNS Antimicrobial Susceptibility, Nocardia species and other

82019 Aerobic Actinomycetes, Varies
Clinical Information: Nocardia species and other aerobic actinomycetes can cause significant
disease, often in immunocompromised patients. Clinical presentation can include, but is not limited to,
pneumonia, skin abscess, bacteremia, brain abscess, eye infection, and joint infection. Antimicrobial
susceptibility testing may aid with selection of appropriate antimicrobial agents for patient care.
Useful For: Determining the resistance of species of Nocardia and other aerobic actinomycetes to
antimicrobial agents
Interpretation: Interpretive values for susceptibility testing of Nocardia species using a broth
microdilution method are included in the report, as appropriate. For Rhodococcus equi, the interpretive
values for vancomycin and rifampin will also be included. See Reference Values for additional
information.
Reference Values:
Antimicrobial agent Concentration range mcg/mL Interpretations
S I R
Amikacin 0.5-32 < or =8 - > or =16
Amoxicillin/clavulanate 2/1-128/64 < or =8/4 16/8 > or =32/16
Ceftriaxone 1-64 < or =8 16-32 > or =64
Ciprofloxacin 0.12-16 < or =1 2 > or =4
Clarithromycin 0.03-16 < or =2 4 > or =8
Doxycycline 0.12-16 < or =1 2-4 > or =8
Imipenem 0.12-32 < or =4 8 > or =16
Linezolid 0.5-16 < or =8 - -
Minocycline 0.06-16 < or =1 2-4 > or =8
Moxifloxacin 0.015-8 < or =1 2 > or =4
Tobramycin 2-64 < or =4 8 > or =16
Trimethoprim/ Sulfamethoxazole 0.06/1.19-8/152 < or =2/38 - > or =4/76
For Rhodococcus equi only
Rifampin 0.5-2 < or =1 2 > or =4
Vancomycin 0.5-16 < or =2 4-8 > or =16
Clinical References: 1. Duggai SD, Chugh TD: Nocardiosis: A neglected disease. [published online
ahead of print, 2020 May 18]. Med Princ Pract. 2020;10.1159/000508717. doi:10.1159/000508717 2.
Conville PS, Brown-Elliott BA, Smith T, Zelazny AM: The complexities of Nocardia taxonomy and
identification. J Clin Microbiol. 2017;56(1):e01419-17
SBWB Antimony, Blood
64273 Clinical Information: Antimony is a silvery white metal that is used in alloys for lead batteries,
solder, sheet metal, bearings, castings, ammunition, and pewter. It is also used for pigments, abrasives,
flame-proofing fabrics, and in medications (ie, sodium stibogluconate [Pentostam], which is used to
treat cutaneous leishmaniasis).(1) Antimony typically enters the environment during mining, processing
of ores, emissions from coal-burning power plants, and production of alloys. Exposure to antimony can
occur through inhalation, ingestion, or dermal contact with soil, water, foods, or medications that
contain it. In the workplace, exposure is usually via inhalation. OSHA has set a limit of 0.5 mg/m(3) of
antimony in workroom air to protect workers during an 8-hour work shift (40-hour workweek).(2)
Absorption of antimony through the lungs may take days to weeks. Absorption of antimony from
ingestion typically enters the blood within a few hours.(2) The amount and form of the antimony affects
how much is absorbed. Once in the blood, antimony is distributed to the liver, lungs, intestines, and
spleen. Elimination is primarily through the urine, occurring over several weeks. The half-life varies
depending on the chemical form. Trivalent antimony is primarily bound to erythrocytes, while
pentavalent antimony is primarily found in plasma, which makes whole blood the preferred specimen to
analyze for acute intoxication. Whole blood concentrations in healthy subjects not exposed to antimony
averaged 0.7 mcg/L and usually do not exceed 2 mcg/L.(3) In battery plant workers, median blood
antimony concentrations of 2.6 mcg/L were found in metal casters and 10 mcg/L in metal formers.(4)
The effects of acute or chronic antimony poisoning are similar to arsenic poisoning and include
abdominal pain, dyspnea, nausea, vomiting, dermatitis, and visual disturbances.(1) Additionally,
toxicity can include pneumoconiosis, and altered electrocardiograms.(2)
Useful For: Determining antimony toxicity

Interpretation: Normal blood concentrations are 0.7-2 ng/mL in the unexposed, and 2.6-10 ng/mL
in exposed workers.(3)
Reference Values:
<3 ng/mL (unexposed)
3-10 ng/mL (exposed)
Clinical References: 1. Baselt R: Disposition of Toxic Drugs and Chemicals In Man. 10th ed.
Biomedical Publications; 2014 2. Agency for Toxic Substances and Disease Registry: Toxicological
profile for antimony and compounds. US Department of Health and Human Services; October 2019.
Accessed May 18, 2020. Available at www.atsdr.cdc.gov/toxprofiles/tp23.pdf 3. Gebel T, Claussen K,
Dunkelberg H: Human biomonitoring of antimony. Int Arch Occup Environ Health. 1998
May;71(3):221-224 4. Kentner M, Leinemann M, Schaller KH, Weltle D, Lehnert G: External and
internal antimony exposure in starter battery production. Int Arch Occup Environ Health.
1995;67(2):119-123 5. Roberts NB, Taylor A, Sodi R: Vitamins and trace elements. Rifai N, Horvath
AR, Wittwer CT, eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed.
Elsevier; 2018:chap 37
AMH1 Antimullerian Hormone, Serum

608824 Clinical Information: Antimullerian hormone (AMH), also known as mullerian-inhibiting
substance, is a dimeric glycoprotein hormone belonging to the transforming growth factor-beta family.
It is produced by Sertoli cells of the testis in males and by ovarian granulosa cells in females.
Expression during male fetal development prevents the mullerian ducts from developing into the uterus,
resulting in development of the male reproductive tract. In the absence of AMH, the mullerian ducts and
structures develop into the female reproductive tract. AMH serum concentrations are elevated in boys
under 2 years old and then progressively decrease until puberty, when there is a sharp decline. In female
individuals, serum AMH concentrations are very low at birth, peaking after puberty, decrease
progressively thereafter with age, and become undetectable at menopause. Because of the gender
differences in AMH concentrations, its changes in circulating concentrations with sexual development,
and its specificity for Sertoli and granulosa cells, measurement of AMH has utility in the assessment of
gender, gonadal function, fertility, and as a gonadal tumor marker. In female individuals, AMH is
considered an ovarian reserve marker. It correlates with the primordial follicle pool, has an inverse
correlation with chronologic age, predicts ovarian response in assisted reproductive therapy, and has
been suggested to be predictive of the timing of the onset of menopause. In contrast to other markers of
ovarian reserve that show significant fluctuations during the menstrual cycle, serum AMH
concentrations have been shown to be relatively stable. Women with higher concentrations of AMH
have a better response to ovarian stimulation and tend to produce more retrievable oocytes than women
with low or undetectable AMH. Women at risk of ovarian hyperstimulation syndrome after
gonadotropin administration can have significantly elevated AMH concentrations. Polycystic ovarian
syndrome can elevate serum AMH concentrations because it is associated with the presence of large
numbers of small follicles. AMH measurements are commonly used to evaluate testicular presence and
function in infants with intersex conditions or ambiguous genitalia and to distinguish between
cryptorchidism and anorchia in male infants. Serum AMH concentrations are increased in some patients
with ovarian granulosa cell tumors, which comprise approximately 10% of ovarian tumors. AMH, along
with related tests including inhibin A and B (INHA / Inhibin A, Tumor Marker, Serum; INHB / Inhibin
B, Serum; INHAB / Inhibin A and B, Tumor Marker, Serum), estradiol (EEST / Estradiol, Serum), and
cancer antigen 125 (CA25 / Cancer Antigen 125 [CA 125], Serum), can be useful for diagnosing and
monitoring these patients.
Useful For: Assessing ovarian status, including ovarian reserve and ovarian responsiveness, as part of
an evaluation for infertility and assisted reproduction protocols Assessment of menopausal status,
including premature ovarian failure Evaluation of infants with ambiguous genitalia and other intersex
conditions Evaluating testicular function in infants and children Monitoring patients with antimullerian
hormone-secreting ovarian granulosa cell tumors
Interpretation: Menopausal women or women with premature ovarian failure of any cause, including
after cancer chemotherapy, have very low anti-mullerian hormone (AMH) levels. While the optimal AMH
concentrations for predicting response to in vitro fertilization are still being established, it is accepted that
AMH concentrations in the perimenopausal to menopausal range indicate minimal to absent ovarian
reserve. Depending on patient age, ovarian stimulation is likely to fail in such patients. AMH may be used
as a surrogate to antral follicle count (AFC) at day 2 to 4 of the menstrual cycle to determine ovarian
reserve. Women with an AFC greater than 15 are identified as having high ovarian reserve. In this context
a Roche AMH concentration greater than 1.77 ng/mL at day 2 to 4 of the menstrual cycle, identified
women with an AFC greater than 15 with 88.3% sensitivity and 68.3% specificity.(1) Controlled ovarian
stimulation (COS) with exogenous gonadotropin is an essential step of in-vitro fertilization (IVF)
protocols. Using the Roche AMH assay, a cut-off of 2.10 ng/mL is correlated with the response categories
in women undergoing COS using a gonadotropin-releasing hormone antagonist protocol. A 2.10 ng/mL
cutoff provided reliable prediction of hyper-response to COS(2). Sensitivity for the detection of
hyperresponsive individuals was 81.3%, and the negative predictive value for ruling out hyperresponse
was 96.6%. The 2.10 ng/mL cutoff identified 88.9% of patients with a poor response.(2) In patients with
polycystic ovarian syndrome, AMH concentrations may be 2- to 5-fold higher than age-appropriate
reference range values. Such high levels predict anovulatory and irregular cycles. In children with intersex
conditions, an AMH result above the normal female range is predictive of the presence of testicular tissue,
while an undetectable value suggests its absence. In boys suspected of cryptorchidism, a measurable
AMH concentration is predictive of undescended testes, while an undetectable value is highly suggestive
of anorchia or functional failure. Klinefelter syndrome is characterized by accelerated germ cell depletion
and occurs in approximately 10% to 12% of men presenting with nonobstructive azoospermia. In these
patients, serum AMH concentrations are within the reference interval until puberty, and thereafter, AMH
concentrations decline to abnormally low or undetectable. Pubertal delay and congenital
hypogonadotropic hypogonadism (HH) share the same clinical manifestation of delayed sexual maturation
in prepubertal boys. Levels of gonadotropin and testosterone are very low in prepubertal boys and
therefore have little clinical significance; thus, AMH measurements are useful in the differential diagnosis
of pubertal delay and congenital HH. In patients with congenital HH, AMH concentrations are abnormally
low, while in pubertal delay AMH concentrations will be within the prepubertal reference interval.
Granulosa cell tumors of the ovary may secrete AMH, inhibin A, and inhibin B. Elevated levels of any of
these markers can indicate the presence of such a neoplasm in a woman with an ovarian mass. Levels
should fall with successful treatment. Rising levels indicate tumor recurrence or progression.
Reference Values:
Males
<2 years: 18-283 ng/mL
2-12 years: 8.9-109 ng/mL
>12 years: <13 ng/mL
Females
<3 years: 0.11-4.2 ng/mL
3-6 years: 0.21-4.9 ng/mL
7-11 years: 0.36-5.9 ng/mL
12-14 years: 0.49-6.9 ng/mL
15-19 years: 0.62-7.8 ng/mL
20-24 years: 1.2-12 ng/mL
25-29 years: 0.89-9.9 ng/mL
30-34 years: 0.58-8.1 ng/mL
35-39 years: 0.15-7.5 ng/mL
40-44 years: 0.03-5.5 ng/mL
45-50 years: <2.6 ng/mL
51-55 years: <0.88 ng/mL
>55 years: <0.03 ng/mL
Clinical References: 1. Jacobs MH, Reuter LM, Baker VL, et al: A multicentre evaluation of the
Elecsys anti-Mullerian hormone immunoassay for prediction of antral follicle count. Reprod Biomed
Online. 2019 May;38(5):845-852 2. Anckaert E, Denk B, He Y, Torrance HL, Broekmans F, Hund M:
Evaluation of the Elecsys anti-Mullerian hormone assay for the prediction of hyper-response to
controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol. Eur J
Obstet Gynecol Reprod Biol. 2019 May;236:133-138 3. Bedenk J, Vrtacnik-Bokal E, Virant-Klun I:
The role of anti-Mullerian hormone (AMH) in ovarian disease and infertility. J Assist Reprod Genet.
2020 Jan;37(1):89-100 4. Xu HY, Zhang HX, Xiao Z, Qiao J, Li R: Regulation of anti-Mullerian
hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility. Asian
J Androl. 2019 Mar-Apr;21(2):109-114 5. Grinspon RP, Bergada I, Rey RA: Male hypogonadism and
disorders of sex development. Front Endocrinol (Lausanne). 2020 April15;11:211 6. Shankar RK,
Dowlut-McElroy T, Dauber A, Gomez-Lobo V: Clinical utility of anti-Mullerian hormone in pediatrics.
J Clin Endocrinol Metab. 2021 Sep 19;dgab687. doi: 10.1210/clinem/dgab687. Epub ahead of print
VASC Antineutrophil Cytoplasmic Antibodies Vasculitis Panel,

83012 Serum
Clinical Information: Antineutrophil cytoplasmic antibodies (ANCA) occur in patients with
autoimmune vasculitis including Wegener granulomatosis (WG), microscopic polyangiitis (MPA), or
organ-limited variants thereof such as pauci-immune necrotizing glomerulonephritis.(1) ANCA react
with enzymes in the cytoplasmic granules of human neutrophils including proteinase 3 (PR3),
myeloperoxidase (MPO), elastase, and cathepsin G. Autoantibodies to PR3 occur in patients with WG
(both classical WG and WG with limited end-organ involvement) and produce a characteristic pattern of
granular cytoplasmic fluorescence on ethanol-fixed neutrophils called the cANCA pattern. Antibodies
to MPO occur predominately in patients with MPA and produce a pattern of perinuclear cytoplasmic
fluorescence on ethanol-fixed neutrophils called the pANCA pattern. Autoantibodies to PR3 and MPO
can also be detected by EIA methods and are referred to as PR3 ANCA and MPO ANCA, respectively.
Useful For: Evaluating patients suspected of having autoimmune vasculitis, both Wegener
granulomatosis and microscopic polyangiitis
Interpretation: Positive results for proteinase 3 (PR3) antineutrophil cytoplasmic antibodies

(ANCA) and cANCA or pANCA are consistent with the diagnosis of Wegener granulomatosis (WG),
either systemic WG with respiratory and renal involvement or limited WG with more restricted
end-organ involvement. Positive results for MPO ANCA and pANCA are consistent with the diagnosis
of autoimmune vasculitis including microscopic polyangiitis (MPA) or pauci-immune necrotizing
glomerulonephritis. A positive result for PR3 ANCA or MPO ANCA has been shown to detect 89% of
patients with active WG or MPA (with or without renal involvement) with fewer than 1% false-positive
results in patients with other diseases.(1)
Reference Values:
MYELOPEROXIDASE ANTIBODIES, IgG
<0.4 U (negative)
0.4-0.9 U (equivocal)
PROTEINASE 3 ANTIBODIES, IgG

<0.4 U (negative)
0.4-0.9 U (equivocal)
Clinical References: 1. Russell KA, Wiegert E, Schroeder DR, et al: Detection of anti-neutrophil
cytoplasmic antibodies under actual clinical testing conditions. Clin Immunol 2002 May;103(2):196-203
2. Specks U, Homburger HA, DeRemee RA: Implications of cANCA testing for the classifications of
Wegner's Granulomatosis: performance of different detection systems. Adv Exp Med Biol
1993;336:65-70
ANA2 Antinuclear Antibodies (ANA), Serum

9026 Clinical Information: Measurement of antinuclear antibodies (ANA) in serum is the most commonly
performed screening test for patients suspected of having a systemic autoimmune rheumatic disease
(SARD), also referred to as connective tissue disease.(1) ANA occur in patients with various autoimmune
diseases, both systemic and organ specific, but they are particularly common in SARDs, whichÂ include
systemic lupus erythematosus (SLE), discoid lupus erythematosus, drug-induced lupus erythematosus,
mixed connective tissue disease (MCTD), Sjogrenâ€™s syndrome (SjS), systemic sclerosis, CREST
syndrome (calcinosis, Raynaudâ€™s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia),
and idiopathic inflammatory myopathies. ANA can be detected by different technologies, including
indirect immunofluorescence assay (IFA) and solid phase assays, such as enzyme immunoassays and
multiplex bead immunoassays. In a study performed in the Mayo Clinic Antibody Immunology
Laboratory, no significant differences were demonstrated between ANA IFA and ANA enzyme-linked
immunosorbent assay (ELISA) for a cohort of patients with connective tissue disease consisting
predominantly of patients with SLE, SjS, and MCTD. Weakly positive ANA ELISA results were not a
strong indicator of SARD in this laboratory cohort. The likelihood of finding an autoantibody to a specific
extractable nuclear antigen including double-stranded DNA on a second-order testing increased directly
with the level of ANA: 88% of sera that had detectable autoantibodies on second-order testing had an
ANA level greater than 3.0 U.(2) Overall, an ANA ELISA result of greater than or equal to 3.0 U was
demonstrated as the optimal cutoff for CTDC / Connective Tissue Disease Cascade, Serum. This
algorithm is intended to evaluate patients with common connective tissue diseases such as SLE, SjS, and
MCTD. See Connective Tissue Disease Cascade (CTDC)
Useful For: Evaluating patients at-risk for antinuclear antibodies-associated systemic autoimmune
rheumatic disease particularly systemic lupus erythematosus, Sjogren syndrome, and mixed connective
tissue disease
Interpretation: A large number of healthy individuals have weakly-positive (1.1 - 2.9 U) antinuclear
antibody (ANA) enzyme-linked immunosorbent assay (ELISA) results, many of which are likely to be
clinical false-positive results; therefore, second-order testing of all positive ANA yields a very low
percentage of positive results to extractable nuclear antigens including double-stranded (ds) DNA.(2)
Positive ANA results greater than 3.0 U are associated with the presence of detectable autoantibodies to
specific extractable nuclear antigens (SM, SS-A, SS-B, Sm/RNP or RNP 68 and RNP A, Jo-1, Scl-70)
including dsDNA.
Reference Values:
Negative: < or =1.0 U
Weakly positive: 1.1-2.9 U
Positive: 3.0-5.9 U
Strongly positive: > or =6.0 U
Clinical References: 1. Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International

recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear
antibodies. Ann Rheum Dis. 2014 Jan;73(1):17-23. doi: 10.1136/annrheumdis-2013-203863 2. Deng X,
Peters B, Ettore MW, et al: Utility of antinuclear antibody screening by various methods in a clinical
laboratory patient cohort: J Appl Lab Med. 2016 Jul 1;1(1):36-46. doi: 10.1373/jalm.2016.020172 3.
Sparchez M, Delean D, Samasca G, Miu N, Sparchez Z: Antinuclear antibody screening by ELISA and
IF techniques: discrepant results in juvenile idiopathic arthritis but consistency in childhood systemic
lupus erythematous. Clin Rheumatol. 2014 May;33(5):643-647. doi: 10.1007/s10067-014-2529-y 4.
Bossuyt X, De Langhe E, Borghi MO, Meroni PL: Understanding and interpreting antinuclear antibody
tests in systemic rheumatic diseases. Nat Rev Rheumatol. 2020 Dec;16(12):715-726. doi:
10.1038/s41584-020-00522-w 5. Bossuyt X, Claessens J, De Langhe E, et al: Antinuclear antibodies by
indirect immunofluorescence and solid phase assays. Ann Rheum Dis. 2020 Jun;79(6):e65. doi:
10.1136/annrheumdis-2019-215443 6. Alsaed OS, Alamlih LI, Al-Radideh O, Chandra P, Alemadi S,
Al-Allaf AW. Clinical utility of ANA-ELISA vs ANA-immunofluorescence in connective tissue
diseases. Sci Rep. 2021 Apr 15;11(1):8229. doi: 10.1038/s41598-021-87366-w
NAIFA Antinuclear Antibodies, HEp-2 Substrate, IgG, Serum

65161 Clinical Information: Autoantibodies targeting antigens in the nuclear region in the HEp-2 cell line
substrate using the indirect immunofluorescence assay (IFA) have traditionally been called antinuclear
antibody (ANA). ANA is the commonly performed antibody test in the initial evaluation of patients
with systemic autoimmune rheumatic diseases (also referred to as connective tissue disease). Classic
ANA-associated rheumatic diseases include systemic lupus erythematosus (SLE), mixed connective
tissue disease (MCTD), Sjogren syndrome (Sjs), and systemic sclerosis (SSc) including CREST
(calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) and
inflammatory myopathies (IM) such as dermatomyositis (DM).(1-4) Testing for ANA may also be of
diagnostic relevance in the differential evaluation of autoimmune liver diseases (ALD).(5-6) The
classical ANA patterns (antibodies targeting the nuclear region) include homogeneous, speckled,
centromere, nuclear dots, and nucleolar. These patterns are routinely reported by most clinical
laboratories. SLE patients and those with SSc, Sjs, IM (such as anti-synthetase syndrome and
necrotizing autoimmune myopathy) or ALD have also been shown to have clinically significant
antibodies that react with antigens in other cellular compartments such as the cytoplasm and structures
associated mitosis or mitotic patterns with HEp-2 substrate (reviewed in 1-3). Based on the increasing
recognition of these non-nuclear antigenic targets and their documented clinical relevance, the first
International Consensus on ANA Patterns established a classification tree for ANA with alpha-numeric
anti-cell (AC) code for each pattern with a recommendation for a change in terminology from
antinuclear antibody to anticellular antibody.(2) These changes are relevant as in addition the nuclear
patterns, the classification includes cytoplasmic and mitotic patterns with descriptions for their
interpretation, associated antibody targets and clinical associations when available.(4) The diagnosis of
ANA-associated rheumatic diseases is usually based on a set of criteria of which the presence on
anticellular antibody or specific associated antibodies may be components. Of all ANA-associated
rheumatic diseases, the presence of anticellular antibody is considered mandatory entry criterion by the
2019 European League Against Rheumatism and the American College of Rheumatology classification
criteria for SLE.(7) Since cytoplasmic staining patterns may be reported as "ANA negative" or as a
comment with no quantitative or titer result, some patients with clinicopathological symptoms
consistent with neuropsychiatric SLE would not qualify for entry based on where testing is
performed.(8-10) This limitation may therefore exclude patients who may meet the clinical and other
laboratory criteria for disease but are not reported as "ANA positive" due to the use of the current
terminology. In an international inception cohort of newly diagnosed SLE patients, 6.2% were
anticellular antibody-negative with 1.5% testing positive for isolated cytoplasmic or mitotic pattern.(11)
Although the anticellular antibody is a sensitive test, it lacks diagnostic specificity.(1-4) Therefore,
positive results require confirmation with the use of specific ANA-associated antibody tests except for
the centromere pattern which is very characteristic for patients with limited diffuse SSc. Confirmation
of a positive anticellular antibody test result may be guided by HEp-2 IFA patterns and/or titer,
patientâ€™s clinical presentation or in some cases the patientâ€™s demographic.(12)
Useful For: Evaluation of patients suspected of having systemic autoimmune rheumatic disease
(ANA-associated rheumatic diseases or connective tissue disease) or organ-specific autoimmune diseases
such as autoimmune liver diseases
Interpretation: Presence of anticellular antibody (formerly antinuclear antibody) is a feature of

systemic autoimmune rheumatic diseases such as systemic lupus erythematosus, mixed connective tissue
disease, Sjogren syndrome and systemic sclerosis and some inflammatory myopathies (dermatomyositis,
anti-synthetase syndrome and necrotizing autoimmune myopathy). It may also be of diagnostic relevance
in patients with autoimmune liver diseases. Patientsâ€™ sera are screened at 1:80. The following nuclear
patterns and their titers are reported: centromere, homogeneous, nuclear dots, nucleolar, speckled, fine
dense speckled (also referred to as DFS70), and proliferating cell nuclear antigen (PCNA). If observed,
the following cytoplasmic patterns are reported: reticular/AMA (antimitochondrial antibody), cytoplasmic
speckled, fibrillar, polar/Golgi-like, or rods and rings. The spindle fiber and centrosome mitotic patterns
are also reported if observed. Reported patterns may help guide differential diagnosis, although they may
not be specific for individual antibodies or diseases. Negative results do not necessarily rule out systemic
autoimmune rheumatic disease. Anticellular antibody test lacks diagnostic specificity and is associated
with some cancers, infectious, and inflammatory conditions, with variable prevalence in healthy
individuals. The lack of diagnostic specificity requires confirmation of positive results using associated
antibody tests such as those targeting extractable nuclear antigens.
Reference Values:
<1:80 (Negative)
Clinical References: 1. Agmon-Levin N, Damoiseaux J, Kallenberg C, et al: International

recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear
antibodies. Ann Rheum Dis. 2014;73:17-23 2. Chan EK, Damoiseaux J, Gabriel Carballo O, et al: Report
of the First International Consensus on Standardized Nomenclature of Antinuclear Antibody HEp-2 Cell
Patterns 2014-2015. Front Immunol. 2015;6:412 3. Bossuyt X, De Langhe E, Borghi MO, Meroni PL:
Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases. Nat Rev
Rheumatol. 2020;16:715-726 4. International Consensus on ANA Patterns: Nomenclature and
Classification Tree. ICAP; 2021 Accessed August 13, 2021. Available at www.anapatterns.org/trees.php
5. European Association for the Study of the Liver: EASL Clinical Practice Guidelines: The diagnosis and
management of patients with primary biliary cholangitis. J Hepatol. 2017;67:145-172 6. Younossi ZM,
Bernstein D, Shiffman ML, et al: Diagnosis and management of primary biliary cholangitis. Am J
Gastroenterol. 2019;114:48-63 7. Aringer M, Costenbader K, Daikh D, et al: 2019 European League
Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus
erythematosus. Arthritis Rheumatol. 2019;71:1400-1412 8. Naides SJ, Genzen JR, Abel G, Bashleben C,
Ansari MQ: Antinuclear antibodies testing method variability: A survey of participants in the College of
American Pathologists' Proficiency Testing Program. J Rheumatol. 2020;47:1768-1773 9. Van Hoovels L,
Broeders S, Chan EKL, et al: Current laboratory and clinical practices in reporting and interpreting
anti-nuclear antibody indirect immunofluorescence (ANA IIF) patterns: results of an international survey.
Auto Immun Highlights. 2020;11:17 10. Tebo AE, Schmidt RL, Kadkhoda K, et al: The antinuclear
antibody HEp-2 indirect immunofluorescence assay: a survey of laboratory performance, pattern
recognition and interpretation. Auto Immun Highlights. 2021;12:14 11. Choi MY, Clarke AE, ST Pierre
Y, et al: Antinuclear antibody-negative systemic lupus erythematosus in an international inception cohort.
Arthritis Care Res. 2019;71:893-902 12. Nandjwada SL, Peterson LK, Mayes MD, et al: Ethnic
differences in autoantibody diversity and hierarchy: More clues from a US cohort of patients with
systemic sclerosis. J Rheumatol. 2016;43:1816-1824
ASO Antistrep-O Titer, Serum

80205 Clinical Information: A number of bacterial antigens have been identified in cultures of group A
streptococci. These extracellular products are primarily enzymatic proteins and include streptolysin O,
streptokinase, hyaluronidase, deoxyribonucleases (DNases A, B, C, and D), and nicotinamide adenine
nucleotidase. Infections by the group A streptococci are unique because they can be followed by serious
nonpurulent complications of rheumatic fever and glomerulonephritis. Recent information suggests that
rheumatic fever is associated with infection by certain rheumatogenic serotypes (M1, M3, M5, M6, M18,
and M19), while glomerulonephritis follows infection by nephritogenic serotypes (M2, M12, M49, M57,
M59, and M60). Glomerulonephritis and rheumatic fever occur following the infection, after a period of
latency following the infection, during which the patient is asymptomatic. The latency period for
glomerulonephritis is approximately 10 days, and the latency period for rheumatic fever is 20 days.
Useful For: Demonstration of acute or recent streptococcal infection

Interpretation: Elevated values are consistent with an antecedent infection by group A streptococci.
Reference Values:
<5 years: < or =70 IU/mL
5-17 years: < or =640 IU/mL
> or =18 years: < or =530 IU/mL
Clinical References: 1. Ayoub EM, Harden E: Immune response to streptococcal antigens:

diagnostic methods. In: Rose NR, de Marco EC, Folds JD, et al, eds. Manual of Clinical and Laboratory
Immunology. 5th ed. ASM Press; 1997 2. Antistreptolysin O (ASO). Testing.com; Updated July 24,
2020. Accessed February 11, 2022. Available at www.testing.com/tests/antistreptolysin-o-aso/
ATTF Antithrombin Activity, Plasma

9030 Clinical Information: Antithrombin is a member of the serine protease inhibitor (serpin)
superfamily. It is the principal plasma anticoagulant serpin mediating inactivation of serine protease
procoagulant enzymes, chiefly thrombin and coagulation factors Xa and IXa.(1) Heparin and certain
other naturally occurring glycosaminoglycans markedly enhance the anticoagulant activity of
antithrombins (approximately 1000-fold) by providing a template to catalyze formation of covalently
bonded, inactive complexes of serine protease and antithrombin that are subsequently cleared from
circulation. Antithrombin is the mediator of anticoagulant activity of heparin. The antithrombin gene on
chromosome 1 encodes a glycoprotein with a molecular weight of approximately 58,000 Da that is
synthesized in the liver and is present in a relatively high plasma concentration (approximately 2.3
mcmol/L). The biological half-life of antithrombin is 2 to 3 days. Hereditary antithrombin deficiency, a
relatively rare autosomal dominant disorder, produces a thrombotic diathesis (thrombophilia).
Individuals with hereditary antithrombin deficiency are usually heterozygous with plasma antithrombin
activity results of approximately 40% to 70%. These patients primarily manifest with venous
thromboembolism (deep vein thrombosisÂ and pulmonary embolism ) with the potential of
development as early as adolescence or younger adulthood. More than 100 different genetic alterations
have been identified throughout the gene producing either the more common type I defects (low
antithrombin activity and antigen) or the rarer type II defects (dysfunctional protein with low activity
and normal antigen).(2) Homozygous antithrombin deficiency appears to be incompatible with life. The
incidence of hereditary antithrombin deficiency is approximately 1:2000 to 1:3000 in general
populations, although minor deficiency (antithrombin activity =70%-75%) may be more frequent
(approximately 1:350-650). In populations with venous thrombophilia, approximately 1% to 2% of
individuals have antithrombin deficiency. Among the recognized hereditary thrombophilic disorders
(including deficiencies of proteins C and S, as well as activated protein C -resistance [factor V Leiden
variant]), antithrombin deficiency may have the highest phenotypic penetrance (greater risk of venous
thromboembolism). Arterial thrombosis (eg, stroke, myocardial infarction) has occasionally been
reported in association with hereditary antithrombin deficiency. Hereditary deficiency of antithrombin
activity can also occur because of defective glycosylation of this protein in individuals with
carbohydrate-deficient glycoprotein syndromes (CDGS).(3) Antithrombin activity assessment may be
useful as an adjunct in the diagnosis and management of CDGS. Acquired deficiency of antithrombin is
much more common than hereditary deficiency. Acquired deficiency can occur due to: -Heparin therapy
(catalysis of antithrombin consumption) -Intravascular coagulation and fibrinolysis , disseminated
intravascular coagulation , or other consumptive coagulopathies -Liver disease (decreased synthesis
and/or increased consumption) or with nephritic syndrome (urinary protein loss) -L-asparaginase
chemotherapy (decreased synthesis) -Other conditions(1) In general, the clinical implications
(thrombotic risk) of antithrombin deficiency in these disorders are not well defined, although
antithrombin replacement in severe disseminated intravascular coagulation/intravascular coagulation
and fibrinolysisÂ is being evaluated.(4) Assay of antithrombin activity may be of diagnostic or
prognostic value in some acquired deficiency states.
Useful For: Diagnosis of antithrombin deficiency, acquired or congenital Monitoring treatment of

antithrombin deficiency disorders, including infusion of antithrombin therapeutic concentrate
Interpretation: Antithrombin deficiencies due to inherited causes are much less common than those
due to acquired causes (see Clinical Information). Diagnosis of hereditary deficiency requires clinical
correlation, with the prospect of repeat testing (including antithrombin antigen assay), and family studies
(with appropriate counseling). DNA-based diagnostic testing may be helpful, see ATNGS / Antithrombin
Deficiency, SERPINC1 Gene, Next-Generation Sequencing, Varies. The clinical significance (thrombotic
risk) of acquired antithrombin deficiency is not well established, but accumulating information suggests
possible benefit of antithrombin replacement therapy in carefully selected situations.(4) Antithrombin
deficiency, acquired or congenital, may contribute to the phenomenon of "heparin therapy resistance"
(requirement of larger heparin doses than expected for achievement of therapeutic anticoagulation
responses). However, it may more often have other pathophysiology, such as "acute-phase" elevation of
coagulation factor VIII or plasma heparin-binding proteins. Increased antithrombin activity is of unknown
hemostatic significance. Direct factor Xa inhibitors, rivaroxaban (Xarelto), apixaban (Eliquis), and
edoxaban (Savaysa) may falsely elevate the antithrombin activity and mask a diagnosis of antithrombin
deficiency.
Reference Values:
Normal values: 80-130%
Normal, full-term newborn infants have lower levels (> or =35-40%) that reach normal values by age 90
days. Premature infants (30-36 weeks gestation) have lower levels that reach normal values by age 180
days.
Clinical References: 1. Lane DA, Olds RJ, Thein SL: Antithrombin and its deficiency. In: Bloom
AL, Forbes CD, Thomas DP, eds. Haemostasis and Thrombosis. 3rd ed. Churchill Livingstone;
1994:655-670 2. Lane DA, Bayston T, Olds RJ, et al: Antithrombin mutation database: For the Plasma
Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International
Society on Thrombosis and Haesmostasis. Thromb Haemost. 1997 Jan;77(1):197-211 3. Young G,
Dricsoll MC: Coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome: case report
and review of the literature. Am J Hematol. 1999 Jan;60(1):66-69. doi:
10.1002/(sici)1096-8652(199901)60:1<66:aid-ajh11>3.0.co;2-d 4. Mammen EF: Antithrombin: its
physiological importance and role in DIC. Semin Thromb Haemost. 1998;24:19-25. doi:
10.1055/s-2007-995819 5. Yohe S, Olson J: Thrombophilia: Assays and Interpretation. In:
Kottke-Marchant Wiley K, ed. Laboratory Hematology Practice. Blackwell Publishing; 2012:492-508
ATTI Antithrombin Antigen, Plasma

9031 Clinical Information: Antithrombin is a member of the serine protease inhibitor (serpin) superfamily.
It is the principal plasma anticoagulant serpin mediating inactivation of serine protease procoagulant
enzymes, chiefly thrombin and coagulation factors Xa and IXa.(1) Heparin and certain other naturally
occurring glycosaminoglycans markedly enhance antithrombin's anticoagulant activity (approximately
1000-fold) by providing a template to catalyze formation of covalently bonded, inactive complexes of
serine protease and antithrombin that are subsequently cleared from circulation. Antithrombin is the
mediator of heparin's anticoagulant activity. The antithrombin gene on chromosome 1 encodes a
glycoprotein of approximately 58,000 molecular weight that is synthesized in the liver and is present in a
relatively high plasma concentration (approximately 2.3 mcmol/L). The biological half-life of
antithrombin is 2 to 3 days. Hereditary antithrombin deficiency, a relatively rare, autosomal dominant
disorder, produces a thrombotic diathesis (thrombophilia). Individuals with hereditary antithrombin
deficiency are usually heterozygous with plasma antithrombin activity results of approximately 40% to
70%. These patients primarily manifest with venous thromboembolism (deep vein thrombosis and
pulmonary embolism), with the potential of development as early as adolescence or younger adulthood.
More than 100 different variants have been identified throughout the gene, producing either the more
common type I defects (low antithrombin activity and antigen) or the rarer type II defects (dysfunctional
protein with low activity and normal antigen).(2) Homozygous antithrombin deficiency appears to be
incompatible with life. The incidence of hereditary antithrombin deficiency is approximately 1:2000 to
1:3000 in general populations, although minor deficiency (antithrombin activity =70% to 75%) may be
more frequent (approximately 1:350 to 1:650). In populations with venous thrombophilia, approximately
1% to 2% have antithrombin deficiency. Among the recognized hereditary thrombophilic disorders
(including deficiencies of proteins C and S, as well as activated protein C-resistance [factor V Leiden
variant]), antithrombin deficiency may have the highest phenotypic penetrance (greater risk of venous
thromboembolism). Arterial thrombosis (eg, stroke, myocardial infarction) has occasionally been reported
in association with hereditary antithrombin deficiency. Hereditary deficiency of antithrombin activity can
also occur because of defective glycosylation of this protein in individuals with carbohydrate-deficient
glycoprotein syndromes (CDGS).(3) Antithrombin activity assessment may be useful as an adjunct in the
diagnosis and management of CDGS. Acquired deficiency of antithrombin is much more common than
hereditary deficiency. Acquired deficiency can occur due to: -Heparin therapy (catalysis of antithrombin
consumption) -Intravascular coagulation and fibrinolysis (ICF) or disseminated intravascular coagulation
(DIC), and other consumptive coagulopathies -Liver disease (decreased synthesis and/or increased
consumption) -Nephrotic syndrome (urinary protein loss) -L-asparaginase chemotherapy (decreased
synthesis) -Other conditions(1) In general, the clinical implications (thrombotic risk) of antithrombin
deficiency in these disorders are not well defined, although antithrombin replacement in severe DIC/IFC
is being evaluated.(4) Assay of antithrombin activity may be of diagnostic or prognostic value in some
acquired deficiency states.
Useful For: Assessing abnormal results of the antithrombin activity assay (ATTF / Antithrombin
Activity, Plasma), which is recommended as the primary (screening) antithrombin assay Diagnosing
antithrombin deficiency, acquired or congenital, in conjunction with measurement of antithrombin
activity An adjunct in the diagnosis and management of carbohydrate-deficient glycoprotein syndromes
Interpretation: Hereditary antithrombin deficiency is much less common than acquired deficiency.
Diagnosis of hereditary deficiency requires clinical correlation, testing of both antithrombin activity and
antithrombin antigen, and may be aided by repeated testing and by family studies. DNA-based
diagnostic testing may be helpful, but is generally not readily available. Acquired antithrombin
deficiency may occur in association with a number of conditions (see Clinical Information). The clinical
significance (thrombotic risk) of acquired antithrombin deficiency is not well established, but
accumulating information suggests possible benefit of antithrombin replacement therapy in carefully
selected situations.(4) Increased antithrombin activity has no definite clinical significance.
Reference Values:
Adults: 80-120%
Normal, full-term newborn infants may have decreased levels (> or =35-40%), which reach adult
levels by 180 days postnatal.*
Healthy, premature infants (30-36 weeks gestation) may have decreased levels, which reach adult
levels by 180 days postnatal.*
Processing.
Clinical References: 1. Bock SC: Antithrombin III and heparin cofactor II. In: Colman RW, Hirsh
J, Marder VJ, et al, eds. Hemostasis and Thrombosis. 4th ed. Lippencott Williams and Wilkins;
2001:321-333 2. Viazzer H: Hereditary and acquired antithrombin deficiency. Semin Thromb Hemost.
1999;25(3):257-263 3. Conrad J: Antithrombin activity and antigen. In: Laboratory Techniques in
Thrombosis-A Manual. 2nd ed. Kluwer Academic Publishers; 1999:121-128 4. Lane DA, Bayston T,
Olds RJ, et al: Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation
Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society
on Thrombosis and Haemostasis. Thromb Haemost. 1997 Jan;77(1):197-211 5. Van Cott EM, Orlando
C, Moore GW, et al: Recommendations for clinical laboratory testing for antithrombin deficiency;
Communication from the SSC of the ISTH. J Thromb Haemost. 2020 Jan;18(1):17-22
ATNGS Antithrombin Deficiency, SERPINC1 Gene, Next-Generation

606366 Sequencing, Varies
Clinical Information: Antithrombin (AT) deficiency is a rare hereditary thrombophilia that puts
patients at a significantly increased risk of venous thromboembolism. In selected cases, patients manifest
heparin resistance. Individuals with AT deficiency are at increased risk for venous thromboembolism
(VTE) and late (2nd or 3rd trimester) pregnancy loss.(1,2) It has been estimated that individuals with
inherited AT deficiency have a 16-fold increase in risk of VTE compared to individuals without AT
deficiency.(4) Women with AT deficiency are at particularly high risk for developing clots during
pregnancy and after delivery.(5) Hereditary AT deficiency is uncommon, with prevalence in the general
population of 1 in 2000 to 5000.(1, 2) Hereditary AT deficiency is inherited in an autosomal dominant
manner with variable penetrance. Both men and women may be affected. AT deficiency is a result of
defects in the concentration or function of AT, a natural anticoagulant in blood plasma. AT is the major
inhibitor of blood coagulation by inactivating thrombin and factor Xa. The SERPINC1 gene encodes for
antithrombin. Genetic testing of SERPINC1 is indicated if plasma AT activity assay is abnormally low
(ie, typically less than 80% of normal or lower than the reference range established in the local
laboratory). AT activity testing should not be performed during acute thrombosis or illness as these could
cause a temporary reduction in AT levels. Likewise, it should not be performed while the patient is taking
an anticoagulant such as heparin (which may falsely lower levels) or an oral direct factor Xa inhibitor (eg,
rivaroxaban, apixaban or edoxaban), which may falsely elevate AT levels. Additionally, causes of
acquired (non-genetic) AT deficiency are much more common than inherited AT deficiency and should
be excluded prior to genetic testing. These causes of acquired AT deficiency include liver disease, acute
thrombosis, heparin therapy, nephrotic syndrome, disseminated intravascular coagulation, and effects of
chemotherapeutic agents such an L-asparaginase. These and other acquired causes of AT deficiency
should be excluded prior to genetic testing.
Useful For: Ascertaining a causative alteration in SERPINC1 and the affected region of antithrombin
(AT) protein in an individual clinically diagnosed with antithrombin deficiency Genetic confirmation of a
clinical AT deficiency diagnosis, particularly in patients with borderline low AT activity levels Prognosis
and risk assessment based on the genotype-phenotype correlations Ascertaining alteration status of family
members related to an individual with a confirmed SERPINC1 alteration for the purposes of informing
clinical management and genetic counseling Evaluating individuals with apparent heparin resistance This
test is not intended for prenatal diagnosis
Interpretation: An interpretive report will be provided. Evaluation and categorization of variants is

performed using the most recent published American College of Medical Genetics and Genomics
(ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible
Consultations with the Mayo Clinic Special Coagulation Clinic, Molecular Hematopathology Laboratory,
and Thrombophilia Center are available for DNA diagnosis cases. This may be especially helpful in
complex cases or in situations where the diagnosis is atypical or uncertain.
Reference Values:
Clinical References: 1. Patnaik MM, Moll S: Inherited Antithrombin deficiency: a review.

Haemophilia 2008;14(6):1229-1239 2. Blajchamn MA, Austin RC, Fernandez-Rachubinski F, et al:
Blood 1992;80(9):2159-2171 3. Patnaik MM, Guenther J, Pruthi RK, et al: The Potential Role of
Molecular Analysis in Hereditary Antithrombin (AT) Deficiency Diagnosis and Management. Blood
2009;114:2976 (Abstract) 4. Di Minno MN, Ambrosino P, Ageno W, et al: Natural anticoagulants
deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb
Haemost 2015;135(5):923-932 5. Rogenhofer N, Bohlmann MK, Beuter-Winkler P, et al: Prevention,
management and extent of adverse pregnancy outcomes in women with hereditary antithrombin
deficiency. Ann Hematol 2014;93(3):385-392 6. Luxembourg B, Delev D, Geisen C, et al: Molecular
basis of antithrombin deficiency. Thromb Haemost 2011;105(4):635-646
APIXA Apixaban, Anti-Xa, Plasma

65848 Clinical Information: Apixaban, an oral anticoagulant that directly inhibits factor Xa, has been
approved by the FDA for prophylaxis of thrombosis in atrial fibrillation and surgical patients and
treatment of venous thromboembolism (VTE). Unlike warfarin, it does not require routine therapeutic
monitoring. However, in selected clinical situations, measurement of drug level would be useful (eg,
kidney insufficiency, assessment of compliance, periprocedural measurement of drug concentration,
suspected overdose, advanced age, and extremes of body weight). Predicted Apixaban Steady-State
Exposure Concentrations(1) Dosage Apixaban C-min (ng/mL) trough plasma concentration (predose)
Apixaban C-max (ng/mL) peak plasma concentration (2-4 hours postdose) Prevention of VTE: elective
hip or knee replacement surgery 2.5 mg twice daily 51 (23-109) 77 (41-146) Prevention of stroke and
systemic embolism: NVAF 2.5 mg twice daily 79 (34-162) 123 (69-221) 5 mg twice daily 103 (41-230)
171 (91-321) Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE) 2.5 mg
twice daily 32 (11-90) 67 (30-153) 5 mg twice daily 63 (22-177) 132 (59-302) 10 mg twice daily 120
(41-335) 251 (111-572) Median (5th-95th percentile) VTE-venous thromboembolism, NVAF-
nonvalvular atrial fibrillation, DVT-deep vein thrombosis, PE-pulmonary embolism
Useful For: Measuring apixaban concentration in selected clinical situations (eg, renal insufficiency,
assessment of compliance, periprocedural measurement of drug concentration, suspected overdose,
advanced age, and extremes of body weight)
Interpretation: The lower limit of detection of this assay is 10 ng/mL. Therapeutic reference ranges
have not been established. See Clinical Information for peak and trough drug concentrations observed
from clinical trials.
Reference Values:
<10 ng/mL
Clinical References: 1. Eliquis (apixaban). Package insert. Bristol-Meyers Squibb Company;

Revised 11/2019 2. Hurst KV, O'Callaghan JM, Handa A: Quick reference guide to apixaban. Vasc
Health Risk Manag. 2017;13:263-267 3. Granger CB, Alexander JH, McMurray JJ, et al: Apixaban
versus warfarin in patient with atrial fibrillation. N Engl J Med. 2011 Sep;365(11):981-992 4. Frost C,
Nepal S, Wang J, et al: Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of
apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmocol. 2013 Nov;76:(5):776-786 5.
Agnelli G, Buller HR, Cohen A, et al: Oral apixaban for the treatment of acute venous
thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808 6. Siegal DM, Curnutte JT, Connolly
SJ, et al: Andexanet alfa for reversal of factor Xa inhibitor activity. N Engl J Med. 2015 Dec
17;373:2413-2424 7. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S:
Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb
Haemost. 2016 Jun;14(6):1308-1313
FAPIX Apixaban, Plasma

75395 Interpretation: In a study of 1691 patients taking apixaban, doses ranging from 2.5 mg twice a day
to 20 mg once a day, apixaban plasma concentrations ranged from 1 to 933 ng/mL, with a median value
of 105 ng/mL.
Reference Values:
Mean peak plasma concentrations of apixaban following a single oral administration of 5, 10, 25, or 50
mg oral tablets are as follows:
5 mg: 104.7 ng/mL (range, 79.7 to 129.7)

10 mg: 176.3 ng/mL (range, 134.3 to 218.3)
25 mg: 365.1 ng/mL (range, 348.1 to 382.1)
50 mg: 685.2 ng/mL (range, 663.2 to 707.2)
APOL1 APOL1 Genotype, Varies

605251 Clinical Information: The APOL1 gene encodes apolipoprotein L-1, a serum apolipoprotein bound
to high-density lipoprotein (HDL) particles. Two alleles, commonly called G1 and G2, have been
associated with increased risk for development or progression of nondiabetic chronic kidney diseases,
including HIV-associated nephropathy (HIVAN), primary focal segmental glomerulosclerosis (FSGS),
and lupus-associated collapsing glomerulopathy.(1-4) The G1 allele is a haplotype consisting of 2
missense variants: c.1024A>G (p.Ser342Gly) and c.1152T>G (p.Ile384Met). The G2 allele is
comprised of a 6 base pair deletion that results in the deletion of 2 amino acids:
c.1164_1169delTTATAA (p.Asn388_Tyr389del). The G1 and G2 alleles are thought to be in complete
linkage disequilibrium, meaning when both the G1 and G2 alleles are detected, they are on opposite
chromosomes.(1) Risk for chronic kidney disease is only increased when 2 risk alleles are inherited (ie,
genotypes G1/G1, G2/G2, or G1/G2), following an autosomal recessive pattern of inheritance.(1)
Individuals with one risk allele or no risk alleles do not appear to be at an increased risk. The G1 and G2
risk alleles are enriched in individuals of African ancestry. Population studies show that in individuals
of African descent, the G1 allele is found on 20% to 22.5% of chromosomes, and the G2 allele is found
on 13% to 15% of chromosomes.(5-6) More importantly, it is estimated that 10% to15% of individuals
of African descent carry 2 risk alleles.(5-6) The high frequency of the G1 and G2 alleles in this
population is likely due to the protective effect these alleles confer against Trypanosoma rhodesiense, a
parasite that causes trypanosomiasis, a disease endemic to Africa.(1) The G1 and G2 alleles are
extremely rare or absent in individuals not of recent African descent (eg, European and Asian
descent).(1,5) For this reason, increased risk associated with the G1 and G2 alleles has only been
stratified in populations of recent African ancestry, and it remains unclear if similar risk effects
associated with the APOL1 risk genotypes are applicable to individuals without African ancestry.
Currently, there are no guidelines for clinical management of individuals with APOL1 risk genotypes.
Evidence exists that the donor APOL1 genotype may impact both donor and recipient outcomes of
kidney allografts. Results from 2 studies have shown that donor kidneys from individuals with 2 risk
alleles were more likely to fail after transplantation when compared to donor kidneys from individuals
with one or no risk alleles.(7-8) Another study suggests that living donors with two risk alleles may be
at an increased risk for reduced kidney function following kidney donation.(9) At this time, there has
been no association between the genotype of the allograft recipient and transplant outcomes, suggesting
that allograft recipients with two risk alleles have similar outcomes to recipients with one or no risk
alleles.(10) However, a prospective, large scale study to assess kidney allograft survival from donors
with recent African ancestry based on donor and recipient APOL1 genotypes is currently ongoing.(11)
Based on presently available data, guidelines advise that an individualâ€™s APOL1 genotype alone
should not determine eligibility for donation or receipt of kidney allografts.(12)Â
Useful For: Determining an individualâ€™s APOL1 genotype This test is not useful for clinical
management of individuals with APOL1 risk genotypes. This test alone is not useful for determining
eligibility for donation or receipt of kidney allografts.(12)

Reference Values:
Clinical References: 1. Genovese G, Friedman DJ, Ross MD, et al: Association of trypanolytic
ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841-845. doi:
10.1126/science.1193032 2. Parsa A, Kao WH, Xie D, et al: APOL1 risk variants, race, and progression
of chronic kidney disease. N Engl J Med. 2013;369(23):2183-2196. doi: 10.1056/NEJMoa1310345 3.
Kopp JB, Nelson GW, Sampath K, et al: APOL1 genetic variants in focal segmental glomerulosclerosis
and HIV-associated nephropathy. J Am Soc Nephrol. 2011;22(11):2129-2137. doi:
10.1681/ASN.2011040388 4. Larsen CP, Beggs ML, Saeed M, Walker PD: Apolipoprotein L1 risk
variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc
Nephrol. 2013;24(5):722-725. doi: 10.1681/ASN.2012121180 5. Friedman DJ, Kozlitina J, Genovese G,
Jog P, Pollak MR: Population-based risk assessment of APOL1 on renal disease. J Am Soc Nephrol.
2011;22(11):2098-2105. doi: 10.1681/ASN.2011050519 6. Duran CE, RamÃrez A, Posada JG, et al:
Prevalence of APOL1 risk variants in afro-descendant patients with chronic kidney disease in a Latin
American Country. Int J Nephrol. 2019 Dec 18;2019:7076326 doi: 10.1155/2019/7076326 7.
Reeves-Daniel AM, DePalma JA, Bleyer AJ, et al: The APOL1 gene and allograft survival after kidney
transplantation. Am J Transplant. 2011;11(5):1025-1030. doi: 10.1111/j.1600-6143.2011.03513.x 8.
Freedman BI, Julian BA, Pastan SO, et al: Apolipoprotein L1 gene variants in deceased organ donors are
associated with renal allograft failure. Am J Transplant. 2015;15(6):1615-1622. doi: 10.1111/ajt.13223 9.
Doshi MD, Ortigosa-Goggins M, Garg AX, et al: APOL1 genotype and renal function of black living
donors. J Am Soc Nephrol. 2018;29(4):1309-1316. doi: 10.1681/ASN.2017060658 10. Lee BT, Kumar V,
Williams TA, et al: The APOL1 genotype of African American kidney transplant recipients does not
impact 5-year allograft survival. Am J Transplant. 2012;12(7):1924-1928. doi:
10.1111/j.1600-6143.2012.04033.x 11. Freedman BI, Moxey-Mims MM, Alexander AA, et al: APOL1
long-term kidney transplantation outcomes network (APOLLO): Design and rationale. Kidney Int Rep.
2019;5(3):278-288. doi: 10.1016/j.ekir.2019.11.022 12. Newell KA, Formica RN, Gill JS, et al:
Integrating APOL1 gene variants into renal transplantation: Considerations arising from the American
Society of Transplantation Expert Conference. Am J Transplant. 2017;17(4):901-911. doi:
10.1111/ajt.14173
APO1Z Apolipoprotein A-I (APOA1) Gene, Full Gene Analysis, Varies

35355 Clinical Information: The systemic amyloidoses are a number of disorders of varying etiology
characterized by extracellular protein deposition. The most common form is an acquired amyloidosis
secondary to multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) in which
the amyloid is composed of immunoglobulin light chains. In addition to light chain amyloidosis, there
are a number of acquired amyloidoses caused by the misfolding and precipitation of a wide variety of
proteins. There are also hereditary forms of amyloidosis. The hereditary amyloidoses comprise a group
of autosomal dominant, late-onset diseases that show variable penetrance. A number of genes have been
associated with hereditary forms of amyloidosis including those that encode transthyretin,
apolipoprotein A-I, apolipoprotein A-II, fibrinogen alpha chain, gelsolin, cystatin C, and lysozyme.
Apolipoprotein A-I, apolipoprotein A-II, lysozyme, and fibrinogen alpha-chain amyloidosis present as
non-neuropathic systemic amyloidosis, with renal dysfunction being the most prevalent manifestation.
Apolipoprotein A-I amyloidosis is also associated with additional organ system involvement, including
clinical manifestations in the liver, heart, skin, and larynx. In addition, the G26R APOA1 mutation has
been associated with a neuropathic presentation. To date, at least 16 amyloidogenic mutations have been
identified within the APOA1 gene. The majority of these are missense mutations, although
deletion/insertion mutations have also been described. There is some evidence of genotype-phenotype
correlations. Mutations that occur near the amino terminal portion of the protein are more often
associated with hepatic and renal amyloidosis, while mutations occurring near the carboxyl terminal
portion of the gene are more often associated with cardiac, cutaneous, and laryngeal amyloidosis. The
majority of mutations reported to date occur at 1 of 2 hot spots spanning amino acid residues 50 through
93 and 170 through 178. Mutations in the APOA1 gene have also been linked to familial
hypoalphalipoproteinemia. Patients carrying 1 APOA1 mutation typically demonstrate reduced levels of
high-density lipoprotein (HDL) cholesterol, which is associated with increased risk for coronary artery
disease. Comparatively, the presence of 2 APOA1 mutations generally results in complete absence of
HDL cholesterol and may include additional clinical features such as xanthomas or corneal opacities.
Due to the clinical overlap between the acquired and hereditary forms, it is imperative to determine the
specific type of amyloidosis in order to provide an accurate prognosis and consider appropriate
therapeutic interventions. Tissue-based, laser capture tandem mass spectrometry might serve as a useful
test preceding gene sequencing to better characterize the etiology of the amyloidosis, particularly in
cases that are not clear clinically.
Useful For: Diagnosis of individuals suspected of having apolipoprotein A-I (APOA1)

gene-associated familial amyloidosis
Reference Values:
May;17(5):405-424 2. Eriksson M, Schonland S, Yumlu S, et al: Hereditary apolipoprotein
AI-associated amyloidosis in surgical pathology specimens: identification of three novel mutations in
the APOA1 gene. J Mol Diagn 2009;11(3):257-262 3. Benson MD: Ostertage revisited: The inherited
systemic amyloidoses without neuropathy. Amyloid 2005:12(2):75-80 4. von Eckardstein A:
Differential diagnosis of familial high density lipoprotein deficiency syndromes. Atherosclerosis
2006;186:231-239 5. Shiller SM, Dogan A, Highsmith WE: Laboratory methods for the diagnosis of
hereditary amyloidoses. In Amyloidosis-Mechanisms and Prospects for Therapy. Edited by S
Sarantseva. InTech 2011, pp 101-120
APO2Z Apolipoprotein A-II (APOA2) Gene, Full Gene Analysis, Varies

35357 Clinical Information: The systemic amyloidoses are a number of disorders of varying etiology
characterized by extracellular protein deposition. The most common form is an acquired amyloidosis
secondary to multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) in which
the amyloid is composed of immunoglobulin light chains. In addition to light chain amyloidosis, there are
a number of acquired amyloidoses caused by the misfolding and precipitation of a wide variety of
proteins. There are also hereditary forms of amyloidosis. The hereditary amyloidoses comprise a group of
autosomal dominant, late-onset diseases that show variable penetrance. A number of genes have been
associated with hereditary forms of amyloidosis, including those that encode transthyretin, apolipoprotein
A-I, apolipoprotein A-II, fibrinogen alpha chain, gelsolin, cystatin C, and lysozyme. Apolipoprotein A-I,
apolipoprotein A-II, lysozyme, and fibrinogen alpha chain amyloidosis present as non-neuropathic
systemic amyloidosis, with renal dysfunction being the most prevalent manifestation. Apolipoprotein A-II
amyloidosis typically presents as a very slowly progressive disease. Age of onset is highly variable,
ranging from adolescence to the fifth decade. To date, all mutations that have been identified within the
APOA2 gene occur within the stop codon and result in a 21-residue C-terminal extension of the
apolipoprotein A-II protein. Due to the clinical overlap between the acquired and hereditary forms, it is
imperative to determine the specific type of amyloidosis in order to provide an accurate prognosis and
consider appropriate therapeutic interventions. Tissue-based, laser capture tandem mass spectrometry
might serve as a useful test preceding gene sequencing to better characterize the etiology of the
amyloidosis, particularly in cases that are not clear clinically.
Useful For: Diagnosis of individuals suspected of having apolipoprotein A-II-associated familial

amyloidosis
Reference Values:
May;17(5):405-424 2. Benson MD. Ostertage revisited: The inherited systemic amyloidoses without
neuropathy. Amyloid 2005;12(2):75-80 3. Benson MD, Liepnieks JJ, Yazaki M, et al: A new human
hereditary amyloidosis: The result of a stop-codon mutation in the Apolipoprotein AII gene. Genomics
2001;72:272-277 4. Yazaki M, Liepnieks JJ, Yamashita T, et al: Renal amyloidosis caused by a novel
stop-codon mutation in the apolipoprotein A-II gene. Kidney Int 2001;60:1658-1665 5. Yazaki M,
Liepnieks JJ, Barats MS, et al: Hereditary systemic amyloidosis associated with a new apolipoprotein AII
stop-codon mutation Stop78Arg. Kidney Int 2003;64:11-16
APOAB Apolipoprotein A1 and B, Serum

607593 Clinical Information: Apolipoprotein B (ApoB) is the primary protein component of low-density
lipoprotein (LDL). Apolipoprotein A1 (ApoA1) is the primary protein component of high-density
lipoprotein (HDL). Elevated ApoB and decreased ApoA1 are associated with increased risk of
cardiovascular disease. Multiple studies have reported that ApoB and ApoA1 are more strongly associated
with cardiovascular disease than the corresponding lipoprotein cholesterol fraction (see APOA1 /
Apolipoprotein A1, Serum and APOLB / Apolipoprotein B, Serum). ApoB is present in all atherogenic
lipoproteins including LDL, Lp(a), intermediate-density lipoprotein (IDL), and very low-density
lipoprotein (VLDL) remnants. ApoA1 is the nucleating protein around which HDL forms during reverse
cholesterol transport. The ApoB:ApoA1 ratio represents the balance between atherogenic and
antiatherogenic lipoproteins. Several large prospective studies have shown that the ApoB:ApoA1 ratio
performs as well, and often better, than traditional lipids as an indicator of risk.(1-3)
Useful For: Assessment of cardiovascular risk Follow-up studies in individuals with basic lipid
measures inconsistent with risk factors or clinical presentation Definitive studies of cardiac risk factors
in individuals with significant family histories of coronary artery disease or other increased risk factors
Interpretation: Elevated apolipoprotein B (ApoB) confers increased risk of atherosclerotic

cardiovascular disease, even in a context of acceptable LDL cholesterol concentrations. Extremely low
values of ApoB (<48 mg/dL) are related to malabsorption of food lipids and can lead to polyneuropathy.
Reduced apolipoprotein A1 (ApoA1) confers an increased risk of coronary artery disease. Extremely
low ApoA1 (<20 mg/dL) is suggestive of liver disease or a genetic disorder. Elevated ApoB:ApoA1
ratio confers increased risk of atherosclerotic cardiovascular disease, independently of LDL and HDL
cholesterol concentrations.
Reference Values:
Age Apolipoprotein A (mg/dL) Apolipoprotein B (mg/dL) Apolipoprotein B/A1 ratio
Not established Not established Not established
2-17 years Low: low: 115-120 Acceptable:Acceptable: high: 90-109 High:

>120 > or =110
>18 years > or =120 Desirable: Desirable: 90-99 Lower Risk: Risk: 0.7-0.9
Borderline high: 100-119 Higher Risk: >0.9 Females
High: 120-139 Very high: > or
=140
Age Apolipoprotein A (mg/dL) Apolipoprotein B (mg/dL) Apolipoprotein B/A1 ratio
Not established Not established Not established
2-17 years Low: low: 115-120 Acceptable:Acceptable: high: 90-109 High:

>120 > or =110
>18 years > or =140 Desirable: Desirable: 90-99 Lower Risk: Risk: 0.6-0.8
Borderline high: 100-119 Higher Risk: >0.8
High: 120-139 Very high: > or
=140
Clinical References: 1. Reiner Z, Catapano AL, De Backer G, et al: ESC/EAS Guidelines for the
management of dyslipidaemias: The task force for the management of dyslipidaemias of the European
Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J
2011;32(14):1769-1818 2. McQueen MJ, Hawken S, Wang X, et al: Lipids, lipoproteins, and
apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a
case-control study. Lancet 2008;372:224-233 3. Thompson A, Danesh J: Associations between
apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary heart disease: a
literature-based meta-analysis of prospective studies. J Intern Med 2006;259:481-492 4. Jacobson TA,
Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management
of dyslipidemia: Part 1-executive summary. J Clin Lipidol 2014 Sep-Oct;8(5):473-488 5. Expert panel
on integrated guidelines for cardiovascular health and risk reduction in children and adolescents:
summary report. Pediatrics 2011 Dec;128 Suppl 5:S213-S256
APOA1
607591as of July 20, 2022 12:05 pm CDT
Apolipoprotein A1, Serum
Clinical Information: Apolipoprotein A1 (ApoA1) is the primary protein associated with
high-density lipoprotein (HDL) particles, and plays a central role in reverse cholesterol transport.(1) HDL
cholesterol (HDL-C) and ApoA1 concentrations are inversely related to the risk for coronary artery
disease (CAD).(2) There are a variable number of ApoA1 proteins per HDL particle. Therefore, ApoA1 is
not a 1:1 surrogate marker for HDL particles. Similarly, the number of ApoA1 proteins and the amount of
cholesterol contained in HDL particles is highly variable. This heterogeneity has led to unique clinical
findings related to ApoA1 compared with HDL-C. Increased ApoA1 concentrations are more strongly
associated with a reduction in risk of a first myocardial infarction than HDL-C concentrations.(3) Low
concentrations of ApoA1, but not HDL-C, are predictive of preclinical atherosclerosis as assed by
computed tomography estimated coronary artery calcium (CAC) scoring.(4) Increased ApoA1, but not
HDL-C concentrations, are associated with reduced cardiovascular events among statin-treated patients,
even when LDL-C <50 mg/dL.(5) In statin-treated patients, patients whose ApoA1 increased while on
treatment were at lower risk than those whose ApoA1 did not increase.
Useful For: Evaluating risk for atherosclerotic cardiovascular disease Aiding in the detection of
Tangier disease
Interpretation: Low levels of apolipoprotein A1 (ApoA1) confer increased risk of atherosclerotic

cardiovascular disease. ApoA1 below 25 mg/dL may aid in the detection of a genetic disorder such as
Tangier disease. ApoA1 is often interpreted as a ratio with apolipoprotein B (ApoB).
Reference Values:
Age Apolipoprotein A (mg/dL)
Not established
2-17 years Low: low: 115-120 Acceptable: >120
>18 years > or =120 Females
Age Apolipoprotein A (mg/dL)
Not established
2-17 years Low: low: 115-120 Acceptable: >120
>18 years > or =140
Clinical References: 1. Sorci-Thomas MG, Thomas MJ: Why Targeting HDL Should Work as a
Therapeutic Tool, but Has Not. J Cardiovasc. Pharmacol 2013;62:239-246 2. Di Angelantonio E, Sarwar
N, Perry P, et al: Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular
disease. JAMA 2009;302:1993-2000 3. McQueen MJ, Hawken S, Wang X, et al: Lipids, lipoproteins, and
apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a
case control study. Lancet 2008;372:224-233 4. Sung KC, Wild SH, Byrne CD: Controlling for
apolipoprotein A-I concentrations changes the inverse direction of the relationship between high HDL-C
concentration and a measure of pre-clinical atherosclerosis. Atherosclerosis 2013;231:181-186 5.
Boekholdt SM, Arsenault BJ, Hovingh GK, et.al: Levels and Changes of HDL Cholesterol and
Apolipoprotein A-I in Relation to Risk of Cardiovascular Events Among Statin-Treated Patients: A
Meta-Analysis. Circulation 2013;128:1504-1512
APOLB Apolipoprotein B, Serum

614544 Clinical Information: Apolipoprotein B (ApoB) is the primary protein component of low-density
lipoprotein (LDL). The amount of cholesterol contained within LDL varies, but each LDL contains
exactly one ApoB protein. Therefore, ApoB is a more reliable indicator of circulating LDL compared to
LDL cholesterol (LDL-C). ApoB has been demonstrated to perform equally with LDL particles measured
by nuclear magnetic resonance spectroscopy.(1) ApoB is strongly associated with increased risk of
developing cardiovascular disease (CVD) and often outperforms LDL-C at predicting risk of coronary
heart disease.(2-4) Patients with acceptable non-high-density lipoprotein cholesterol (HDL-C) or LDL-C
but elevated ApoB remain at higher risk of developing CVD; conversely, patients with acceptably low
ApoB but moderate non-HDL-C or LDL-C elevations are at a reduced risk for CVD.(5,6) Finally, in 7
different placebo-controlled randomized clinical trials, on-statin reduction of ApoB was more closely
related to CVD risk reduction than non-HDL-C or LDL-C.(7)
Useful For: Assessment of cardiovascular risk Follow-up studies in individuals with basic lipid
measures inconsistent with risk factors or clinical presentation Definitive studies of cardiac risk factors
in individuals with significant family histories of coronary artery disease or other increased risk factors
Confirmation of suspected abetalipoproteinemia or hypobetalipoproteinemia
Interpretation: Elevated apolipoprotein B (ApoB) confers increased risk of atherosclerotic

cardiovascular disease, even in a context of acceptable low-density lipoprotein cholesterol. Extremely
low values of ApoB (<48 mg/dL) are related to malabsorption of food lipids and can lead to
polyneuropathy.
Reference Values:
<2 years: Not established
2-17 years:
Acceptable: <90 mg/dL
Borderline high: 90-109 mg/dL
High: > or =110 mg/dL
>18 years:
Desirable: <90 mg/dL
Above Desirable: 90-99 mg/dL
Borderline high: 100-119 mg/dL
High: 120-139 mg/dL
Very high: > or =140 mg/dL
Clinical References: 1. Cole TG, Contois JH, Csako G, et al: Association of apolipoprotein B and
nuclear magnetic resonance spectroscopy-derived LDL particle number with outcomes in 25 clinical
studies: assessment by the AACC Lipoprotein and Vascular Diseases Division Working Group on best
practices. Clin Chem. 2013;59:752-770 2. Sierra-Johnson J, Fisher RM, Romero-Corral A, et al:
Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and
better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings
from a multi-ethnic US population. Eur Heart J. 2009;30(6):710-717 3. Steffen BT, Guan W, Remaley
AT, et al: Use of lipoprotein particle measures for assessing coronary heart disease risk Post-American
Heart Association / American College of Cardiology Guidelines: The Multi-Ethnic Study of
Atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35:448-454 4. Thompson A, Danesh J:
Associations between apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary
heart disease: a literature-based meta-analysis of prospective studies. J Intern Med. 2006;259:481-492 5.
Mora S, Buring JE, Ridker PM: Discordance of low-density lipoprotein (LDL) cholesterol with
alternative LDL-related measures and future coronary events. Circulation. 2014;129:553-561 6. Pencina
MJ, D'Agostino RB, Zdrojewski T, et al: Apolipoprotein B improves risk assessment of future coronary
heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C. Eur J Prev Cardiol. 2015
Oct;22(10):1321-7. doi: 10.1177/2047487315569411 7. Thanassoulis G, Williams K, Ye K, et al:
Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin
therapy: a meta-analysis of randomized trials. J Am Heart Assoc. 2014;3:e000759 8. Jacobson TA, Ito
MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management of
dyslipidemia: Part 1-executive summary. J Clin Lipidol. 2014 Sep-Oct;8(5):473-488 9. Expert panel on
integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary
report. Pediatrics. 2011 Dec;128 Suppl 5:S213-S256 10. Contois JH, McConnell JP, Sethi AA, et al:
Apolipoprotein B and Cardiovascular Disease Risk: Position Statement from the AACC Lipoproteins
and Vascular Diseases Division Working Group on Best Practices. Clinical Chemistry.
2009:55:3:407-419
APOEG Apolipoprotein E Genotyping, Blood
35358 Clinical Information: Apolipoproteins are structural constituents of lipoprotein particles that
participate in lipoprotein synthesis, secretion, processing, and metabolism. Apolipoproteins have critical
roles in blood lipid metabolism. Defects in apolipoprotein E (ApoE) are responsible for familial
dysbetalipoproteinemia, or type III hyperlipoproteinemia, in which increased plasma cholesterol and
triglycerides result from impaired clearance of chylomicron and very-low-density lipoprotein remnants.
The human APOE gene is located on chromosome 19. The 3 common APOE alleles are designated e2, e3,
and e4, which encode the ApoE isoforms E2, E3, and E4, respectively. E3, the most common isoform in
the White population, shows cysteine (Cys) at amino acid position 112 and arginine (Arg) at position 158.
E2 and E4 differ from E3 by single amino acid substitutions at positions 158 and 112, respectively (E2:
Arg158->Cys; E4: Cys112->Arg). The allele frequencies for most White populations are as follows:
-e2=8% to 12% -e3=74% to 78% -e4=14% to 15% E2 and E4 are both associated with higher plasma
triglyceride concentrations. Over 90% of individuals with type III hyperlipoproteinemia are homozygous
for the e2 allele. However, less than 10% of individuals homozygous for the e2 allele have overt type III
hyperlipoproteinemia. This suggests that other genetic, hormonal, or environmental factors must
contribute to the phenotypic expression of the disease. The e4 allele has been linked to pure elevations of
low-density lipoproteins. Patients with a lipid profile consistent with type III hyperlipidemia are
candidates for analysis of their APOE genotype. The APOE gene is also a known susceptibility gene for
Alzheimer disease. The e4 allele is associated with an increased risk for Alzheimer disease, particularly
late-onset disease, in a dose-dependent manner. This risk is also influenced by other factors. It is
estimated that individuals with the APOE e3/e4 genotype have a 4-fold relative risk for Alzheimer
disease, while homozygotes for e4 allele have a 12-fold relative risk. Several studies have suggested a
protective effect of the APOE e2 allele. The APOE e4 allele, however, is neither sufficient nor necessary
for the development of Alzheimer disease. Approximately 50% of individuals with Alzheimer disease
carry an e4 allele, and many individuals who have an e4 allele will never develop Alzheimer disease. The
use of APOE analysis for predictive testing for Alzheimer disease is not currently recommended by the
American College of Medical Genetics and Genomics due to limited clinical utility and poor predictive
value.
Useful For: Determining the specific apolipoprotein E (APOE) genotypes in patients with type III
hyperlipoproteinemia APOE genotyping has been used to assess susceptibility for Alzheimer disease.
However, the use of APOE analysis for predictive testing for Alzheimer disease is not currently
recommended by the American College of Medical Genetics due to limited clinical utility and poor
predictive value.

Clinical References: 1. Smelt AH, de Beer F: Apolipoprotein E and familial
dysbetalipoproteinemia: Clinical, biochemical, and genetic aspects. Semin Vasc Med. 2004
Aug;4(3):249-257 2. Utermann G: Morgagni lecture: genetic polymorphism of apolipoprotein E-impact
on plasma lipoprotein metabolism In: Crepaldi G, Tiengo A, Baggio G. Diabetes, Obesity and
Hyperlipidemias 3: Proceedings of the 4th European Symposium on Metabolism 1985. Elsevier;
1985:1-28 3. Elosua R, Ordovas JM, Cupples LA, et al: Association of APOE genotype with carotid
atherosclerosis in men and women: the Framingham Heart Study. J Lipid Res. 2004
Oct;45(10):1868-1875 4. Poirier J, Davignon J, Bouthillier D, et al: Apolipoprotein E polymorphism and
Alzheimer's disease. Lancet. 1993 Sep;342(8873): 697-699 5. Farrer L, Cupples A, Haines J, et al: Effects
of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a
meta-analysis. JAMA. 1997 Oct 22-29;278(16):1349-1356 6. Goldman JS, Hahn SE, Catania JW, et al:
Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College
of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011 Jun;13(6):597-605
7. American College of Medical Genetics and Genomics: Five things physicians and patients should
question. Choosing Wisely; 2015. Updated July 1, 2021. Accessed October 27, 2021. Available at
www.choosingwisely.org/societies/american-college-of-medical-genetics-and-genomics/
FAPLG Apple IgG

57629
Interpretation:
Reference Values:
APPL Apple, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to apples Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
APR Apricot, IgE, Serum

82835
Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are
Useful For: Establishing a diagnosis of an allergy to apricots Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
ARBOP Arbovirus Antibody Panel, IgG and IgM, Serum

83267 Clinical Information: California (LaCrosse) Virus: California (LaCrosse) virus is a member of the
Bunyaviridae family and is one of the arthropod-borne encephalitides. It is transmitted by various Aedes
and Culex mosquitoes and is found in such intermediate hosts as the rabbit, squirrel, chipmunk, and field
mouse. California meningoencephalitis is usually mild and occurs in late summer. Ninety percent of
infections are seen in children less than 15 years of age, usually from rural areas. The incubation period is
estimated to be 7 days, and acute illness lasts 10 days or less in most instances. Typically, the first
symptoms are nonspecific, lasting 1 to 3 days, and are followed by the appearance of central nervous
system (CNS) signs and symptoms such as stiff neck, lethargy, and seizures, which usually abate within 1
week. Symptomatic infection is almost never recognized in those over 18 years old. The most important
sequela of California virus encephalitis is epilepsy, which occurs in about 10% of children; almost always
in patients who have had seizures during the acute illness. A few patients (estimated 2%) have persistent
paresis. Learning disabilities or other objective cognitive deficits have been reported in a small proportion
(no more than 2%) of patients. Learning performance and behavior of most recovered patients are not
distinguishable from comparison groups in these same areas. Eastern Equine Encephalitis: Eastern equine
encephalitis (EEE) is within the alphavirus group. It is a low prevalence cause of human disease in the
eastern and Gulf Coast states. EEE is maintained by a cycle of mosquito/wild bird transmission, peaking
in the summer and early fall, when man may become an adventitious host. The most common clinically
apparent manifestation is a mild undifferentiated febrile illness, usually with headache. CNS involvement
is demonstrated in only a minority of infected individuals, it is more abrupt and more severe than with
other arboviruses, with children being more susceptible to severe disease. Fatality rates are approximately
70%. St. Louis Encephalitis: Areas of outbreaks of St. Louis encephalitis (SLE) since 1933 have involved
the western United States, Texas, the Ohio-Mississippi Valley, and Florida. The vector of transmission is
the mosquito. Peak incidence occurs in summer and early autumn. Disease onset is characterized by
generalized malaise, fever, chills, headache, drowsiness, nausea, and sore throat or cough, followed in 1 to
4 days by meningeal and neurologic signs. The severity of illness increases with advancing age; persons
over 60 years have the highest frequency of encephalitis. Symptoms of irritability, sleeplessness,
depression, memory loss, and headaches can last up to 3 years. Western Equine Encephalitis: The virus
that causes western equine encephalitis (WEE) is widely distributed throughout the United States and
Canada; disease occurs almost exclusively in the western states and Canadian provinces. The relative
absence of the disease in the eastern United States probably reflects a paucity of the vector mosquito
species, Culex tarsalis, and possibly a lower pathogenicity of local virus strains. The disease usually
begins suddenly with malaise, fever, and headache, often with nausea and vomiting. Vertigo,
photophobia, sore throat, respiratory symptoms, abdominal pain, and myalgia are also common. Over a
few days, the headache intensifies; drowsiness and restlessness may merge into a coma in severe cases. In
infants and children, the onset may be more abrupt than for adults. WEE should be suspected in any case
of febrile CNS disease from an endemic area. Infants are highly susceptible to CNS disease, with about
20% of cases under 1 year of age. There is an excess of males with WEE clinical encephalitis, averaging
about twice the number of infections detected in females. After recovery from the acute disease, patients
may require from several months to 2 years to overcome the fatigue, headache, and irritability. Infants and
children are at higher risk of permanent brain damage after recovery than adults.
Useful For: Aiding the diagnosis of arboviral encephalitis (California [LaCrosse], St. Louis, eastern
equine and western equine encephalitis)
Interpretation: In patients infected with these or related viruses, IgM class antibody is reliably
detected within 1 to 3 weeks of onset, peaking and rapidly declining within 3 months. Results from a
single serum specimen can differentiate early (acute) infection from past infection with immunity if IgM
is positive (suggests acute infection). IgG antibody is generally detectable within 1 to 3 weeks of onset,
peaking within 1 to 2 months, and declining slowly thereafter. A single serum specimen IgG of 1:10 or
greater indicates exposure to the virus. A 4-fold or greater rise in IgG antibody titer in acute and
convalescent sera indicates recent infection. In the United States, it is unusual for any patient to show
positive reactions to more than 1 of the arboviral antigens, although Western equine encephalitis and
Eastern equine encephalitis antigens will show a noticeable cross-reactivity.
Reference Values:
CALIFORNIA VIRUS (La CROSSE) ENCEPHALITIS ANTIBODY
IgG: <1:10
IgM: <1:10
EASTERN EQUINE ENCEPHALITIS ANTIBODY

IgG: <1:10
IgM: <1:10
ST. LOUIS ENCEPHALITIS ANTIBODY

IgG: <1:10
IgM: <1:10
WESTERN EQUINE ENCEPHALITIS

IgG: <1:10
IgM: <1:10
Clinical References: 1. Gonzalez-Scarano F, Nathanson N: Bunyaviruses. In: Fields BN, Knipe DN,
eds. Fields Virology. Vol. 1. 2nd ed. Raven Press; 1990:1195-1228 2. Donat JF, Hable-Rhodes KH,
Groover RV, Smith TF: Etiology and outcome in 42 children with acute nonbacterial
meningo-encephalitis. Mayo Clin Proc. 1980;55:156-160 3. Tsai TF: Arboviruses. In: Murray PR, Baron
EJ, Pfaller MA, et al: eds. Manual of Clinical Microbiology. 7th ed. American Society for Microbiology;
1999:1107-1124 4. Calisher CH: Medically important arboviruses of the United States and Canada. Clin
Microbiol Rev. 1994;7:89-116
ABOPC Arbovirus Antibody Panel, IgG and IgM, Spinal Fluid

83897 Clinical Information: California (LaCrosse) Virus: California (LaCrosse) virus is a member of the
Bunyaviridae family and it is one of the arthropod-borne encephalitides. It is transmitted by various Aedes
and Culex mosquitoes and is found in such intermediate hosts as the rabbit, squirrel, chipmunk, and field
mouse. California meningoencephalitis is usually mild and occurs in late summer. Ninety percent of
infections are seen in children younger than 15 years of age, usually from rural areas. The incubation
period is estimated to be 7 days and acute illness lasts 10 days or less in most instances. Typically, the
first symptoms are nonspecific, lasting 1 to 3 days, and are followed by the appearance of central nervous
system (CNS) signs and symptoms such as stiff neck, lethargy, and seizures, which usually abate within 1
week. Symptomatic infection is almost never recognized in those over 18 years old. The most important
sequela of California virus encephalitis is epilepsy, which occurs in about 10% of children; almost always
in patients who have had seizures during the acute illness. An estimated 2% of patients have persistent
paresis. Learning disabilities or other objective cognitive deficits have been reported in a small proportion
(2%) of patients. Learning performance and behavior of most recovered patients are not distinguishable
from comparison groups in these same areas. Eastern Equine Encephalitis: Eastern equine encephalitis
(EEE) is within the alphavirus group. It is a low-prevalence cause of human disease in the eastern and
Gulf Coast states. EEE is maintained by a cycle of mosquito/wild bird transmission, peaking in the
summer and early fall, when man may become an adventitious host. The most common clinically apparent
manifestation is a mild undifferentiated febrile illness, usually with headache. CNS involvement is
demonstrated in only a minority of infected individuals, and is more abrupt and more severe than with
other arboviruses, with children being more susceptible to severe disease. Fatality rates are approximately
70%. St. Louis Encephalitis: Areas or outbreaks of St. Louis encephalitis (SLE) since 1933 have involved
the western United States, Texas, the Ohio-Mississippi Valley, and Florida. The vector of transmission is
the mosquito. Peak incidence occurs in summer and early autumn. Disease onset is characterized by
generalized malaise, fever, chills, headache, drowsiness, nausea, and sore throat or cough, followed in 1 to
4 days by meningeal and neurologic signs. The severity of illness increases with advancing age; persons
over 60 years have the highest frequency of encephalitis. Symptoms of irritability, sleeplessness,
depression, memory loss, and headaches can last up to 3 years. Western Equine Encephalitis: The virus
that causes Western equine encephalitis (WEE) is widely distributed throughout the United States and
Canada; disease occurs almost exclusively in the western states and Canadian provinces. The relative
absence of the disease in the eastern United States probably reflects a paucity of the vector mosquito
species, Culex tarsalis, and possibly a lower pathogenicity of local virus strains. The disease usually
begins suddenly with malaise, fever, and headache, often with nausea and vomiting. Vertigo,
photophobia, sore throat, respiratory symptoms, abdominal pain, and myalgia are also common. Over a
few days, the headache intensifies; drowsiness and restlessness may merge into a coma in severe cases. In
infants and children, the onset may be more abrupt than for adults. WEE should be suspected in any case
of febrile CNS disease from an endemic area. Infants are highly susceptible to CNS disease, with about
20% of cases under 1 year of age. There is an excess of male patients with WEE clinical encephalitis,
averaging about twice the number of infections detected in female patients. After recovery from the acute
disease, patients may require from several months to 2 years to overcome the fatigue, headache, and
irritability. Infants and children are at a higher risk of permanent brain damage after recovery than adults.
Useful For: Aiding in the diagnosis of arboviral encephalitis (California [LaCrosse], St. Louis, Eastern
equine, and Western equine encephalitis)
Interpretation: Detection of organism-specific antibodies in the cerebrospinal fluid (CSF) may
suggest central nervous system (CNS) infection. However, these results are unable to distinguish
between intrathecal antibodies and serum antibodies introduced into the CSF at the time of lumbar
puncture or from a breakdown in the blood-brain barrier. The results should be interpreted with other
laboratory and clinical data prior to a diagnosis of CNS infection.
Reference Values:
CALIFORNIA VIRUS (La CROSSE) ENCEPHALITIS ANTIBODY
IgG: <1:1
IgM: <1:1
EASTERN EQUINE ENCEPHALITIS ANTIBODY

IgG: <1:1
IgM: <1:1
ST. LOUIS ENCEPHALITIS ANTIBODY

IgG: <1:1
IgM: <1:1
WESTERN EQUINE ENCEPHALITIS

IgG: <1:1
IgM: <1:1
Clinical References: 1. Gonzalez-Scarano F, Nathanson N: Bunyaviruses. In: Fields BN, Knipe

DM, eds. Fields Virology. Vol 1. 2nd ed. Raven Press; 1990: 1195-1228 2. Donat JF, Rhodes KH,
meningoencephalitits. Mayo Clin Proc. 1980;55:156-160 3. Tsai TF: Abroviruses. In: Murray PR,
Baron EJ, Pfaller MA, et al, eds. Manual of Clinical Microbiology. 7th ed. ASM Press; 1999:
1107-1124 4. Calisher CH: Medically important arboviruses of the United States and Canada. Clin
Microbiol Rev. 1994;7:89-116 5. Beckham JD, Tyler KL: Arbovirus Infections. Continuum (Minneap
Minn). 2015 Dec;21(6 Neuroinfectious Disease):1599-1611. doi: 10.1212/CON.0000000000000240
ARGAT Argatroban, Ecarin, Plasma

609425 Clinical Information: Argatroban, a parenteral direct thrombin inhibitor (DTI) that directly inhibits
factor IIa, is indicated for use in patients with heparin-induced thrombocytopenia (HIT). Argatroban is
administered via continuous infusion, is eliminated by the liver, and can inhibit both soluble and
clot-bound thrombin. Argatroban effect is typically monitored using activated partial thromboplastin
time (APTT) measurements with a target of 1.5 to 3.0 times the patientâ€™s baseline value. However,
in instances where patients have a prolonged baseline APTT (eg, lupus anticoagulants and factor XII
deficiency), APTT monitoring of argatroban is not reliable and measurement of argatroban's effect on
factor IIa may be more reliable. There are no clinical studies directly correlating argatroban
concentration to clinical outcomes. The available data suggest that plasma concentrations of argatroban
1.2 to 2.3 mcg/mL correspond to an APTT ratio of 1.5 to 3.0.(1)
Useful For: Measuring argatroban concentration in plasma This assay is not useful for measurement
of other direct thrombin inhibitors eg, dabigatran or bivalirudin.
Interpretation: Therapeutic reference ranges have not been established. See Clinical Information for
activated partial thromboplastin time correlative information.
Reference Values:
<0.10 mcg/mL
Clinical References: 1. Ahmad S, Iqbal O, Ahsan A, et al: Clinical laboratory monitoring of a
synthetic antithrombin agent, argatroban, using high performance liquid chromatography and functional
methods. Int Angiol. 1999;18:198-205 2. Argatroban Injection. Package insert: Sandoz, Inc; 2019 3. Van
Cott EM, Roberts AJ, Dager WE: Laboratory monitoring of parenteral direct thrombin inhibitors. Semin
Thromb Hemost. 2017;43: 270-276 4. Gosselin RC, King JH, Janatpour KA, et al: Comparing direct
thrombin inhibitors using aPTT, Ecarin clotting times, and thrombin inhibitor management testing. Ann
Pharmacother. 2004;38:1383-1388 5. Gosselin RC, Adcock DM, Bates SM, et al: International Council
for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral
anticoagulants. Thromb Haemost. 2018 Mar;118(3):437-450 6. Lind SE, Boyle ME, Fisher S, Ishimoto J,
Trujillo TC, Kiser TH: Comparison of the aPTT with alternative tests for monitoring direct trombin
inhibitors in patient samples. Am J Clin Pathol. May 2014;141:665-674 7. Curvers J, van de Kerkhof D,
Stroobants AK, van den Dool EJ, Scharnhorst V: Measuring direct thrombin inhibitors with routine and
dedicated coagulation assays.Â Am J Clin Pathol. 2012;138: 551-558 8. Seidel H, Kolde HJ: Monitoring
of argatroban and lepirudin: what is the input of laboratory values in "real life"?Â Clin Appl Thromb
Hemost .2018 Mar;24(2):287-294 9. Fenyvesi T, Jorg I, Harenberg J: Monitoring of anticoagulant effects
of direct thrombin inhibitors. Semin Thromb Hemost. 2002;28(4):361-368
ARGIN Arginase-1 Immunostain, Technical Component Only

70359 Clinical Information: Arginase-1 is a urea cycle metalloenzyme specifically expressed in
hepatocytes. This protein serves as a marker in the identification and differentiation of hepatocellular
carcinoma within the context of an antibody panel.
Useful For: Identification and differentiation of hepatocellular carcinoma

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation
is performed). Mayo Clinic cannot provide an interpretation of tech only stains outside the context of a
pathology consultation. If an interpretation is needed, refer to PATHC / Pathology Consultation for a full
diagnostic evaluation or second opinion of the case. All material associated with the case is required.
Additional specific stains may be requested as part of the pathology consultation, and will be performed
as necessary at the discretion of the Mayo pathologist. Â The positive and negative controls are verified
as showing appropriate immunoreactivity and documentation is retained at Mayo Clinic Rochester. If a
control tissue is not included on the slide, a scanned image of the relevant quality control tissue is
available upon request. Contact 855-516-8404. Â Interpretation of this test should be performed in the
context of the patient's clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Radwan NA, Ahmed NS: The diagnostic value of arginase-1
immunostaining in differentiating hepatocellular carcinoma from metastatic carcinoma and
cholangiocarcinoma as compared to HepPar-1. Diagn Pathol 2012;7:149 2. Timek DT, Shi J, Liu H, Lin
F: Arginase-1, HepPar-1, and Glypican-3 are the most effective panel of markers in distinguishing
hepatocellular carcinoma from metastatic tumor on fine-needle aspiration specimens. Am J Clin Pathol
2012;138(2):203-210 3. Fujiwara M, Kwok S, Yano H, Pai RK: Arginase-1 is a more sensitive marker of
hepatic differentiation than HepPar-1 and glypican-3 in fine-needle aspiration biopsies. Cancer
Cytopathol 2012;120(4):230-237 4. Yan BC, Gong C, Song J, et al: Arginase-1: a new
immunohistochemical marker of hepatocytes and hepatocellular neoplasms. Am J Surg Pathol
2010;34(8):1147-1154
FARI Aripiprazole (Abilify)

Units: ng/mL
Expected steady state plasma levels in patients receiving recommended daily dosages: 109.0 - 585.0
ng/mL
ARVGP Arrhythmogenic Cardiomyopathy Multi-Gene Panel, Blood
63160 Clinical Information: The cardiomyopathies are a group of disorders characterized by disease of
the heart muscle. Cardiomyopathy can be caused by inherited, genetic factors, or by nongenetic
(acquired) causes such as infection or trauma. When the presence or severity of the cardiomyopathy
observed in a patient cannot be explained by acquired causes, genetic testing for the inherited forms of
cardiomyopathy may be considered. Overall, the cardiomyopathies are some of the most common
genetic disorders. The inherited forms of cardiomyopathy include hypertrophic cardiomyopathy (HCM),
dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC or AC), and
left ventricular noncompaction. ARVD is characterized by breakdown of the myocardium and
replacement of the muscle tissue with fibrofatty tissue, resulting in an increased risk of arrhythmia and
sudden death. The incidence of ARVC is approximately 1 in 1000 to 1 in 2500. Age of onset and
severity are variable, but symptoms typically develop in adulthood. ARVC is present in 4% to 22% of
athletes with sudden cardiac death, and there is some debate whether high-intensity endurance exercise
may cause development of ARVC. ARVC is typically considered a disease of the desmosome, the
structure that attaches heart muscle cells to one another. The desmosome provides strength to the
muscle tissue and plays a role in signaling between neighboring cells. Variants in the genes associated
with ARVC disrupt this function, causing detachment and death of myocardial cells when the heart
muscle is under stress. Damaged myocardium is replaced with fat and scar tissue, eventually leading to
structural and electrical abnormalities that can lead to arrhythmia. Inheritance of ARVC typically
follows an autosomal dominant pattern of inheritance, and variants in DSC2, DSP, and PKP2 account
for approximately half of the variants identified in ARVC. However, simultaneous testing of all known
ARVC genes is recommended due to the potential for compound heterozygosity (biallelic variants on
the same gene) or digenic heterozygosity (variants in 2 different genes). See table for details regarding
the genes tested by this panel and associated diseases. Table: Genes included in this panel Gene Protein
Inheritance Disease association DES Desmin AD, AR DCM, ARVC, myofibrillar myopathy, RCM with
AV block, neurogenic scapuloperoneal syndrome Kaeser type, LGMD DSC2 Desmocollin AD, AR
ARVC, ARVC + skin and hair findings DSG2 Desmoglein AD ARVC DSP Desmoplakin AD, AR
ARVC, DCM, Carvajal syndrome JUP Junction plakoglobin AD, AR ARVC, Naxos disease LMNA
Lamin A/C AD, AR DCM, EMD, LGMD, congenital muscular dystrophy, ARVC (see OMIM for full
listing) PKP2 Plakophilin 2 AD ARVC RYR2 Ryanodine receptor 2 AD ARVC, CPVT, LQTS
TMEM43 Transmembrane protein 43 AD ARVC, EMD TTN Titin AD, AR HCM, DCM, ARVC,
myopathy Abbreviations not previously defined: Restrictive cardiomyopathy (RCM), limb-girdle
muscular dystrophy (LGMD), Emory muscular dystrophy (EMD), catecholaminergic polymorphic
ventricular tachycardia (CPVT), long QT syndrome (LQTS), autosomal dominant (AD), autosomal
recessive (AR)
Useful For: Providing a comprehensive genetic evaluation for patients with a personal or family
history suggestive of hereditary arrhythmogenic right ventricular cardiomyopathy (ARVC or AC)
Establishing a diagnosis of ARVC, and in some cases, allowing for appropriate management and
surveillance for disease features based on the gene involved Identifying a pathogenic variant within a
gene known to be associated with disease that allows for predictive testing of at-risk family members
Interpretation: Evaluation and categorization of variants is performed using the most recent
published American College of Medical Genetics and Genomics (ACMG) recommendations as a
guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported
with interpretive comments detailing their potential or known significance. Multiple in silico evaluation
tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in
silico evaluation tools is highly dependent upon the data available for a given gene, and predictions
made by these tools may change over time. Results from in silico evaluation tools should be interpreted
with caution and professional clinical judgment.
Reference Values:
Clinical References: 1. McNally E, MacLeod H, Dellefave-Castillo L: Arrhythmogenic right

ventricular dysplasia/cardiomyopathy. In: Adam MP, Ardinger HH, Pagon RA, eds. GeneReviews
[Internet]. University of Washington, Seattle; 2005. Updated May 25, 2017. Accessed June 2018.
Available at www.ncbi.nlm.nih.gov/books/NBK1131/ 2. Ackerman MJ, Priori SG, Willems S, et al:
HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and
cardiomyopathies. Heart Rhythm 2011;8:1308-1339 3. Taylor M, Graw S, Sinagra G, et al: Genetic
variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation.
2011;124.9:876-885
ASOU Arsenic Occupational Exposure, Random, Urine

608890 Clinical Information: Arsenic is a naturally occurring element that is widely distributed in the
Earthâ€™s crust. Arsenic is classified chemically as a metalloid, having properties of both a metal and a
nonmetal. Elemental arsenic is a steel grey solid material. However, arsenic is usually found in the
environment combined with other elements such as oxygen, chlorine, and sulfur. Arsenic combined with
these elements is called inorganic arsenic. Arsenic combined with carbon and hydrogen is referred to as
organic arsenic. The organic forms (eg, arsenobetaine and arsenocholine) are relatively nontoxic, while
the inorganic forms are toxic. The toxic inorganic forms are arsenite (As[3+]/As[III]) and arsenate
(As[5+]/As[V]). Inorganic As(V) is readily reduced to inorganic As(III), which is then primarily broken
down to the less toxic methylated metabolites monomethylarsinic acid (MMA) and subsequently
dimethylarsinic acid (DMA). In the past, inorganic arsenic compounds were predominantly used as
pesticides, primarily on cotton fields and in orchards. Inorganic arsenic compounds can no longer be used
in agriculture. However, organic arsenic compounds, namely cacodylic acid, disodium methylarsenate
(DSMA), and monosodium methylarsenate (MSMA), are still used as pesticides, principally on cotton.
Some organic arsenic compounds are used as additives in animal feed. Small quantities of elemental
arsenic are also added to other metals to form metal mixtures or alloys with improved properties. The
greatest use of arsenic in alloys is in lead-acid batteries for automobiles. Another important use of arsenic
compounds is in semiconductors and light-emitting diodes. People are exposed to arsenic by eating food,
drinking water, or breathing air. Of these, food is usually the largest source of arsenic. The predominant
dietary source of arsenic is seafood, followed by rice/rice cereal, mushrooms, and poultry. While seafood
contains the greatest amounts of arsenic, from fish and shellfish, this is mostly in an organic form of
arsenic called arsenobetaine, which is much less harmful. Some seaweed may contain arsenic in the
inorganic form, which is more toxic. In the United States, some areas also contain high natural levels of
arsenic in rock, which can lead to elevated levels in the soil and drinking water. Occupational (eg, copper
or lead smelting, wood treating, or pesticide application) exposure is another source where people may be
introduced to elevated levels of arsenic. Lastly, hazardous waste sites may contain large quantities of
arsenic and, if not disposed of properly, may get into the surrounding water, air, or soil. A wide range of
signs and symptoms may be seen in acute arsenic poisoning including headache, nausea, vomiting,
diarrhea, abdominal pain, hypotension, fever, hemolysis, seizures, and mental status changes. Symptoms
of chronic poisoning, also called arseniasis, are mostly insidious and nonspecific. The gastrointestinal
tract, skin, and central nervous system are usually involved. Nausea, epigastric pain, colic abdominal pain,
diarrhea, and paresthesias of the hands and feet can also occur. Since arsenic is excreted predominantly by
glomerular filtration, measurement of arsenic in urine is the most reliable means of detecting arsenic
exposures within the last several days.
Useful For: Screening test for detection of occupational exposure to arsenic in random urine specimens
Interpretation: Mayo Clinic uses the American Conference of Governmental Industrial Hygienists
(ACGIH) biological exposure index (BEI) as the reference value. The BEI is the sum of all the toxic
species (inorganic arsenic plus methylated arsenic metabolites). Physiologically, arsenic exists in a
number of toxic and nontoxic forms. The total arsenic concentration reflects all the arsenic present in the
sample regardless of species (eg, inorganic vs. methylated vs. organic arsenic). The measurement of
urinary total arsenic levels is generally accepted as the most reliable indicator of recent arsenic exposure.
However, if the total urine arsenic concentration is elevated, arsenic speciation must be performed to
identify if it is the toxic forms (eg, inorganic and methylated arsenic forms) or the relatively nontoxic
organic forms (eg, arsenobetaine and arsenocholine). The inorganic toxic forms of arsenic (eg, As[III] and
As[V]) are found in the urine shortly after ingestion, whereas the less toxic methylated forms,
monomethylarsinic acid (MMA) andÂ dimethylarsinic acid (DMA)are the species that predominate
longer than 24 hours after ingestion. In general, urinary As(III) and As(V) concentrations peak in the
urine at approximately 10 hours and return to normal 20 to 30 hours after ingestion. Urinary MMA and
DMA concentrations normally peak at approximately 40 to 60 hours and return to baseline 6 to 20 days
after ingestion. This test can determine if apatient has been exposed to above-average levels of arsenic. It
cannot predict whether the arsenic levels in their body will affect their health.
Reference Values:
Only orderable as part of profile. For more information see:
-ASUOE / Arsenic Occupational Exposure with Reflex, Random, Urine
-HMUOE / Heavy Metal Occupational Exposure, with Reflex, Random, Urine
Clinical References: 1. Fillol CC, Dor F, Labat L, et al: Urinary arsenic concentrations and
speciation in residents living in an area with naturally contaminated soils. Sci Total Environ. 2010 Feb
1;408(5):1190-1194 2. Caldwell KL, Jones RL, Verdon CP, Jarrett JM, Caudill SP, Osterloh JD: Levels
of urinary total and speciated arsenic in the US population: National Health and Nutrition Examination
Survey 2003-2004. J Expo Sci Environ Epidemiol. 2009 Jan;19(1):59-68 3. Agency for Toxic
Substances and Disease Registry: Toxicological profile for arsenic. US Department of Health and
Human Services. August 2007. Available at www.atsdr.cdc.gov/ToxProfiles/tp2.pdf 4. Strathmann FG,
Blum LM: Toxic elements. In: Rafai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:chap 42 5. Keil DE, Berger-Ritchie J,
McMillin GA: Testing for toxic elements: A focus on arsenic, cadmium, lead, and mercury. Lab Med.
2011 Dec;42(12):735-742 doi: 10.1309/LMYKGU05BEPE7IAW 6. Navas-Acien A, Francesconi KA,
Silbergeld EK, Guallar E: Seafood intake and urine concentrations of total arsenic, dimethylarsinate and
arsenobetaine in the US population. Environ Res. 2011 Jan;111(1):110-118 doi:
10.1016/j.envres.2010.10.009 7. Tchounwou PB, Yedjou CG, Udensi UK, et al: State of the science
review of the health effects of inorganic arsenic: Perspectives for future research. Environ Toxicol. 2019
Feb;34(2):188-202 doi: 10.1002/tox.22673
ASUOE Arsenic Occupational Exposure, with Reflex, Random, Urine

environment combined with other elements such as oxygen, chlorine, and sulfur. Arsenic combined
with these elements is called inorganic arsenic. Arsenic combined with carbon and hydrogen is referred
to as organic arsenic. The organic forms (eg, arsenobetaine and arsenocholine) are relatively nontoxic,
while the inorganic forms are toxic. The toxic inorganic forms are arsenite (As[3+]/As[III]) and arsenate
(As[5+]/As[V]).Â Inorganic As(V) is readily reduced to inorganic As(III) which is then primarily
broken down to the less toxic methylated metabolites, monomethylarsinic acid (MMA) and
subsequently dimethylarsinic acid (DMA). Â In the past, inorganic arsenic compounds were
predominantly used as pesticides, primarily on cotton fields and in orchards. Inorganic arsenic
compounds can no longer be used in agriculture. However, organic arsenic compounds, namely
cacodylic acid, disodium methylarsenate (DSMA), and monosodium methylarsenate (MSMA), are still
used as pesticides, principally on cotton. Some organic arsenic compounds are used as additives in
animal feed. Small quantities of elemental arsenic are also added to other metals to form metal mixtures
or alloys with improved properties. The greatest use of arsenic in alloys is in lead-acid batteries for
automobiles. Another important use of arsenic compounds is in semiconductors and light-emitting
diodes. People are exposed to arsenic by eating food, drinking water, or breathing air. Of these, food is
usually the largest source of arsenic. The predominant dietary source of arsenic is seafood, followed by
rice/rice cereal, mushrooms, and poultry. While seafood contains the greatest amounts of arsenic, from
fish and shellfish, this is mostly in an organic form of arsenic called arsenobetaine, which is much less
harmful. Some seaweed may contain arsenic in the inorganic form, which is more toxic. In the United
States, some areas also contain high natural levels of arsenic in rock, which can lead to elevated levels
in the soil and drinking water. Occupational (eg copper or lead smelting, wood treating, or pesticide
application) exposure is another source where people may be introduced to elevated levels of arsenic.
Lastly, hazardous waste sites may contain large quantities of arsenic and, if not disposed of properly,
may get into the surrounding water, air, or soil. A wide range of signs and symptoms may be seen in
acute arsenic poisoning including headache, nausea, vomiting, diarrhea, abdominal pain, hypotension,
fever, hemolysis, seizures, and mental status changes. Symptoms of chronic poisoning, also called
arseniasis, are mostly insidious and nonspecific. The gastrointestinal tract, skin, and central nervous
system are usually involved. Nausea, epigastric pain, colic abdominal pain, diarrhea, and paresthesias of
the hands and feet can also occur. Since arsenic is excreted predominantly by glomerular filtration,
measurement of arsenic in urine is the most reliable means of detecting arsenic exposures within the last
several days.
Useful For: Preferred screening test for detection of occupational exposure to arsenic in random urine
specimens
Interpretation: Mayo Clinic uses the American Conference of Governmental Industrial Hygienists
(ACGIH) biological exposure index (BEI) as the reference value. The BEI is the sum of all the toxic
species (inorganic arsenic plus methylated arsenic metabolites). Physiologically, arsenic exists in a
number of toxic and nontoxic forms. The total arsenic concentration reflects all the arsenic present in the
sample regardless of species (eg, inorganic vs. methylated vs. organic arsenic). The measurement of
urinary total arsenic levels is generally accepted as the most reliable indicator of recent arsenic exposure.
However, if the total urine arsenic concentration is elevated, arsenic speciation must be performed to
identify if it is the toxic forms (eg, inorganic and methylated arsenic forms) or the relatively nontoxic
organic forms (eg, arsenobetaine and arsenocholine). The inorganic toxic forms of arsenic (eg, As[III] and
As[V]) are found in the urine shortly after ingestion, whereas the less toxic methylated forms,
monomethylarsinic acid (MMA) andÂ dimethylarsinic acid (DMA), are the species that predominate
longer than 24 hours after ingestion. In general, urinary As[III] and As[V] concentrations peak in the
urine at approximately 10 hours and return to normal 20 to 30 hours after ingestion. Urinary MMA and
DMA concentrations normally peak at approximately 40 to 60 hours and return to baseline 6 to 20 days
after ingestion. This test can determine if a patient has been exposed to above-average levels of arsenic. It
cannot predict whether the arsenic levels in their body will affect their health.
Reference Values:
Biological Exposure Indices (BEI): <35 mcg/L at end of work week
Survey 2003-2004. J Expo Sci Environ Epidemiol. 2009 Jan;19(1):59-68 3. Agency for Toxic Substances
and Disease Registry: Toxicological profile for arsenic. US Department of Health and Human Services.
August 2007. Available at www.atsdr.cdc.gov/ToxProfiles/tp2.pdf 4. Strathmann FG, Blum LM: Toxic
elements. In: Rifai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:chap 42 5. Keil DE, Berger-Ritchie J, McMillin GA:
Testing for toxic elements: A focus on arsenic, cadmium, lead, and mercury. Lab Med. 2011 Dec;
42(12):735-742. doi: 10.1309/LMYKGU05BEPE7IAW 6. Navas-Acien A, Francesconi KA, Silbergeld
EK, Guallar E: Seafood intake and urine concentrations of total arsenic, dimethylarsinate and
Feb;34(2):188-202 doi: 10.1002/tox.22673
SPASU Arsenic Speciation, 24 Hour, Urine

609383 Clinical Information: Arsenic (As) exists in a number of different forms; some are toxic, while
others are not. The toxic inorganic forms are arsenite (As[3+]/As[III]) and arsenate (As[5+]/As[V]), and
their partially detoxified metabolites are monomethylarsine (MMA) and dimethylarsine (DMA). As(III) is
more toxic than As(V) and both are more toxic than MMA- and DMA. The biologic half-life of inorganic
arsenic is 4 to 6 hours, while the biologic half-life of the methylated metabolites is 20 to 30 hours. Target
organs of As(III)-induced effects are the heart, gastrointestinal tract, skin and other epithelial tissues,
kidney, and nervous system. Inorganic arsenic is carcinogenic to humans. Symptoms of chronic
poisoning, called arseniasis, are mostly insidious and nonspecific. The gastrointestinal tract, skin, and
central nervous system are usually involved. Nausea, epigastric pain, colic abdominal pain, diarrhea, and
paresthesias of the hands and feet can occur. Nontoxic, organic forms of arsenic are present in many
foods. Arsenobetaine and arsenocholine are the two most common forms of organic arsenic found in food.
The most common foods that contain significant concentrations of organic arsenic are shellfish and other
predators in the seafood chain (cod, haddock, etc). Some meats, such as meats from chickens that have
been fed on seafood remnants, may also contain the organic forms of arsenic. Following ingestion of
arsenobetaine and arsenocholine, these compounds undergo rapid renal clearance to become concentrated
in the urine. Organic arsenic is completely excreted within 1 to 2 days after ingestion and there are no
residual toxic metabolites. The biologic half-life of organic arsenic is 4 to 6 hours. For reporting purposes,
the concentrations of the inorganic forms (As[3+] and As[5+]) along with the methylated forms (MMA
and DMA) will be summed and reported together as 'Inorganic' arsenic. This is consistent with how the
biological exposure index (BEI) reference range is reported.
Useful For: Diagnosis of arsenic intoxication using 24-hour urine specimens

Interpretation: The quantitative reference range for fractionated arsenic applies only to the
inorganic forms. Concentrations of 20 mcg inorganic arsenic per liter or higher are considered toxic.
There is no limit to the normal range for the organic forms of arsenic, since they are not considered to
be toxic and are normally present after consumption of certain food types. For example, a typical
finding in a urine specimen with total 24-hour excretion of arsenic of 350 mcg/24 hours would be that
more than 95% is present as the organic species from a dietary source, and less than 5% is present as the
inorganic species. This would be interpreted as indicating the elevated total arsenic was due to ingestion
of the nontoxic form of arsenic, usually found in seafood. A normal value for blood arsenic does not
exclude a finding of elevated urine inorganic arsenic due to the very short half-life of blood arsenic.
Reference Values:
TOXIC ARSENIC
<35 mcg/L
Arsenic Speciation Interpretive Information:

The toxic arsenic concentration represents the sum of the inorganic and methylated arsenic species.
The reference value for toxic arsenic is <35 mcg/L. This value is based on the American Conference of
Governmental Industrial Hygienists (ACGIH) Biological Exposure Index (BEI), which does not include
the non-toxic organic arsenic.
SPAS Arsenic Speciation, Random, Urine

607691 Clinical Information: Arsenic (As) exists in a number of different forms; some are toxic, while
others are not. The toxic forms are the inorganic species of As(3+) (As-III), As(5+) (As-V), and their
partially detoxified metabolites, monomethylarsine, and dimethylarsine. As-III is more toxic than As-V,
and both are more toxic than mono- and dimethylarsine. The biologic half-life of inorganic arsenic is 4
to 6 hours, while the biologic half-life of the methylated metabolites is 20 to 30 hours. Target organs of
As-III-induced effects are the heart, gastrointestinal tract, skin and other epithelial tissues, kidney, and
nervous system. Inorganic arsenic is carcinogenic to humans. Symptoms of chronic poisoning, called
the hands and feet can occur. Nontoxic, organic forms of arsenic are present in many foods.
Arsenobetaine and arsenocholine are the 2 most common forms of organic arsenic found in food. The
most common foods that contain significant concentrations of organic arsenic are shellfish and other
predators in the seafood chain (cod, haddock, etc). Some meats, such as meats from chickens that have
been fed on seafood remnants, may also contain the organic forms of arsenic. Following ingestion of
arsenobetaine and arsenocholine, these compounds undergo rapid renal clearance to become
concentrated in the urine. Organic arsenic is completely excreted within 1 to 2 days after ingestion and
there are no residual toxic metabolites. The biologic half-life of organic arsenic is 4 to 6 hours. For
reporting purposes, the concentrations of the inorganic forms (As[3+] and As[5+]) along with the
methylated forms (monomethylarsine and dimethylarsine) will be summed and reported together as
'Inorganic' arsenic. This is consistent with how the biological exposure index (BEI) reference range is
reported.
Useful For: Diagnosis of arsenic intoxication in random urine specimens

Interpretation: The quantitative reference range for fractionated arsenic applies only to the inorganic
forms. Concentrations of 20 mcg inorganic arsenic per liter or higher are considered toxic. There is no
limit to the normal range for the organic forms of arsenic, since they are not considered to be toxic and are
normally present after consumption of certain food types. For example, a typical finding in a urine
specimen with total 24-hour excretion of arsenic of 350 mcg/24 hours would be that more than 95% is
present as the organic species from a dietary source, and less than 5% is present as the inorganic species.
This would be interpreted as indicating the elevated total arsenic was due to ingestion of the nontoxic
form of arsenic, usually found in seafood. A normal value for blood arsenic does not exclude a finding of
elevated urine inorganic arsenic, due to the very short half-life of blood arsenic.
Reference Values:
TOXIC ARSENIC
<35 mcg/L
Arsenic Speciation Interpretive Information:

The toxic arsenic concentration represents the sum of the inorganic and methylated arsenic species. The
reference value for toxic arsenic is <35 mcg/L. This value is based on the ACGIH Biological Exposure
Index (BEI), which does not include the nontoxic organic arsenic.
Clinical References: 1. Caldwell KL, Jones RL, Verdon CP, Jarrett JM, Caudill SP, Osterloh JD:
Levels of urinary total and speciated arsenic in the US population: National Health and Nutrition
Examination Survey 2003-2004. J Expo Sci Environ Epidemiol. 2009;19:59-68 2. Agency for Toxic
Substances and Disease Registry: Toxicological profile for arsenic. US Department of Health and Human
Services. 2007. Available at www.atsdr.cdc.gov/ToxProfiles/tp2.pdf 3. Strathmann FG, Blum LM: Toxic
elements. In: Rafai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:chap 42
ASU24 Arsenic with Reflex, 24 Hour, Urine

Earthâ€™s crust. Arsenic is classified chemically as a metalloid, having both properties of a metal and a
down to the less toxic methylated metabolites monomethylarsinic acid (MMA) and subsequently
dimethylarsinic acid (DMA). In the past, inorganic arsenic compounds were predominantly used as
contains the greatest amounts of arsenic, for fish and shellfish, this is mostly in an organic form of arsenic
called arsenobetaine, which is much less harmful. Some seaweed may contain arsenic in the inorganic
form, which is more toxic. In the United States, some areas also contain high natural levels of arsenic in
rock, which can lead to elevated levels in the soil and drinking water. Occupational (eg, copper or lead
smelting, wood treating, or pesticide application) expose is another source where people may be
Useful For: Preferred screening test for detection of arsenic exposure using 24-hour urine specimens
Interpretation: Physiologically, arsenic exists in a number of toxic and nontoxic forms. The total
arsenic concentration reflects all the arsenic present in the sample regardless of species (eg, inorganic
vs. methylated vs. organic arsenic). The measurement of urinary total arsenic levels is generally
accepted as the most reliable indicator of recent arsenic exposure. However, if the total urine arsenic
concentration is elevated, arsenic speciation must be performed to identify if it is the toxic forms (eg,
inorganic and methylated forms) or the relatively non-toxic organic forms (eg, arsenobetaine and
arsenocholine). The inorganic toxic forms of arsenic (eg, As[III] and As[V]) are found in the urine
shortly after ingestion, whereas the less toxic methylated forms (monomethylarsinic acid: MMA
dimethylarsinic acid: DMA) are the species that predominate longer than 24 hours after ingestion. In
general, urinary As(III) and As(V) concentrations peak in the urine at approximately 10 hours and
return to normal 20 to 30 hours after ingestion. Urinary MMA and DMA concentrations normally peak
at approximately 40 to 60 hours and return to baseline 6 to 20 days after ingestion. After a seafood meal
(seafood generally contains the nontoxic, organic form of arsenic (eg, arsenobetaine), the urine output
of arsenic may increase to over 300 mcg/24 hour specimen, after which it will decline. This test can
determine if you have been exposed to above-average levels of arsenic. It cannot predict whether the
arsenic levels in your body will affect your health.
Reference Values:
> or =18 years: <35 mcg/24 hour
1;408(5):1190-1194 2. Caldwell K, Jones R, Verdon C, et al: Levels of urinary total and speciated
arsenic in the US population: National Health and Nutrition Examination Survey 2003-2004. J Expo Sci
Environ Epidemiol. 2009 Jan;19(1):59-68 3. Agency for Toxic Substances and Disease Registry:
Toxicological profile for arsenic. US Department of Health and Human Services. August 2007.
https://www.atsdr.cdc.gov/ToxProfiles/tp2.pdf 4. Strathmann FG, Blum LM: Toxic elements. In: Rafai
N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics.
6th ed. Elsevier; 2018:chap 42 5. Keil DE, Berger-Ritchie J, McMillin GA: Testing for toxic elements:
A focus on arsenic, cadmium, lead, and mercury. Lab Med. 2011 Dec;42(12):735-742.
https://academic.oup.com/labmed/article/42/12/735/2504927 6. Navas-Acien A, Francesconi KA,
arsenobetaine in the US population. Environ Res. 2011 Jan;111(1):110-8. doi:
Feb;34(2):188-202. doi: 10.1002/tox.22673
ASB Arsenic, Blood

8645 Clinical Information: Arsenic (As) exists in a number of toxic and nontoxic forms. The toxic
forms are the inorganic species As(5+), also denoted as As(V), the more toxic As(3+), also known as
As(III), and their partially detoxified metabolites, monomethylarsine (MMA) and dimethylarsine
(DMA). Detoxification occurs in the liver as As(3+) is oxidized to As(5+) and then methylated to MMA
and DMA. As a result of these detoxification steps, As(3+) and As(5+) are found in the urine shortly
after ingestion, whereas MMA and DMA are the species that predominate more than 24 hours after
ingestion. Blood concentrations of arsenic are elevated for a short time after exposure, after which
arsenic rapidly disappears into tissues because if its affinity for tissue proteins. The body treats arsenic
like phosphate, incorporating it wherever phosphate would be incorporated. Arsenic "disappears" into
the normal body pool of phosphate and is excreted at the same rate as phosphate (excretion half-life of
12 days). The half-life of inorganic arsenic in blood is 4 to 6 hours, and the half-life of the methylated
metabolites is 20 to 30 hours. Abnormal blood arsenic concentrations (>12 ng/mL) indicate significant
exposure, but will only be detected immediately after exposure. Arsenic is not likely to be detected in
blood specimens drawn more than 2 days after exposure because it has become integrated into
nonvascular tissues. Consequently, blood is not a good specimen to screen for arsenic, although periodic
blood levels can be determined to follow the effectiveness of therapy. Urine is the preferred specimen
for assessment of arsenic exposure. A wide range of signs and symptoms may be seen in acute arsenic
poisoning including headache, nausea, vomiting, diarrhea, abdominal pain, hypotension, fever,
hemolysis, seizures, and mental status changes. Symptoms of chronic poisoning, also called arseniasis,
are mostly insidious and nonspecific. The gastrointestinal tract, skin, and central nervous system are
usually involved. Nausea, epigastric pain, colic (abdominal pain), diarrhea, and paresthesias of the
hands and feet can occur.
Useful For: Detection of acute or very recent arsenic exposure Monitoring the effectiveness of therapy
This test is not useful for evaluation of chronic arsenic exposure.
Interpretation: Abnormal blood arsenic concentrations (>12 ng/mL) indicate significant exposure.
Absorbed arsenic is rapidly distributed into tissue storage sites with a blood half-life of <6 hours. Unless a
blood specimen is drawn within 2 days of exposure, arsenic is not likely to be detected in a blood
specimen.
Reference Values:
<13 ng/mL
Clinical References: 1. Hall M, Chen Y, Ahsan H, et al: Blood arsenic as a biomarker of arsenic
exposure: results from a prospective study. Toxicology. 2006;225 (2-3):225-233 2. Strathmann FG, Blum
LM: Toxic Elements. In: Rafai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical Chemistry
and Molecular Diagnostics 6th ed. Elsevier, 2018;chap 42
ASHA Arsenic, Hair

8651 Clinical Information: Arsenic circulating in the blood will bind to protein by formation of a covalent
complex with sulfhydryl groups of the amino acid cysteine. Keratin, the major structural protein in hair
and nails, contains many cysteine residues and, therefore, is one of the major sites for accumulation of
arsenic. Since arsenic has a high affinity for keratin, the concentration of arsenic in hair is higher than in
other tissues. Arsenic binds to keratin at the time of exposure, "trapping" the arsenic in hair. Therefore,
hair analysis for arsenic is not only used to document that an exposure occurred, but when it occurred.
Hair collected from the nape of the neck can be used to document recent exposure. Axillary or pubic hair
is used to document long-term (6 months-1 year) exposure.
Useful For: Detection of nonacute arsenic exposure in hair specimens

Interpretation: Hair grows at a rate of approximately 0.5 inch/month. Hair keratin synthesized today
will protrude through the skin in approximately 1 week. Thus, a hair specimen collected at the skin level
represents exposure of 1 week ago, 1 inch distally from the skin represents exposure 2 months ago, etc.
Hair arsenic levels above 1.00 mcg/g dry weight may indicates excessive exposure. It is normal for some
arsenic to be present in hair, as everybody is exposed to trace amounts of arsenic from the normal diet.
The highest hair arsenic observed at Mayo Clinic was 210 mcg/g dry weight in a case of chronic exposure
that was the cause of death.
Reference Values:
> or =16 years: <1.0 mcg/g of hair
Clinical References: 1. Sthiannopkao S, Kim K-W, Cho KH, et al: Arsenic levels in human hair,
Kandal Province, Cambodia: The influences of groundwater arsenic, consumption period, age and gender.
Applied Geochemistry 2010;25:81-90 2. Pearse DC, Dowling K, Gerson AR, et al: Arsenic
microdistribution and speciation in toenail clippings of children living in a historic gold mining area. Sci
Total Environ 2010;408:2590-2599
ASNA Arsenic, Nails

89848 Clinical Information: Arsenic circulating in the blood will bind to protein by formation of a
covalent complex with sulfhydryl groups of the amino acid cysteine. Keratin, the major structural
protein in hair and nails, contains many cysteine residues and, therefore, is one of the major sites for
accumulation of arsenic. Since arsenic has a high affinity for keratin, the concentration of arsenic in
nails is higher than in other tissues. Several weeks after exposure, transverse white striae, called Mees'
lines, may appear in the fingernails.
Useful For: Detection of nonacute arsenic exposure

Interpretation: Nails grow at a rate of approximately 0.1 inch/month. Nail keratin synthesized today
will grow to the distal end in approximately 6 months. Thus, a nail specimen collected at the distal end
represents exposure of 6 months ago. Nail arsenic above 1.0 mcg/g dry weight may indicate excessive
exposure. It is normal for some arsenic to be present in nails, as everybody is exposed to trace amounts
of arsenic from the normal diet. The highest hair or nail arsenic observed at Mayo Clinic was 210 mcg/g
dry weight in a case of chronic exposure that was the cause of death.
Reference Values:
> or =16 years: <1.0 mcg/g of nails
Clinical References: Hindmarsh JT, McCurdy RF: Clinical and environmental aspects of arsenic
toxicity. Crit Rev Clin Lab Sci 1986;23:315-347
ASCU Arsenic/Creatinine Ratio, Urine

environment combined with other elements such as oxygen, chlorine, and sulfur. Arsenic combined
with these elements is called inorganic arsenic. Arsenic combined with carbon and hydrogen is referred
to as organic arsenic. The organic forms (eg, arsenobetaine and arsenocholine) are relatively nontoxic,
while the inorganic forms are toxic. The toxic inorganic forms are arsenite (As[3+]/AsIII) and arsenate
(As[5+]/As[V]).Â Inorganic As(V) is readily reduced to inorganic As(III), which is then primarily
broken down to the less toxic methylated metabolites, monomethylarsinic acid (MMA) and
subsequently dimethylarsinic acid (DMA).Â In the past, inorganic arsenic compounds were
predominantly used as pesticides, primarily on cotton fields and in orchards. Inorganic arsenic
compounds can no longer be used in agriculture. However, organic arsenic compounds, namely
cacodylic acid, disodium methylarsenate (DSMA), and monosodium methylarsenate (MSMA), are still
used as pesticides, principally on cotton. Some organic arsenic compounds are used as additives in
animal feed. Small quantities of elemental arsenic are also added to other metals to form metal mixtures
or alloys with improved properties. The greatest use of arsenic in alloys is in lead-acid batteries for
automobiles. Another important use of arsenic compounds is in semiconductors and light-emitting
diodes. People are exposed to arsenic by eating food, drinking water, or breathing air. Of these, food is
usually the largest source of arsenic. The predominant dietary source of arsenic is seafood, followed by
rice/rice cereal, mushrooms, and poultry. While seafood contains the greatest amounts of arsenic, from
fish and shellfish, this is mostly in an organic form of arsenic called arsenobetaine, which is much less
harmful. Some seaweed may contain arsenic in the inorganic form, which is more toxic. In the United
States, some areas also contain high natural levels of arsenic in rock, which can lead to elevated levels
in the soil and drinking water. Occupational (eg, copper or lead smelting, wood treating, or pesticide
application) exposure is another source where people may be introduced to elevated levels of arsenic.
Lastly, hazardous waste sites may contain large quantities of arsenic and, if not disposed of properly,
may get into the surrounding water, air, or soil. A wide range of signs and symptoms may be seen in
acute arsenic poisoning including headache, nausea, vomiting, diarrhea, abdominal pain, hypotension,
fever, hemolysis, seizures, and mental status changes. Symptoms of chronic poisoning, also called
the hands and feet can also occur. Since arsenic is excreted predominantly by glomerular filtration,
measurement of arsenic in urine is the most reliable means of detecting arsenic exposures within the last
several days.
Useful For: Screening for arsenic exposure using random urine specimens
arsenic concentration reflects all the arsenic present in the sample regardless of species (eg, inorganic vs.
methylated vs. organic arsenic). The measurement of urinary total arsenic levels is generally accepted as
the most reliable indicator of recent arsenic exposure. However, if the total urine arsenic concentration is
elevated, arsenic speciation must be performed to identify if it is the toxic forms (eg, inorganic and
methylated forms) or the relatively nontoxic organic forms (eg, arsenobetaine and arsenocholine). The
inorganic toxic forms of arsenic (eg, As[III] and As[V]) are found in the urine shortly after ingestion,
whereas the less toxic methylated forms monomethylarsinic acid (MMA) and dimethylarsinic acid
(DMA), are the species that predominate longer than 24 hours after ingestion. In general, urinary As[III]
and As[V] concentrations peak in the urine at approximately 10 hours and return to normal 20 to 30 hours
after ingestion. Urinary MMA and DMA concentrations normally peak at approximately 40 to 60 hours
and return to baseline 6 to 20 days after ingestion. This test can determine if a patient has been exposed to
above-average levels of arsenic. It cannot predict whether the arsenic levels in their body will affect their
health.
Reference Values:
-ASUCR / Arsenic/Creatinine Ratio, with Reflex, Random, Urine
-HMUCR / Heavy Metal/Creatinine Ratio, with Reflex, Random, Urine
Survey 2003-2004. J Expo Sci Environ Epidemiol. 2009 Jan;19(1):59-68 3. Agency for Toxic Substances
and Disease Registry: Toxicological profile for arsenic. US Department of Health and Human Services.
August 2007. Available at www.atsdr.cdc.gov/ToxProfiles/tp2.pdf 4. Strathmann FG, Blum LM: Toxic
elements. In: Riafai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:chap 42 5. Keil DE, Berger-Ritchie J, McMillin GA:
Testing for toxic elements: A focus on arsenic, cadmium, lead, and mercury. Lab Med. 2011 Dec;
42(12):735-742. doi: 10.1309/LMYKGU05BEPE7IAW 6. Navas-Acien A, Francesconi KA, Silbergeld
EK, Guallar E: Seafood intake and urine concentrations of total arsenic, dimethylarsinate and
Feb;34(2):188-202 doi: 10.1002/tox.22673
ASUCR Arsenic/Creatinine, Ratio, with Reflex, Random, Urine

down to the less toxic methylated metabolites, monomethylarsinic acid (MMA) and subsequently
dimethylarsinic acid (DMA).Â In the past, inorganic arsenic compounds were predominantly used as
contains the greatest amounts of arsenic, from fish and shellfish, this is mostly in an organic form of
arsenic called arsenobetaine, which is much less harmful. Some seaweed may contain arsenic in the
inorganic form, which is more toxic. In the United States, some areas also contain high natural levels of
arsenic in rock, which can lead to elevated levels in the soil and drinking water. Occupational (eg, copper
or lead smelting, wood treating, or pesticide application) exposure is another source where people may be
Useful For: Preferred screening test for detection of arsenic exposure using random urine specimens
arsenic concentration reflects all the arsenic present in the sample regardless of species (eg, inorganic
vs. methylated vs. organic arsenic). The measurement of urinary total arsenic levels is generally
accepted as the most reliable indicator of recent arsenic exposure. However, if the total urine arsenic
concentration is elevated, arsenic speciation must be performed to identify if it is the toxic forms (eg,
inorganic and methylated forms) or the relatively nontoxic organic forms (eg, arsenobetaine and
arsenocholine). The inorganic toxic forms of arsenic (eg, As[III] and As[V]) are found in the urine
shortly after ingestion, whereas the less toxic methylated forms, monomethylarsinic acid (MMA) andÂ
dimethylarsinic acid (DMA) are the species that predominate longer than 24 hours after ingestion. In
general, urinary As(III) and As(V) concentrations peak in the urine at approximately 10 hours and
return to normal 20 to 30 hours after ingestion. Urinary MMA and DMA concentrations normally peak
at approximately 40 to 60 hours and return to baseline 6 to 20 days after ingestion. This test can
determine if a patient has been exposed to above-average levels of arsenic. It cannot predict whether the
arsenic levels in their body will affect their health.
Reference Values:
> or =18 years: <24 mcg/g creatinine
Survey 2003-2004. J Expo Sci Environ Epidemiol. 2009 Jan;19(1):59-68 3. Agency for Toxic
Substances and Disease Registry: Toxicological profile for arsenic. US Department of Health and
Human Services. August 2007. Available at www.atsdr.cdc.gov/ToxProfiles/tp2.pdf 4. Strathmann FG,
Blum LM: Toxic elements. In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:chap 42 5. Keil DE, Berger-Ritchie J,
McMillin GA: Testing for toxic elements: A focus on arsenic, cadmium, lead, and mercury. Lab Med.
2011 Dec;42(12):735-742. doi: 10.1309/LMYKGU05BEPE7IAW 6. Navas-Acien A, Francesconi KA,
Feb;34(2):188-202 doi: 10.1002/tox.22673
FART Artichoke (Cynara scolymus) IgE

57913 Interpretation: Class IgE (kU/L) Comment 0 <0.35 Below Detection 1 0.35 Ã¢â‚¬â€œ 0.69 Low
Positive 2 0.70 Ã¢â‚¬â€œ 3.49 Moderate Positive 3 3.50 Ã¢â‚¬â€œ 17.49 Positive 4 17.50 Ã¢â‚¬â€œ
49.99 Strong Positive 5 50.00 Ã¢â‚¬â€œ 99.99 Very Strong Positive 6 >99.99 Very Strong Positive
Reference Values:
<0.35
ARSU Arylsulfatase A, 24 Hour, Urine

8777 Clinical Information: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused
by a deficiency of the arylsulfatase A (ARSA) enzyme, which leads to the accumulation of sulfatides
(both galactosyl and lactosyl sulfatide) in the white matter of the central nervous system, the peripheral
nervous system, and to a lesser extent, in visceral organs including the kidney and gallbladder. Cells that
produce myelin are especially affected causing the characteristic leukodystrophy seen in MLD. Patients
with MLD excrete excessive amounts of sulfatides in their urine. The 3 clinical forms of MLD are
late-infantile, juvenile, and adult, depending on age of onset. All forms result in progressive neurologic
changes and leukodystrophy demonstrated on magnetic resonance imaging. Late-infantile MLD is the
most common (50%-60% of cases) and usually presents before 30 months of age with hypotonia,
clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration occurs and, unless
successfully treated, most patients do not survive past childhood. Juvenile MLD (20%-30% of cases) is
characterized by onset between 30 months to 16 years. Presenting features are behavior problems,
declining school performance, clumsiness, and slurred speech. Neurodegeneration occurs at a somewhat
slower and more variable rate than the late-infantile form. Adult MLD (15%-20% of cases) has an onset
after puberty and can be as late as the fourth or fifth decade. Presenting features are often behavior and
personality changes, including psychiatric symptoms. Clumsiness, neurologic symptoms, and seizures are
also common. The disease course has variable progression and may occur over 2 to 3 decades. The
disease prevalence is estimated to be approximately 1 in 100,000. MLD is an autosomal recessive disorder
and is caused by variants in the ARSA gene coding for the ARSA enzyme. This disorder is distinct from
conditions caused by deficiencies of arylsulfatase B (Maroteaux-Lamy disease) and arylsulfatase C
(steroid sulfatase deficiency). Saposin B deficiency is a rare autosomal recessive disorder with symptoms
that mimic MLD; however, the ARSA enzyme level is normal. Like MLD, patients with saposin B
deficiency can also excrete excessive amounts of sulfatides in their urine. Individuals with multiple
sulfatase deficiency, which is clinically distinct from MLD, will also have deficiency of arylsulfatase A,
however, other sulfatase enzymes will also be deficient. Individuals with "pseudodeficiency" of ARSA
have very low levels of ARSA activity but are otherwise healthy. Pseudodeficiency is being recognized
with increasing frequency among patients with other apparently unrelated neurologic conditions as well as
among the general population, therefore a diagnosis of MLD cannot be based upon reduced ARSA
activity alone To confirm a diagnosis, additional studies, such as molecular genetic testing of ARSA
(CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify Gene List ID:
IEMCP-WHFH2K), urinary excretion of sulfatides (CTSA / Ceramide Trihexosides and Sulfatides,
Urine), and/or histological analysis for metachromatic lipid deposits in nervous system tissue are
recommended. Current treatment options for MLD are focused on managing disease manifestations such
as seizures, decline in mobility and cognitive ability, and feeding difficulties. Hematopoietic stem cell
transplantation is an option but outcomes are dependent on the clinical stage and the presence of
neurologic symptoms.
Useful For: Detection of arylsulfatase A deficiency using urine specimens This test is not suitable for
carrier detection.
Interpretation: Reduced levels of arylsulfatase A are seen in patients with metachromatic
leukodystrophy (MLD). Individuals with pseudodeficiency of arylsulfatase A can have results in the
affected range but are otherwise unaffected with MLD. Abnormal results should be confirmed using
CTSA / Ceramide Trihexosides and Sulfatides, Urine. If molecular confirmation is desired, consider
molecular genetic testing of ARSA (CGPH / Custom Gene Panel, Hereditary, Next-Generation
Sequencing, Varies; specify Gene List ID: IEMCP-WHFH2K).
Reference Values:
> or =19 nmol/h/mL
Note: Results from this assay may not reflect carrier status because of individual variation of
arylsulfatase A enzyme levels. Low normal values may be due to the presence of pseudodeficiency or
carrier alleles. Patients with these depressed levels may be phenotypically normal.
Clinical References: 1. Gieselmann V, Ingeborg KM: Metachromatic leukodystrophy. In: Valle

D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular
Bases of Inherited Disease. McGraw-Hill; 2019. Accessed March 29, 2021. Available at
https://ommbid.mhmedical.com/content.aspx?sectionid=225546629 2. Gomez-Ospina N: Arylsulfatase
A deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of
Washington, Seattle; Updated April 30, 2020. Accessed March 29, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK1130/ 3. Fumagalli F, Zambon AA, Rancoita PMV, et al.
Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients. J Inherit Metab Dis.
2021 Sep;44(5):1151-1164. doi: 10.1002/jimd.12388. 4. van Rappard DF, Boelens JJ, Wolf NI:
Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best Pract Res Clin
Endocrinol Metab. 2015 Mar;29(2):261-273. doi: 10.1016/j.beem.2014.10.001
ARSAW Arylsulfatase A, Leukocytes

8779 Clinical Information: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder
caused by a deficiency of the enzyme arylsulfatase A (ARSA), which leads to the accumulation of
sulfatides (both galactosyl and lactosyl sulfatide) in the white matter of the central nervous system, the
peripheral nervous system, and, to a lesser extent, in visceral organs including the kidney and
gallbladder. Cells that produce myelin are especially affected causing the characteristic leukodystrophy
seen in MLD. Patients with MLD excrete excessive amounts of sulfatides in their urine. The 3 clinical
forms of MLD are late-infantile, juvenile, and adult, depending on age of onset. All forms result in
progressive neurologic changes and leukodystrophy demonstrated on magnetic resonance imaging.
Late-infantile MLD is the most common (50%-60% of cases) and usually presents before 30 months of
age with hypotonia, clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration
occurs and, unless successfully treated, most patients do not survive past childhood. Juvenile MLD
(20%-30% of cases) is characterized by onset between 30 months to 16 years old. Presenting features
are behavior problems, declining school performance, clumsiness, and slurred speech.
Neurodegeneration occurs at a somewhat slower and more variable rate than the late-infantile form.
Adult MLD (15%-20% of cases) has an onset after puberty and can be as late as the fourth or fifth
decade. Presenting features are often behavior and personality changes, including psychiatric symptoms.
Clumsiness, neurologic symptoms, and seizures are also common. The disease course has variable
progression and may occur over 2 to 3 decades. The disease prevalence is estimated to be approximately
1 in 100,000. MLD is an autosomal recessive disorder caused by variants in the ARSA gene. This
disorder is distinct from conditions caused by deficiencies of arylsulfatase B (Maroteaux-Lamy disease)
and arylsulfatase C (steroid sulfatase deficiency). Saposin B deficiency is a rare autosomal recessive
disorder with symptoms that mimic MLD; however, the ARSA enzyme level is normal. Like MLD,
patients with saposin B deficiency can excrete excessive amounts of sulfatides in their urine. Individuals
with multiple sulfatase deficiency, which is clinically distinct from MLD, will also have deficiency of
arylsulfatase A, however, other sulfatase enzymes will also be deficient. Individuals with
"pseudodeficiency" of ARSA have very low levels of ARSA activity but are otherwise healthy.
Pseudodeficiency is being recognized with increasing frequency among patients with other apparently
unrelated neurologic conditions as well as among the general population, therefore a diagnosis of MLD
cannot be based upon reduced ARSA activity alone To confirm a diagnosis, additional studies, such as
molecular genetic testing of ARSA (CGPH / Custom Gene Panel, Hereditary, Next-Generation
Sequencing, Varies; specify Gene List ID: IEMCP-WHFH2K), urinary excretion of sulfatides (CTSU /
Ceramide Trihexosides and Sulfatides, Random, Urine), and/or histological analysis for metachromatic
lipid deposits in nervous system tissue are recommended. Current treatment options for MLD are
focused on managing disease manifestations such as seizures, decline in mobility and cognitive ability,
and feeding difficulties. Hematopoietic stem cell transplantation is an option but outcomes are
dependent on the clinical stage and the presence of neurologic symptoms.
Useful For: Preferred enzymatic test for detection of arylsulfatase A deficiency This test is not suitable
for carrier detection.
Interpretation: Reduced levels of arylsulfatase A are seen in patients with metachromatic

leukodystrophy (MLD), however some patients with MLD may have normal results by this method.
Individuals with pseudodeficiency of arylsulfatase A can have results in the affected range but are
otherwise unaffected with MLD. Abnormal results and/or clinical suspicion should be confirmed using
CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine. If molecular confirmation is desired,
consider molecular genetic testing of ARSA (CGPH / Custom Gene Panel, Hereditary, Next-Generation
Sequencing, Varies; specify Gene List ID: IEMCP-WHFH2K).
Reference Values:
> or =62 nmol/h/mg
Note: Results from this assay may not reflect carrier status because of individual variation of
arylsulfatase A enzyme levels. Low normal values may be due to the presence of pseudodeficiency or
carrier alleles. Patients with these depressed levels may be phenotypically normal.
Clinical References: 1. Gieselmann V, Ingeborg KM: Metachromatic leukodystrophy. In: Valle D,

Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of
Inherited Disease. McGraw-Hill; 2019. Accessed March 29, 2021. Available at
https://ommbid.mhmedical.com/content.aspx?sectionid=225546629 2. Gomez-Ospina N: Arylsulfatase A
deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of
Washington, Seattle; Updated April 30, 2020. Accessed March 29, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK1130/ 3. Fumagalli F, Zambon AA, Rancoita PMV, et al.
Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients. J Inherit Metab Dis.
2021 Sep;44(5):1151-1164. doi: 10.1002/jimd.12388 4. van Rappard DF, Boelens JJ, Wolf NI:
Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best Pract Res Clin
Endocrinol Metab. 2015 Mar;29(2):261-273. doi: 10.1016/j.beem.2014.10.001
ASCRI Ascaris, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Ascaris worms Defining the allergen responsible
for eliciting signs and symptoms Identifying allergens: -Responsible for allergic disease and/or

Reference Values:
0 Negative

apply to all ages.
VITC Ascorbic Acid (Vitamin C), Plasma

42362 Clinical Information: Vitamin C, also known as L-ascorbic acid or simply ascorbic acid, is a
water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary
supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an
essential dietary component. Vitamin C is required for the enzymatic amidation of neuropeptides,
production of adrenal cortical steroid hormones, promotion of the conversion of tropocollagen to
collagen, and metabolism of tyrosine and folate. It also plays a role in lipid and vitamin metabolism and
is a powerful reducing agent or antioxidant. Specific actions include activation of detoxifying enzymes
in the liver; antioxidation, interception and destruction of free radicals; preservation and restoration of
the antioxidant potential of vitamin E; and blockage of the formation of carcinogenic nitrosamines. In
addition, vitamin C appears to function in a variety of other metabolic processes in which its role has
not been well characterized. Â Prolonged deficiency of vitamin C leads to the development of scurvy, a
disease characterized by an inability to form adequate intercellular substance in connective tissues. This
results in the formation of swollen, ulcerative lesions in the gums, mouth, and other tissues that are
structurally weakened. Early symptoms may include weakness, easy fatigue and listlessness, as well as
shortness of breath, and aching joints, bones, and muscles. Â The need for vitamin C can be increased
by the use of aspirin, oral contraceptives, tetracycline, and a variety of other medications. Psychological
stress and advancing age also tend to increase the need for vitamin C. Among older adults, lack of fresh
fruit and vegetables often adds vitamin C depletion to the inherently increased need, with development
of near-scurvy status
Useful For: Identifying vitamin C deficiency

Interpretation: Values below 0.2 mg/dL indicate significant deficiency. Values greater than or equal
to 0.2 mg/dL and less than 0.4 mg/dL are consistent with a moderate risk of deficiency due to
inadequate tissue stores. Values of 0.4 to 2.0 mg/dL indicate adequate supply. The actual level at which
vitamin C is excessive has not been defined. Values above 3.0 mg/dL are suggestive of excess intake.
Whether vitamin C in excess is indeed toxic continues to be uncertain. However, limited observations
suggest that this condition may induce uricosuria and, in individuals with glucose-6-phosphate
dehydrogenase deficiency, may induce increased red blood cell fragility.
Reference Values:
0.4-2.0 mg/dL
Clinical References: 1.Vitamin C toxicity. Nutr Rev. 1976 Aug;34(8):236-237. doi:

10.1111/j.1753-4887.1976.tb05776.x 2 2. Moser U, Bendich A: Vitamin C. In: Machlin LJ, ed.
Handbook of Vitamins. 2nd ed. Marcel Dekker; 1991:195-232 3. Ball GFM: Vitamins: Their Role in
the Human Body. Blackwell Publishing; 2004:393-420 4. Zlatuse DC, Frank EL: Development and
implementation of an HPLC-ECD method for analysis of vitamin C in plasma using single column and
automatic alternating dual column regeneration. Prac Lab Med. 2016 Dec 1;6:25-37. doi:
10.1016/j.plabm.2016.09.001 5. Marshall WJ, Ayling RM: Nutrition: Laboratory and clinical aspects.
Diagnostics 6th ed. Elsevier; 2018:chap 56
ASPAR Asparagus, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to asparagus Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
AST Aspartate Aminotransferase (AST) (GOT), Serum
8360 Clinical Information: Aspartate aminotransferase (AST) is found in high concentrations in liver,
heart, skeletal muscle, and kidney. AST is present in both cytoplasm and mitochondria of cells. In cases
involving mild tissue injury, the predominant form of AST is that from the cytoplasm. Severe tissue
damage results in more of the mitochondrial enzyme being released. High levels of AST can be found in
cases such as myocardial infarction, acute liver cell damage, viral hepatitis, and carbon tetrachloride
poisoning. Slight to moderate elevation of AST is seen in muscular dystrophy, dermatomyositis, acute
pancreatitis, and crushed muscle injuries.
Useful For: Diagnosing and monitoring liver disease, particularly diseases resulting in a destruction
of hepatocytes
Interpretation: Elevated aspartate aminotransferase (AST) values are seen in parenchymal liver
diseases characterized by a destruction of hepatocytes. Values are typically at least 10 times above the
normal range. Levels may reach values as high as 100 times the upper reference limit, although 20- to
50-fold elevations are most frequently encountered. In infectious hepatitis and other inflammatory
conditions affecting the liver, alanine aminotransferase (ALT) is characteristically as high as or higher
than AST, and the ALT:AST ratio, which normally and in other condition is less than 1, becomes
greater than unity. AST levels are usually elevated before clinical signs and symptoms of disease
appear. Five- to 10-fold elevations of both AST and ALT occur in patients with primary or metastatic
carcinoma of the liver, with AST usually being higher than ALT, but levels are often normal in the early
stages of malignant infiltration of the liver. Elevations of ALT activity persist longer than do those of
AST activity. Elevated AST values may also be seen in disorders affecting the heart, skeletal muscle,
and kidney.
Reference Values:
Males
0-11 months: not established
1-13 years: 8-60 U/L
> or =14 years: 8-48 U/L
Females
1-13 years: 8-50 U/L
> or =14 years: 8-43 U/L
Clinical References: Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood.

Philadelphia, WB Saunders Company, 1994
FASPE Aspen (Populus tremuloides) IgE

Reference Values:
<0.35 kU/L
ASPAG Aspergillus (Galactomannan) Antigen, Serum

84356 Clinical Information: Invasive aspergillosis (IA) is a severe infection that occurs in patients with
prolonged neutropenia, following transplantation or in conjunction with aggressive immunosuppressive
regimens (eg, prolonged corticosteroid usage, chemotherapy). The incidence of IA is reported to vary
from 5% to 20% depending on the patient population. IA has an extremely high mortality rate of 50% to
80% due in part to the rapid progression of the infection (ie, 1-2 weeks from onset to death).
Approximately 30% of cases remain undiagnosed and untreated at death. Definitive diagnosis of IA
requires histopathological evidence of deep-tissue invasion or a positive culture. However, this evidence
is often difficult to obtain due to the critically ill nature of the patient and the fact that severe
thrombocytopenia often precludes the use of invasive procedures to obtain a quality specimen. The
sensitivity of culture in this setting also is low, reportedly ranging from 30% to 60% for
bronchoalveolar lavage fluid. Accordingly, the diagnosis is often based on nonspecific clinical
symptoms (unexplained fever, cough, chest pain, dyspnea) in conjunction with radiologic evidence
(computed tomography: CT scan); definitive diagnosis is often not established before fungal
proliferation becomes overwhelming and refractory to therapy. Recently, a serologic assay was
approved by the FDA for the detection of galactomannan, a molecule found in the cell wall of
Aspergillus species. Serum galactomannan can often be detected a mean of 7 to 14 days before other
diagnostic clues become apparent, and monitoring of galactomannan can potentially allow initiation of
preemptive antifungal therapy before life-threatening infection occurs.
Useful For: Aiding in the diagnosis of invasive aspergillosis Assessing response to therapy
Interpretation: A positive result supports a diagnosis of invasive aspergillosis (IA). Positive results
should be considered in conjunction with other diagnostic procedures, such as microbiologic culture,
histological examination of biopsy specimens, and radiographic evidence. See Cautions. A negative result
does not rule out the diagnosis of IA. Repeat testing is recommended if the result is negative but IA is
suspected. Patients at risk of IA should have a baseline serum tested and should be monitored twice a
week for increasing galactomannan antigen levels. Galactomannan antigen levels may be useful in the
assessment of therapeutic response. Antigen levels decline in response to antimicrobial therapy.
Reference Values:
<0.5 index
Clinical References: 1. Maertens J, Verhaegen J, Lagrou K, Boogaerts M: Screening for circulating

galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic
patients and stem cell transplantation recipients: a prospective evaluation. Blood. 2001 March
15;97(6):1604-1610 2. Pinel C, Fricker-Hidalgo H, Lebeau B, et al: Detection of circulating Aspergillus
fumigatus galactomannan: value and limits of the Platelia test for diagnosing invasive aspergillosis. J Clin
Microbiol. 2003 May;41(5):2184-2186 3. Swanink CM, Meis JF, Rijs AJ, Donnelly JP, Verweij PE:
Specificity of a sandwich enzyme-linked immunosorbent assay for detecting Aspergillus galactomannan.
J Clin Microbiol. 1997 Jan;35(1):257-260 4. Ansorg R, van den Boom R, Rath P: Detection of
Aspergillus galactomannan antigen in foods and antibiotics. Mycoses. 1997 Dec;40(9-10):353-357 5.
Connolly P, Durkin M, Wheat LJ, et al: Rapid diagnosis of systemic and invasive mycoses. Clinical
Microbiology Newsletter 2007 Jan;29(1):1-5 6. Thompson GR, Patterson TF: Aspergillus species. In:
Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of
Infectious Diseases. 9th ed. Elsevier; 2020:3103-3116
FASAB Aspergillus Antibodies, Quantitative, DID

Aspergillus fumigatusÂ Â Â Neg: <1:1
Aspergillus flavusÂ Â Â Â Â Â Â Â Â Neg: <1:1
Aspergillus nigerÂ Â Â Â Â Â Â Â Â Â Neg: <1:1
ASPBA Aspergillus Antigen, Bronchoalveolar Lavage

61009 Clinical Information: Invasive aspergillosis (IA) is a severe infection that occurs in patients with
prolonged neutropenia following transplantation or in conjunction with aggressive immunosuppressive
regimens (eg, prolonged corticosteroid use, chemotherapy). The incidence of IA is reported to vary from
5% to 20% depending on the patient population. IA has an extremely high mortality rate of 50% to 80%,
due in part to the rapid progression of the infection (ie, 1-2 weeks from onset to death). Approximately
30% of cases remain undiagnosed and untreated at death. Definitive diagnosis of IA requires
histopathological evidence of deep-tissue invasion or a positive culture. However, this evidence is often
difficult to obtain due to the critically ill nature of the patient and the fact that severe thrombocytopenia
often precludes the use of invasive procedures to obtain a quality specimen. The sensitivity of culture in
this setting also is low, reportedly ranging from 30% to 60% for bronchoalveolar lavage (BAL) fluid.
Accordingly, the diagnosis is often based on nonspecific clinical symptoms (unexplained fever, cough,
chest pain, dyspnea) in conjunction with radiologic evidence (computed tomography scan), and a
definitive diagnosis is often not established before fungal proliferation becomes overwhelming and
refractory to therapy. Recently, a serologic assay was approved by the FDA for the detection of
galactomannan, a molecule found in the cell wall of Aspergillus species. Serum galactomannan
(Aspergillus antigen) can often be detected a mean of 7 to 14 days before other diagnostic clues become
apparent, and monitoring of Aspergillus antigen can potentially allow initiation of preemptive antifungal
therapy before life-threatening infection occurs. The clinical utility of Aspergillus antigen testing in BAL
specimens as an early prognostic indicator of IA has recently been assessed. These studies demonstrated
equivalent or higher sensitivity compared to detection of Aspergillus antigen in serum.(1-4) This assay
may be useful in the assessment of therapeutic response as antigen levels typically decline in response to
effective antimicrobial therapy.
Useful For: Aiding in the diagnosis of invasive aspergillosis and assessing response to therapy
Interpretation: A positive result in bronchoalveolar lavage (BAL) fluid supports a diagnosis of
invasive, pulmonary aspergillosis. Positive results should be considered in conjunction with other
diagnostic procedures, such as microbiologic culture, histological examination of biopsy specimens, and
radiographic evidence (see Cautions). A negative result in BAL fluid does not rule out the diagnosis of
invasive aspergillosis (IA). Patients at risk of IA should be monitored twice a week for Aspergillus
antigen levels in serum until determined to be clinically unnecessary. Aspergillus antigen levels
typically decline in response to effective antimicrobial therapy.
Reference Values:
<0.5 Index
Clinical References: 1. Park SY, Lee S, Choi S, et al: Aspergillus galactomannan antigen assay in
bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis. J Infect.
2010;61:492-498 2. Husain S, Clancy CJ, Nguyen MH, et al: Performance characteristics of the Platelia
aspergillus enzyme immunoassay for detection of Aspergillus galactomannan antigen in
bronchoalveolar lavage fluid. Clin Vaccine Immunol. 2008;15(12):1760-1763 3. Meersseman W,
Lagrou K, Maertens J, et al: Galactomannan in bronchoalveolar lavage fluid a tool for diagnosing
aspergillosis in intensive care unit patients. Am J Respir Crit Care Med. 2008;177:27-34 4. Becker MJ,
Lugtenburg EJ, Cornelissen JJ, Van Der Schee C, Hoogsteden HC, De Mari Se: Galactomannan
detection in computerized tomography-based bronchoalveolar lavage fluid and serum in haematological
patients at risk for invasive pulmonary aspergillosis. Br J Haematol. 2003;121:448-457 5. Xavier MO,
Pasqualotto AC, Cardoso IC, Severo LC: Cross-reactivity of Paracoccidioides brasiliensis, Histoplasma
capsulatum, and Cryptococcus species in the commercial Platelia Aspergillus enzyme immunoassay.
Clin Vaccine Immunol. 2009 Jan;16(1):132-133
FAFE Aspergillus flavus IgE

Reference Values:
<0.35 kU/L
ASP Aspergillus fumigatus, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Aspergillus fumigatus Defining the allergen

Reference Values:
0 Negative

apply to all ages.
SASP Aspergillus fumigatus, IgG Antibodies, Serum

9678 Clinical Information: Hypersensitivity pneumonitis (HP) is a type of interstitial lung disease caused
by an immune-mediated response to inhaled environmental antigens.(1) Patients with HP commonly
display symptoms of cough, dyspnea, and midinspiratory squeaks. Patients may present with an acute
onset of symptoms (within hours of antigen exposure) or a chronic onset (which may occur over a course
of weeks to months). The nature of an individualâ€™s disease course will be affected by several factors,
including quantity of inhaled antigen, intensity/frequency of exposure, and genetic background. The
epidemiology of HP is also challenging to understand, as incidence and prevalence of the disease varies
with geographic areas, climate, and local customs. While the immunopathogenesis of HP is not
completely understood, it is presumed to involve both type III and type IV hypersensitivity reactions, with
the type III reaction characterized by the presence of IgG antibodies specific for the inciting antigen.
There are many antigens, both organic and inorganic, that have been associated with development of
HP.(2) Causative organic antigens include a wide array of bacteria, mycobacteria, fungi, and animal
proteins. Aspergillus fumigatus is a fungus found in locations with high humidity, including soil,
greenhouses, and compost heaps. It is fairly ubiquitous and may even be found in household dust. Some
individuals exposed to A fumigatus, particularly those individuals with routine exposure to high-humidity
environments, may develop IgG antibodies against this antigen, which could lead to development of HP.
Clinical practice guidelines for HP include a diagnostic algorithm which focuses on exposure
identification, imaging evaluation, and bronchoalveolar lavage/histopathology.(3) Detection of IgG
antibodies specific for certain environmental antigens can help to document the causative exposure for an
individual. This is critical, as an important treatment for these patients is antigen avoidance. However,
IgG testing is only useful as supportive information for the diagnosis of HP; a positive result only
indicates sensitization to the antigen and a negative result does not exclude the possibility that a patient
with HP may be sensitized to another antigen.
Useful For: Evaluation of patients suspected of having hypersensitivity pneumonitis (HP) induced by
exposure to Aspergillus fumigatus Evaluation of patients suspected of having HP who have documented
environmental exposures to high-humidity environments
Interpretation: Positive results for IgG antibodies to Aspergillus fumigatus, in patients with signs
and symptoms of hypersensitivity pneumonitis, may be consistent with sensitization to this fungus.
Reference Values:
<4 years: not established
> or =4 years: < or =102 mg/L
Clinical References: 1. Sforza GG, Marinou A: Hypersensitivity pneumonitis: a complex lung

disease. Clin Mol Allergy. 2017; Mar 7;15(6). doi: 10.1186/s12948-017-0062-7 2. Costabel U,
Miyazaki Y, Pardo A, et al: Hypersensitivity pneumonitis. Nat Rev Dis Primers. 2020 Aug 6;6(1):65.
doi: 10.1038/s41572-020-0191-z 3. Raghu G, Remy-Jardin M, Ryerson CJ, et al: Diagnosis of
hypersensitivity pneumonitis in adults. An Official ATS/JRS/ALAT Clinical Practice Guideline.Â Am
J Respir Crit Care Med. 2020 August 1;202(3):e36-e69. doi: 10.1164/rccm.202005-2032ST
FASPG Aspergillus IgG Precipitins Panel

75681 Interpretation: The gel diffusion method was used to test this patients serum for the presence of
precipitating antibodies (IgG) to the antigens indicated. These antibodies are serological markers for
exposure and immunological sensitization. The clinical significance varies, depending on the history
and symptoms.
Reference Values:
Negative
ASPG Aspergillus niger, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Aspergillus niger Defining the allergen

Reference Values:
0 Negative

apply to all ages.
ADMA Asymmetric Dimethylarginine, Plasma

607697 Clinical Information: Asymmetric dimethylarginine (ADMA) is an independent risk factor for major
adverse cardiovascular events.(1-7) ADMA inhibits nitric oxide (NO) synthesis and is elevated in diseases
related to endothelial dysfunction including hypertension, hyperlipidemia, and type II diabetes mellitus.
Elevation in ADMA and subsequent NO synthesis inhibition leads to vasoconstriction, reduced peripheral
blood flow, and reduced cardiac output. Elevated plasma ADMA confers a 4- to 6-fold increased risk of
subsequent cardiovascular events or mortality among patients with acute coronary syndrome,(3) unstable
angina,(4) type II diabetes mellitus,(5) end-stage renal disease,(6) coronary heart disease,(7) and
peripheral artery disease.(1) Baseline ADMA remained a significant risk factor of adverse events even
after adjusting for low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol
(HDL-C), triglycerides, creatinine, and high-sensitivity C-reactive protein. Plasma ADMA concentrations
are lowered by rosuvastatin and atorvastatin, but not simvastatin in patients with hypercholesterolemia.(8)
Addition of vildagliptin (Galvus) to metformin significantly reduced ADMA concentrations among
patients with type II diabetes mellitus.(9)
Useful For: Assessing the likelihood of future coronary events in patients with coronary heart disease,
type II diabetes mellitus, or kidney disease Prompting intervention and assessing improvements among
subjects with elevated ADMA and hypercholesterolemia or type II diabetes mellitus
Interpretation: In patients with preexisting coronary conditions or at high risk for coronary events
(diabetes, renal insufficiency), asymmetric dimethylarginine (ADMA) levels in the upper tertile, above
112 ng/mL, confer an increased risk for future coronary events.
Reference Values:
> or =18 years: 63-137 ng/mL
Reference values have not been established for patients who are <18 years of age
Clinical References: 1. Chu R, Yu D, Chu J, et al: Prognostic efficacy of circulating asymmetric

dimtheylarginine in patients with peripheral arterial disease: A meta-analysis of prospective cohort
studies. Vascular. 2018;26:322-330 2. Schulze F, Lenzen H, Hanefeld C, et al.: Asymmetric
dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter
Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC)
study. Am Heart J. 2006 Sep;152(3):493.e1-8 3. Cavusoglu E, Ruwende C, Chopra V, et al: Relationship
of baseline plasma ADMA levels to cardiovascular outcomes at 2 years in men with acute coronary
syndrome referred for coronary angiography. Coron Artery Dis. 2009;20:112-117 4. Krempl TK, Maas R,
Sydow K, et al: Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent
cardiovascular events. Eur Heart J. 2005;26:1846-1851 5. Cavusoglu E, Ruwende C, Chopra V, et al:
Relation of baseline plasma ADMA levels to cardiovascular morbidity and mortality at two years in men
with diabetes mellitus referred for coronary angiography. Atherosclerosis. 2010 May;210(1):226-231 6.
Abedini S, Meinitzer A, Holme I, et al: Asymmetrical dimethylarginine is associated with renal and
cardiovascular outcomes and all-cause mortality in renal transplant recipients. Kidney Int. 2010
Jan;77(1):44-50 7. Valkonen VP, Paiva H, Salonen JT, et al: Risk of acute coronary events and serum
concentration of asymmetrical dimethylarginine. Lancet. 2001;358:2127-2128 8. Kurtoglu E, Sevket B,
Sincer I, et al: Comparison of effects of Rosuvastatin versus Atorvastatin treatment on plasma levels of
asymmetric dimethylarginine in patients with hyperlipidemia having coronary artery disease. Angiology.
2014;65:788-793 9. Cakirca M, Karatoprak C, Zorlu M, et al: Effect of vildagliptin add-on treatment to
metformin on plasma asymmetric dimethylarginine in type 2 diabetes mellitus patients. Drug Des Devel
Ther. 2014;8:239-243 10. Ravani P, Tripepi G, Malberti F, et al: Asymmetrical dimethylarginine predicts
progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling
approach. J Am Soc Nephrol. 2005;16:2449-2455 11. Elesber AA, Solomon H, Lennon RJ, et al:Â
Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric
dimethylarginine in patients with early atherosclerosis. Eur Heart J. 2006 Apr;27(7):824-31
ATRX ATRX Immunostain, Technical Component Only

70360 Clinical Information: This test is intended to identify the presence of ATP-dependent helicase
ATRX, X-linked helicase II (ATRX) protein. ATRX is produced by most mitotically active normal cells
and can be useful in the distinction of differentiated from undifferentiated neoplasms.
Useful For: Distinguishing differentiated from undifferentiated neoplasms

Interpretation: This test does not include pathologist interpretation; only technical performance of
Clinical References: 1. Wiestler B, Capper D, Holland-Letz T, et al: ATRX loss refines the
classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with
better prognosis. Acta Neuropathol. 2013 Sep;126(3):443-451 2. De La Fuente R, Baumann C, Viveiros
MM: Role of ATRX in chromatin structure and function: implications for chromosome instability and
human disease. Reproduction. 2011 Aug;142(2):221-234 3. Zhang J, Francois R, Iyer R, Seshadri M,
Zajac-Kaye M, Hochwald SN: Current understanding of the molecular biology of pancreatic
neuroendocrine tumors. J Natl Cancer Inst. 2013 Jul 17;105(14):1005-1017
AHUSD Atypical Hemolytic Uremic Syndrome Complement Panel,

64881 Serum and Plasma
Clinical Information: Individuals presenting with thrombotic microangiopathies (TMA) require
clinical testing to identify the underlying cause. Thrombotic thrombocytopenic purpura (TTP) and
hemolytic uremic syndrome (HUS) are both acute syndromes with many overlapping clinical features.
Reduced levels of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1
motives, member 13) activity is associated with TTP and is one laboratory feature that distinguishes
TTP from HUS. HUS can also have a number of causes; one of the rarer forms of disease is caused by
defects in the alternative pathway of the complement system, so called atypical-HUS (aHUS). Patients
with defective alternative pathway regulation can benefit from biologics that suppress the complement
system. The purpose of this panel is to aid in the differential diagnosis of TMA. The suggested approach
is to rule-out other causes of TMA first, since aHUS is one of the rarer causes of TMA. Additionally,
the assays can be used in the setting of membranoproliferative glomerulonephritis (MPGN) and can
help distinguish between immune-complex mediated or complement-mediated kidney disease. MPGN
mediated by immune-complexes are ones resulting from infectious processes, autoimmune diseases, or
monoclonal gammopathies; whereas complement-mediated MPGN can be subdivided in C3
glomerulonephritis and dense deposit disease, based on electron microscopy of the kidney biopsy
histological findings. Despite phenotypic differences, these glomerular diseases share dysfunction of the
alternative pathway as the defining pathophysiology.
Useful For: Detecting deficiencies in the alternative pathway that can cause atypical-hemolytic uremic
syndrome, dense deposit disease, and C3 glomerulonephritis A second-tier test that aids in the differential
diagnosis of thrombotic microangiopathies
Interpretation: An interpretive report will be included.

Reference Values:
FACTOR B COMPLEMENT ANTIGEN
15.2-42.3 mg/dL
SC5b-9 COMPLEMENT
< or =250 ng/mL
FACTOR H COMPLEMENT ANTIGEN

18.5 to 40.8 mg/dL
C4d COMPLEMENT ACTIVATION FRAGMENT

< or =9.8 mcg/mL
CBb COMPLEMENT ACTIVATION FRAGMENT

< or =1.6 mcg/mL
COMPLEMENT C4
14-40 mg/dL
COMPLEMENT C3
75-175 mg/dL
ALTERNATIVE COMPLEMENT, PATHWAY (AH50) FUNCTIONAL

> or =46% normal
COMPLEMENT, TOTAL
30-75 U/mL
Clinical References: 1. Daha MR: Role of complement in innate immunity and infections. Crit Rev
Immunol. 2010;30(1):47-52. doi: 10.1615/critrevimmunol.v30.i1.30 2. Prohaszka Z, Varga L, Fust G: The
use of "real-time" complement analysis to differentiate atypical haemolytic uraemic syndrome from other
forms of thrombotic microangiopathies. Br J Haematol. 2012;158(3):424-425. doi:
10.1111/j.1365-2141.2012.09168.x 3. Cataland SR, Holers VM, Geyer S, Yang S, Wu HM: Biomarkers
of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP.
Blood. 2014;123(24):3733-3738. 10.1182/blood-2013-12-547067 4. Go RS, Winters JL, Leung N, et al:
Thrombotic microangiopathy care pathway: A consensus statement for the Mayo Clinic Complement
Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin
Proc. 2016;91(9):1189-1211. doi: 10.1016/j.mayocp.2016.05.015 5. Willrich MAV, Andreguetto BD,
Sridharan M, et al: The impact of eculizumab on routine complement assays. J Immunol Methods.
2018;460:63-71. doi: 10.1016/j.jim.2018.06.010
HHLP AudioloGene Hereditary Hearing Loss Panel, Varies

606144 Clinical Information: Hereditary hearing loss encompasses a heterogeneous group of syndromic and
nonsyndromic conditions. A comprehensive diagnostic genetic test is useful to help determine a molecular
etiology for hearing loss and, therefore, identify other organ systems that may be involved, establish
long-term prognosis, and ascertain the inheritance pattern and recurrence risk within a family. Individuals
with syndromic hearing loss typically have involvement of other organs or organ systems and may have
malformations of the external ear. Individuals with nonsyndromic hearing loss may have abnormalities of
the middle ear and/or inner ear but typically do not have visible abnormalities of the external ear and often
do not have additional organ system involvement or other related medical problems. Approximately 50%
of individuals with hearing loss have a genetic etiology that can be identified. Of those, approximately
70% of individuals have a nonsyndromic condition, and the remaining 30% have 1 of over 400 syndromes
involving hearing loss. Of the individuals with nonsyndromic hearing loss, at least three-quarters have an
autosomal recessive condition, approximately 25% of whom have variants in the GJB2 or GJB6 genes.
Useful For: Establishing a diagnosis of a syndromic or nonsyndromic hereditary hearing loss

disorder Identifying variants within genes known to be associated with hereditary hearing loss, allowing
for predictive testing of at-risk family members
Interpretation: Variant curation is performed using published American College of Medical

Genetics and Genomics and the Association for Molecular Pathology recommendations as a
guideline.(1) Other gene-specific guidelines may also be considered. Variants are classified based on
known, predicted, or possible pathogenicity, and reported with interpretive comments detailing their
potential or known significance.
Reference Values:
May;17(5):405-424 2. Alford R, Arnos K, Fox M, et al: American College of Medical Genetics and
Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med. 2014
Apr;16(4):347-355 3. DiStefano MT, Hemphill SE, Oza AM, et al: ClinGen expert clinical validity
curation of 164 hearing loss gene-disease pairs. Genet Med. 2019 Oct;21(10):2239-2247 4. Oza AM,
DiStefano MT, Hemphill SE, et al: Expert specification of the ACMG/AMP variant interpretation
guidelines for genetic hearing loss. Hum Mutat. 2018 Nov;39(11):1593-1613 5. Shearer AE, Hildebrand
MS, Smith RJH: Hereditary hearing loss and deafness overview. In: Adam MP, Ardinger HH, Pagon
RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 1999. Updated July 27,
2017. Accessed September 15, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1434/ 6.
Sloan-Heggen CM, Bierer AO, Shearer AE, et al: Comprehensive genetic testing in the clinical
evaluation of 1119 patients with hearing loss. Hum Genet. 2016 Apr;135(4):441-450
AUPU Aureobasidium pullulans, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Aureobasidium pullulans Defining the allergen
Reference Values:
0 Negative

apply to all ages.
APIN Australian Pine, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to the Australian pine Defining the allergen

Reference Values:
0 Negative

apply to all ages.
ALDG Autoimmune Liver Disease Panel, Serum

609516 Clinical Information: Autoimmune liver diseases result from damage to hepatocytes or
cholangiocytes caused by an inflammatory immune reaction. Included within this disease group are
autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).
In some cases, patients with these diseases may present asymptomatically, with increases in various
liver enzymes being identified incidentally during an unrelated clinical evaluation. On the other end of
the spectrum are patients who present with clinical evidence of liver disease, including fatigue,
hepatomegaly, ascites, esophageal varices, and jaundice. Diagnosis of an autoimmune liver disease first
requires that other etiologies of liver injury, including viral, drug, and metabolic causes, be excluded. In
some situations, a liver biopsy may be indicated. For those patients in whom an autoimmune liver
disease is suspected, autoantibody serology testing may be considered. This assay includes markers that
may support a diagnosis of an autoimmune liver disease, specifically AIH or PBC. Unfortunately, there
are no known autoantibodies specific for PSC that are useful as diagnostic markers. Patients with AIH
may be positive for smooth muscle antibodies (SMA) and/or antinuclear antibodies (ANA). The SMA
associated with AIH are generally specific for F-actin. SMA have a specificity of 80% to 90% for AIH,
although the sensitivity is only in the range of 70% to 80%. In contrast, ANA, although relatively
sensitive for AIH, lack specificity, being associated with a variety of autoimmune diseases. Both SMA
and ANA, along with other lab markers and biopsy evaluation, are included in the international
diagnostic criteria for AIH. Antimitochondrial antibodies (AMA) are a diagnostic marker for PBC.
AMA are found in more than 90% of patients with PBC, with a specificity of greater than 95%. AMA
are included in the diagnostic criteria for PBC, which were developed through an international
collaborative effort.
Useful For: Evaluation of patients with suspected autoimmune liver disease, specifically
autoimmune hepatitis or primary biliary cirrhosis Evaluation of patients with liver disease of unknown
etiology
Interpretation: The presence of smooth muscle antibodies (SMA) or antinuclear antibodies (ANA)
is consistent with a diagnosis of chronic autoimmune hepatitis, in patients with clinical or laboratory
evidence of hepatocellular damage. The presence of antimitochondrial antibodies (AMA) is consistent
with a diagnosis of primary biliary cirrhosis, in patients with clinical or laboratory evidence of
hepatobiliary damage.
Reference Values:
SMOOTH MUSCLE ANTIBODIES
Negative
If positive, results are titered.
MITOCHONDRIAL ANTIBODIES (M2)

Negative: <0.1 Units
Borderline: 0.1-0.3 Units
Weakly positive: 0.4-0.9 Units
Positive: > or =1.0 Units
ANTINUCLEAR ANTIBODIES (ANA2)
Negative: < or =1.0 Units
Weakly positive: 1.1-2.9 Units
Positive: 3.0-5.9 Units
Strongly positive: > or =6.0 Units
Clinical References: 1. Invernizzi P, Lleo A, Podda M: Interpreting serological tests in diagnosing

autoimmune liver diseases. Sem Liver Dis. 2007;27(2):161-172 2. Hennes EM, Zeniya M, Czaja AJ, et al:
Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatol. 2008;48:169-176 3. Muratori L,
Granito A, Muratori P, et al: Antimitochondrial antibodies and other antibodies in primary biliary
cirrhosis: diagnostic and prognostic value. Clin Liver Dis. 2008;12:261-276 4. Karlsen TH, Schrumpf E,
Boberg KM: Update on primary sclerosing cholangitis. Dig Liver Dis. 2010;42:390-400
FARP Autoimmune Retinopathy Panel by Immunoblot (ARP)

AUTOP Autoinflammatory Primary Immunodeficiency (PID) Gene Panel,

65666 Varies
Clinical Information: Autoinflammatory disorders include several monogenic defects associated
with abnormal activation of the innate immune system leading to clinically evident inflammation and high
levels of acute-phase reactants. These disorders typically present in childhood, often manifesting with
unexplained fevers. While these features can mimic infections or hematological neoplasias, the
inflammatory lesions are non-neoplastic and sterile. While periodic fever adenitis pharyngitis aphthous
ulcerÂ syndrome (aphthous stomatitis, pharyngitis, and adenitis), systemic juvenile idiopathic arthritis
(sJIA), adult-onset Still disease, and Behcet disease overlap phenotypically with autoinflammatory
conditions, a genetic cause of these disorders has not been identified and, therefore, they are not included
on this panel. Several of the autoinflammatory conditions represented on this panel are responsive to
interleukin-1 (IL-1) blocking therapies; therefore, determining the underlying genetic cause may help
guide treatment decisions. Monogenic autoinflammatory conditions include the periodic fever syndromes
(ie, familial Mediterranean fever, cryopyrinopathy-associated periodic syndrome, Muckle-Wells
syndrome, familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease or
chronic infantile neurologic cutaneous and articular syndrome, tumor necrosis factor [TNF]
receptor-associated periodic syndrome, hyper IgD syndrome/Mevalonate kinase deficiency), diseases with
pyogenic lesions (ie, deficiency of Il-1 receptor antagonist [DIRA]; pyogenic arthritis, pyoderma
gangrenosum and acne [PAPA]; Majeed syndrome), diseases with granulomatous lesions (ie, Blau
syndrome), diseases with psoriasis (ie, deficiency of interleukin 36-receptor antagonist [DITRA]);
diseases with panniculitis-induced lipodystrophy (JMP syndrome, chronic atypical neutrophilic
dermatosis with lipodystrophy and elevated temperature syndrome [CANDLE], Nakajo-Nishimura
syndrome [NNS], proteasome-associated autoinflammatory syndromes [PRAAS]). DITRA and
CARD14-mediated psoriasis (CAMPS) both present with pustular skin lesions and early-onset
inflammatory bowel disease . See the table for a summary of genes included in this panel, associated
diseases, and the mode of inheritance. NOD2-associated autoinflammatory disease (NAID), also known
as Yao syndrome, is a newly described clinical entity characterized by recurrent fever, dermatitis, and
inflammatory arthritis along with GI symptoms in a majority of the patients. Variants in NOD2 have been
associated with NAID; however, the variants that have been implicated to date are common variants that
confer risk for development of the disorder and are not diagnostic. These common variants are not
included in the report for this panel; however, a list of all common variants identified is available by
request. While several of the autoinflammatory conditions, including those without a known genetic basis,
are responsive to IL-1 blocking therapies, PRAAS, CANDLE, DITRA, and CAMPS are not responsive to
IL-1 blockade. Anakinra, rilonacept, and canakinumab are several examples of medications that target
IL-1. The NOD-like receptors (NLR), which include 23 family members in humans, are an integral part of
the innate immune system. NLR are involved in the formation of the inflammasome, of which the NLRP3
(NALP3) inflammasome is most relevant to human disease and is responsible for activation of the
proinflammatory cytokine IL-1 beta. Table. Genes included in this panel Gene symbol (alias) Protein
OMIM Incidence Inheritance Phenotype disorder CARD14 Caspase recruitment domain-containing
protein 14 isoform 1 607211 Rare AD Pityriasis rubra pilaris, psoriasis 2 (CAMPS) IL10RA
Interleukin-10 receptor subunit alpha precursor 146933 Rare AR Very early onset inflammatory bowel
disease 28 (VEOIBD) IL10RB Interleukin-10 receptor subunit beta precursor 123889 Rare AR Very early
onset inflammatory bowel disease 25 (VEOIBD) IL1RN Interleukin-1 receptor antagonist protein isoform
2 147679 Rare AR Deficiency of interleukin 1 receptor antagonist (DIRA) IL36RN Interleukin-36
receptor antagonist protein 605507 Rare AR Pustular psoriasis 14, deficiency of IL36 receptor antagonist
(DITRA) ISG15 Ubiquitin-like protein ISG15 precursor 147571 Rare AR Immunodeficiency 38 Â
LPIN2 Phosphatidate phosphatase LPIN2 605519 Primarily identified in Arab ethnicities AR Majeed
syndrome MEFV Pyrin isoform 1 608107 Primarily identified in Armenian, Arab, Turkish, Italian, and
Jewish ethnicities AR (most), AD (rarely) Familial Mediterranean fever (FMF) MVK Mevalonate kinase
isoform a 251170 Primarily identified in Caucasians of western European ancestry AR/AD
Hyperimmunoglobulinemia D syndrome (HIDS), Mevalonate kinase-associated periodic fever syndrome,
Mevalonic aciduria, Porokeratosis 3, multiple types (AD) NLRP12 (NALP12) NACHT, leucine rich
repeat (LRR) and PYD domains-containing protein 12 isoform 2 609648 Rare AD Familial cold
autoinflammatory syndrome 2 (FCAS2) NLRP3 (NALP3) (CIAS1) NACHT, LRR, and PYD
domains-containing protein 3 isoform a 606416 Primarily identified in Caucasians of western European
ancestry AD Familial cold autoinflammatory syndrome 1 (FCAS1), Muckle-Wells syndrome; Neonatal
onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular
syndrome (CINCA) NOD2 (CARD15) Nucleotide-binding oligomerization domain-containing protein 2
isoform 1 605956 Rare AD Blau syndrome, Early-onset Sarcoidosis, Inflammatory bowel disease 1
Pediatric granulomatous arthritis (PGA) PLCG2 1-Phosphatidylinositol 4,5-bisphosphate
phosphodiesterase gamma-2 600220 Rare AD PLC gamma 2-associated antibody deficiency and immune
dysregulation (PLAID), autoinflammation and PLC gamma 2-associated antibody deficiency and immune
dysregulation (APLAID) PSMB8 Proteasome subunit beta type-8 isoform E2 precursor 177046 Rare AR
CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy); JMP (joint contractures,
muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy); PRASS
(proteasome-associated auto-inflammatory syndrome); JASL (Japanese autoinflammatory syndrome with
lipodystrophy) PSTPIP1 (CD2BP1) Proline-serine-threonine phosphatase-interacting protein 1 606347
Rare AD Pyogenic sterile arthritis pyoderma gangrenosum acne (PAPA) RBCK1 (HOIL1) RanBP-type
and C3HC4-type zinc finger-containing protein 1 isoform 2 610924 Rare AR Polyglucosan body
myopathy 1 with or without immunodeficiency; chronic autoinflammation, invasive bacterial infections,
muscle amylopectinosis SH3BP2 SH3 domain-binding protein 2 isoform a 602104 Rare AD Cherubism,
autoinflammatory bone disease TNFRSF1A Tumor necrosis factor receptor superfamily member 1A
precursor 191190 Primarily identified in Caucasians of western European ancestry AD Tumor necrosis
factor receptor-associated periodic syndrome (TRAPS) AD=autosomal dominant AR=autosomal
recessive XL=X-linked
history suggestive of autoinflammatory syndromes and related disorders Establishing a diagnosis of
autoinflammatory disease, and in some cases guiding management and allowing for surveillance of
disease features Identification of pathogenic variants within genes known to be associated with
autoinflammatory disorders allowing for predictive testing of at-risk family members
Reference Values:
May;17(5):405-424 2. Ozen S, Bilginer T: A clinical guide to autoinflammatory diseases: FMF and next
of kin. Nature Rev. Rheumatol. 2014;10:135-147 3. Canna SW, Goldbach-Mansky R: New monogenic
autoinflammatory diseases-a clinical overview. Semin Immunopathol. 2015;37:387-394 4. Henderson C,
Goldbach-Mansky R: Monogenic IL-1-mediated autoinflammatory and immunodeficiency syndromes:
finding the right balance in response to danger signals. Clin Immunol. 2010;135:210-222 5. Caso F,
Galozzi P, Costa L, et al: Autoinflammatory granulomatous diseases: from Blau syndrome and
early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. RMD Open. 2015;1:e000097 6.
Stern SM, Ferguson PJ: Autoinflammatory bone diseases. Rheum Dis Clin North Am. 2013;39:735-749
7. Martinon F, Aksentijevich I: New Players driving inflammation in monogenic autoinflammatory
diseases. Nat Rev Rheumatol. 2015;11:11-20 8. Jesus AA, Goldbach-Mansky R: IL-1 blockade in
autoinflammatory syndromes. Annu Rev Med. 2014;65:223-244 9. Picard C, Gaspar HB, Al-Herz W, et
al: International Union of Immunological Societies: 2017 Primary Immunodeficiency Disease Committee
Report on Inborn Errors of Immunity. J Clin Immunol. 2018;38:96-128
ARPKZ Autosomal Recessive Polycystic Kidney Disease, Full Gene

Clinical Information: Autosomal recessive polycystic kidney disease (ARPKD) is a disorder caused
by variants in the polycystic kidney and hepatic disease 1 (PKHD1) gene. The incidence of ARPKD is
approximately 1:20,000 and the estimated carrier frequency in the general population is 1:70. ARPKD is
characterized by enlarged echogenic kidneys, congenital hepatic fibrosis, and pulmonary hypoplasia
(secondary to oligohydramnios [insufficient volume of amniotic fluid] in utero). Most individuals with
ARPKD present during the neonatal period and, of those, nearly one-third die of respiratory insufficiency.
Early diagnosis, in addition to initiation of renal replacement therapy (dialysis or transplantation) and
respiratory support, increases the 10-year survival rate significantly. Presenting symptoms include
bilateral palpable flank masses in infants and subsequent observation of typical findings on renal
ultrasound, often within the clinical context of hypertension and prenatal oligohydramnios. In rarer cases,
individuals may present during childhood or adulthood with hepatosplenomegaly. Of those who survive
the neonatal period, one-third progress to end-stage kidney disease and up to one-half develop chronic
kidney insufficiency. The PKHD1 gene maps to 6p12 and includes 67 exons. The PKHD1 gene encodes a
protein called fibrocystin, which is localized to the primary cilia and basal body of renal tubular and
biliary epithelial cells. Because ARPKD is an autosomal recessive disease, affected individuals must carry
2 deleterious variants within the PKHD1 gene. Although disease penetrance is 100%, intrafamilial
variation in disease severity has been observed. Variant detection is often difficult due to the large gene
size and the prevalence of private variants that span the entire length of the gene.
Useful For: Diagnosis of individuals suspected of having autosomal recessive polycystic kidney
disease (ARPKD) Prenatal diagnosis if there is a high suspicion of ARPKD based on ultrasound findings
Carrier testing of individuals with a family history of ARPKD, but an affected individual is not available
for testing or disease-causing variants have not been identified
Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known, predicted,
or possible pathogenicity and reported with interpretive comments detailing their potential or known
significance.
Reference Values:
May;17(5):405-424. doi: 10.1038/gim.2015.30 2. Guay-Woodford LM, Desmond RA: Autosomal
recessive polycystic kidney disease: the clinical experience in North America. Pediatrics.
2003;111:1072-1080. doi: 10.1542/peds.111.5.1072 3. Guay-Woodford LM, Bissler JJ, Braun MC, et al:
Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic
kidney disease: Report of an international conference. J Pediatr. 2014 Sep;165(3):611-617. doi:
10.1016/j.jpeds.2014.06.015 4. Gunay-Aygun M, Avner E, Bacallao RL, et al: Autosomal recessive
polycystic kidney disease and congenital hepatic fibrosis: summary of a first National Institutes of
Health/Office of Rare Diseases conference. J Pediatr. 2006;149:159-164. doi:
10.1016/j.jpeds.2006.03.014 5. Harris PC, Rossetti S: Molecular genetics of autosomal recessive
polycystic kidney disease. Mol Genet Metab. 2004;81:75-85. doi: 10.1016/j.ymgme.2003.10.010
FAVCG Avocado IgG

Reference Values:
AVOC Avocado, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to avocados Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
AIAES Axonal Neuropathy, Autoimmune/Paraneoplastic Evaluation,

606974 Serum
Clinical Information: Neuropathy patients have variable sensory disturbance (loss or exaggerated
sensation) with pain, weakness, and autonomic involvements such as sweat abnormalities, gastrointestinal
dysfunction, and lightheadedness on standing. These symptoms are as a result of injury to the distal
nerves, roots, ganglia or their gathering points (nerve plexus in the thighs and arms). Patients may have
symmetric or asymmetric involvements of the extremities, trunk, and head including extraocular muscles.
Subacute onsets and asymmetric involvements favor inflammatory or immune causes over inherited or
metabolic forms. Depending on the specific inflammatory or immune mediated causes other parts of the
nervous system may also be affected (brain, cerebellum, spinal cord). In the evaluation of patients with
immune mediated autoantibody neuropathies, nerve conduction studies and needle electromyography can
help to classify the neuropathy as either: 1) primary axonal; 2) primary demyelinating; or 3) mixed axonal
and demyelinating. This evaluation focuses on persons with primary axonal forms. Well established
neuronal autoantibodies responsible for axonal neuropathies include: antineuronal nuclear antibodies
(ANNA1 and 3), Purkinje cytoplasmic antibody (PCA1 and 2), amphiphysin antibody, collapsin response
mediator protein 5 (CRMP5) antibody, leucine-rich glioma inactivated 1 protein (LGI1) antibody, and
contactin-associated response protein 2 (CASPR2) antibody. Other autoantibodies have preliminary
evidence to support their association with neuropathy including:
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antibody, antiglial
nuclear antibody (AGNA); antineuronal nuclear type 2 antibody (ANNA2), gamma-aminobutyric acid B
receptor (GABABR) antibody, glutamic acid decarboxylase 65 (GAD65) receptor antibody, glial
fibrillary acidic protein (GFAP) antibody, N-methyl-D-aspartate receptor (NMDAR) antibody, Purkinje
cell cytoplasmic Tr (PCA-Tr) antibody, dipeptidyl-peptidase-like protein-6 (DPPX) antibody, and
metabotropic glutamate receptor 1 (mGluR1). A patient's humoral and cellular immune response leads to
the neurological syndrome. This may be related to an underlying cancer or unidentified antigen trigger. If
related to cancer it may be a new or recurrent malignancy, is usually limited in metastatic volume, and is
often occult by standard imaging procedures. Autoantibodies specific for onconeural proteins found in the
plasma membrane, cytoplasm, and nucleus of neurons, glia, or muscle are generated in this immune
response and serve as serological markers of paraneoplastic autoimmunity. Cancers recognized in this
context most commonly are small-cell lung carcinoma, thymoma, ovarian (or related Mullerian)
carcinoma, breast carcinoma, and Hodgkin lymphoma. Pertinent childhood neoplasms recognized thus far
include neuroblastoma, thymoma, Hodgkin lymphoma, and chondroblastoma. This evaluation focuses on
those antibodies with known associations with varied forms of peripheral axonal neuropathy. Seropositive
patients usually present with subacute neurological symptoms of radiculopathy; plexopathy; or sensory,
sensorimotor, or autonomic neuropathy, with or without a neuromuscular transmission disorder such as
neuromuscular hyperexcitability. Other peripheral manifestation includes cranial neuropathies, especially
loss of vision, hearing, smell, or taste. Commonly beyond the peripheral manifestation are
encephalopathy, seizures, cerebellar ataxia, and myelopathy. Initial signs may be subtle, but a subacute
multifocal and progressive syndrome usually evolves. Sensorimotor neuropathy and cerebellar ataxia are
common presentations, but the clinical picture in some patients is dominated by striking gastrointestinal
dysmotility, and limbic encephalopathy. Some patients may present with mostly pain and have a limited
small fiber neuropathy with or without autonomic symptoms. Cancer risk factors include past or family
history of cancer, history of smoking, or social or environmental exposure to carcinogens.
Useful For: Evaluation of patients who present with a subacute neurological disorder of undetermined
etiology, especially those with known risk factors for cancer Directing a focused search for cancer
Investigating neurological symptoms that appear in the course of, or after, cancer therapy, and are not
explainable by metastasis Differentiating autoimmune neuropathies from neurotoxic effects of
chemotherapy Detecting early evidence of cancer recurrence in previously seropositive patients
Interpretation: Antibodies directed at onconeural proteins shared by neurons, glia, muscle, and
certain cancers are valuable serological markers of a patient's immune response to cancer. They are not
found in healthy subjects and are usually accompanied by subacute neurological symptoms and signs.
Several autoantibodies have a syndromic association, but no autoantibody predicts a specific
neurological syndrome. More than one paraneoplastic autoantibody may be detected and associated
with specific cancers.
Reference Values:
Test ID Reporting name Methodology Reference value
AIAEI Autoimmune Axonal Interp, S Medical Interpretation NA
AGN1S Anti-Glial Nuclear Ab, Type 1 IFA
AMPHS Amphiphysin Ab, S IFA
ANN1S ANNA-1, S IFA

ANN3S ANNA-3, S IFA
CRMS CRMP-5-IgG, S IFA
CRMWS CRMP-5-IgG Western Blot, S WB Negative
CS2CS CASPR2-IgG CBA, S CBA Negative
LG1CS LGI1-IgG CBA, S CBA Negative
PCAB2 PCA-2, S IFA
PCABP PCA-1, S IFA Reflex Information:
AGNBS AGNA-1 Immunoblot, S IB Negative
AMIBS Amphiphysin Immunoblot, IB Negative

S
AMPCS AMPA-R Ab CBA, S CBA Negative
AMPIS AMPA-R Ab IF Titer IFA

Assay, S
AN1BS ANNA-1 Immunoblot, S IB Negative
ANN2S ANNA-2, S IFA
DPPCS DPPX Ab CBA, S CBA Negative
DPPTS DPPX Ab IFA, S IFA
GABCS GABA-B-R Ab CBA, S CBA Negative
GABIS GABA-B-R Ab IF Titer IFA

Assay, S
GD65S GAD65 Ab Assay, S RIA < or =0.02 nmol/L Reference values

apply to all ages
GFACS GFAP CBA, S CBA Negative
GFATS GFAP IFA Titer, S IFA
GL1CS mGluR1 Ab CBA, S CBA Negative
GL1TS mGluR1 Ab IFA, S IFA

NMDCS NMDA-R Ab CBA, S CBA Negative
NMDIS NMDA-R Ab IF Titer IFA

Assay, S
PC1BS PCA-1 Immunoblot, S IB Negative
PCATR Purkinje Cell Cytoplasmic IFA

Ab Type Tr
PCTBS PCA-Tr Immunoblot, S IB Negative *Methodology

abbreviations: Immunofluorescence
assay (IFA) Cell-binding assay
(CBA) Western blot (WB)
Radioimmunoassay (RIA)
Immunoblot (IB) Neuron-restricted
patterns of IgG staining that do not
fulfill criteria for ANNA-1,
ANNA-2, CRMP-5-IgG, PCA-1,
PCA-2, or PCA-Tr may be reported
as "unclassified anti-neuronal IgG."
Complex patterns that include
nonneuronal elements may be
reported as "uninterpretable."
Clinical References: 1. Klein CJ: Autoimmune-mediated peripheral neuropathies and autoimmune

pain. In: Pittock SJ, Vincent A, eds. Handbook of Clinical Neurology; Autoimmune Neurology.
Elsevier; 2016:417-446 2. Cutsforth-Gregory JK, McKeon A, Coon EA, et al: Ganglionic antibody level
as a predictor of severity of autonomic failure. Mayo Clin Proc. 2018 Oct;93(10):1440-1447 3. Wei YC,
Huang CC, Liu CH, Kuo HC, Lin JJ: Peripheral neuropathy in limbic encephalitis with anti-glutamate
receptor antibodies: Case report and systematic literature review. Brain Behav. 2017 Aug;7(9):e00779
4. Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncologic profiles of patients
seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998 Mar;50(3):652-657 5.
Pittock SJ, Lucchinetti CF, Lennon VA: Anti-neuronal nuclear autoantibody type 2: paraneoplastic
accompaniments. Ann Neurol. 2003 May;53(5):580-587 6. Chan KH, Vernino S, Lennon VA: ANNA-3
anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol. 2001
Sep;50(3):301-311 7. Dubey D, Lennon VA, Gadoth A, et al. Autoimmune CRMP5 neuropathy
phenotype and outcome defined from 105 cases. Neurology. 2018 Jan;90(2):e103-e110 8. Gadoth A,
Pittock SJ, Dubey D, et al: Expanded phenotypes and outcomes among 256
LGI1/CASPR2-IgG-positive patients. Ann Neurol. 2017 Jul;82:79-92 9. Honnorat J, Trouillas P,
Thivolet C, Aguera M, Belin MF: Autoantibodies to glutamate decarboxylase in a patient with
cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol. 1995
May;52(5):462-468 10. McKeon A, Tracy JA: GAD65 neurological autoimmunity. Muscle Nerve. 2017
Jul;56(1):15-27 11. Bradshaw MJ, Haluska P, McKeon A, Klein CJ: Multifocal neuropathy as the
presenting symptom of Purkinje cell cytoplasmic autoantibody-1. Muscle Nerve. 2013;48:827-831 12.
Pittock SJ, Lucchinetti CF, Parisi JE, et al: Amphiphysin autoimmunity: paraneoplastic
accompaniments. Ann Neurol. 2005 Jul;58(1):96-107
FAZAT Azathioprine (Imuran) as 6-Mercaptopurine

Units: ng/mL
Azathioprine is measured as the metabolite, 6-mercaptopurine. Therapeutic and toxic ranges have not
been established. Usual therapeutic doses produce 6-mercaptopurine serum concentrations of less than
1000 ng/ml.
COGBF
Current 113530
as of July 20, 2022 12:05 pm CDT 800-533-1710 or 507-266-5700 or mayocliniclabs.com Page 290
B-Cell Acute Lymphoblastic Leukemia/Lymphoma (ALL),
Children's Oncology Group Enrollment Testing, FISH, Varies
Clinical Information: In the United States the incidence of acute lymphoblastic leukemia (ALL) is
roughly 6000 new cases per year (as of 2019). ALL accounts for approximately 70% of all childhood
leukemia cases (ages 0-19 years), making it the most common type of childhood cancer. Approximately
85% of pediatric cases of ALL are B-cell lineage (B-ALL) and 15% are T-cell lineage (T-ALL). It has a
peak incidence at 2 to 5 years of age. The incidence decreases with increasing age, before increasing
again at around 50 years of age. ALL is slightly more common in males than females. There is an
increased incidence of ALL in individuals with Down syndrome, Fanconi anemia, Bloom syndrome,
ataxia telangiectasia, X-linked agammaglobulinemia, and severe combined immunodeficiency. The
overall cure rate for ALL in children is about 90% and about 45% to 60% of adults have long-term
disease-free survival. CRLF2/IGH rearrangements are more commonly observed in patients with Down
syndrome or of Hispanic descent. Specific genetic abnormalities are identified in the majority of cases
of B-ALL, either by conventional chromosome studies or fluorescence in situ hybridization (FISH)
studies. For more than 25 years, the Mayo Clinic Genomics Laboratory has served as a Children's
Oncology Group (COG) accredited laboratory for the performance of cytogenetic testing in pediatric
patients being considered for enrollment in COG clinical trials and research. The laboratory is highly
equipped to perform the time sensitive and critical cytogenetic testing necessary to assign risk
stratification and facilitate enrollment in COG protocols. Each of the B-ALL genetic subgroups are
important to detect and can be critical prognostic markers. The decision for early transplantation may be
made if t(9;22)(q34;q11.2), MLL (KMT2A) translocations, RUNX1 duplication/amplification
(iAMP21) or a hypodiploid clone is identified. In contrast, if ETV6/RUNX1 fusion is detected by FISH
or hyperdiploidy is identified by chromosome studies, the patient has a favorable prognosis and
transplantation is rarely considered. A newly recognized World Health Organization (WHO) entity
BCR-ABL1-like ALL, also known as Philadelphia chromosome-like acute lymphoblastic leukemia
(Ph-like ALL), is increasing in importance due to the poor prognosis seen in pediatric, adolescent, and
young adult and adolescent ALL (AYA). Common features of this entity involve rearrangements with
tyrosine kinase genes involving the following genes: ABL2, PDGFRB, JAK2, ABL1, CRLF2, and
P2RY8. Deletion of IKZF1 often accompanies this entity. Some patients who have failed conventional
therapies have demonstrated favorable responses to targeted therapies on clinical trials when
rearrangements involving these specific gene regions have been identified. Evaluation of the MYC gene
region is included in all diagnostic B-ALL panels to evaluate for Burkitt lymphoma. If a positive result
is obtained, additional testing for the BCL2 and BCL6 gene regions will be performed. Metaphase FISH
confirmation of classic translocations that are cryptic and not visually detectable by chromosome
analysis (ie, t(12;21) associated with ETV6/RUNX1 fusion) is performed, as required by COG, and is
included as part of the electronic case submission by the Mayo Clinic Genomics Laboratory to COG for
central review. Additional cytogenetic techniques such as chromosomal microarray (CMAH /
Chromosomal Microarray, Hematologic Disorders, Varies) may be helpful to resolve questions related
to ploidy (hyperdiploid clone vs doubled hypodiploid clone) or to resolve certain clonal structural
rearrangements such as the presence or absence of intra-chromosomal amplification of chromosome 21
(iAMP21). A summary of the characteristic chromosome abnormalities identified in B-ALL is listed in
the following table. Table. Common Chromosome Abnormalities in B-cell Acute Lymphoblastic
Leukemia Leukemia type Cytogenetic change Typical demographic Risk category B-cell acute
lymphoblastic leukemia t(12;21)(p13;q22), ETV6(TEL)/RUNX1(AML1) Pediatric Favorable
Hyperdiploidy Pediatric Favorable t(1;19)(q23;p13.3), PBX1/TCF3 Pediatric Intermediate
t(9;22)(q34;q11.2), BCR/ABL1 Pediatric/adult Unfavorable iAMP21, RUNX1 Pediatric Unfavorable
del(9p), CDKN2A(p16) All ages Unknown t(11q23;var), MLL All ages Unfavorable t(4;11)(q21;q23),
AFF1(AF4)/MLL All ages Unfavorable t(6 ;11)(q27;q23), MLLT4(AFDN)/MLL All ages Unfavorable
t(9;11)(p22;q23), MLLT3(AF9)/MLL All ages Unfavorable t(10;11)(p12;q23), MLLT10/MLL All ages
Unfavorable t(11;19)(q23;p13.1), MLL/ELL All ages Unfavorable t(11;19)(q23;p13.3),
MLL/MLLT1(ENL) All ages Unfavorable t(14q32;var), IGH All ages Variable
t(X;14)(p22;q32)/t(Y;14)(p11;q32), CRLF2/IGH Adolescent/young adult Unfavorable t(Xp22.33;var)
or t(Yp11.32;var), CRLF2 All ages Unfavorable t(Xp22.3;var) or t(Yp11.32;var), P2RY8 All ages
Unfavorable -17/17p-, TP53 All ages Unfavorable t(8q24.1;var), MYC Pediatric/ adolescent/ young
adult Complex karyotype (> or =4 abnormalities) Adult Unfavorable Low hypodiploidy/near triploidy
Adult Unfavorable Near-haploid/hypodiploid All ages Unfavorable 7p-, IKZF1 All ages Unfavorable in
absence of ERG deletion Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL)
t(1q25;var), ABL2 Pediatric/ adolescent/ young adult Unfavorable t(5q33;var), PDGFRB t(9p24.1;var),
JAK2 t(9q34;var), ABL1 t(Xp22.33;var) or t(Yp11.32;var), CRLF2 t(Xp22.33;var) or t(Yp11.32;var),
P2RY8
situ hybridization probe analysis for classic rearrangements and chromosomal copy number changes
associated with B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) and Philadelphia
chromosome-like acute lymphoblastic leukemia (Ph-like ALL) in patients being considered for enrollment
in Children's Oncology Group (COG) clinical trials and research protocols As an adjunct to conventional
chromosome studies in performed in pediatric patients with B-ALL and Ph-like ALL being considered for
enrollment in COG protocols
Reference Values:
Clinical References: 1. Moorman AV, Harrison CJ, Buck GAN, et al: Karyotype is an independent
prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients
treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group
(ECOG) 2993 trial. Blood. 2007 Apr 15;109(8):3189-3197 2. Moorman AV: The clinical relevance of
chromosomal and genetic abnormalities in B-cell precursor acute lymphoblastic leukemia. Blood Rev.
2012 May;26(3):123-135 3. Roberts KG, Li Y, Payne-Turner D, et al: Targetable kinase-activating lesions
in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014 Sep 11;371(11):1005-1015 4. Mullighan
CG: The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematology
Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):174-180 5. Swerdlow SH, Campo E, Harris NL, et
al, eds: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press; 2017
BALAF B-Cell Acute Lymphoblastic Leukemia/Lymphoma (ALL), FISH,

609537 Adult, Varies
Clinical Information: In the United States, the incidence of acute lymphoblastic leukemia (ALL) is
85% of pediatric cases of ALL are of B-cell lineage (B-ALL) and 15% are of T-cell lineage (T-ALL). It
has a peak incidence at 2 to 5 years of age. The incidence decreases with increasing age, before increasing
overall cure rate for ALL in children is about 90%, and about 45% to 60% of adults have long-term
syndrome or of Hispanic descent. Specific genetic abnormalities are identified in the majority of cases of
B-ALL, either by conventional chromosome studies or fluorescence in situ hybridization (FISH) studies.
Each of the B-ALL genetic subgroups are important to detect and can be critical prognostic markers. The
decision for early transplantation may be made if t(9;22)(q34;q11.2), MLL (KMT2A) translocations,
RUNX1 duplication/amplification (iAMP21) or a hypodiploid clone is identified. In contrast, if
ETV6/RUNX1 fusion is detected by FISH or hyperdiploidy is identified by chromosome studies, the
patient has a favorable prognosis and transplantation is rarely considered. A newly recognized World
Health Organization entity BCR-ABL1-like ALL, also known as Philadelphia chromosome-like acute
lymphoblastic leukemia, is increasing in importance due to the poor prognosis seen in pediatric,
adolescent, and young adult and adolescent ALL. Common features of this entity involve rearrangements
with tyrosine kinase genes involving the following genes: ABL2, PDGFRB, JAK2, ABL1, CRLF2, and
P2RY8. Deletion of IKZF1 often accompanies this entity. Some patients who have failed conventional
therapies have demonstrated favorable responses to targeted therapies on clinical trials when
region is included in all diagnostic B-ALL panels to evaluate for Burkitt lymphoma. If a positive result is
obtained, additional testing for the BCL2 and BCL6 gene regions will be performed. Per National
Comprehensive Cancer Network guidelines, a combination of cytogenetic and FISH testing is currently
recommended in all pediatric and adult patients with B-ALL/lymphoblastic lymphoma (LBL). Additional
cytogenetic techniques such as chromosomal microarray (CMAH / Chromosomal Microarray,
Hematologic Disorders, Varies) may be helpful to resolve questions related to ploidy (hyperdiploid clone
vs doubled hypodiploid clone) or to resolve certain clonal structural rearrangements such as the presence
or absence of intra-chromosomal amplification of chromosome 21 (iAMP21). A summary of the
characteristic chromosome abnormalities identified in B-ALL is listed in the following table. A summary
of the characteristic chromosome abnormalities identified in B-ALL is listed in the following table. Table.
Common Chromosome Abnormalities in B-cell Acute Lymphoblastic Leukemia Leukemia type
Cytogenetic change Typical demographic Risk category B-acute lymphoblastic leukemia
t(12;21)(p13;q22), ETV6/RUNX1 Pediatric Favorable Hyperdiploidy Pediatric Favorable
t(1;19)(q23;p13.3), PBX1/TCF3 Pediatric Intermediate to favorable t(9;22)(q34;q11.2), BCR/ABL1 All
ages Unfavorable iAMP21, RUNX1 Pediatric Unfavorable del(9p), CDKN2A All ages Unknown
t(11q23;var), MLL All ages Unfavorable t(4;11)(q21;q23), AFF1/MLL All ages Unfavorable
t(6;11)(q27;q23), MLLT4(AFDN)/MLL All ages Unfavorable t(9;11)(p22;q23), MLLT3/MLL All ages
Unfavorable t(10;11)(p12;q23), MLLT10/MLL All ages Unfavorable t(11;19)(q23;p13.1), MLL/ELL All
ages Unfavorable t(11;19)(q23;p13.3), MLL/MLLT1 All ages Unfavorable t(14q32;var), IGH All ages
Variable t(X;14)(p22;q32)/t(Y;14)(p11;q32), CRLF2/IGH Adolescent/Â Â young adult Unfavorable
t(Xp22.33;var) or t(Yp11.32;var), CRLF2 All ages Unfavorable t(Xp22.33;var) or t(Yp11.32;var), P2RY8
All ages Unfavorable -17/17p-, TP53 All ages Unfavorable t(8q24.1;var), MYC *representing Burkitt or
other mature B-cell lymphoma Pediatric/ adolescent/ young adult Complex karyotype (> or =4
abnormalities) Adult Unfavorable Low hypodiploidy/near triploidy Adult Unfavorable
Near-haploid/hypodiploid All ages Unfavorable del(7p) IKZF1 All ages Unfavorable in absence of ERG
deletion Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) t(1q25;var), ABL2
Pediatric/ adolescent/ young adult Unfavorable t(5q33;var), PDGFRB t(9p24.1;var), JAK2 t(9q34;var),
ABL1 t(Xp22.33;var) or t(Yp11.32;var), CRLF2 t(Xp22.33;var) or t(Yp11.32;var), P2RY8
classic rearrangements seen in adult patients with B-cell acute lymphoblastic leukemia/lymphoma
(B-ALL/LBL) An adjunct to conventional chromosome studies in patients with B-ALL/LBL Evaluating
specimens in which standard cytogenetic analysis is unsuccessful
Reference Values:
Clinical References: 1. Moorman AV, Harrison CJ, Buck GA, et al: Karyotype is an independent
prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from
patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology
Group (ECOG) 2993 trial. Blood. 2007 Apr 15;109(8):3189-3197. doi: 10.1182/blood-2006-10-051912
2. Moorman AV: The clinical relevance of chromosomal and genetic abnormalities in B-cell precursor
acute lymphoblastic leukemia. Blood Rev. 2012;26:123-135. doi: 10.1016/j.blre.2012.01.001 3. Roberts
KG, Li Y, Payne-Turner D, et al: Targetable kinase-activating lesions in Ph-like acute lymphoblastic
leukemia. N Engl J Med. 2014 Sept;371(11):1005-1015. i: 10.1056/NEJMoa1403088 4. Mullighan CG:
The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematology Am
Soc Hematol Educ Program. 2014 Dec 5;2014(1):174-180. doi: 10.1182/asheducation-2014.1.174 5.
Swerdlow SH, Campo E, Harris NL, et al, eds: WHO Classification of Tumours of Haematopoietic and
Lymphoid Tissues. IARC Press; 2017
BALPF B-Cell Acute Lymphoblastic Leukemia/Lymphoma (ALL),

609547 Pediatric, FISH, Varies
Clinical Information: In the United States the incidence of acute lymphoblastic leukemia (ALL) is
85% of pediatric cases of ALL are of B-cell lineage (B-ALL) and 15% are of T-cell lineage (T-ALL). It
has a peak incidence at 2 to 5 years of age. The incidence decreases with increasing age, before increasing
overall cure rate for ALL in children is about 90% and about 45% to 60% of adults have long-term
syndrome or of Hispanic descent. Specific genetic abnormalities are identified in the majority of cases of
B-ALL, either by conventional chromosome studies or fluorescence in situ hybridization (FISH) studies.
For more than 25 years, the Mayo Clinic Genomics Laboratory has served as a Children's Oncology
Group (COG) accredited laboratory for the performance of cytogenetic testing in pediatric patients being
considered for enrollment in COG clinical trials and research. The laboratory is highly equipped to
perform the time sensitive and critical cytogenetic testing necessary to assign risk stratification and
facilitate enrollment in COG protocols. Each of the B-ALL genetic subgroups are important to detect and
can be critical prognostic markers. The decision for early transplantation may be made if
t(9;22)(q34;q11.2), MLL (KMT2A) translocations, RUNX1 duplication/amplification (iAMP21) or a
hypodiploid clone is identified. In contrast, if ETV6/RUNX1 fusion is detected by FISH or hyperdiploidy
is identified by chromosome studies, the patient has a favorable prognosis and transplantation is rarely
considered. A newly recognized World Health Organization entity BCR-ABL1-like ALL, also known as
Philadelphia chromosome-like acute lymphoblastic leukemia, is increasing in importance due to the poor
prognosis seen in pediatric, adolescent, and young adult and adolescent ALL. Common features of this
entity involve rearrangements with tyrosine kinase genes involving the following genes: ABL2,
PDGFRB, JAK2, ABL1, CRLF2, and P2RY8. Deletion of IKZF1 often accompanies this entity. Some
patients who have failed conventional therapies have demonstrated favorable responses to targeted
therapies on clinical trials when rearrangements involving these specific gene regions have been
identified. Evaluation of the MYC gene region is included in all diagnostic B-ALL panels to evaluate for
Burkitt lymphoma. If a positive result is obtained, additional testing for the BCL2 and BCL6 gene regions
will be performed. Additional cytogenetic techniques such as chromosomal microarray (CMAH /
Chromosomal Microarray, Hematologic Disorders, Varies) may be helpful to resolve questions related to
ploidy (hyperdiploid clone vs doubled hypodiploid clone) or to resolve certain clonal structural
(iAMP21). A summary of the characteristic chromosome abnormalities identified in B-ALL is listed in
the following table. Table. Common Chromosome Abnormalities in B-cell Acute Lymphoblastic
Leukemia Leukemia type Cytogenetic change Typical demographic Risk category B-acute lymphoblastic
leukemia t(12;21)(p13;q22), ETV6/RUNX1 Pediatric Favorable Hyperdiploidy Pediatric Favorable
t(1;19)(q23;p13.3), PBX1/TCF3 Pediatric Intermediate to favorable t(9;22)(q34;q11.2), BCR/ABL1 All
ages Unfavorable iAMP21, RUNX1 Pediatric Unfavorable del(9p), CDKN2A All ages Unknown
t(11q23;var), MLL All ages Unfavorable t(4;11)(q21;q23), AFF1/MLL All ages Unfavorable
t(6;11)(q27;q23), MLLT4(AFDN)/MLL All ages Unfavorable t(9;11)(p22;q23), MLLT3/MLL All ages
Unfavorable t(10;11)(p12;q23), MLLT10/MLL All ages Unfavorable t(11;19)(q23;p13.1), MLL/ELL All
ages Unfavorable t(11;19)(q23;p13.3), MLL/MLLT1 All ages Unfavorable t(14q32;var), IGH All ages
Variable t(X;14)(p22;q32)/t(Y;14)(p11;q32), CRLF2/IGH Adolescent/Â Â young adult Unfavorable
t(Xp22.33;var) or t(Yp11.32;var), CRLF2 All ages Unfavorable t(Xp22.33;var) or t(Yp11.32;var), P2RY8
All ages Unfavorable -17/17p-, TP53 All ages Unfavorable t(8q24.1;var), MYC *representing Burkitt or
other mature B-cell lymphoma Pediatric/ adolescent/ young adult Complex karyotype (> or =4
abnormalities) Adult Unfavorable Low hypodiploidy/near triploidy Adult Unfavorable
Near-haploid/hypodiploid All ages Unfavorable del(7p) IKZF1 All ages Unfavorable in absence of ERG
deletion Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) t(1q25;var), ABL2
ABL1 t(Xp22.33;var) or t(Yp11.32;var), CRLF2 t(Xp22.33;var) or t(Yp11.32;var), P2RY8
situ hybridization probe analysis for classic rearrangements and chromosomal copy number changes
associated with B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) and Philadelphia
chromosome-like acute lymphoblastic leukemia (Ph-like ALL) As an adjunct to conventional
chromosome studies in performed in pediatric patients with B-ALL and Ph-like ALL Evaluating
specimens in which standard cytogenetic analysis is unsuccessful
Reference Values:
prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from
patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology
Group (ECOG) 2993 trial. Blood. 2007 Apr 15;109(8):3189-3197 2. Moorman AV: The clinical
relevance of chromosomal and genetic abnormalities in B-cell precursor acute lymphoblastic leukemia.
Blood Rev. 2012;26:123-135 3. Roberts KG, Li Y, Payne-Turner D, et al: Targetable kinase-activating
lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014 Sept;371(11):1005-1015 4.
Mullighan CG: The genomic landscape of acute lymphoblastic leukemia in children and young adults.
Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):174-180 5. Swerdlow SH, Campo E,
Harris NL, et al, eds: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC
Press; 2017
BALMF B-Cell Acute Lymphoblastic Leukemia/Lymphoma (ALL),

614215 Specified FISH, Varies
Clinical Information: In the United States, the incidence of B-lymphoblastic leukemia/lymphoma
(B-ALL/LBL) is roughly 6000 new cases per year, or approximately 1 in 50,000. B-ALL/LBL accounts
for approximately 70% of all childhood leukemia cases (ages 0 to 19 years), making it the most
common type of childhood cancer. It has a peak incidence at 2 to 5 years of age. This incidence
decreases with age before increasing again at around 50 years of age. B-ALL/LBL is slightly more
common in males than females. There is also an increased incidence of B-ALL/LBL in individuals with
genetic conditions such as Down syndrome, Fanconi anemia, Bloom syndrome, ataxia telangiectasia,
Li-Fraumeni syndrome, X-linked agammaglobulinemia, and severe combined immunodeficiency. The
overall cure rate for B-ALL/LBL in children is approximately 90%, and about 45% to 60% of adults
have long-term disease-free survival. Of note, CRLF2/IGH rearrangements are more commonly
observed in patients with Down syndrome or of Hispanic descent. Specific cytogenetic abnormalities
are identified in the majority of cases of B-ALL/LBL, either by conventional chromosome studies or
fluorescence in situ hybridization (FISH) studies. Each of the genetic subgroups are important to detect
and can be critical prognostic markers. For example, a decision for early transplantation may be made if
t(9;22)(q34;q11.2), KMT2A rearrangement, iAMP21, or a hypodiploid clone is identified. In contrast, if
ETV6/RUNX1 fusion or hyperdiploidy is identified, the patient has a more favorable prognosis and
transplantation is rarely initially considered. A newly recognized World Health Organization entity
called BCR-ABL1-like ALL (also known as Philadelphia chromosome-like acute lymphoblastic
leukemia), is increasing in importance due to the poor prognosis seen in pediatric, adolescent, and
young adult ALL. Common features of this entity involve rearrangements with tyrosine kinase genes
involving the following genes: ABL2, PDGFRB, JAK2, ABL1, CRLF2, and P2RY8, as well as
deletions involving IKZF1. Patients who have failed conventional therapies have demonstrated
favorable responses to targeted therapies when rearrangements involving these specific gene regions
have been identified. Evaluation of the MYC gene region is included in all diagnostic B-ALL panels to
evaluate for Burkitt lymphoma. If a positive result is obtained, additional testing for the BCL2 and
BCL6 gene regions may be considered. Per National Comprehensive Cancer Network guidelines, a
combination of cytogenetic and FISH testing is currently recommended in all pediatric and adult
patients with B-ALL/ lymphoblastic lymphoma (LBL).
classic rearrangements seen in patients with B-cell acute lymphoblastic leukemia/lymphoma
(B-ALL/LBL) using client specified probes An adjunct to conventional chromosome studies in patients
with B-ALL/LBL Evaluating specimens in which standard cytogenetic analysis is unsuccessful
Reference Values:
(ECOG) 2993 trial. Blood. 2007 Apr 15;109(8):3189-3197. doi: 10.1182/blood-2006-10-051912 2.
Moorman AV: The clinical relevance of chromosomal and genetic abnormalities in B-cell precursor acute
lymphoblastic leukemia. Blood Rev. 2012;26:123-135. doi: 10.1016/j.blre.2012.01.001 3. Roberts KG, Li
Y, Payne-Turner D, et al: Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N
Engl J Med. 2014 Sept;371(11):1005-1015. i: 10.1056/NEJMoa1403088 4. Mullighan CG: The genomic
landscape of acute lymphoblastic leukemia in children and young adults. Hematology Am Soc Hematol
Educ Program. 2014 Dec 5;2014(1):174-180. doi: 10.1182/asheducation-2014.1.174 5. Arber DA, Orazi
A, Hasserjian R, et al: The 2016 revision to the World Health Organization classification of myeloid
neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-2405. doi:
10.1182/blood-2016-03-643544
CD40 B-Cell CD40 Expression by Flow Cytometry, Blood

89009 Clinical Information: The adaptive immune response includes both cell-mediated (mediated by T
cells and natural killer [NK] cells) and humoral (mediated by B cells) immunity. After antigen recognition
and maturation in secondary lymphoid organs, some antigen-specific B cells terminally differentiate into
antibody-secreting plasma cells. Decreased numbers or aberrant function of B cells result in humoral
immune deficiency states with increased susceptibility to infections, and these may be either primary
(genetic) or secondary immunodeficiencies. Secondary causes include medications, malignancies,
infections, and autoimmune disorders (this does not cause immunodeficiency with increased infection).
CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell
types including B cells, macrophages, and dendritic cells.(1) CD40 is the receptor for CD40 ligand
(CD40LG), a molecule predominantly expressed by activated CD4+ T cells. CD40/CD40LG interaction is
involved in the formation of memory B lymphocytes and promotes immunoglobulin (Ig) isotype
switching.(1) CD40LG expression in T cells requires cellular activation, while CD40 is constitutively
expressed on the surface of B cells and other antigen-presenting cells. Hyperimmunoglobulin M
(hyper-IgM or HIGM) syndrome is a rare primary immunodeficiency characterized by increased or
normal levels of IgM with low IgG and/or IgA.(2) Patients with hyper-IgM syndromes may have genetic
variants in 1 of several known genes. Some of these genes are CD40LG, CD40, AICDA
(activation-induced cytidine deaminase), UNG (uracil DNA glycosylase), and IKBKG (inhibitor of kappa
light polypeptide gene enhancer in B cells, kinase gamma; also known as NEMO).(2) Not all cases of
hyper-IgM syndrome fit into these known genetic defects. Variants in CD40LG and IKBKG are inherited
in an X-linked fashion, while variants in the other 3 genes are autosomal recessive in inheritance.
Elevated IgM is only one of the features of NEMO deficiency and therefore, it is no longer classified
exclusively with the hyper-IgM syndromes. Distinguishing between the different forms of hyper-IgM
syndrome is very important because of differing prognoses. CD40 and CD40LG deficiency are among the
more severe forms, which typically manifest in infancy or early childhood, and are characterized by an
increased susceptibility to opportunistic pathogens (eg, Pneumocystis carinii, Cryptosporidium, and
Toxoplasma gondii).(3) CD40 deficiency, also known as hyper-IgM type 3 (HIGM3), accounts for less
than 1% of hyper-IgM syndromes. Flow cytometry analysis shows complete lack of CD40 expression on
the B cells of these patients.(4) Intravenous injection with IgG is the treatment of choice along with
immune reconstitution with hematopoietic cell transplantation. To date, all documented CD40-deficient
patients have been diagnosed before age 1. Consequently, when used in the context of HIGM3, this test is
only indicated in children (for diagnosis). In the case of CD40L deficiency, this test can be used for male
patients or in female patients of child-bearing age (to identify carriers). A larger age spectrum has been
reported with CD40L deficiency, ranging from infancy to early adulthood. CD40 expression on B cells is
also an indicator of immune status (eg, after the use of biological immunomodulatory therapy for
autoimmune disease, cancer, and transplantation).
Useful For: Evaluating patients for hyper-IgM type 3 (HIGM3) syndrome due to defects in CD40,
typically seen in patients less than 10 years of age Assessing B-cell immune competence in other
clinical contexts, including autoimmunity, malignancy, and transplantation
Interpretation: This assay is qualitative; CD40 expression is reported as present (normal) or absent
(abnormal). Normal B cells express surface CD40 on the majority of cells. Hyper-IgM (HIGM3)
syndrome patients typically do not express CD40 on the surface of B cells. Genotyping of CD40 is
required for a definite diagnosis of HIGM3. Call 800-533-1710 for ordering assistance.
Reference Values:
Present (normal)
Clinical References: 1. Bishop GA, Hostager BS: The CD40-CD154 interaction in B cell-T cell
liaisons. Cytokine Growth Factor Rev. Jun-Aug 2003;14(3-4):297-309 2. Lee WI, Torgerson TR,
Schumacher MJ, et al: Molecular analysis of a large cohort of patients with hyper immunoglobulin M
(IgM) syndrome. Blood. 2005 Mar 1;105(5):1881-1890 3. Kutukculer N, Moratto D, Aydinok Y, et al:
Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40
deficiency. J Pediatr. 2003 Feb;142(2):194-196 4. Ferrari S, Giliani S, Insalaco A, et al: Mutations of
CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad
Sci USA. 2001 Oct 23;98(22):12614-12619 5. Yazdani R, Fekrvand S, Shahkarami S, et al: The hyper
IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clin
Immunol. 2019 Jan;198:19-30. doi: 10.1016/j.clim.2018.11.007
BCLGP B-Cell Deficiency Primary Immunodeficiency Disorder Panel

65664 (34 genes), Next-Generation Sequencing, Varies
Clinical Information: Primary B-cell disorders/humoral immunodeficiencies are characterized by
an insufficient number of B cells or impaired functioning/differentiation of B cells. B-cell disorders
account for approximately two-thirds of all genetic primary immunodeficiency disorders (PIDD) and
may result in decrease or dysfunction of one or more isotypes of immunoglobulin, leading to increased
susceptibility to infection, particularly bacterial infections such as sinopulmonary infections,
gastrointestinal infections, otitis, skin infections, and conjunctivitis. In the absence of infection, patients
may be asymptomatic and, thus, difficult to diagnose. In addition, primary B-cell disorders may result in
lymphoproliferative disorders or be associated with autoimmune (AI) manifestations, including AI
cytopenias, AI endocrine disorders, and AI enteropathy among others. There are several PIDD that also
have an associated T-cell and/or other cellular immunodeficiency, in addition to the B-cell defects. In
some disorders with agammaglobulinemia or hypogammaglobulinemia, patients may have reduced
numbers of B cells, resulting in a severe reduction in all antibody isotypes. Often, they present in the
first few years of life with recurrent bacterial infections, a severe life-threatening bacterial infection (ie,
meningitis, sepsis), and decreased lymphoid tissue (ie, small adenoids, tonsils, and lymph nodes in
X-linked agammaglobulinemia, due to Bruton tyrosine kinase [BTK] gene variants). Inheritance can be
either X-linked (eg, due to variants in BTK), or autosomal recessive (eg, IGHM, CD79A, CD79B,
IGLL1, BLNK, LRRC8A, and PIK3R1). B-cell lymphopenia with hypogammaglobulinemia can also be
observed in WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), which
results from pathogenic gain-of-function variants in the CXCR4 gene. These patients also have severe
peripheral neutropenia (absolute neutrophil count <500) with evidence of myelokathexis (neutrophil
retention) in the bone marrow. In addition to recurrent infections (sinopulmonary, urinary tract,
omphalitis, deep soft tissue abscesses, skin), patients are also susceptible to warts and condyloma
acuminata due to human papillomavirus infection. Common variable immunodeficiency (CVID) is the
most common adult humoral immunodeficiency disorder with an incidence of approximately 1:25,000
to 1:50,000. CVID may present with frequent and unusual infections during early childhood,
adolescence, or adulthood. As per current diagnostic criteria, CVID is not considered in children
younger than 4 years of age. In addition, a significant proportion of patients may have autoimmune or
inflammatory manifestations, enlarged lymphoid tissues, granulomas, and an increased susceptibility to
cancer. These patients typically have normal numbers of B cells (<5% of CVID patients have less than
1% of B cells, which are considered to be due to early B-cell defects) but have impaired terminal
differentiation, resulting in decreased levels of IgG and IgA, with or without a decrease in IgM. Over
two-thirds of patients have quantitative defects in switched memory B cells. Some patients may also
have quantitative and functional T-cell defects or NK-cell deficiency. Patients with decreased naive
T-cell numbers are considered to have late-onset combined immunodeficiency (LOCID). Genetic
variants have been identified in several genes, including ICOS, TNFRSF13B (TACI), CD19,
TNFRSF13C (BAFFR), MS4A1 (CD20), CR2 (CD21), CD81, LRBA, NFKB2, IKZF1 (IKAROS),
among others, in a subset of CVID patients. However, the majority of these patients have unknown
genetic defects and may have oligogenic or polygenic causes of disease. Dysgammaglobulinemias
including hyper-IgM syndrome and selective antibody deficiencies may also occur where a patient is
either lacking a specific immunoglobulin isotype (eg, selective IgA deficiency) or a specific vaccine
antibody response (impaired pneumococcal polysaccharide responsiveness) or may have an
elevated/normal IgM level. Selective deficiencies (ie, IgA deficiency, IgG deficiency) may be due to
variants in genes encoding immunoglobulin heavy or light chains. Selective IgA deficiency (sIgAD) is
the most common PIDD with an incidence of 1:200 to 1:1000, depending on the cohort studied. Most
patients with sIgAD are asymptomatic though some may have frequent infections. There is also a higher
incidence of celiac disease in this group. Most patients with selective antibody deficiencies are treated if
they have frequent infections in addition to impaired vaccine antibody responses. Some patients with
sIgAD may have autoantibodies to IgA. Hyper IgM syndrome (mostly commonly due to variants in
CD40LG but also due to other genes, eg, CD40, AICDA, PI3KCD, UNG) is characterized by an
inability to switch from the production of IgM-type antibodies to IgG, IgA, or IgE isotypes. These
individuals typically have a normal number of B cells. Patients with CD40L and CD40 deficiency tend
to present with severe opportunistic infections more reminiscent of a cellular immunodeficiency and,
therefore, may also be considered as combined immunodeficiencies. Primary B-cell disorders may also
result in lymphoproliferative diseases characterized by
dysgammaglobulinemia/hypogammaglobulinemia, persistent or severe complications of Epstein-Barr
virus (including hemophagocytic lymphohistiocytosis), and lymphoproliferative disorders (including
malignant lymphomas). Lymphomas that are associated with these disorders are typically high-grade
B-cell lymphomas, non-Hodgkin type, extranodal, and often involve the intestine. Inflammatory bowel
disease has also been associated with some forms. Inheritance of these lymphoproliferative diseases can
be X-linked or autosomal recessive. For example, X-linked lymphoproliferative disease (XLP) is due to
pathogenic variants in SH2D1A (XLP-1), while autosomal recessive lymphoproliferative syndrome 2 is
caused by pathogenic variants in TNFRSF7, which encodes CD27. Some of these lymphoproliferative
disorders clinically manifest following infection, especially with Epstein-Barr virus. Post-meiotic
segregation disorder, due to pathogenic variants in PMS2, leads to defective class switching from IgM
and results in low serum IgG and IgA with elevated IgM. Patients also often demonstrate cafe-au-lait
macules and are predisposed to several types of malignancy due to Lynch syndrome. PMS2 testing will
be performed only for patients who demonstrate defective class switching. Table. Genes included in this
panel Gene symbol (alias) Protein OMIM Incidence Inheritance Phenotype disorder AICDA
Single-stranded DNA cytosine deaminase 605257 Unknown AR Immunodeficiency with hyper IgM,
type 2 BLNK B-cell linker protein isoform 1 604515 Unknown AR Agammaglobulinemia BTK
Tyrosine-protein kinase BTK isoform 1 300300 1-9/million XL X-linked agammaglobulinemia CD79A
B-cell antigen receptor complex-associated protein alpha chain isoform 1 precursor 112205 Unknown
AR Agammaglobulinemia CD79B (B29) B-cell antigen receptor complex-associated protein beta chain
isoform 1 precursor 147245 Unknown AR Agammaglobulinemia CARD11 Caspase recruitment
domain-containing protein 11 607210 AR/AD Immunodeficiency 11 (AR), B-cell expansion with
NFKB and T-cell anergy (AD) CD19 B-lymphocyte antigen CD19 isoform 2 precursor 107265
Unknown AR Common variable immunodeficiency (CVID) 3 CD27 (TNFRSF7) CD27 antigen
precursor 186711 AR Lymphoproliferative syndrome 2 (CD27 deficiency) CD40 Tumor necrosis factor
receptor superfamily member 5 isoform 1 precursor 109535 Unknown AR Immunodeficiency with
hyper IgM CD40LG CD40 ligand 300386 2/million males XL Immunodeficiency with X-linked hyper
IgM CD81 CD81 antigen isoform 1 186845 Unknown AR Common variable immunodeficiency
(CVID) 6 CR2 (CD21) Complement receptor type 2 isoform 1 precursor 120650 Unknown AR
Common variable immunodeficiency (CVID) 7 CXCR4 C-X-C chemokine receptor type 4 isoform b
162643 AD Myelokathexis, isolated, WHIM syndrome (AD) GATA2 Endothelial transcription factor
GATA-2 isoform 1 137295 AD Immunodeficiency 21, Emberger syndrome,Â susceptibility to acute
myeloid Leukemia and myelodysplastic syndrome ICOS Inducible T-cell costimulator precursor
604558 Unknown AR Common variable immunodeficiency (CVID) 1 IGHM IMMUNOGLOBULIN
HEAVY CHAIN CONSTANT REGION MU 147020 Unknown AR Agammaglobulinemia 1 IGLL1
(LAMBDA-5) Immunoglobulin lambda-like polypeptide 1 isoform a precursor 146770 Unknown AR
Agammaglobulinemia IKZF1 (IKAROS) DNA-binding protein Ikaros isoform 2 603023 AD with
incomplete penetrance Late-onset B-cell PIDÂ Â LRBA Lipopolysaccharide-responsive and
beige-like anchor protein isoform 2 606453 Unknown AR Common variable immunodeficiency (CVID)
8 with autoimmunity LRRC8A Volume-regulated anion channel subunit LRRC8A 608360 Unknown
AD Agammaglobulinemia MALT1 Mucosa-associated lymphoid tissue lymphoma translocation protein
1 isoform a 604860 AR Immunodeficiency 12 MS4A1 (CD20) B-lymphocyte antigen CD20 112210
AR Common variable immunodeficiency (CVID) 5 NFKB2 Nuclear factor NF-kappa-B p100 subunit
isoform a 164012 Unknown AD Common variable immunodeficiency (CVID) 10 PIK3CD
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform 602839 Unknown AD
Immunodeficiency 14, hyper IgM PIK3R1 Phosphatidylinositol 3-kinase regulatory subunit alpha
isoform 1 171833 Unknown AR Agammaglobulinemia PLCG2 1-Phosphatidylinositol 4,5-bisphosphate
phosphodiesterase gamma-2 600220 Rare AD Autoinflammation, antibody deficiency, and immune
dysregulation syndrome familial cold autoinflammatory syndrome PRKCD Protein kinase C delta type
176977 Unknown AR Autoimmune lymphoproliferative syndrome, type III RNF168 E3
ubiquitin-protein ligase RNF168 612688 AR RIDDLE syndrome SH2D1A SH2 domain-containing
protein 1A isoform 1 300490 1/million males XL X-linked lymphoproliferative syndrome TCF3 (E47)
Transcription factor E2-alpha isoform E12 147141 AD Agammaglobulinemia 8 TNFRSF13B (TACI)
Tumor necrosis factor receptor superfamily member 13B 604907 Unknown AD or AR Common
variable immunodeficiency (CVID) 2, immunoglobulin A deficiency TNFRSF13C Tumor necrosis
factor receptor superfamily member 13C 606269 Unknown AD or AR Common variable
immunodeficiency (CVID) 4 TNFSF12 (TWEAK) Tumor necrosis factor ligand superfamily member
12 proprotein 602695 AD Low IgM and IgA UNG Uracil-DNA glycosylase isoform UNG2 191525
Unknown AR Immunodeficiency with hyper IgM syndrome, type 5 AD=autosomal dominant
AR=autosomal recessive XL=X-linked
history suggestive of primary B-cell deficiencies and related disorders Patients with B-cell
immunodeficiency disorders who may have other clinical presentations, besides the humoral immune
defect, such as inflammatory bowel disease, autoimmunity, or other as indicated above Establishing a
diagnosis of a B-cell deficiency or related disorder, in some cases, allowing for appropriate management
and surveillance for disease features based on the gene involved Identifying variants within genes
known to be associated with increased risk for disease features allowing for predictive testing of at-risk
family members
Reference Values:
May;17(5):405-424 2. Picard C, Gaspar HB, Al-Herz W, Bousfina A, et al: International Union of
Immunological Societies: 2017 Primary Immunodeficiency Disease Committee Report on Inborn Errors
of Immunity, J Clin Immunol. 2018;38:96-128 3. Conley ME, Dobbs AK, Farmer DM, et al: Primary B
cell immunodeficiencies: Comparisons and contrasts. Ann Rev Immunol. 2009;27:199-277 4. Park MA,
Li JT, Hagan JB, et al: Common Variable Immunodeficiency: a new look at an old disease. Lancet.
2008;372:489-502 5. Ameratunga R, Brewerton M, Slade C, et al: Comparison of diagnostic criteria for
common variable immunodeficiency disorder. Front Immunol.2014;415(5):1-9 6. Schaffer AA, Salzer
U, Hammarstrom L, et al: Deconstructing common variable immunodeficiency by genetic analysis.
Curr Opin. Genetics and Dev 2007;7:201-212 7. Conley ME: Early defects in B cell development. Curr
Opin Allergy Clin Immunol .2002;2:517-522 8. Notarangelo LD, Lanzi G, Peron S, et al: Defects of
class-switch recombination. J Allergy Clin Immunol .2006;117:855-864 9. Bousfiha AA, Jeddane L,
Ailal F, et al: A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians
at the bedside. J Clin Immunol. 2013;33:1078-1087
BALLM B-Cell Lymphoblastic Leukemia Monitoring, Minimal Residual

608251 Disease Detection, Flow Cytometry, Varies
Clinical Information: B-cell acute lymphoblastic leukemia (B-ALL) is a neoplasm of precursor cells
(lymphoblasts) committed to B-cell lineage. B-ALL is the most common acute leukemia in children and
adolescents and can also occur in adults. Patients with B-ALL typically present with a high blast count in
the peripheral blood and bone marrow replacement with the disease. The diagnosis of B-ALL is based on
a combination of morphologic features showing primarily small blasts with open chromatin and high N:C
ratio, and an immunophenotype showing immaturity (CD34 and/or TdT expression) associated with
B-cell lineage markers (CD19, CD22, and CD79a). New therapeutic approaches in B-ALL have been
increasingly successful. One of the most important predictors of the disease relapse is the ability to detect
minimal residual disease (MRD) in the bone marrow specimens following induction phase of the therapy
(day 28). Immunophenotyping studies are necessary as morphologic features are not sufficient to detect
MRD. The absence of MRD (at 0.002% sensitivity) is an important prognostic indicator in these patients.
This test may also be used to establish an immunophenotypic fingerprint of tumor cells at diagnosis to
monitor MRD in these patients after treatments or allogeneic stem cell transplant.
Useful For: Aids in monitoring a previously confirmed diagnosis of B-cell acute lymphoblastic
leukemia
Interpretation: An interpretive report for the presence or absence of B-cell acute lymphoblastic
leukemia (B-ALL) minimal residual disease (MRD) is provided. Patients who have detectable MRD by
this assay are considered to have residual/recurrent B-ALL.
Reference Values:
This test will be processed as a laboratory consultation. An interpretation of the immunophenotypic
findings and correlation with the morphologic features will be provided by a hematopathologist for every
case.
Clinical References: 1. Bader P, Kreyenberg H, Henze GHR, et al: Prognostic value of minimal
residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute
lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol. 2009 Jan 20;27:377-384 2.
Borowitz MJ, Devidas M, Hunger SP, et al: Clinical significance of minimal residual disease in childhood
acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology
Group study. Blood. 2008 Jun 15;111(12):5477-5485 3. Borowitz MJ, Pullen DJ, Winick N, Martin PL,
Bowman WP, Camitta B: Comparison of diagnostic and relapse flow cytometry phenotypes in childhood
acute lymphoblastic leukemia: implications for residual disease detection: a report from the children's
oncology group. Cytometry B Clin Cytom. 2005 Nov;68(1):18-24 4. Campana D: Role of minimal
residual disease monitoring in adult and pediatric acute lymphoblastic leukemia. Hematol Oncol Clin
North Am. 2009 Oct;23(5):1083-1098 5. Chen W, Karadikar NJ, McKenna RW, Kroft SH: Stability of
leukemia-associated immunophenotypes in precursor B-lymphoblastic leukemia/lymphoma: a single
institution experience. Am J Clin Pathol. 2007 Jan;127(1):39-46 6. Coustan-Smith E, Ribeiro RC, Stow P,
et al: A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have
a superior clinical outcome. Blood. 2006 Jul 1;108(1):97-102 7. Coustan-Smith E, Sancho J, Behm FG, et
al: Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood
acute lymphoblastic leukemia. Blood. 2002 Jul 1;100(1):52-58 8. Guillaume N, Penther D, Vaida I, et al:
CD66c expression in B-cell lymphoblastic leukemia: strength and weakness. Int J Lab Hematol. 2011
Feb;33(1):92-96 9. Stow P, Key L, Chen X, et al: Clinical significance of low levels of minimal residual
disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood. 2010
Jun 10;115(23):4657-4663 10. Wood BL: Principals of minimal residual disease detection for
hematopoietic neoplasms by flow cytometry. Cytometry B Clin Cytom. 2016 Jan;90(1):47-53
BLBLF B-Cell Lymphoblastic Leukemia/Lymphoma, FISH, Tissue

609451 Clinical Information: In the United States, the incidence of B-lymphoblastic leukemia/lymphoma
(B-ALL/LBL) is roughly 6000 new cases per year or approximately 1 in 50,000 individuals.
B-ALL/LBL accounts for approximately 70% of all childhood leukemia cases (ages 0 to 19 years),
making it the most common type of childhood cancer. It has a peak incidence at 2 to 5 years of age.
This incidence decreases with age before increasing again at around 50 years of age. B-ALL/LBL is
slightly more common in male patients than female patients. There is also an increased incidence of
B-ALL/LBL in individuals with genetic conditions such as Down syndrome, Fanconi anemia, Bloom
syndrome, ataxia telangiectasia, Li-Fraumeni syndrome, X-linked agammaglobulinemia, and severe
combined immunodeficiency. The overall cure rate for B-ALL/LBL in children is approximately 90%,
and about 45% to 60% of adults have long-term disease-free survival. Of note, CRLF2/IGH
rearrangements are more commonly observed in patients with Down syndrome or of Hispanic descent.
Specific cytogenetic abnormalities are identified in the majority of cases of B-ALL/LBL, either by
conventional chromosome studies or fluorescence in situ hybridization studies. Each of the genetic
subgroups are important to detect and can be critical prognostic markers. For example, a decision for
early transplantation may be made if t(9;22)(q34;q11.2), KMT2A rearrangement, iAMP21, or a
hypodiploid clone is identified. In contrast, if ETV6/RUNX1 fusion or hyperdiploidy is identified, the
patient has a more favorable prognosis and transplantation is rarely initially considered. A newly
recognized World Health Organization entity called BCR-ABL1-like ALL, also known as Philadelphia
chromosome-like acute lymphoblastic leukemia, is increasing in importance due to the poor prognosis
seen in pediatric, adolescent, and young adult ALL. Common features of this entity involve
rearrangements with tyrosine kinase genes involving the following genes: ABL2, PDGFRB, JAK2,
ABL1, CRLF2, and P2RY8, as well as deletions involving IKZF1. Patients who have failed
conventional therapies have demonstrated favorable responses to targeted therapies when
region is included in all diagnostic B-ALL panels to evaluate for Burkitt lymphoma. If a positive result
is obtained, additional testing for the BCL2 and BCL6 gene regions will be performed. Per National
Comprehensive Cancer Network guidelines, a combination of cytogenetic and FISH testing is currently
recommended in all pediatric and adult patients with B-ALL/LBL. Table. Common Chromosome
Abnormalities in B-cell Acute Lymphoblastic Leukemia/Lymphoma Leukemia type Cytogenetic
change Typical demographic Risk category B-cell acute lymphoblastic leukemia t(12;21)(p13;q22),
ETV6/RUNX1 Pediatric Favorable Hyperdiploidy Pediatric Favorable t(1;19)(q23;p13.3), PBX1/TCF3
Pediatric Intermediate to favorable t(9;22)(q34;q11.2), BCR/ABL1 All ages Unfavorable iAMP21,
RUNX1 Pediatric Unfavorable del(9p), CDKN2A All ages Unknown t(11q23;var), MLL All ages
Unfavorable t(4;11)(q21;q23), AFF1/MLL All ages Unfavorable t(6;11)(q27;q23),
MLLT4(AFDN)/MLL All ages Unfavorable t(9;11)(p22;q23), MLLT3/MLL All ages Unfavorable
t(10;11)(p12;q23), MLLT10/MLL All ages Unfavorable t(11;19)(q23;p13.1), MLL/ELL All ages
Unfavorable t(11;19)(q23;p13.3), MLL/MLLT1 All ages Unfavorable t(14q32;var), IGH All ages
Variable -17/17p-, TP53 All ages Unfavorable t(8q24.1;var),
MYCÂ Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â *representing Burkitt or other mature B-cell lymphoma
Pediatric/ adolescent/ young adult Complex karyotype (> or =4 abnormalities) Adult Unfavorable Low
hypodiploidy/near triploidy Adult Unfavorable Near-haploid/hypodiploid All ages Unfavorable
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) t(1q25;var), ABL2
ABL1
Useful For: Detecting a neoplastic clone in paraffin embedded specimens associated with the
common chromosome abnormalities seen in patients with B-cell lymphoblastic leukemia/lymphoma
the normal reference range for any given probe. A positive result is not diagnostic for B-cell
lymphoblastic lymphoma but may provide relevant prognostic information. The absence of an abnormal
clone does not rule out the presence of a neoplastic disorder.
Reference Values:
(ECOG) 2993 trial. Blood 2007. Apr 15;109(8):3189-3197 2. Moorman AV: The clinical relevance of
chromosomal and genetic abnormalities in B-cell precursor acute lymphoblastic leukemia. Blood Rev.
2012 May;26(3):123-135 3. Roberts KG, Li Y, Payne-Turner D, et al: Targetable kinase-activating lesions
in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014 Sept 11;371(11):1005-1015 4. Mullighan
CG: The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematology
Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):174-180 5. Arber DA, Orazi A, Hasserjian R, et al:
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute
leukemia. Blood. 2016 May 19;127(20):2391-2405 6. Swerdlow SH, Campo E, Harris NL, et al, eds:
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press; 2017
BLYM B-Cell Lymphoma, FISH, Tissue

65878 Clinical Information: Mature B-cell lymphoma can be low grade, intermediate grade, or high grade,
and the prognosis and clinical course are highly variable. Genetic abnormalities have emerged as one of
the most important prognostic markers in B-cell lymphomas and can aid in diagnosis. Several
chromosome abnormalities and variants of these abnormalities have been associated with various
lymphoma subtypes (see Table). Conventional chromosome studies cannot be employed on
paraffin-embedded tissue, and molecular genetic analyses are often problematic in the study of
lymphomas. FISH permits the detection of abnormal gene associated with various chromosome
translocations and inversions in B-cell lymphoma (see Table). Table. Common Chromosome
Abnormalities in B-cell Lymphomas Lymphoma type Chromosome abnormality FISH probe Burkitt
(pediatric, < or =18 years old) 8q24.1 rearrangement 5'/3' MYC t(2;8)(p12;q24.1) IGK/MYC
t(8;14)(q24.1;q32) MYC/IGH t(8;22)(q24.1;q11.2) MYC/IGL 3q27 rearrangement 3'/5' BCL6 18q21
rearrangement 3'/5' BCL2 Diffuse large B-cell, Burkitt-like "double-hit" 8q24.1 rearrangement 5'/3' MYC
t(8;14)(q24.1;q32) MYC/IGH ----Reflex: t(8;22)(q24.1;q11.2) MYC/IGL ----Reflex: t(2;8)(p12;q24.1)
IGK/MYC ----Reflex: 3q27 rearrangement 3'/5' BCL6 ----Reflex: 18q21 rearrangement 3'/5' BCL2 Large
BCL with IRF4 rearranged 6p24.3 rearrangement 3'/5' IRF4 18q21 rearrangement 3'/5' BCL2 3q27
rearrangement 3'/5' BCL6 Follicular 18q21 rearrangement 3'/5' BCL2 3q27 rearrangement 3'/5' BCL6
Predominantly diffuse subtype only: deletion of 1p36 TNFRSF14/1q22 Mantle cell t(11;14)(q13;q32)
CCND1/IGH Blastoid subtype only: deletion of 17p TP53/D17Z1 Blastoid subtype only: 8q24.1
rearrangement 5'/3' MYC MALT 18q21 rearrangement 5'/3' MALT1 Splenic marginal zone Deletion of
7q D7Z1/7q32 Deletion of 17p TP53/D17Z1
Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities seen
in patients with various B-cell lymphomas Tracking known chromosome abnormalities and response to
therapy in patients with B-cell lymphomas
the normal reference range for any given probe. Detection of an abnormal clone is supportive of a
diagnosis of a B-cell lymphoma. The specific abnormality detected may help subtype the neoplasm. The
absence of an abnormal clone does not rule out the presence of a neoplastic disorder.
Reference Values:
Clinical References: Swerdlow SH, Campo E, Harris NL, eds, et al: WHO Classification of
Tumours of Haematopoietic and Lymphoid Tissues. IARC; 2017
BLPMF B-Cell Lymphoma, Specified FISH, Varies

Current 614227
Clinical Information: Mature B-cell lymphomas represent a diverse group of neoplasms with a
varied prognosis and clinical course based on the B-cell lymphoma subtype. Several characteristic
genetic abnormalities have emerged as important diagnostic and prognostic markers in specific B-cell
lymphoma subtypes (see Table). Table. Common Chromosome Abnormalities in B-cell Lymphomas
Lymphoma subtype Chromosome abnormality FISH probe Burkitt (pediatric, < or =18 years old)
8q24.1 rearrangement 5'/3' MYC t(2;8)(p12;q24.1) IGK/MYC t(8;14)(q24.1;q32) MYC/IGH
t(8;22)(q24.1;q11.2) MYC/IGL 3q27 rearrangement (evaluated for exclusion) 3'/5' BCL6 18q21
rearrangement (evaluated for exclusion) 3'/5' BCL2 Diffuse large B-cell, "double-hit" or "triple hit"
8q24.1 rearrangement 5'/3' MYC t(8;14)(q24.1;q32) MYC/IGH -Reflex: t(2;8)(p12;q24.1) IGK/MYC
-Reflex: t(8;22)(q24.1;q11.2) MYC/IGL -Reflex: 3q27 rearrangement 3'/5' BCL6 -Reflex: 18q21
rearrangement 3'/5' BCL2 Follicular 18q21 rearrangement 3'/5' BCL2 3q27 rearrangement 3'/5' BCL6
Mantle cell t(11;14)(q13;q32) CCND1/IGH -Reflex: 11q13 rearrangement 5'/3' CCND1 Blastoid
subtype only: deletion of 17p TP53/D17Z1 Blastoid subtype only: 8q24.1 rearrangement 5'/3' MYC
Blastoid subtype only: t(8;14)(q24.1;q32) MYC/IGH Splenic marginal zone lymphoma Deletion of 7q
D7Z1/7q32 Deletion of 17p TP53/D17Z1
Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities
seen in patients with various B-cell lymphomas Tracking known chromosome abnormalities and
response to therapy in patients with B-cell lymphoma Evaluating specimens in which standard
Interpretation: Detecting a neoplastic clone associated with the common chromosome abnormalities
seen in patients with various B-cell lymphomas Tracking known chromosome abnormalities and
response to therapy in patients with B-cell lymphoma Evaluating specimens in which standard
Reference Values:
Clinical References: 1. Swerdlow S, Campo E, Harris NL, et al, eds. WHO Classification of
Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. IARC Press; 2017 2. King RL, McPhail
ED, Meyer RG, et al: False-negative rates for MYC fluorescence in situ hybridization probes in B-cell
neoplasms Haematologica. Jun;104(6): e248-e251, 2019 3. Pophali PA, Marinelli LM, Ketterling RP, et
al: High level MYC amplification in B-cell lymphomas: is it a marker of aggressive disease? Blood
Cancer J. 2020 Jan 13;10(1):5
IABCS B-Cell Phenotyping Profile for Immunodeficiency and Immune

88800 Competence Assessment, Blood
Clinical Information: Normal immunity requires a balance between the activities of various
lymphocyte subpopulations with different effector and regulatory functions. Different immune cells can
be characterized by unique surface membrane antigens described by a cluster of differentiation
nomenclature (eg, CD3 is an antigen found on the surface of T lymphocytes). Abnormalities in the
number and percent of T (CD3, CD4, CD8), B (CD19), and natural killer (CD16+CD56) lymphocytes
have been described in a number of different diseases. In patients who are infected with HIV, the CD4
count is measured for AIDS diagnosis and for initiation of antiviral therapy. The progressive loss of
CD4 T lymphocytes in patients infected with HIV is associated with increased infections and
complications. The US Public Health Service has recommended that all HIV-positive patients be tested
every 3 to 6 months for the level of CD4 T lymphocytes. The adaptive immune response includes both
cell-mediated (mediated by T cells and natural killer [NK] cells) and humoral immunity (mediated by B
cells). After antigen recognition and maturation in secondary lymphoid organs, some antigen-specific B
cells terminally differentiate into antibody-secreting plasma cells or become memory B cells. Memory
B cells are 3 subsets: marginal zone B cells (MZ or non-switched memory), class-switched memory B
cells, and IgM-only memory B cells. Decreased B-cell numbers, B-cell function, or both result in
immune deficiency states and increased susceptibility to infections. These decreases may be either
primary (genetic) or secondary. Secondary causes include medications, malignancies, infections, and
autoimmune disorders. Common variable immunodeficiency (CVID), a disorder of B-cell function, is
the most prevalent primary immunodeficiency with a prevalence of 1 to 25,000 to 1 to 50,000.(1) CVID
has a bimodal presentation with a subset of patients presenting in early childhood and a second set
presenting between 15 and 40 years of age or, occasionally, even later. Many different genetic defects
have been associated with CVID, including variants in the ICOS, CD19, BAFF-R, and TACI genes.
TACI variants account for 8% to 15% of CVID cases. CVID is characterized by
hypogammaglobulinemia usually involving most or all of the Ig classes (IgG, IgA, IgM, and IgE),
impaired functional antibody responses, and recurrent sinopulmonary infections.(1,2) B-cell numbers
may be normal or decreased. A minority of patients with CVID (5%-10%) have very low B-cell counts
(<1% of peripheral blood leukocytes), while another subset (5%-10%) exhibit noncaseating,
sarcoid-like granulomas in different organs and also tend to develop a progressive T-cell deficiency.(1)
Of all patients with CVID, 25% to 30% have increased numbers of CD8 T cells and a reduced CD4 to
CD8 ratio (<1). Studies have shown the clinical relevance of classifying patients with CVID by
assessing B-cell subsets, since changes in different B-cell subsets are associated with particular clinical
phenotypes or presentations.(3,4) The B-cell phenotyping assay can be used in the diagnosis of
hyper-IgM syndromes, which are characterized by increased or normal levels of IgM with low IgG
and/or IgA.(5) Patients with hyper-IgM syndromes can have 1 of 5 known genetic defects- in the
CD40L, CD40, AID (activation-induced cytidine deaminase), UNG (uracil DNA glycosylase), and
NEMO (NF-kappa B essential modulator) genes.(5) Variants in CD40L and NEMO are inherited in an
X-linked fashion, while variants in the other 3 genes are inherited in an autosomal recessive fashion.
Patients with hyper-IgM syndromes have a defect in isotype class-switching, which leads to a decrease
in class-switched memory B cells, with or without an increased in non-switched memory B cells and
IgM-only memory B cells. In addition to its utility in the diagnosis of the above-described primary
immunodeficiencies, B-cell phenotyping may be used to assess reconstitution of B-cell subsets after
hematopoietic stem cell or bone marrow transplant. This test is also used to monitor B-cell-depicting
therapies, such as Rituxan (rituximab) and Zevalin (ibritumomab tiuxetan). The etiology of CVID is
heterogeneous. Variants of the gene that encodes TACI, TNFRSF13B (tumor necrosis factor receptor
superfamily, member 13B) probably account for about 10%to 15% of all CVID cases.(6-8) Patients
with variants in the TACI gene are particularly prone to developing autoimmune disease, including
cytopenias as well as lymphoproliferative disease. The other variants each have been reported in only a
handful of patients. The etiopathogenesis is still undefined in 65% to 75% of patients with CVID. A
BAFF-R (B-cell activating factor receptor, encoded by the TNFRSF13C) defect should be suspected in
patients with low to very low class switched and non-switched memory B cells and very high numbers
of transitional B cells. Class switching is the process that allows B cells, which possess IgD and IgM on
their cell surface as a part of the antigen-binding complex, to produce IgA, IgE, or IgG antibodies. A
TACI defect is suspected in patients with low IgM with normal to low switched B cells, with
autoimmune and/or lymphoproliferative manifestations, and normal B cell responses to mitogens. The
absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors,
including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in
lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day,
while CD8 T cells and CD19+ B cells increase between 8:30 a.m. and noon, with no change between
noon and afternoon. Natural killer (NK) cell counts, on the other hand, are constant throughout the
day.(9) Circadian variations in circulating T-cell counts have been shown to be negatively correlated
with plasma cortisol concentration.(10-12) In fact, cortisol and catecholamine concentrations control
distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(10) It is generally
accepted that lower CD4 T-cell counts are seen in the morning compared with the evening,(13) and
during summer compared to winter.(14) These data, therefore, indicate that timing and consistency in
timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.
Useful For: Screening for common variable immunodeficiency (CVID) and hyper-IgM syndromes
Assessing B-cell subset reconstitution after stem cell or bone marrow transplant Assessing response to
B-cell-depleting immunotherapy Identifying defects in transmembrane activator and calcium modulator
and cyclophilin ligand(CAML) interactor (TACI)and B-cell-activating factor receptor(BAFF-R) in
patients presenting with clinical symptoms and laboratory features consistent with CVID This test is not
indicated for the evaluation of lymphoproliferative disorders (eg, leukemia, lymphoma, multiple
myeloma).
Interpretation: Quantitative Lymphocyte Subsets: T, B, and natural killer: When the CD4 count falls
below 500 cells/mcL, patients who are HIV-positive can be diagnosed with AIDS and can receive
antiretroviral therapy. When the CD4 count falls below 200 cells/mcL, prophylaxis against Pneumocystis
jiroveci pneumonia is recommended. Immune Assessment B Cell Subsets: The assay provides
quantitative information on the various B-cell subsets (percentage and absolute counts in cells/microliter).
Each specimen is evaluated for B-cell subsets with respect to the total number of CD19+ B cells present
in the peripheral blood mononuclear cell population, compared to the reference range. In order to verify
that there are no CD19-related defects, CD20 is used as an additional pan-B-cell marker (expressed as
percentage of CD45+ lymphocytes). The B-cell panel assesses the following B-cell subsets: -CD19+=B
cells expressing CD19 as a percent of total lymphocytes -CD19+ CD27+=total memory B cells -CD19+
CD27+ IgD+ IgM+=marginal zone or non-switched memory B cells -CD19+ CD27+ IgD-
IgM+=IgM-only memory B cells -CD19+ CD27+ IgD- IgM-=class-switched memory B cells -CD19+
IgM+=IgM B cells -CD19+ CD38+ IgM+=transitional B cells -CD19+ CD38+ IgM-=plasmablasts
-CD19+ CD21-=CD21 low ("immature") B cells -CD19+ CD21+=mature B cells -CD19+ CD20+=B
cells coexpressing both CD19 and CD20 as a percent of total lymphocytes For isotype class-switching
and memory B-cell analyses, the data will be reported as being consistent or not consistent with a defect
in memory and/or class switching. If a defect is present in any of these B-cell subpopulations, further
correlation with clinical presentation and additional functional, immunological, and genetic laboratory
studies will be suggested. Since each of the 11 B-cell subsets listed above contributes to the diagnosis of
common variable immunodeficiency (CVID) and hyper-IgM syndromes and provides further information
on the likely specific genetic defect, all the B-cell subsets are carefully evaluated to determine if further
testing is needed for confirmation, including functional assays and genotyping, which is suggested as
follow-up testing in the interpretive report. If abnormalities are found in the B-cell phenotyping panel, the
specimen will be reflexed to the CVID confirmation panel for assessment of defects in surface expression
of B-cell-activating factor receptor (BAFF-R) and transmembrane activator and calcium modulator and
cyclophilin ligand (CAML) interactor (TACI) (2 genes/proteins associated with CVID). To conclusively
determine if TACI variants are present, TNFRSF13B gene sequencing should be performed. CVID
Confirmation Flow Panel: BAFF-R is normally expressed on over 95% of B cells, while TACI is
expressed on a smaller subset of B cells and a proportion of activated T cells. The lack of TACI or
BAFF-R surface expression on the appropriate B-cell population is consistent with a CVID defect.
Results will be interpreted in the context of the B-cell phenotyping results and correlation to clinical
presentation will be recommended.
Reference Values:
The appropriate age-related reference values will be provided on the report.
Clinical References: 1. Warnatz K, Denz A, Drager R, et al: Severe deficiency of switched

memory B cells (CD27+ IgM- IgD-) in subgroups of patients with common variable immunodeficiency:
a new approach to classify a heterogeneous disease. Blood. 2002 Mar 1;99(5):1544-1551 2. Brouet JC,
Chedeville A, Fermand JP, Royer B: Study of the B cell memory compartment in common variable
immunodeficiency. Eur J Immunol. 2000 Sept;30(9):2516-2520 3. Wehr C, Kivioja T, Schmitt C, et al:
The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008 Jan
1;111(1):77-85 4. Alachkar H, Taubenheim N, Haeney MR, et al: Memory switched B-cell percentage
and not serum immunoglobulin concentration is associated with clinical complications in children and
adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol. 2006
Sep;120(3):310-318 5. Lee WI, Torgerson TR, Schumacher MJ, et al: Molecular analysis of a large
cohort of patients with hyper immunoglobulin M (hyper IgM) syndrome. Blood. 2005 Mar
1;105(5):1881-1890 6. Ramirez NJ, Posadas-Cantera S, Caballero-Oteyza A, Camacho-Ordonez N,
Grimbacher B. There is no gene for CVID - novel monogenetic causes for primary antibody deficiency.
Curr Opin Immunol. 2021 Oct;72:176-185. doi: 10.1016/j.coi.2021.05.010 7. Salzer U, Chapel HM,
Webster ADB, et al: Mutations in TNFRSF13B encoding TACI are associated with common variable
immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-828 8. Salzer U, Grimbacher B. TACI
deficiency - a complex system out of balance.Curr Opin Immunol. 2021 Aug;71:81-88. doi:
10.1016/j.coi.2021.06.004 9. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte
subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on
AIDS, Bangkok, Thailand, 2004, Abstract B11052 10. Dimitrov S, Benedict C, Heutling D, et al:
Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood. 2009 May
21;113(21);5134-5143 11. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of
circulating antigen presenting cells regulated by sleep. Sleep 2007 Apr;30(4):401-411 12. Kronfol Z,
Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to
hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Pyschosom Med.
1997 Jan-Feb;59(1):42-50 13. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated
T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and
diurnal cycle are important. J AIDS. 1990;3(2):144-151 14. Paglieroni TG, Holland PV: Circannual
variation in lymphocyte subsets, revisited. Transfusion. 1994 Jun;34(6):512-516 15. U.S. Department of
Health and Human Services: Recommendations for prophylaxis against Pneumocystis carinii
pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR Morb
Mortal Wkly Rep. 1994;43(RR-3):1-21 16. Thompson MA, Horberg MA, Agwu AL, et al: Primary care
guidance for persons with human immunodeficiency virus: 2020 update by the HIV Medicine
Association of the Infectious Diseases Society of America. Clin Infect Dis. 2021 Dec
6;73(11):e3572-e3605. Erratum in: Clin Infect Dis. 2021 Dec 08
BNP B-Type Natriuretic Peptide, Plasma

83873 Clinical Information: B-type natriuretic peptide (BNP: formerly brain natriuretic peptide) is a
32-amino acid-ringed peptide secreted by the heart to regulate blood pressure and fluid balance.(1) BNP is
stored in, and secreted predominantly from, membrane granules in the heart ventricles and is continuously
released from the heart in response to both ventricle volume expansion and pressure overload.(2) The
natriuretic peptide system and the renin-angiotensin system counteract each other in arterial pressure
regulation. When arterial pressure decreases, the kidneys release renin, which activates angiotensinogen
resulting in increased peripheral resistance of the arterioles, thus increasing arterial pressure. The
natriuretic peptides counteract the effects of renin secretion, causing a reduction of blood pressure and
extracellular fluid volume.(3) Both BNP and atrial natriuretic peptide (ANP) are activated by atrial and
ventricular distension due to increased intracardiac pressure. These peptides have both natriuretic and
diuretic properties: they raise sodium and water excretion by increasing the glomerular filtration rate and
inhibiting sodium reabsorption by the kidney. The New York Heart Association (NYHA) developed a
functional classification system for congestive heart failure (CHF) consisting of 4 stages based on the
severity of the symptoms. Various studies have demonstrated that circulating BNP concentrations increase
with the severity of CHF based on the NYHA classification.(4-6)
Useful For: Aiding in the diagnosis of congestive heart failure (CHF) The role of B-type natriuretic
peptide in monitoring CHF therapy is under investigation
Interpretation: >Normal to <200 pg/mL: likely compensated congestive heart failure (CHF) > or =200
to < or =400 pg/mL: likely moderate CHF >400 pg/mL: likely moderate-to-severe CHF B-type natriuretic
peptide (BNP) levels are loosely correlated with New York Heart Association (NYHA) functional class
(see Table). Interpretive Levels for CHF Functional Class 5th to 95th Percentile Median I 15 to 499
pg/mL 95 pg/mL II 10 to 1080 pg/mL 222 pg/mL III 38 to >1300 pg/mL 459 pg/mL IV 147 to >1300
pg/mL 1,006 pg/mL All CHF 22 to >1300 pg/mL 360 pg/mL Elevation in BNP can occur due to right
heart failure with cor pulmonale (200-500 pg/mL), pulmonary hypertension (300-500 pg/mL), and acute
pulmonary embolism (150-500 pg/mL). Elevations also occur in patients with acute coronary syndromes.
Reference Values:
Males
< or =45 years: < or =35 pg/mL
46 years: < or =36 pg/mL
> or =83 years: < or =93 pg/mL
Females
< or =45 years: < or =64 pg/mL
> or =83 years: < or =167 pg/mL
Clinical References: 1. Krishnaswamy P, Lubien E, Clopton P, et al: Utility of B-natriuretic peptide

as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left
ventricular dysfunction. Am J Med. 2001;111(4):274-279 2. McNairy M, Gardetto N, Clopton P, et al:
Stability of B-type natriuretic peptide levels during exercise in patients with congestive heart failure:
implications for outpatient monitoring with B-type natriuretic peptide. Am Heart J. 2002
March;143(3):406-411 3. Redfield MM, Rodeheffer RJ, Mahoney DW, et al: What is a normal BNP? - a
community-based study employing two assays for measurement of BNP. J Card Fail. 2001
September;7(3):30 4. Apple FS, Goetze JP, Jaffe AS: Cardiac function. In: Rifai N, Horvath AR, Wittwer
CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier;
2018:1201-1255 5. Dietzen DJ: Amino acids, peptides, and proteins. In: Rifai N, Horvath AR, Wittwer
BABG Babesia microti IgG Antibodies, Serum

81128 Clinical Information: Babesiosis is a zoonotic infection caused by the protozoan parasite Babesia
microti. The infection is acquired by contact with Ixodes ticks carrying the parasite. The deer mouse is the
animal reservoir and, overall, the epidemiology of this infection is much like that of Lyme disease.
Babesiosis is most prevalent in the Northeast, upper Midwest, and Pacific Coast of the United States.
Infectious forms (sporozoites) are injected during tick bites and the organism enters the vascular system
where it infects red blood cells (RBC). In this intraerythrocytic stage, it becomes disseminated throughout
the reticuloendothelial system. Asexual reproduction occurs in RBC, and daughter cells (merozoites) are
formed that are liberated on rupture (hemolysis) of the RBC. Most cases of babesiosis are probably
subclinical or mild, but the infection can be severe and life threatening, especially in older or asplenic
patients. Fever, fatigue, malaise, headache, and other flu-like symptoms occur most commonly. In the
most severe cases, hemolysis, acute respiratory distress syndrome, and shock may develop. Patients may
have hepatomegaly and splenomegaly. A serologic test can be used as an adjunct in the diagnosis and
follow-up of babesiosis, when infection is chronic or persistent, or in seroepidemiologic surveys of the
prevalence of the infection in certain populations. Babesiosis is usually diagnosed by observing the
organisms in infected RBC on Giemsa-stained thin blood films of smeared peripheral blood. Serology
may also be useful if the parasitemia is too low to detect or if the infection has cleared naturally or
following treatment.
Useful For: An adjunct in the diagnosis of babesiosis Follow-up of documented babesiosis

Interpretation: A positive result of an indirect fluorescent antibody test (titer > or =1:64) suggests
current or previous infection with Babesia microti. In general, the higher the titer, the more likely it is that
the patient has an active infection. Patients with documented infections have usually had titers ranging
from 1:320 to 1:2560.
Reference Values:
<1:64
Clinical References: 1. Spach DH, Liles WC, Campbell GL, Quick RE, Anderson Jr DE, Fritsche
TR: Tick-borne diseases in the United States. N Engl J Med. 1993 Sep 23;329:936-947 2. Vannier E,
Gelfand JA: Babesia species. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's
Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020:3400-3409
LBAB Babesia species, Molecular Detection, PCR, Blood
62847 Clinical Information: Babesiosis is a tick-transmitted zoonosis caused by intraerythrocytic
protozoa in the genus Babesia. Babesia microti is responsible for the vast majority of human cases in the
United States, with most cases occurring along the Northeast Coast and the upper Midwestern states. A
small number of cases of B duncani human infection have also been reported along Pacific Coast states
from Washington to northern California, and B divergens/B divergens-like strains have been detected in
humans in Missouri (MO-1 strain), Kentucky, and Washington. In Europe, B divergens and B
venatorum are the primary causes of human babesiosis. Humans most commonly acquire infection
through the bite of an infected tick. The most common tick vectors in the United States are Ixodes
scapularis and Ixodes pacificus, while Ixodes ricinus and other ticks transmit the parasite in Europe and
Asia. Less commonly, babesiosis may be acquired through blood transfusion and across the placenta
from the mother to the fetus. Most patients with babesiosis are asymptomatic or have only a self-limited
mild flu-like illness, but some develop a severe illness that may result in death. Patient symptoms may
include fever, chills, extreme fatigue, and severe anemia. The most severe cases occur in asplenic
individuals and those over 50 years of age. Rare cases of chronic parasitemia, usually in
immunocompromised patients, have been described. Babesiosis is conventionally diagnosed through
microscopic examination of Giemsa-stained thick and thin peripheral blood films looking for
characteristic intraerythrocytic Babesia parasites. This method is relatively rapid, widely available, and
capable of detecting (but not differentiating) human-infective Babesia species. It is also necessary for
calculating the percentage of parasitemia which is used to predict prognosis, guide patient management,
and monitor response to treatment. However, microscopic examination requires skilled microscopists
and may be challenging in the setting of low parasitemia or prior drug therapy. Also, Babesia species
may closely resemble those of Plasmodium falciparum. The Mayo Clinic real-time PCR assay provides
a rapid and more sensitive alternative to blood film examination for detection and differentiation of B
microti, B duncani, and B divergens/B divergens-like parasites. It does not cross-react with malaria
parasites.
Useful For: An initial screening or confirmatory testing method for suspected babesiosis during the
acute febrile stage of infection in patients from endemic areas, especially when Giemsa-stained
peripheral blood smears do not reveal any organisms or the organism morphology is inconclusive.
Interpretation: A positive result indicates the presence of Babesia species DNA and is consistent
with active or recent infection. While positive results are highly specific indicators of disease, they
should be correlated with blood smear microscopy, serological results and clinical findings. A negative
result indicates absence of detectable DNA from Babesia species in the specimen, but does not always
rule out ongoing babesiosis in a seropositive person, since the parasitemia may be present at a very low
level or may be sporadic. Other tests to consider in the evaluation of a patient presenting with an acute
febrile illness following tick exposure include serologic tests for Lyme disease (Borrelia burgdorferi),
and molecular detection (PCR) for ehrlichiosis/anaplasmosis. For patients who are past the acute stage
of infection, serologic tests for these organisms should be ordered prior to PCR testing.
Reference Values:
Negative
Clinical References: 1. Anderson JF, Mintz ED, Gadbaw JJ, et al: Babesia microti, human
babesiosis and Borrelia burgdorferi in Connecticut. J Clin Microbiol 1991;29(12):2779-2783 2.
Herwaldt BL, de Bruyn G, Pieniazek NJ, et al: Babesia divergens-like infection, Washington State.
Emerg Infect Dis 2004;10(4):622-629 3. Herwaldt B, Persing DH, Precigout EA, et al: A fatal case of
babesiosis in Missouri: identification of another piroplasm that infects humans. Ann Intern Med
1996;124(7):643-650 4. Persing DH, Herwaldt BL, Glaser C, et al: Infection with a Babesia-like
organism in northern California. N Engl J Med 1995;332(5):298-303 5. Quick RE, Herwaldt BL,
Thomford JW, et al: Babesiosis in Washington State: a new species of Babesia? Ann Intern Med
1993;119(4):284-290 6. Vannier E, Krause PJ: Human Babesiosis. N Engl J Med 2012 Jun
21;366(25):2397-2407 7. Burgess MJ, Rosenbaum ER, Pritt BS, et al. Possible Transfusion-Transmitted
Babesia divergens-like/MO-1 in an Arkansas Patient. Clin Infect Dis 2017
FBACS Baclofen, Serum
75397 Interpretation: Serum concentrations required for therapeutic effects reportedly range from 0.08 -
0.40 mcg/mL.
Reference Values:
Units: mcg/mL
GENS Bacterial Culture, Aerobic with Antimicrobial Susceptibilities,

60518 Varies
Clinical Information: Sterile Body Fluids and Normally Sterile Tissues: In response to infection,
fluid may accumulate in any body cavity. Wound, Abscess, Exudates: Skin and soft tissue infections can
occur as a result of a break in the skin surface, or they can occur as complications of surgery, trauma,
human, animal, or insect bites or diseases that interrupt a mucosal or skin surface. Specimen collection is
of utmost importance for these specimen types. For most open lesions and abscesses, remove the
superficial flora by decontaminating the skin before collecting a specimen from the advancing margin or
base. A closed abscess is the specimen site of choice. Aspirate the abscess contents with a syringe. The
specific anatomic site is required to establish possible contaminating flora in the area of specimen
collection for appropriate reporting of culture results. For this reason, specimens should be labeled as to
the specific anatomic source and to distinguish between â€œsurface" and â€œdeep/surgical" specimens.
Do not label only as â€œwound." Antimicrobial susceptibility testing should be performed on pure culture
isolates of pathogenic (or potentially pathogenic in special situations) bacteria grown from specimens that
have been appropriately collected so as not to confuse clinically significant isolates with normal flora.
Antimicrobial susceptibility testing determines the minimal inhibitory concentration (MIC) value of
selected antimicrobial agents against isolated potentially pathogenic bacteria. The MIC is the lowest
antimicrobial concentration (of a series of increasing concentrations) that inhibits growth of the
bacterium. Agar dilution MIC testing is performed by testing for growth of bacteria on agar plates
containing varying concentrations of antimicrobial agents. For each organism-antimicrobial agent
combination, the Clinical and Laboratory Standards Institute and/or the European Committee on
Antimicrobial Susceptibility Testing provides interpretive criteria for determining whether the MIC
should be interpreted as susceptible, susceptible dose dependent, intermediate, nonsusceptible, resistant,
or epidemiological cutoff value.
Useful For: Detecting bacteria responsible for infections of sterile body fluids, tissues, or wounds
Determining the in vitro antimicrobial susceptibility of potentially pathogenic aerobic bacteria, if
appropriate This test is not intended for medicolegal use.
Interpretation: Any microorganism is considered significant and is reported when the anatomical
source is considered sterile and no resident flora is expected. For specimens contaminated with the usual
bacterial flora, bacteria that are potentially pathogenic are identified. A "susceptible" category result and a
low minimum inhibitory concentration value indicate in vitro susceptibility of the organism to the
antimicrobial tested. Refer to the Reference Values section for interpretation of various antimicrobial
susceptibility interpretive categories (ie, susceptible, susceptible-dose dependent, intermediate,
nonsusceptible, resistant, or epidemiological cutoff value).
Reference Values:
No growth or usual flora
Susceptibility results are reported as minimal inhibitory concentration (MIC) in mcg/mL. Breakpoints
dependent, intermediate, resistant, or nonsusceptible according to breakpoint setting organizations, either
interpretations."

Susceptible:
clinical efficacy.
literature-supported dosage regimens, because higher-exposure gives the highest probability of adequate
organ function.
Intermediate:
physiologically concentrated or when a higher-than-normal dosage of a drug can be used. This category
Resistant:
Nonsusceptible:
nonsusceptible.

-Wild-type (WT)-an interpretive category defined by an ECV that describes the microbial population
-Non-wild-type (NWT)-an interpretive category defined by an ECV that describes the microbial
intermediate, or resistant but rather as WT or NWT. The ECVâ€™s should not be used as clinical
breakpoints.(Clinical and Laboratory Standards Institute [CLSI]: Performance Standards for
Antimicrobial Susceptibility Testing. 31st ed. CLSI supplement M100. CLSI; 2021:4-6 and 268-269)

Definitions:
S-Susceptible, standard dosing regimen: A microorganism is categorized as "Susceptible, standard
of the agent
I-Susceptible, increased exposure*: A microorganism is categorized as "Susceptible, Increased

R-Resistant: A microorganism is categorized as "Resistant" when there is a high likelihood of

therapeutic failure even when there is increased exposure.*
infection.(The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for
interpretation of MICs and zone diameters. Version 11.0, 2021. Available at www.eucast.org)
Clinical References: 1. Forbes BA, Sahm DF, Weissfeld AS, eds: Bailey and Scott's Diagnostic
Microbiology. 12th ed. Mosby; 2007:chap 55, 56, 58, 60, 61 2. Miller JM, Binnicker JM, Campbell S, et
al: A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2018 Update
by the Infectious Diseases Society of America and the American Society for Microbiology. Clin Infect
Dis. 2018 Aug 31;67(6):e1-e94. doi: 10.1093/cid/ciy381 3. Procop GW, Church DL, Hall GS, eds, et al:
Introduction to Microbiology Part II: Guidelines for the collection, transport, processing, analysis, and
reporting of cultures from specific specimen sources. In: Koneman's Color Atlas and Textbook of
Diagnostic Microbiology. 7th ed. Wolters Kluwer Health; 2017:66-110
SPUT Bacterial Culture, Aerobic, Respiratory

8095 Clinical Information: Common bacterial agents of acute pneumonia include: Streptococcus
pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and members of
the Enterobacteriaceae (Escherichia coli, Klebsiella species, and Enterobacter species). Clinical history,
physical examination, and chest X-ray are usually adequate for the diagnosis of pneumonia, and
antimicrobial treatment is typically based on these findings. Culture of expectorated sputum is used by
some for the evaluation of pneumonia, although controversy exists regarding this practice; both sensitivity
and specificity of sputum cultures are generally regarded as poor (<50%). Specificity is improved by
collecting expectorated purulent matter from the lower respiratory tract and avoiding mouth and
oropharyngeal matter, thereby reducing contamination. Prior to culture, the specimen should be examined
for the presence of white blood cells (evidence of purulent matter) and a paucity of squamous cells
(evidence of minimal contamination by oral matter). Blood cultures should be performed to establish the
definitive etiology of an associated pneumonia. However, only 20% to 30% of patients with bacterial
pneumonia are bacteremic.
Useful For: Aiding in the diagnosis of lower respiratory bacterial infections including pneumonia
Interpretation: A negative test result is no growth of bacteria or growth of only usual flora. A
negative result does not rule out all causes of infectious lung disease (see Cautions). Organisms
associated with lower respiratory tract infections are reported. For positive test results, pathogenic
bacteria are identified. Cystic fibrosis (CF) patients may be colonized or chronically infected by some
organisms over a long period of time, therefore, positive results must be interpreted in conjunction with
previous findings and the clinical picture to appropriately evaluate results.
Reference Values:
Clinical References: 1. Miller JM, Binnicker MJ, Campbell S, et al: A guide to utilization of the
microbiology laboratory for diagnosis of infectious diseases: 2018 Update by the Infectious Diseases
Society of America and the American Society for Microbiology. Clin Infect Dis. 2018 Aug
31;67(6):e1-e94. doi: 10.1093/cid/ciy381 2. Procop GW, Church DL, Hall GS, et al: Introduction to
Microbiology Part II: Guidelines for the collection, transport, processing, analysis, and reporting of
cultures from specific specimen sources. In: Koneman's Color Atlas and Textbook of Diagnostic
Microbiology. 7th ed. Wolters Kluwer Lippincott Williams and Wilkins; 2017:66-110
SPUTS Bacterial Culture, Aerobic, Respiratory with Antimicrobial

60517 Susceptibilities, Varies
Clinical Information: Common bacterial agents of acute pneumonia include Streptococcus
pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and members
of the Enterobacterales (eg, Escherichia coli, Klebsiella species, and Enterobacter species). Clinical
history, physical examination, and chest X-ray are usually adequate for the diagnosis of pneumonia, and
antimicrobial treatment is typically based on these findings. Culture of expectorated sputum is used by
some for the evaluation of pneumonia, although controversy exists regarding this practice; both
sensitivity and specificity of sputum cultures are generally regarded as poor (<50%). Specificity is
improved by collecting expectorated purulent matter from the lower respiratory tract and avoiding
mouth and oropharyngeal matter, thereby reducing contamination. Prior to culture, the specimen should
be examined for the presence of white blood cells (evidence of purulent matter) and a paucity of
squamous cells (evidence of minimal contamination by oral matter). Blood cultures should be
performed to establish the definitive etiology of an associated pneumonia. However, only 20% to 30%
of patients with bacterial pneumonia are bacteremic. Antimicrobial susceptibility testing should be
performed on pure culture isolates of pathogenic (or potentially pathogenic in special situations)
bacteria grown from specimens that have been appropriately collected so as not to confuse clinically
significant isolates with normal flora. Antimicrobial susceptibility testing determines the minimual
inhibitory concentration (MIC) value of selected antimicrobial agents against isolated potentially
pathogenic bacteria. The MIC is the lowest antimicrobial concentration (of a series of increasing
concentrations) that inhibits growth of the bacterium. Agar dilution MIC testing is performed by testing
for growth of bacteria on agar plates containing varying concentrations of antimicrobial agents. For
each organism-antimicrobial agent combination, the Clinical and Laboratory Standards Institute and/or
the European Committee on Antimicrobial Susceptibility Testing provides interpretive criteria for
determining whether the MIC should be interpreted as susceptible, susceptible dose dependent,
intermediate, nonsusceptible, resistant, or epidemiological cutoff value.
Useful For: Aiding the diagnosis of lower respiratory bacterial infections, including pneumonia
appropriate This test is not intended for medicolegal use.
bacteria are identified. Cystic fibrosis patients may be colonized or chronically infected by some
previous findings and the clinical picture to appropriately evaluate results. A susceptible category result
and a low minimal inhibitory concentration value indicate in vitro susceptibility of the organism to the
antimicrobial tested. Refer to the Reference Values section for interpretation of various antimicrobial
susceptibility interpretive categories (ie, susceptible, susceptible-dose dependent, intermediate,
nonsusceptible, resistant, or epidemiological cutoff value).
Reference Values:
dependent, intermediate, resistant, or nonsusceptible according to breakpoint setting organizations, either
interpretations."

Susceptible:
clinical efficacy.
organ function.
Intermediate:
Resistant:
Nonsusceptible:
nonsusceptible.
-Wild-type (WT) - an interpretive category defined by an ECV that describes the microbial population
-Non-wild-type (NWT) - an interpretive category defined by an ECV that describes the microbial
â€œNoteâ€•: MIC values for which ECVâ€™s are defined are not to be interpreted or reported as
susceptible, intermediate or resistant but rather as WT or NWT. The ECVâ€™s should not be used as
clinical breakpoints.(Clinical and Laboratory Standards Institute [CLSI]. Performance Standards for

Definitions:
of the agent


infection.
(The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation
of MICs and zone diameters. Version 11.0, 2021. Available at www.eucast.org)
Clinical References: 1. Miller JM, Binnicker JM, Campbell S, et al: A guide to utilization of the
31;67(6):e1-e94. doi: 10.1093/cid/ciy381 2. Procop GW, Church DL, Hall GS, eds, et al: Introduction to
Microbiology Part II: Guidelines for the collection, transport, processing, analysis, and reporting of
cultures from specific specimen sources. In: Koneman's Color Atlas and Textbook of Diagnostic
Microbiology. 7th ed. Wolters Kluwer Health; 2017:66-110 3. Leber AL, ed. Clinical Microbiology
Procedures Handbook. Vol 1. 4th ed. ASM Press; 2016:chap 3.11.2
UR Bacterial Culture, Aerobic, Urine

8105 Clinical Information: Urinary tract infection (UTI) encompasses a broad range of clinical entities
that vary in their clinical presentation, degree of tissue invasion, epidemiologic setting, and antibiotic
therapy requirements. There are 4 major types of UTIs: urethritis, cystitis, acute urethral syndrome, and
pyelonephritis. UTIs may also be classified as uncomplicated or complicated. Escherichia coli is the
leading cause of uncomplicated community-acquired UTI. Risk factors that predispose one to
complicated UTIs include: underlying diseases that are associated with kidney infection (eg, diabetes),
kidney stones, structural or functional urinary tract abnormalities, and indwelling urinary catheters.
Another classification of UTIs is as upper UTI (related to the kidney, renal pelvis, or ureter) or lower
UTI (urinary bladder and urethra). The classic symptoms of upper UTI are fever (often with chills) and
flank pain; frequent painful urination, urgency, and dysuria are more often associated with lower UTI.
Useful For: Diagnosis of urinary tract infections Quantitative culture results may be helpful in
discriminating contamination, colonization, and infection
Interpretation: In general, the isolation of more than 100,000 cfu/mL of a urinary pathogen is
indicative of urinary tract infection (UTI). Isolation of 2 or more organisms above 10,000 cfu/mL may
suggest specimen contamination. For specimens contaminated with the usual bacterial flora, bacteria that
are potentially pathogenic are identified.
Reference Values:
No growth (Organism present <10,000 cfu/mL, or mixed flora.)
Identification of probable pathogens with colony count ranges
Clinical References: 1. Forbes BA, Sahm DF, Weissfeld AS: Infections of the urinary tract. In
Bailey and Scott's Diagnostic Microbiology. 12th edition. St. Louis, MO, Mosby, 2007, pp 842-855 2.
Procop GW, Church DL, Hall GS, et al: Koneman's Color Atlas and Textbook of Diagnostic
Microbiology. Seventh edition. Philadelphia: Wolters Kluwer|Lippincott Williams and Wilkins; 2017.
Chapter 2, Introduction to Microbiology Part II:Â Guidelines for the Collection, Transport, Processing,
Analysis, and Reporting of Cultures From Specific Specimen Sources; p. 66-110
GEN Bacterial Culture, Aerobic, Varies

8108 Clinical Information: Sterile Body Fluids and Normally Sterile Tissues: In response to infection,
fluid may accumulate in any body cavity. Wound, Abscess, Exudates: Skin and soft tissue infections can
occur as a result of a break in the skin surface, as complications of surgery, from trauma; human, animal,
or insect bites, or from diseases that interrupt a mucosal or skin surface. Specimen collection is of utmost
importance for these specimen types. For most open lesions and abscesses, remove the superficial flora by
decontaminating the skin before collecting a specimen from the advancing margin or base. A closed
abscess is the specimen site of choice. Aspirate the abscess contents with a syringe. The specific anatomic
site is required to establish possible contaminating flora in the area of specimen collection for appropriate
reporting of culture results. For this reason, specimens should be labeled as to the specific anatomic
source and to distinguish between â€œsurfaceâ€• and â€œdeep/surgicalâ€• specimens. Do not label only
as â€œwound.â€•
Useful For: Detecting bacteria responsible for infections of sterile body fluids, tissues, or wounds This
test is not intended for medicolegal use.
Interpretation: When no resident flora is present, any microorganism found is considered significant
and is reported. For specimens contaminated with normal bacterial flora, bacteria that are potentially
pathogenic are identified.
Reference Values:
Clinical References: 1. Forbes BA, Sahm DF, Weissfeld AS: Infections of the urinary tract. In:
Bailey and Scott's Diagnostic Microbiology. 12th ed. Mosby; 2007:842-855 2. Miller JM, Binnicker MJ,
Campbell S, et al: A guide to utilization of the microbiology laboratory for diagnosis of infectious
diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for
Microbiology. Clin Infect Dis. 2018 Aug 31;67(6):e1-e94. doi: 10.1093/cid/ciy381 3. Procop GW, Church
DL, Hall GS, et al: Introduction to Microbiology Part II: Guidelines for the collection, transport,
processing, analysis, and reporting of cultures from specific specimen sources. In: Koneman's Color Atlas
and Textbook of Diagnostic Microbiology. 7th ed. Wolters Kluwer Lippincott Williams and Wilkins;
2017:66-110
URNS Bacterial Culture, Aerobic, with Antimicrobial Susceptibilities,

60515 Urine
Clinical Information: Urinary tract infection (UTI) encompasses a broad range of clinical entities
that vary in their clinical presentation, degree of tissue invasion, epidemiologic setting, and antibiotic
therapy requirements. There are 4 major types of UTIs: urethritis, cystitis, acute urethral syndrome, and
pyelonephritis. UTIs may also be classified as uncomplicated or complicated. Escherichia coli is the
leading cause of uncomplicated community-acquired UTI. Risk factors that predispose one to
complicated UTIs include: underlying diseases that are associated with kidney infection (eg, diabetes),
kidney stones, structural or functional urinary tract abnormalities, and indwelling urinary catheters.
Another classification of UTIs is as upper UTI (related to the kidney, renal pelvis, or ureter) or lower
UTI (urinary bladder and urethra). The classic symptoms of upper UTI are fever (often with chills) and
flank pain. Frequent painful urination, urgency, and dysuria are more often associated with lower UTI.
Antimicrobial susceptibility testing determines the minimum inhibitory concentration (MIC) value of
selected antimicrobial agents against isolated potentially pathogenic bacteria. The MIC is the lowest
antimicrobial concentration (of a series of increasing concentrations) that inhibits growth of the
Antimicrobial Susceptibility Testing provides interpretive criteria for determining whether the MIC
should be interpreted as susceptible, susceptible-dose dependent, intermediate, nonsusceptible, resistant,
or epidemiological cutoff value
Useful For: Diagnosis of urinary tract infections Quantitative culture results may be helpful in
discriminating contamination, colonization, and infection Determining the in vitro antimicrobial
susceptibility of potentially pathogenic aerobic bacteria, if appropriate This test is not intended for
medicolegal use.
Interpretation: In general, the isolation of more than 100,000 colony forming units (cfu)/mL of a
urinary pathogen is indicative of urinary tract infection (UTI), however, pediatric patients (< or =2 years
of age) may have symptomatic UTI at a lower threshold or more than 50,000 cfu/mL. Isolation of 2 or
more organisms with more than 10,000 cfu/mL may suggest specimen contamination. For specimens
contaminated with the usual bacterial flora, bacteria that are potentially pathogenic are identified. A
"susceptible" category result and a low minimum inhibitory concentration value indicate in vitro
susceptibility of the organism to the antimicrobial tested. Refer to the Reference Values section for
interpretation of various antimicrobial susceptibility interpretive categories (ie, susceptible,
susceptible-dose dependent, intermediate, nonsusceptible, resistant, or epidemiological cutoff value.
Reference Values:
No growth, Organism present <10,000 cfu/mL, or mixed flora.
Identification of probable pathogens with colony count ranges.
susceptible-dose dependent, intermediate, resistant, or nonsusceptible according to breakpoint setting
on Antimicrobial Susceptibility Testing (EUCAST), as applicable.
In some instances, an interpretive category cannot be provided based on available data and the
following comment will be included: "There are no established interpretive guidelines for agents
reported without interpretations."
Susceptible:
for organ function.
Intermediate:
Resistant:
Nonsusceptible:

-Wild-type (WT) - an interpretive category defined by an ECV that describes the microbial population
with no phenotypically detectable mechanisms of resistance or reduced susceptibility for an
-Non-wild-type (NWT) - an interpretive category defined by an ECV that describes the microbial
Note: MIC values for which ECV's are defined are not to be interpreted or reported as susceptible,
intermediate, or resistant but rather as WT or NWT. The ECV's should not be used as clinical
breakpoints.(Clinical and Laboratory Standards Institute [CLSI]: Performance Standards for
Antimicrobial Susceptibility Testing. 31st ed. CLSI supplement M100. CLSI; 2021:4-6 and 268-269)

Definitions:
S -Susceptible, standard dosing regimen: A microorganism is categorized as "Susceptible, standard
of the agent
I -Susceptible, increased exposure*: A microorganism is categorized as "Susceptible, Increased

R -Resistant: A microorganism is categorized as "Resistant" when there is a high likelihood of

therapeutic failure even when there is increased exposure.*
site of infection.

Clinical References: 1. Forbes BA, Sahm DF, Weissfeld AS: Infections of the urinary tract. In:
Bailey and Scott's Diagnostic Microbiology. 12th ed. Mosby; 2007:842-855 2. Miller JM, Binnicker
JM, Campbell S, et al: A guide to utilization of the microbiology laboratory for diagnosis of infectious
diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for
Microbiology. Clin Infect Dis. 2018 Aug 31;67(6):e1-e94. doi: 10.1093/cid/ciy381 3. Procop GW,
Church DL, Hall GS, et al: Introduction to Microbiology Part II: Guidelines for the collection, transport,
processing, analysis, and reporting of cultures from specific specimen sources. In: Koneman's Color
Atlas and Textbook of Diagnostic Microbiology. 7th ed. Wolters Kluwer Health; 2017:66-110 4.
Clinical and Laboratory Standards Institute (CLSI): Performance Standards for Antimicrobial
Susceptibility Testing. 30th ed. CLSI supplement M100. CLSI; 2020;3-5:254
ANAES Bacterial Culture, Anaerobic with Antimicrobial

Clinical Information: Anaerobic bacteria are the greatest component of the human body's normal
bacterial flora. Anaerobes colonize the skin, oral cavity, and genitourinary and lower gastrointestinal
tracts, and generally do not cause infection. Their presence is important for vitamin and other nutrient
absorption and in preventing infection with pathogenic bacteria. When usual skin and mucosal barriers
are compromised, in an anaerobic environment, these bacteria can behave as pathogens. Typical
anaerobic infections include periodontitis, abdominal or pelvic abscesses, endometritis, pelvic
inflammatory disease, aspiration pneumonia, empyema and lung abscesses, sinusitis, brain abscesses,
gas gangrene, and other soft tissue infections. Anaerobes grow aggressively in the body under anaerobic
conditions and may possess a variety of virulence factors including capsules and extracellular enzymes.
They also can develop resistance to antimicrobials by producing beta-lactamase and other modifying
enzymes, and by alterations in membrane permeability and structure of penicillin-binding proteins.
Susceptibility testing results are useful to clinicians because anaerobic bacteria are a significant cause of
human infection, and they are often resistant to commonly used antimicrobials. Bacteroides and
Parabacteroides species produce beta-lactamases. Ertapenem, metronidazole, and clindamycin are
generally effective agents although resistance to clindamycin, and occasionally ertapenem, is increasing.
The minimal inhibitory concentration (MIC) obtained during antimicrobial susceptibility testing is
helpful in indicating the concentration of antimicrobial agent required at the site of infection necessary
to inhibit the infecting organism. For each organism-antimicrobial agent combination, the Clinical and
Laboratory Standards Institute and/or the European Committee on Antimicrobial Susceptibility Testing
provides interpretive criteria for determining whether the MIC should be interpreted as susceptible,
susceptible dose dependent, intermediate, nonsusceptible, resistant, or epidemiological cutoff value.
Useful For: Diagnosing anaerobic bacterial infections Directing antimicrobial therapy for anaerobic
infections
Interpretation: Isolation of anaerobes in significant numbers from specimens collected under sterile
conditions including blood, other normally sterile body fluids, or closed collections of purulent fluid
indicates infection with those organisms. A susceptible category result and a low minimum inhibitory
concentration value indicate in vitro susceptibility of the organism to the antimicrobial tested. For
interpretation of various antimicrobial susceptibility interpretive categories (ie, susceptible, intermediate,
resistant, or epidemiological cutoff value), see Reference Values.
Reference Values:
No growth
Susceptibility results are reported as minimal inhibitory concentration (MIC) in mcg/mL. Breakpoints
dependent, intermediate, resistant or nonsusceptible according to breakpoint setting organizations, either
interpretations."

Susceptible:
clinical efficacy.
organ function.
Intermediate:
Resistant:
Nonsusceptible:
nonsusceptible.

(WITH/WITHOUT) acquired resistance; however, correlation with treatment outcome is unknown."
Wild-type (WT): An interpretive category defined by an ECV that describes the microbial population
Non-wild-type (NWT): An interpretive category defined by an ECV that describes the microbial

Definitions:
of the agent.


infection.(The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for
interpretation of MICs and zone diameters. v11.0, 2021. Available at www.eucast.org)
Clinical References: 1. Rosenblatt JE, Brook I: Clinical relevance of susceptibility testing of
anaerobic bacteria. Clin Infect Dis. 1993 Jun;16(Suppl 4):S446-S448 2. Summanen P, Baron EJ, Citron
DM, et al: Wadsworth Anaerobic Bacteriology Manual. 6th ed. Star Publishing Co; 2002 3. Schuetz AN,
Carpenter DE: Susceptibility test methods: anaerobic bacteria. In: Carroll KC, Pfaller MA, eds. Manual of
Clinical Microbiology. 12th ed. ASM Press; 2019:1377-1397 4. Hall GS: Anaerobic Bacteriology. In:
Leber AL, ed. Clinical Microbiology Procedures Handbook. Vol 1. 4th ed. ASM Press; 2016:section 4 5.
Jenkins SG, Schuetz AN: Current concepts in laboratory testing to guide antimicrobial therapy. Mayo
Clin Proc. 2012 Mar;87(3):290-308
ANAE Bacterial Culture, Anaerobic, Varies

84292 Clinical Information: Anaerobic bacteria are the greatest component of the human body's normal
bacterial flora colonizing the skin, oral cavity, and genitourinary and lower gastrointestinal tracts and
generally do not cause infection. Their presence is important for vitamin and other nutrient absorption and
in preventing infection with pathogenic bacteria. When usual skin and mucosal barriers are penetrated as
well as in an anaerobic environment, these bacteria can behave as pathogens. Typical anaerobic infections
include periodontitis, abdominal or pelvic abscesses, endometritis, pelvic inflammatory disease, aspiration
pneumonia, empyema and lung abscesses, sinusitis, brain abscesses, gas gangrene, and other soft tissue
infections. Anaerobes grow aggressively in the body under anaerobic conditions and may possess a
variety of virulence factors including capsules and extracellular enzymes. They also can develop
resistance to antimicrobials by producing beta-lactamase and other modifying enzymes as well as by
alterations in membrane permeability and structure of penicillin-binding proteins. Because anaerobic
bacteria are a significant cause of human infection and are often resistant to commonly used
antimicrobials, susceptibility testing results are useful to clinicians. Bacteroides and Parabacteroides
species produce beta-lactamases. Ertapenem, metronidazole, and clindamycin are generally effective
agents although resistance to clindamycin, and occasionally ertapenem, is increasing.
Useful For: Diagnosing anaerobic bacterial infections

Interpretation: Isolation of anaerobes in significant numbers from well-collected specimens including
blood, other normally sterile body fluids, or closed collections of purulent fluid, indicates infection with
the identified organisms.
Reference Values:
No growth
Clinical References: 1. Summanen P, Baron EJ, Citron DM, et al: Wadsworth Anaerobic
Bacteriology Manual. 6th ed. Star Publishing Co; 2002 2. Schuetz AN, Carpenter DE: Susceptibility test
methods: anaerobic bacteria. In: Carroll KC, Pfaller MA, eds. Manual of Clinical Microbiology. 12th ed.
ASM Press; 2019:1377-1397 3. Hall GS: Anaerobic bacteriology. In: Leber AL, ed. Clinical
Microbiology Procedures Handbook. Vol 1. 4th ed. ASM Press; 2016:chap 44
CFRCS Bacterial Culture, Cystic Fibrosis with Antimicrobial

Clinical Information: Life expectancy of patients with cystic fibrosis (CF) has increased steadily
over the past 50 years, in large part due to improvements in the management of lung disease in this patient
population. Still, chronic lung infection is responsible for 75% to 85% of deaths in patients with CF.
Appropriate treatment for the causative organism can reduce morbidity and mortality. The number of
microbial species associated with CF lung disease is relatively limited. These include Pseudomonas
aeruginosa (mucoid and nonmucoid), Staphylococcus aureus, Burkholderia cepacia complex,
Stenotrophomonas maltophilia, other non-fermenting Gram-negative rods, Haemophilus influenzae, and
Streptococcus pneumoniae. Nontuberculous mycobacteria and Aspergillus species may also play a role in
CF lung disease, in addition to common respiratory viruses. This culture is specifically designed and
utilizes conventional and additional selective media (compared to non-CF respiratory cultures) to isolate
bacteria commonly associated with pulmonary disease in patients with CF. In selected centers, lung
transplantation is performed on patients with CF. This test is appropriate for lung transplant patients with
underlying CF because they can continue to harbor the same types of organisms as they did prior to
transplantation. Patients with CF may be colonized or chronically infected by these organisms over a long
period of time. Antimicrobial susceptibility testing determines the minimal inhibitory concentration
(MIC) value of selected antimicrobial agents against isolated potentially pathogenic bacteria. The MIC is
the lowest antimicrobial concentration (of a series of increasing concentrations) that inhibits growth of the
Antimicrobial Susceptibility Testing provide interpretive criteria for determining whether the MIC should
be interpreted as susceptible, susceptible-dose dependent, intermediate, nonsusceptible, resistant, or
epidemiological cutoff value.
Useful For: Detection of aerobic bacterial pathogens in specimens from patients with cystic fibrosis
appropriate
bacteria are identified. Patients with cystic fibrosis may be colonized or chronically infected by some
previous findings and the clinical picture to appropriately evaluate results. A susceptible category result
and a low minimum inhibitory concentration value indicate in vitro susceptibility of the organism to the
antimicrobial tested. For interpretation of various antimicrobial susceptibility interpretive categories (ie,
susceptible, susceptible-dose dependent, intermediate, nonsusceptible, resistant, or epidemiological
cutoff value), see Reference Values.
Reference Values:
Identification of probable pathogens:

susceptible-dose dependent, intermediate, resistant or nonsusceptible according to breakpoint setting
on Antimicrobial Susceptibility Testing (EUCAST), as applicable. In some instances, an interpretive
category cannot be provided based on available data and the following comment will be included:
"There are no established interpretive guidelines for agents reported without interpretations."

Susceptible:
for organ function.
Intermediate:
Resistant:
Nonsusceptible:

Wild-type (WT) - an interpretive category defined by an ECV that describes the microbial population
with no phenotypically detectable mechanisms of resistance or reduced susceptibility for an
Non-wild-type (NWT) - an interpretive category defined by an ECV that describes the microbial

Definitions:
of the agent


site of infection.

31;67(6):e1-e94. doi: 10.1093/cid/ciy381 2. York MK, Gilligan P, Alby K: Lower respiratory tract
cultures. In: Leber AL, ed. Clinical Microbiology Procedures Handbook, Vol 1, 4th ed. ASM Press;
2016:section 3.11.2 3. LiPuma JJ, Currie BJ, Peacock SJ, VanDamme PAR: Burkholderia,
Stenotrophomonas, Ralstonia, Cupriavidus, Pandoraea, Brevundimonas, Comamonas, Delftia, and
Acidovorax. In: Carroll KC, Pfaller MC, eds. Manual of Clinical Microbiology. 12th ed. ASM Press;
2019:807-828
CFRC Bacterial Culture, Cystic Fibrosis, Respiratory

89653 Clinical Information: Life expectancy of patients with cystic fibrosis (CF) has increased steadily
over the past 50 years, in large part due to improvements in the management of lung disease in this
patient population. Still, chronic lung infection is responsible for 75% to 85% of deaths in patients with
CF. Appropriate treatment for the causative organism can reduce morbidity and mortality. The number
of microbial species associated with CF lung disease is relatively limited. These include Pseudomonas
aeruginosa (mucoid and nonmucoid), Staphylococcus aureus, Burkholderia cepacia complex,
Stenotrophomonas maltophilia, other non-fermenting gram-negative rods, Haemophilus influenzae, and
Streptococcus pneumoniae. Nontuberculous mycobacteria and Aspergillus species may also play a role
in CF lung disease, in addition to common respiratory viruses. This culture is specifically designed and
utilizes conventional and additional selective media (compared to non-CF respiratory cultures) to isolate
bacteria commonly associated with pulmonary disease in patients with CF. In selected centers, lung
transplantation is performed on patients with CF. This test is appropriate for lung transplant patients
with underlying CF because they can continue to harbor the same types of organisms as they did
pretransplantation. Patients with CF may be colonized or chronically infected by these organisms over a
long period of time.
Useful For: Detection of aerobic bacterial pathogens in specimens from patients with cystic fibrosis
bacteria are identified. Patients with cystic fibrosis may be colonized or chronically infected by some
previous findings and the clinical picture to appropriately evaluate results.
Reference Values:
31;67(6):e1-e94. doi: 10.1093/cid/ciy381 2. York MK, Gilligan P, Alby K: Lower respiratory tract
cultures. In: Leber AL, ed. Clinical Microbiology Procedures Handbook. Vol 1. 4th ed. ASM Press;.
2016:section 3.11.2 3. LiPuma JJ, Currie BJ, Peacock SJ, VanDamme PAR: Burkholderia,
Stenotrophomonas, Ralstonia, Cupriavidus, Pandoraea, Brevundimonas, Comamonas, Delftia, and
Acidovorax. In: Carroll KC, Pfaller MC, eds. Manual of Clinical Microbiology. 12th ed. ASM Press;
2019:807-828
BTWGS Bacterial Typing, Whole Genome Sequencing, Varies

65162 Clinical Information: Bacterial strain typing may be useful for determining strain relatedness in the
setting of possible nosocomial transmission or community outbreaks. Serial isolates obtained from the
same patient may be typed to assess similarity. Typing may allow discrimination of 2 or more isolates of
the same species, which can inform recognition of an outbreak, nosocomial transmission, or identify a
potential source of infection in an individual patient. Pulse-field gel electrophoresis (PFGE) has
traditionally been used for strain typing, but does not always discriminate between different bacterial
strains (eg, 2 genetically dissimilar strains may have indistinguishable PFGE patterns). Whole genome
sequencing offers a higher level of resolution of genetic relatedness of strains than PFGE does.
Useful For: Aiding in the investigation of a potential outbreak by a single bacterial species May assist
in identification of recurrent infection in an individual patient
Interpretation: The genomic sequence of individual isolates will be determined and compared to the
genomic sequences of the other cosubmitted isolates. The report will indicate the degree of relatedness
between the isolates. A link to the interpretive report will be sent to the registered email address provided
by the client.
Reference Values:
Reported as isolates are "related", "possibly related", or "unrelated".
Clinical References: 1. Cunningham SA, Chia N, Jeraldo PR, et al: Comparison of whole-genome
sequencing methods for analysis of three methicillin-resistant Staphylococcus aureus outbreaks. J Clin
Microbiol. 2017 Jun;55(6):1946-1953. doi; 10.1128/JCM.00029-17 2. Park KH, Greenwood-Quaintance
KE, Uhl JR, et al: Molecular epidemiology of Staphylococcus aureus bacteremia in a single large
Minnesota medical center in 2015 as assessed using MLST, core genome MLST and spa typing. PLoS
ONE. 2017 Jun 2;12(6):e0179003. doi: 10.1371/journal.pone.0179003 3. Madigan T, Cunningham SA,
Patel R, et al: Whole-genome sequencing for methicillin-resistant Staphylococcus aureus (MRSA)
outbreak investigation in a neonatal intensive care unit. Infect Control Hosp Epidemiol. 2018 Dec;
39(12):1412-1418. doi: 10.1017/ice.2018.239 4. Trees E, Fei Fan Ng T, MacCannell D, et al: Molecular
epidemiology. In: Carroll K, Pfaller M, eds. Manual of Clinical Microbiology. 12th ed. ASM Press;
2019:167-196
BAHG Bahia Grass, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Bahia grass Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
BYST Baker's Yeast, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to baker's yeast Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
BCYP Bald Cypress, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to bald cypress Defining the allergen responsible
for eliciting signs and symptoms Identifying allergens: - Responsible for allergic disease and/or
anaphylactic episode - To confirm sensitization prior to beginning immunotherapy - To investigate the
specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens Testing for IgE
antibodies is not useful in patients previously treated with immunotherapy to determine if residual clinical
sensitivity exists, or in patients in whom the medical management does not depend upon identification of
allergen specificity.

Reference Values:

0 Negative

apply to all ages.
2017:1057-1070
BAMB Bamboo Shoot, IgE, Serum
Useful For: Establishing a diagnosis of an allergy to bamboo shoots Defining the allergen

Reference Values:
0 Negative

apply to all ages.
FBANG Banana IgG

Reference Values:
BANA Banana, IgE, Serum
Useful For: Establishing a diagnosis of an allergy to bananas Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
BAP1 BAP1 Immunostain, Technical Component Only

71481 Clinical Information: BRCA1-asssociated protein 1 (BAP1) is a deubiquitinating enzyme that is a
member of the polycomb group proteins of transcriptional repressors and exhibits tumor suppressive
activity. BAP1 is located on chromosome 3p21 where loss of 1 copy of the gene and inactivating
mutations are associated with the increased risk and development of various tumors such as malignant
mesotheliomas, uveal melanomas, clear cell renal cell carcinoma, and esophageal squamous carcinomas.
In some of these cases, loss of nuclear staining for BAP1 has been reported.
Useful For: As part of a panel of immunostains where loss of staining can be used as a marker of
various neoplasms
Clinical References: 1. Carbone M, Ferris LK, Baumann F, et al: BAP1 cancer syndrome:
malignant mesothelioma, uveal and cutaneous melanoma, and MBAITS. J Transl Med 2012;10:179-185
2. Koopmans AE, Verdijk RM, Brouwer RWW, et al: Clinical significance of immunohistochemistry
for detection of BAP1 mutations in uveal melanoma. Mod Path 2014;27:1321-1330 3. Joseph RW,
Kapur P, Serie DJ, et al: Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1
Expression. Jl of Urology 2015;195:1-8 4. Klebe S, Driml J, Nasu M, et al: BAP1 hereditary cancer
predisposition syndrome: a case report and review of literature. Biomark Res 2015;3:14-20 5. Mori T,
Sumii M, Fujishima F, et al: Somatic alteration and depleted nuclear expression of BAP1 in human
esophageal squamous cell carcinoma. Cancer Sci 2015;106:1118-1129 6. Churg A, Sheffield BS,
Galateau-Salle F: New markers for Separating Benign from Malignant Mesothelials: Are we there yet?
Arch Pathol Lab Med 2016;140(4):318-321
BAP1Z BAP1-Tumor Predisposition Syndrome, BAP1 Full Gene

Clinical Information: Germline variants in the BAP1 gene are associated with BAP1-tumor
predisposition syndrome (BAP1-TPDS), a rare autosomal dominant hereditary cancer syndrome.(1)
BAP1-TPDS is characterized by increased risk to develop a variety of tumors, including
BAP1-inactivated melanocytic tumor (also known as atypical Spitz tumor, or "BAPoma"), uveal and
cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma.(1) Many other tumor types,
including basal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, and meningioma, have
also been associated with this syndrome.(1-6) While the true penetrance of BAP1-TDPS is unknown
due to both its rarity and ascertainment bias in the existing data, studies have shown up to 88% of
individuals with an identified variant had a cancer diagnosis.(1,2) Management and surveillance
guidelines have been proposed by several multi-disciplinary expert groups.(1,5)
Useful For: Evaluation of patients with a personal or family history suggestive of BAP1-tumor
predisposition syndrome (BAP1-TPDS) Establishing a diagnosis of BAP1-TPDS allowing for targeted
cancer surveillance based on associated risks Identifying genetic variants associated with increased risk
for BAP1-TPDS, allowing for predictive testing and appropriate screening of at-risk family members
Interpretation: All detected variants are evaluated according to American College of Medical
known significance.
Reference Values:
Clinical References: 1. Pilarski R, Carlo M, Cebulla C, Abdel-Rahman M: BAP1 tumor

predisposition syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet].
University of Washington, Seattle; 2016. Updated September 17, 2020. Accessed July 7, 2021.
Available at www.ncbi.nlm.nih.gov/books/NBK390611/ 2. Walpole S, Pritchard AL, Cebulla CM, et al:
Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide.
J Natl Cancer Inst. 2018 Dec; 110(12):1328â€“1341. doi: 10.1093/jnci/djy171 3. Star P, Goodwin A,
Kapoor R, et al: Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed
interdisciplinary consensus monitoring strategy. Eur J Cancer. 2018 Mar;92:48-53. doi:
10.1016/j.ejca.2017.12.022 4. Carbone M, Ferris LK, Baumann F, et al: BAP1 cancer syndrome:
malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med. 2012;10:179.
doi: 10.1186/1479-5876-10-179 5. Battaglia A: The importance of multidisciplinary approach in early
detection of BAP1 tumor predisposition syndrome: Clinical management and risk assessment. Clin Med
Insights Oncol. 2014;8:37-47. doi: 10.4137/CMO.S15239 6. Rai K, Pilarski R, Cebulla CM,
Abdel-Rahman MH: Comprehensive review of BAP1 tumor predisposition syndrome with report of two
new cases. Clin Genet. 2016;89(3):285-294. doi: 10.1111/cge.12630 7. Richards S, Aziz N, Bale S, et
al: Standards and guidelines for the interpretation of sequence variants: a joint consensus
recommendation of the American College of Medical Genetics and Genomics and the Association for
Molecular Pathology. Genet Med 2015 May;17(5):405-424. doi: 10.1038/gim.2015.30
BARBX Barbiturates Confirmation, Chain of Custody, Random, Urine

62713 Clinical Information: Barbiturates represent a class of drugs that were originally introduced as sleep
inducers. Butalbital is also used to control severe headaches. Mephobarbital and phenobarbital are
frequently used to control major motor (grand mal) seizures. These drugs are commonly abused as
"downers" to induce sleep after an amphetamine- or cocaine-induced "high." Chain of custody is a record
of the disposition of a specimen to document each individual who collected, handled, and performed the
analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it
will withstand regular court scrutiny.
Useful For: Detecting drug abuse involving barbiturates such as amobarbital, butalbital, pentobarbital,
phenobarbital, and secobarbital Chain of custody is required whenever the results of testing could be used
in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by
demonstrating that it was under the control of personnel involved with testing the specimen at all times;
this control implies that the opportunity for specimen tampering would be limited.
Interpretation: The presence of a barbiturate in urine indicates use of one of these drugs. Most of the
barbiturates are fast acting; their presence indicates use within the past 3 days. Phenobarbital, commonly
used to control epilepsy, has a very long half-life. The presence of phenobarbital in urine indicates that the
patient has used the drug sometime within the past 30 days.
Reference Values:
Negative
IMMUNOASSAY SCREEN
<200 ng/mL
GAS CHROMATOGRAPHY-MASS SPECTROSCOPY:

Butalbital: <100 ng/mL
Amobarbital <100 ng/mL
Pentobarbital <100 ng/mL
Secobarbital <100 ng/mL
Phenobarbital <100 ng/mL
Clinical References: 1. Baselt RC, Cravey RH: Disposition of Toxic Drugs and Chemicals in Man.
3rd ed. Year Book Medical Publishers; 1989 2. Langman LJ et al: Clinical toxicology. In: Rifai N,
Elsevier; 2018:832-887
BARBU Barbiturates Confirmation, Random, Urine

80372 Clinical Information: Barbiturates represent a class of drugs that were originally introduced as sleep
inducers. Butalbital is also used to control severe headaches. Mephobarbital and phenobarbital are
frequently used to control major motor (grand mal) seizures. These drugs are commonly abused as
"downers" to induce sleep after an amphetamine- or cocaine-induced "high."
Useful For: Detecting drug abuse involving barbiturates such as amobarbital, butalbital,
pentobarbital, phenobarbital, and secobarbital
Interpretation: The presence of a barbiturate in urine indicates use of one of these drugs. Most of
the barbiturates are fast acting; their presence indicates use within the past 3 days. Phenobarbital,
commonly used to control epilepsy, has a very long half-life. The presence of phenobarbital in urine
indicates that the patient has used the drug sometime within the past 30 days.
Reference Values:
Negative
BUTALBITAL BY GC-MS
<100 ng/mL
AMOBARBITAL BY GC-MS
<100 ng/mL
PENTOBARBITAL BY GC-MS
<100 ng/mL
SECOBARBITAL BY GC-MS
<100 ng/mL
PHENOBARBITAL BY GC-MS
<100 ng/mL
Clinical References: 1. Disposition of Toxic Drugs and Chemicals in Man. 10th edition. Edited by
RC Baselt. Foster City, CA: Biomedical Publications, 2014 2. Langman LJ et al: Clinical Toxicology.
In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by N Rifai, AR Horvath,
CT Wittwer. Sixth edition. Elsevier, 2018, pp 832-887
FCDUB Barbiturates, Umbilical Cord Tissue

Units: ng/g
FBARS Barium, Serum

Units: ng/mL
Reference range has not been established.
BGRS Barley Grass, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Barley grass Defining the allergen responsible for

Reference Values:

0 Negative

apply to all ages.
FBARG Barley IgG

Reference Values:
BRLY Barley, IgE, Serum

bronchospasm) in infants and children <5 years due to food sensitivity (milk, egg, soy, and wheat
Useful For: Establishing a diagnosis of an allergy to barley Defining the allergen responsible for

Reference Values:

0 Negative

apply to all ages.
FBART Bartonella Antibody Panel, IFA CSF

REFERENCE RANGE: <1:1
INTERPRETIVE CRITERIA:
<1:1 Antibody Not Detected
> or = 1:1 Antibody Detected
Infection with Bartonella henselae has been associated with cat scratch disease, bacillary angiomatosis,
peliosis hepatis and febrile bacteremia syndrome. Infection with Bartonella quintana has been
associated with trench fever and bacillary angiomatosis in both HIV positive and negative individuals.
IgG crossreactivity between B. henselae and B. Quintana may occur at any titer; however, the infecting
species will typically have the higher IgG titer. Crossreactivity of IgM between the two species is
limited and typically is not seen.
Diagnosis of infections of the central nervous system can be accomplished by demonstrating the
presence of intrathecally-produced specific antibody. However, interpreting results is complicated by
low antibody levels found in CSF, passive transfer of antibody from blood, and contamination via
bloody taps.
BART Bartonella Antibody Panel, IgG and IgM, Serum

81575 Clinical Information: Bartonella henselae and Bartonella quintana are small, rod-shaped,
pleomorphic, Gram-negative bacteria. The human body louse (Pediculus humanis) is the proposed vector
for B quintana. No animal reservoir has been determined for B quintana. The domestic cat is believed to
be both a reservoir and vector for B henselae. Cats may infect humans directly through scratches, bites, or
licks; or indirectly through an arthropod vector. Humans remain the only host in which Bartonella
infection leads to significant disease. The sight of entry for Bartonella is through openings in the skin.
Microscopically, Bartonella lesions appear as rounded aggregates that proliferate rapidly. These
aggregates are masses of Bartonella bacteria. Warthin-Starry staining has shown that Bartonella
organisms can be present within the vacuoles of endothelial cells, in macrophages, and between cells in
areas of necrosis. Occasionally organisms are seen in the lumens of vessels. While cutaneous lesions are
common, disseminated tissue infection by Bartonella has been seen in the blood, lymph nodes, spleen,
liver, bone marrow, and heart. B henselae has been associated with cat scratch disease (CSD), peliosis
hepatitis (PH), bacillary angiomatosis (BA), and endocarditis. B quintana has been associated with trench
fever, BA, and endocarditis. BA is a vascular proliferative disease usually involving the skin and regional
lymph nodes. CSD begins as a cutaneous papule or pustule that usually develops within a week after an
animal contact. Regional lymphadenopathy follows and is the predominant clinical feature of CSD.
Trench fever, which was a significant problem during World War I and World War II, is characterized by
a relapsing fever and severe pain in the shins. PH and febrile bacteremia syndrome are both syndromes
that have afflicted patients with AIDS and patients who are immunocompromised. While trench fever and
CSD are usually self-limiting illnesses, the other Bartonella-associated diseases can be life-threatening.
Interest in B quintana and B henselae has recently increased since its increased prevalence in patients with
AIDS, in transplant patients, and those with suppressed immunity.
Useful For: Diagnosis of Bartonella infection, especially in the context of a cat scratch
Interpretation: A positive immunofluorescence assay (IFA) IgM (titer >1:20) suggests a current
infection with either Bartonella henselae or Bartonella quintana. A positive IgG (titer >1:128) suggests a
current or previous infection. Increases in IgG titers in serial specimens suggest active infection. Normal
serum specimens usually have an IgG titer of less than 1:128. However, 5% to 10% of healthy controls
exhibit a B henselae and B quintana titer of 1:128. Sera from healthy volunteers rarely show titers of
1:256 or greater. IgM titers in normal serum are typically less than 1:20. IgM titers at 1:20 or greater have
not been seen in the normal population. Molecular testing of tissue for Bartonella species nucleic acid is
recommended in cases of suspected endocarditis.
Reference Values:
Bartonella henselae
IgG: <1:128
IgM: <1:20
Bartonella quintana
IgG: <1:128
IgM: <1:20
Clinical References: 1. Rodino KG, Stone E, Saleh OA, Theel ES: The Brief Case: Bartonella
henselae endocarditis-a case of delayed diagnosis. J Clin Microbiol. 2019 Aug 26;57(9). e00114-19. doi:
10.1128/JCM.00114-19 2. Wolf LA, Cherry NA, Maggi RG, Breitschwerdt EB: In pursuit of a stealth
pathogen: Laboratory diagnosis of bartonellosis. Clin Micro News. 2014;36(5):33-39
BARTB Bartonella, Molecular Detection, PCR, Blood

89983 Clinical Information: Bartonella henselae and B quintana are small, pleomorphic, gram-negative
bacilli that are difficult to isolate by culture due to their fastidious growth requirements. B henselae has
been associated with cat scratch disease, bacillary angiomatosis, peliosis hepatitis, and endocarditis. B
quintana has been associated with trench fever, bacillary angiomatosis, and endocarditis. The diagnosis of
Bartonella infection has traditionally been made by Warthin-Starry staining of infected tissue and
serology. However, these methods may be nonspecific or falsely negative, especially in the early stages of
disease. Evaluation of infected tissue or blood using PCR has been shown to be an effective tool for
diagnosing Bartonella infection. Mayo Clinic Laboratories has developed a real-time PCR test that
permits rapid identification of Bartonella species. The assay targets a unique sequence of the citrate
synthase (gltA) gene present in Bartonella species.
Useful For: Aiding in the diagnosis of Bartonella infection when Bartonella DNA would be expected
to be present in blood, especially endocarditis
Interpretation: A positive result indicates the presence of Bartonella species DNA. A negative result
indicates the absence of detectable Bartonella DNA, but does not negate the presence of the organism
and may occur due to inhibition of PCR, sequence variability underlying primers or probes, or the
presence of Bartonella DNA in quantities less than the limit of detection of the assay.
Reference Values:
Not applicable
Clinical References: 1. Karem KL, Paddock CD, Regnery RL: Bartonella henselae, B quintana,
and B bacilliformis: historical pathogens of emerging significance. Microbes Infect 2000
August;2(10):1193-1205 2. Agan BK, Dolan MJ: Laboratory diagnosis of Bartonella infections. Clin
Lab Med 2002 December;22(4):937-962 3. Maguina C, Gotuzzo E: Bartonellosis. New and old. Infect
Dis Clin North Am 2000 March;14(1):1-22 4. Vikram HR, Bacani AK, Devaleria PA, et al: Bivalvular
Bartonella henselae prosthetic valve endocarditis. J Clin Microbiol 2007 December;45(12):4081-4084
5. Lin EY, Tsigrelis C, Baddour LM, et al: Candidatus Bartonella mayotimonensis and endocarditis.
Emerg Infect Dis 2010 Mar;16(3):500-503
BARRP Bartonella, Molecular Detection, PCR, Varies

84440 Clinical Information: Bartonella henselae and B quintana are small, pleomorphic Gram
stain-negative bacilli that are difficult to isolate by culture due to their fastidious growth requirements.
B henselae has been associated with cat scratch disease, bacillary angiomatosis, peliosis hepatitis, and
endocarditis. B quintana has been associated with trench fever, bacillary angiomatosis, and endocarditis.
The diagnosis of Bartonella infection has traditionally been made by Warthin-Starry staining of infected
tissue or serology. However, these methods may be falsely negative or nonspecific, respectively.
Culture is insensitive. Evaluation of infected tissue using PCR has been shown to be an effective tool
for diagnosing Bartonella infection. Mayo Clinic Laboratories has developed a real-time PCR test that
permits rapid identification of Bartonella species. The assay targets a unique sequence of the citrate
synthase gene present in Bartonella species.
Useful For: Aiding in the diagnosis of Bartonella infection

Interpretation: A positive result indicates the presence of Bartonella species DNA. A negative result
indicates the absence of detectable Bartonella DNA, but does not negate the presence of the organism
presence of Bartonella DNA in quantities less than the limit of detection of the assay.
Reference Values:
Not applicable
Clinical References: 1. Karem KL, Paddock CD, Regnery RL: Bartonella henselae, B. quintana,
and B. bacilliformis: historical pathogens of emerging significance. Microbes Infect 2000
August;2(10):1193-1205 2. Agan BK, Dolan MJ: Laboratory diagnosis of Bartonella infections. Clin
Lab Med 2002 December;22(4):937-962 3. Maguina C, Gotuzzo E: Bartonellosis. New and old. Infect
Dis Clin North Am 2000 March;14(1):1-22 4. Vikram HR, Bacani AK, Devaleria PA, et al: Bivalvular
Bartonella henselae prosthetic valve endocarditis. J Clin Microbiol 2007 December;45(12):4081-4084
5. Lin EY, Tsigrelis C, Baddour LM, et al: Candidatus Bartonella mayotimonensis and endocarditis.
Emerg Infect Dis 2010 Mar;16(3):500-503
BMAMA Basic Metabolic Panel, Serum
113630 Clinical Information: The basic metabolic panel measures 8 analytes and calculates an anion gap. It
is used to assess kidney status, electrolyte, and acid/base balance, and blood glucose.
Useful For: Routine health monitoring or patient monitoring while hospitalized for information
regarding metabolism, including the current kidney status, electrolyte, and acid/base balance, and blood
glucose
Interpretation: Basic metabolic panel results are usually evaluated in conjunction with each other for
patterns of results. A single abnormal test result could be indicative of something different than if more
than 1 of the test results are abnormal. Many conditions will cause abnormal results including kidney
failure, breathing problems, and diabetes-related complications.
Reference Values:
SODIUM
<1 year: not established
> or =1 year: 135-145 mmol/L
POTASSIUM
> or =1 year: 3.6-5.2 mmol/L
CHLORIDE
1-17 years: 102-112 mmol/L
> or =18 years: 98-107 mmol/L
BICARBONATE
Males:
1-2 years: 17-25 mmol/L
3 years: 18-26 mmol/L
Females:
ANION GAP
> or =7 years: 7-15
BLOOD UREA NITROGEN

Males:
<12 months: not established
1-17 years: 7-20 mg/dL
> or =18 years: 8-24 mg/dL
Females:
CREATININE
Males:
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-14 years: 0.35-0.86 mg/dL
> or =15 years: 0.74-1.35 mg/dL
Females:
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-15 years: 0.35-0.86 mg/dL
> or =16 years: 0.59-1.04 mg/dL
ESTIMATED GLOMERULAR FILTRATION RATE (eGFR)

>60 mL/min/BSA
Estimated GFR calculated using the 2009 CKD_EPI creatinine equation
CALCIUM
<1 year: 8.7-11.0 mg/dL
1-17 years: 9.3-10.6 mg/dL
18-59 years: 8.6-10.0 mg/dL
60-90 years: 8.8-10.2 mg/dL
>90 years: 8.2-9.6 mg/dL
GLUCOSE
> or =1 year: 70-140 mg/dL
Clinical References: 1. Oh MS: Chapter 14: Evaluation of renal function, water, electrolytes, and
acid-base balance. In Henry's Clinical Diagnosis and Management by Laboratory Methods. Edited by
RA McPherson, MR Pincus. 22nd edition. Philadelphia, PA. Elsevier Saunders, 2011 2. Lab Tests
Online. Available at https://labtestsonline.org/understanding/analytes/bmp
FBSLG Basil IgG

Reference Values:
BASL Basil, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to basil Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
FBBLE Bass Black (Sea Bass) (Centropristis striata) IgE

57546 Interpretation: Class IgE(kU/L) Comment 0 <0.35 Below Detection 1 0.35 - 0.69 Low Positive 2 0.70
Ã¢â‚¬â€œ 3.49 Moderate Positive 3 3.50 Ã¢â‚¬â€œ 17.49 Positive 4 17.50 Ã¢â‚¬â€œ 49.99 Strong
Positive 5 50.00 Ã¢â‚¬â€œ 99.99 Very Strong Positive 6 >99.99 Very Strong Positive
Reference Values:
<0.35 kU/L
FBSQU Bath Salts Panel (Qualitative), Urine

alpha-PHP/alpha-PiHP: None Detected ng/mL
Alpha-PHP and alpha-PiHP (alpha-Pyrrolindinohexiophenone, alpha-Pyrrolidinohexanophenone,

alpha-Pyrrolidinoisohexanophenone) are psychoactive stimulants of the pyrrolidinophenone series that are
structurally related to alpha-PVP. These compounds have been sold as novel psychoactive substances
(NPS) for their stimulating and empathogenic effects and are used as alternatives to amphetamine,
MDMA, and/or cocaine.
Alpha-PHP and its isomer alpha-PiHP are not differentiated.
If additional testing is needed, please contact the laboratory.
4-chloro alpha-PVP: None Detected ng/mL
4-chloro apha-PVP (4-chloro-alphapyrrolidinovalerophenone) is a psychoactive stimulant of the

pyrrolidinophenone series that is structurally related to alpha-PVP. This compound has been sold as a
novel psychoactive substance (NPS) for its stimulating and empathogenic effects and is used as an
alternative to amphetamine, MDMA and/or cocaine.
Eutylone: None Detected ng/mL
Eutylone is classified as a synthetic stimulant and belongs to the beta-keto-methylenedioxyamphetamine

subclass, which includes synthetic stimulants methylone, butylone, ethylone and N-ethylpentylone.
Benzylone: None Detected ng/mL
Benzylone is classified as a synthetic stimulant and belongs to the

beta-keto-methylenedioxyamphetamine subclass, which includes synthetic stimulants methylone,
butylone, ethylone and N-ethylpentylone.
N-butyl Pentylone: None Detected ng/mL
N-butyl Pentylone is classified as a synthetic stimulant and belongs to the

beta-ketomethylenedioxyamphetamine subclass, which includes synthetic stimulants methylone, butylone,
ethylone and N-ethylpentylone.
BAYL Bay Leaf, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to bay leaf Defining the allergen responsible for
eliciting signs and symptoms Identifying allergens: - Responsible for allergic disease and/or
antibodies is not useful in patients previously treated with immunotherapy to determine if residual
clinical sensitivity exists, or in patients in whom the medical management does not depend upon
identification of allergen specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
FBWME Bayberry/Wax Myrtle (Myrica spp) IgE

57583 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10 - 0.34 Equivocal 1 0.35 - 0.69
Low Positive 2 0.70 - 3.4 Moderate Positive 3 3.5 - 17.4 High Positive 4 5 6 17.5 - 49.9 50.0 - 99.9 > or =
100 Very High Positive Very High Positive Very High Positive
Reference Values:
<0.35 kU/L
BCL2 BCL-2 Immunostain, Technical Component Only

70362 Clinical Information: BCL-2 is in a family of regulators of apoptosis, which together control the
balance between pro- and antiapoptotic signals. BCL-2 protein acts as an inhibitor of apoptosis. It is
normally expressed in mantle zone B cells and T cells, with an intense perinuclear cytoplasmic pattern,
but it is not expressed in reactive germinal center B cells. In the majority of cases of follicular lymphoma,
the BCL-2 gene is involved in a translocation with IgH, t(14;18)(q32;q21), leading to overexpression of
the BCL-2 protein. Thus, BCL-2 expression in germinal center B cells supports a diagnosis of follicular
lymphoma.
Useful For: Classification of lymphomas

Clinical References: 1. Choi WWL, Weisenburger DD, Greiner TC, et al: A New Immunostain
Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy. Clin
Cancer Res 2009; 15:5594-5502 2. Hu S, Xu-Monette ZY, Tzankov A, et al: MYC/BCL2 Protein
Coexpression Contributes to the Inferior Survival of Activated B-cell Subtype of Diffuse Large B-Cell
Lymphoma and Demonstrates High-Risk Gene Expression Signatures: A Report from The International
DLBCL Rituximab-CHOP Consortium Program. Blood 2013; 121(20):4021-4031 3. Iqbal J, Neppalli
VT, Wright G, et al: BCL2 Expression is a Prognostic Marker for the Activated B-Cell-Like Type of
Diffuse Large B-Cell Lymphoma. Journal of Clinical Oncology 2006; 24(6)961-968
BCL6 BCL-6 Immunostain, Technical Component Only

70363 Clinical Information: BCL-6 protein is a transcription factor expressed by follicle center B cells
and other cells of the follicle center and is useful in the classification of lymphomas.

Clinical References: 1. Choi WW, Weisenburger DD, Greiner TC, et al: A new immunostain
algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin
Cancer Res. 2009;15:5594-5502 2. Dogan A, Bagdi E, Munson P, Isaacson PG: CD10 and BCL-6
expression in paraffin sections of normal lymphoid tissue and B-cell lymphomas. Am J Surg Pathol.
2000;24(6):846-852 3. Gualco G, Weiss LM, Harrington WJ Jr, Bacchi CE: BCL6, MUM1, and CD10
expression in mantle cell lymphoma. Appl Immunohistochem Mol Morphol. 2010;18(2):103-108
BCOR BCOR Immunostain, Technical Component Only

605260 Clinical Information: Round cell sarcomas are a heterogeneous group of tumors which have
diverse genetic abnormalities, clinical presentations and outcomes despite similar cytomorphology. The
diagnosis of these emerging entities has relied on molecular tests until recent immunohistochemical
screening markers. BCOR (BCL-6 interacting corepressor) is involved in suppressing gene expression
by either interacting with BCL-6 or binding to PCGF1 (poly-comb-group RING finger homologue1)
and inducing gene silencing by histone modification. BCOR immunohistochemistry is a highly sensitive
marker in identifying round cell sarcomas with BCOR abnormalities.
Useful For: Helping in the distinction of a subset of primitive round cell sarcomas with BCOR
rearrangements from other Ewing/Ewing-like sarcomas
interpretation is performed). If diagnostic consultation by a pathologist is required order PATHC /
Pathology Consultation. The positive and negative controls are verified as showing appropriate
pathologist.
Clinical References: 1. Machado I, Yoshida A, Lopez-Guerrero JA, et al: Immunohistochemical

analysis of NKX2.2, ETV4, and BCOR in a large series of genetically confirmed Ewing sarcoma family
of tumors. Pathol Res Pract 2017; 213:1048-1053 2. Chiang S, Lee CH, Stewart CJR, et al: BCOR is a
robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal
sarcoma, including tumors exhibiting variant morphology. Mod Pathol 2017; 30:1251-1261 3. Kao YC,
Sung YS, Zhang L, et al: BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas
With BCOR Genetic Abnormalities. Am J Surg Pathol 2016;40(12):1670-1678
BCRFX BCR/ABL1 Qualitative Diagnostic Assay with Reflex to

65248 BCR/ABL1 p190 Quantitative Assay or BCR/ABL1 p210
Quantitative Assay, Varies
Clinical Information: The t(9;22)/BCR-ABL1 abnormality is associated with chronic myelogenous
leukemia (CML) and "Philadelphia positive" acute lymphoblastic leukemia of B-cell lineage (Ph+ ALL).
Very rarely, this abnormality has also been identified in cases of acute myeloid leukemia and
T-lymphoblastic leukemia/lymphoma. The fusion gene on the derivative chromosome 22q11 produces a
chimeric BCR-ABL1 messenger RNA (mRNA) transcript and corresponding translated oncoprotein.
Despite substantial breakpoint heterogeneity at the DNA level, a consistent set of BCR-ABL1 mRNA
transcripts are produced that can be readily and sensitively detected by reverse transcription polymerase
chain reaction (RT-PCR) technique. In CML, breakpoints in BCR result in either exons 13 or 14 (e13,
e14) joined to exon 2 of ABL1 (a2). The corresponding e13-a2 or e14-a2 BCR-ABL1 mRNAs produce a
210 kDa protein (p210). Rare cases of CML are characterized by an e19-a2 type mRNA with a
corresponding p230 protein. In Ph+ ALL, the majority of cases harbor an e1-a2 BCR-ABL1 mRNA
transcript, producing a p190 protein. However, chimeric mRNA type is not invariably associated with
disease type, as noted by the presence of p210-positive Ph ALL and very rare cases of p190-positive
CML. Therefore, positive results from a screening (diagnostic) assay for BCR-ABL1 mRNA need to be
correlated with clinical and pathologic findings. In addition to the main transcript variants described
above, rare occurrences of both CML and Ph+ ALL can have alternative break-fusion events resulting in
unusual BCR-ABL1 transcript types. Examples include e6-a2 and BCR exon fusions to ABL1 exon a3
(eg, e13-a3, e14-a3, or e1-a3). In addition to detecting common BCR-ABL1 mRNA transcripts, this assay
also can identify these rarer BCR-ABL1 transcript variants and is therefore a comprehensive screen for
both usual and uncommon BCR-ABL1 gene fusions in hematopoietic malignancies. Given the nature of
genetic events in tumors however, this assay will not identify extremely rare and unexpected BCR-ABL1
events involving other exons (eg, case report level) and is therefore not absolutely specific but is predicted
to detect greater than 99.5% of BCR-ABL1 events. Therefore, it is recommended that for diagnosis,
RT-PCR plus a second method (eg, BCR-ABL1 fluorescence in situ hybridization or cytogenetics) should
be used. However, this RT-PCR assay is invaluable at diagnosis for identifying the precise BCR-ABL1
mRNA type (eg, for future quantitative assay disease monitoring), which complementary methods cannot.
This assay is intended as a qualitative method, providing information on the presence (and specific
mRNA type) or absence of the BCR-ABL1 mRNA. Results from this test can be used to determine the
correct subsequent assay for monitoring of transcript levels following therapy (eg, BCRAB / BCR/ABL1,
p210, mRNA Detection, Reverse Transcription-PCR (RT-PCR), Quantitative, Monitoring Chronic
Myeloid Leukemia (CML), Varies; BA190 / BCR/ABL, p190, mRNA Detection, Reverse
Transcription-PCR (RT-PCR), Quantitative, Monitoring Assay, Varies). Because the assay is analytically
sensitive, it compensates for situations such as partially degraded RNA quality, or low cell number but it
is not intended for quantitative or monitoring purposes.
Useful For: Diagnostic workup of patients with high probability of BCR-ABL1-positive hematopoietic
neoplasms, predominantly chronic myeloid/myelogenous leukemia and acute lymphoblastic leukemia
Interpretation: An interpretive report will be provided. When positive, the test identifies which
specific messenger RNA fusion variant is present to guide selection of an appropriate monitoring assay. If
common p210 or p190 fusion variant detected, quantitative reflex will be performed. -Common fusion
variants detected: e13-a2 or e14-a2 (p210), e1-a2 (p190), and e6-a2 (p205*) -Rare fusion variants
detected: e13-a3 (p210), e14-a3 (p210), e1-a3 (p190), e19-a2 (p230) -Potential rare fusions detected:
e12-a3, e19-a3 *This is formerly observed as the e6-a2 (p185) fusion form
Reference Values:
Clinical References: 1. Burmeister T, Reinhardt R: A multiplex PCR for improved detection of

typical and atypical BCR-ABL fusion transcripts. Leuk Res. 2008 Apr;32(4):579-585 2. Melo JV: The
diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood. 1996 Oct
1;88(7):2375-2384 3. Melo JV: BCR-ABL gene variants. Baillieres Clin Haematol. 1997
Jun;10(2):203-222 4. Baccarini M, Deininger MW, Rosti G, et al: European LeukemiaNet
recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013
Aug;122(6):872-884 5. Cross NC, White HE, Muller MC, et al: Standardized definitions of molecular
response in chronic myeloid leukemia. Leukemia. 2012 Oct;26(10):2172-2175 6. Deininger MW, Shah
NP, Altman JK, et al: Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in
Oncology. J Natl Compr Canc Netw. 2020 Oct 1;18(10):1385-1415. doi: 10.6004/jnccn.2020.0047
BA190 BCR/ABL1, p190, mRNA Detection, Reverse

83336 Transcription-PCR (RT-PCR), Quantitative, Monitoring Assay,
Varies
Clinical Information: Messenger RNA (mRNA) transcribed from BCR/ABL1 (fusion of the
breakpoint cluster region gene [BCR] at chromosome 22q11 to the Abelson gene [ABL1] at
chromosome 9q34) is detected in all patients with chronic myeloid leukemia (CML) and a subset of
patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Although
breakpoints in the BCR and ABL1 genes may occur in a variety of locations, splicing of the primary
RNA transcripts result in only 8 fusion site variants (e1/a2, e6/a2, e13/a2, e14/a2, e19/a2, and e1/a3,
e13/a3, e14/a3), which incorporate the entire sequence of the exons on both sides of the fusion site. The
e1/a2 and e1/a3 fusion forms produce a 190-kDa protein designated p190. This BCR/ABL1 protein
form is found in approximately 75% of patients with childhood ALL and approximately 50% of patients
with adult ALL, with the majority arising from e1/a2 mRNA. The p190 is also the predominant fusion
form in a small subset of patients with CML, although the vast majority of CML cases contain the p210
protein, typically from e13/a2 or e14/a2 mRNA fusions. Other fusion forms are very rare. Quantitative
reverse-transcription polymerase chain reaction (qRT-PCR) is the most sensitive method for monitoring
BCR/ABL1 levels during treatment. This test detects mRNA coding for the most common p190 fusion
form (e1/a2).
Useful For: Monitoring response to therapy in patients with known e1/a2 BCR/ABL1 (p190) fusion
forms

Reference Values:
The presence or absence of the BCR/ABL1 messenger RNA fusion form producing the p190 fusion
protein is reported. If positive, the level is reported as the ratio of BCR/ABL1 (p190) transcript to ABL1
transcript in the form of a percentage.
Clinical References: 1. Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular
responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N
Engl J Med. 2003;349:1423-1432 2. Radich JP, Gooley T, Bryant E, et al: The significance of
BCR/ABL molecular detection in chronic myeloid leukemia patients "late," 18 months or more after
transplantation. Blood. 2001;98:1701-1707 3. Olavarria E, Kanfer E, Szydlo R, et al: Early detection of
BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome
after allogeneic stem cell transplant for chronic myeloid leukemia. Blood. 2001;97:1560-1565 4. Tefferi
A: The classic myeloproliferative neoplasms: Chronic myelogenous leukemia, polycythemia vera,
essential thrombocythemia, and primary myelofibrosis. In: Valle DL, Antonarakis S, Ballabio A,
Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease.
McGraw-Hill; 2019, Accessed March 16, 2022. Available at
https://ommbid.mhmedical.com/content.aspx?sectionid=225078035&bookid=2709
B190R BCR/ABL1, p190, mRNA Detection, Reverse

48391 Transcription-PCR (RT-PCR), Quantitative, Reflex, Varies
Clinical Information: The t(9;22)/BCR-ABL1 abnormality is associated with chronic myeloid
leukemia (CML) and "Philadelphia positive" acute lymphoblastic leukemia of B-cell lineage (Ph+
ALL). Very rarely, this abnormality has also been identified in cases of acute myeloid leukemia and
chain reactionÂ (RT-PCR) technique. In CML, breakpoints in BCR nearly always result in either exons
13 or 14 (e13, e14) joined to exon 2 of ABL1 (a2). The corresponding e13-a2 or e14-a2 BCR-ABL1
mRNAs produce a 210 kDa protein (p210). Rare cases of CML are characterized by an e19-a2 type
mRNA with a corresponding p230 protein. In Ph+ ALL, the majority of cases harbor an e1-a2
BCR-ABL1 mRNA transcript, producing a p190 protein, although some ALL patients may alternatively
present with the e13/e14-a2 (p210) type fusion. This assay provides information at the time of diagnosis
regarding the presence (and specific mRNA type) or absence of the BCR-ABL1 mRNA. If positive, the
reflex test will follow to provide an initial quantitative level of the specific BCR-ABL1 transcript. For
example, when positive for the e1-a2 (p190) type mRNA, the reflex test provides a corresponding p190
quantitative value. Results from this test are also useful to determine the correct quantitative assay for
subsequent monitoring of transcript levels (ie, p190 or p210) during tyrosine kinase inhibitor therapy.
Useful For: Diagnostic workup of patients with a high probability of BCR-ABL1-positive

hematopoietic neoplasms, particularly acute lymphoblastic leukemia (B-lymphoblastic leukemia), to
provide a pretreatment quantitative level of BCR-ABL1 mRNA transcript if the initial diagnostic RT-PCR
screen is positive When positive, the reflex test provides a quantitative value for the corresponding e1-a2
(p190) BCR-ABL1 mRNA fusion variant
Interpretation: An interpretive report will be provided under the BCRFX / BCR/ABL1 Qualitative
Diagnostic Assay with Reflex to BCR/ABL1 p190 Quantitative Assay or BCR/ABL1 p210 Quantitative
Assay, Varies.
Reference Values:
Only orderable as a reflex. For more information see BCRFX / BCR/ABL1 Qualitative Diagnostic Assay
with Reflex to BCR/ABL1 p190 Quantitative Assay or BCR/ABL1 p210 Quantitative Assay, Varies.
Engl J Med. 2003;349:1423-1432 2. Radich JP, Gooley T, Bryant E, et al: The significance of BCR/ABL
molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplantation.
Blood. 2001;98:1701-1707 3. Olavarria E, Kanfer E, Szydlo R, et al: Early detection of BCR-ABL
transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after
allogeneic stem cell transplant for chronic myeloid leukemia. Blood. 2001;97:1560-1565 4. Tefferi A:
The classic myeloproliferative neoplasms: Chronic myelogenous leukemia, polycythemia vera, essential
thrombocythemia, and primary myelofibrosis. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL,
Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019,
Accessed March 16, 2022. Available at
BCRAB BCR/ABL1, p210, mRNA Detection, Reverse Transcription-PCR

89007 (RT-PCR), Quantitative, Monitoring Chronic Myeloid Leukemia
(CML), Varies
Clinical Information: Chronic myeloid leukemia (CML) is a hematopoietic stem cell neoplasm
included in the broader diagnostic category of myeloproliferative neoplasms. CML is consistently
associated with fusion of the breakpoint cluster region gene (BCR) at chromosome 22q11 to the Abelson
gene (ABL1) at chromosome 9q23. This fusion is designated BCR/ABL1 and may be seen on routine
karyotype as the Philadelphia chromosome. Although various breakpoints within the BCR and ABL1
genes have been described, more than 95% of CMLs contain a consistent mRNA transcript in which
either the BCR exon 13 (e13) or BCR exon 14 (e14) is fused to the ABL1 exon 2 (a2), yielding fusion
forms e13/a2 and e14/a2, respectively. The e13/a2 and e14/a2 fusion forms produce a 210-kDa protein
(p210). The p210 fusion protein is an abnormal tyrosine kinase known to be critical for the clinical and
pathologic features of CML, and agents that block the tyrosine kinase activity (ie, tyrosine kinase
inhibitors or TKI, such as imatinib mesylate) have been used successfully for treatment. Monitoring the
level of BCR/ABL1 mRNA in CML patients during treatment is helpful for both prognosis and
management of therapy.(1-3) Rising BCR/ABL1 mRNA levels following attainment of critical
therapeutic milestones (see Clinical References) can be indicative of acquired resistance mutations
involving the ABL1 portion of the BCR/ABL1 fusion gene. Quantitative reverse-transcription PCR
(qRT-PCR) is the most sensitive method for monitoring BCR-ABL1 levels during treatment. This test
detects the BCR/ABL1 mRNA fusion forms found in CML (e13/a2 and e14/a2).
Useful For: Monitoring response to therapy in patients with chronic myeloid leukemia who are
known to have the e13/a2 or e14/a2 BCR/ABL1 fusion transcript forms
Interpretation: An interpretive report will be provided. When BCR/ABL1 mRNA is present,

quantitative results are reported on the international scale (IS), established from data originally reported
in the IRIS (International Randomized Study of Interferon versus STI571) trial involving newly
diagnosed chronic myeloid leukemia patients. Using the IS, a result of less than 0.1% BCR/ABL1
(p210):ABL1 is equivalent to a major molecular remission. This value is also designated on a log scale
(Molecular Response, MR) as MR3. For further discussion of the international scale, see Clinical
References.
Reference Values:
The presence or absence of BCR/ABL1 mRNA fusion form e13/e14-a2 producing the p210 fusion
protein is identified. If positive, the quantitative level is reported as the normalized ratio of BCR/ABL1
(p210) to endogenous ABL1 mRNA with conversion to a percentage referenced to the international
scale (IS), on which 0.1% BCR/ABL1:ABL1 (also represented on a log scale as Molecular Response 3,
or MR3) is designated as a major molecular response (MMR) threshold.
Engl J Med 2003 October 9;349(15):1423-1432 2. Baccarini M, Deininger MW, Rosti G, et al:
European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
Blood 2013;122:872-884 3. Press RD, Kamel-Reid S, Ang D: BCR-ABL1 RT-qPCR for monitoring the
molecular response to tyrosine kinase inhibitors in chronic myeloid leukemia. J Mol Diagn
2013;15:565-576 4. Cross NC, White HE, Muller MC, et al: Standardized definitions of molecular
response in chronic myeloid leukemia. Leukemia 2012;26:2172-2175 5. National Comprehensive
Cancer Network Practice Guidelines in Oncology: Chronic Myeloid Leukemia 2015. Available at
www.nccn.org
B210R BCR/ABL1, p210, mRNA Detection, Reverse

48390 Transcription-PCR (RT-PCR), Quantitative, Reflex, Varies
Clinical Information: The t(9;22)/BCR-ABL1 abnormality is associated with chronic myeloid
leukemia (CML) and "Philadelphia positive" acute lymphoblastic leukemia of B-cell lineage (Ph ALL).
chain reaction technique. In CML, breakpoints in BCR nearly always result in either exons 13 or 14
(e13, e14) joined to exon 2 of ABL1 (a2). The corresponding e13-a2 or e14-a2 BCR-ABL1 mRNAs
produce a 210 kDa protein (p210). Rare cases of CML are characterized by an e19-a2 type mRNA with
a corresponding p230 protein. In Ph ALL, the majority of cases harbor an e1-a2 BCR-ABL1 mRNA
transcript, producing a p190 protein, although some ALL patients may alternatively present with the
e13/e14-a2 or p210 type fusion. This assay provides information at the time of diagnosis regarding the
presence (and specific mRNA type) or absence of the BCR-ABL1 mRNA. If positive, the reflex test
will follow to provide an initial quantitative level of the specific BCR-ABL1 transcript. For example,
when positive for the e13/e14-a2 (p210) type mRNA, the reflex test provides a corresponding p210
quantitative value. Results from this test are also useful to determine the correct quantitative assay for
subsequent monitoring of transcript levels (ie, p190 or p210) during tyrosine kinase inhibitor therapy.

hematopoietic neoplasms, particularly chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia
(B-lymphoblastic leukemia), to provide a pretreatment quantitative level of BCR-ABL1 mRNA transcript
if the initial diagnostic reverse transcription polymerase chain reaction screen is positive When positive,
the reflex test provides a quantitative value for the corresponding e13-a2 or e14-a2 (p210) BCR-ABL1
mRNA fusion variant
Interpretation: An interpretive report will be provided under the BCRFX /BCR/ABL1 Qualitative
Diagnostic Assay with Reflex to BCR/ABL1 p190 Quantitative Assay or BCR/ABL1 p210 Quantitative
Assay, Varies.
Reference Values:
Only orderable as a reflex. See BCRFX /BCR/ABL1 Qualitative Diagnostic Assay with Reflex to
BCR/ABL1 p190 Quantitative Assay or BCR/ABL1 p210 Quantitative Assay, Varies.
BADX BCR/ABL1, Qualitative, Diagnostic Assay, Varies

89006 Clinical Information: The t(9;22)/BCR-ABL1 abnormality is associated with chronic myeloid
leukemia (CML) and "Philadelphia-positive" acute lymphoblastic leukemia of B-cell lineage (Ph+ ALL).
chimeric BCR-ABL1 mRNA transcript and corresponding translated oncoprotein. Despite substantial
breakpoint heterogeneity at the DNA level, a consistent set of BCR-ABL1 messenger RNA (mRNA)
transcripts are produced that can be readily and sensitively detected by reverse transcription-polymerase
chain reactionÂ (RT-PCR) technique. In CML, breakpoints in BCR result in either exons 13 or 14 (e13,
e14) joined to exon 2 of ABL1 (a2). The corresponding e13-a2 or e14-a2 BCR-ABL1 mRNAs produce a
210-kDa protein (p210). Rare cases of CML are characterized by an e19-a2 type mRNA with a
corresponding p230 protein. In Ph+ ALL, the majority of cases harbor an e1-a2 BCR-ABL1 mRNA
transcript, producing a p190 protein. However, chimeric mRNA type is not invariably associated with
disease type, as noted by the presence of p210-positive Ph ALL and very rare cases of p190-positive
CML. Therefore, positive results from a screening (diagnostic) assay for BCR-ABL1 mRNA need to be
correlated with clinical and pathologic findings. In addition to the main transcript variants described
above, rare occurrences of both CML and Ph+ ALL can have alternative break-fusion events resulting in
unusual BCR-ABL1 transcript types. Examples include e6-a2 and BCR exon fusions to ABL1 exon a3
(eg, e13-a3, e14-a3, or e1-a3). In addition to detecting common BCR-ABL1 mRNA transcripts, this assay
also can identify these rarer BCR-ABL1 transcript variants and is, therefore, a comprehensive screen for
both usual and uncommon BCR-ABL1 gene fusions in hematopoietic malignancies. Given the nature of
genetic events in tumors, however, this assay will not identify extremely rare and unexpected BCR-ABL1
events involving other exons (eg, case report level) and is, therefore, not absolutely specific but is
predicted to detect more than 99.5% of BCR-ABL1 events. Therefore, it is recommended that for
diagnosis, RT-PCR plus a second method (eg, BCR-ABL1 fluorescence in situ hybridization or
cytogenetics) should be used. However, this RT-PCR assay is invaluable at diagnosis for identifying the
precise BCR-ABL1 mRNA type (eg, for future quantitative assay disease monitoring), which cannot be
done by complementary methods. This assay is intended as a qualitative method, providing information
on the presence (and specific mRNA type) or absence of the BCR-ABL1 mRNA. Results from this test
can be used to determine the correct subsequent assay for monitoring of transcript levels following
therapy (eg, BCRAB / BCR/ABL1, p210, mRNA Detection, Reverse Transcription-PCR (RT-PCR),
Quantitative, Monitoring Chronic Myeloid Leukemia (CML), Varies; BA190 / BCR/ABL, p190, mRNA
Detection, Reverse Transcription-PCR (RT-PCR), Quantitative, Monitoring Assay, Varies). Because the
assay is analytically sensitive, it compensates for situations such as partially degraded RNA quality, or
low cell number, but it is not intended for quantitative or monitoring purposes.

hematopoietic neoplasms, predominantly chronic myeloid leukemia and acute lymphoblastic leukemia
Interpretation: An interpretive report will be provided. When positive, the test identifies the specific
messenger RNA fusion variant present to guide selection of an appropriate monitoring assay.
Monitoring is available for common p210 or p190 fusion variant detected. -Common fusion variants
detected: e13-a2 or e14-a2 (p210), e1-a2 (p190), and e6-a2 (p205*) -Rare fusion variants detected:
e13-a3 (p210), e14-a3 (p210), e1-a3 (p190), e19-a2 (p230) -Potential rare fusions detected: e12-a3,
e19-a3 *This is formerly observed as the e6-a2 (p185) fusion form.
Reference Values:
A qualitative result is provided that indicates the presence or absence of BCR/ABL1 messenger RNA.
When positive, the fusion variant is also reported.
Clinical References: 1. Burmeister T, Reinhardt R: A multiplex PCR for improved detection of

typical and atypical BCR-ABL fusion transcripts. Leuk Res 2008 Apr;32(4):579-585 2. Melo JV: The
diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood. 1996 Oct
1;88(7):2375-2384 3. Melo JV: BCR-ABL gene variants. Baillieres Clin Haematol. 1997
Jun;10(2):203-222 4. Tefferi A: The classic myeloproliferative neoplasms: Chronic myelogenous
leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. In: Valle DL,
Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases
of Inherited Disease. McGraw-Hill; 2019, Accessed March 16, 2022. Available at
BAKDM BCR/ABL1, Tyrosine Kinase Inhibitor Resistance, Kinase

89609 Domain Mutation Screen, Sanger Sequencing, Varies
Clinical Information: Chronic myeloid leukemia (CML) is characterized by the presence of the
t(9:22) BCR/ABL1 abnormality, resulting in formation of a fusion BCR/ABL1 messenger RNA
(mRNA) and protein. The ABL1 component of this oncoprotein contains tyrosine kinase activity and is
thought to play a central role in the proliferative phenotype of this leukemia. Recent advances have
resulted in a number of therapeutic drugs that inhibit the ABL1 tyrosine kinase, as well as other protein
tyrosine kinases. Imatinib mesylate (Gleevec, Novartis) is the prototype of these tyrosine kinase
inhibitors (TKI), which are capable of inducing durable hematologic and (in most patients) cytogenetic
remissions. Unfortunately, a significant subset of patients can develop functional resistance to TKI, due
in a large number of cases (approximately 50%) to the acquisition of point mutations in the kinase
domain (KD) of the chimeric ABL1 gene. To date, over 50 distinct mutations have been described,
although a smaller subset of these (<20) account for the majority of patients with clinical resistance to
TKI, or have well documented in vitro data in the published literature. Recognition of TKI resistance is
important in CML, as the effect of some mutations can be overcome by increasing imatinib dosage,
whereas others require switching to either a different (second-generation) TKI, or alternative therapy.
The common T315I KD mutation is particularly important, given that this alteration confers
pan-resistance to all currently employed TKI except ponatinib. Typically, TKI resistance is suspected in
a CML patient who shows loss of initial therapeutic response (eg, cytogenetic relapse), or a significant
and sustained increase in molecular BCR/ABL1 quantitative levels. Similar considerations are also
present in patients with Philadelphia chromosome positive B-cell acute lymphoblastic leukemia, who
can also be treated using TKI therapy. Point mutations in the oncogenic BCR/ABL1 are typically
detected by direct sequencing of polymerase chain reaction (PCR) products, following reverse
transcription PCR (RT-PCR) amplification of the BCR/ABL mRNA transcript from a peripheral blood
specimen. This approach ensures comprehensive screening of the clinically relevant KD region.
Because this technique requires inclusion of a longer region of ABL1 in the BCR/ABL1 RT-PCR
product, low levels of the BCR/ABL1 mRNA transcript (below 0.01% normalized BCR/ABL1 on the
International Scale: IS) may not be efficiently amplified (in contrast to similar amplicons generated by
quantitative RT-PCR for diagnosis or monitoring).
Useful For: Evaluating patients with chronic myelogenous leukemia and Philadelphia chromosome
positive B-cell acute lymphoblastic leukemia receiving tyrosine kinase inhibitor (TKI) therapy, who are
apparently failing treatment Preferred initial test to identify the presence of acquired BCR-ABL1
mutations associated with TKI-resistance
Interpretation: The presence of one or more point mutations in the translocated portion of the ABL1
region of the BCR/ABL1 fusion messenger RNA is considered a positive result, indicating tyrosine kinase
inhibitor (TKI) resistance. The specific type of mutation may influence the sensitivity to a specific TKI
and could be useful in guiding therapeutic options for an individual patient.
Reference Values:
Clinical References: 1. Hughes T, Deininger M, Hochhaus A, et al: Monitoring CML patients

responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing
current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing
results. Blood. 2006 Jul 1;108(1):28-37. doi: 10.1182/blood-2006-01-0092 2. Press RD, Kamel-Reid S,
Ang D: BCR-ABL1 RT-qPCR for Monitoring the Molecular Response to Tyrosine Kinase Inhibitors in
Chronic Myeloid Leukemia. J Mol Diagn. 2013 Sep;15(5):565-576. doi: 10.1016/j.jmoldx.2013.04.007 3.
Baccarani M, Deininger MW, Rosti G, et al: European LeukemiaNet recommendations for the
management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872-884. doi:
10.1182/blood-2013-05-501569 4. Jones D, Kamel-Reid S, Bahler D, et al: Laboratory practice guidelines
for detecting and reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and
acute lymphoblastic leukemia: a report of the Association for Molecular Pathology. J Mol Diagn. 2009
Jan;11(1):4-11. doi: 10.2353/jmoldx.2009.080095
FBEBE Bean Black (Phaseolus spp) IgE

Reference Values:
<0.35 kU/L
FBGSG Bean Green/String IgG

Reference Values:
FBKG Bean Kidney IgG

Reference Values:
FBLME Bean Lima (Phaseolus limensis) IgE
57523 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10 - 0.34 Equivocal/Borderline
1 0.35 - 0.69 Low Positive 2 0.70 - 3.49 Moderate Positive 3 3.5 - 17.49 High Positive 4 5 6 17.5 -
49.99 50.0 - 99.99 > 99.99 Very High Positive Very High Positive Very High Positive
Reference Values:
<0.35 kU/L
FNBE Bean Navy/White (Phaseolus vulgaris) IgE

57937 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10 Ã¢â‚¬â€œ 0.34
Equivocal/Borderline 1 0.35 Ã¢â‚¬â€œ 0.69 Low Positive 2 0.70 Ã¢â‚¬â€œ 3.49 Moderate Positive 3
3.50 Ã¢â‚¬â€œ 17.49 High Positive 4 17.50 Ã¢â‚¬â€œ 49.99 Very High Positive 5 50.00 Ã¢â‚¬â€œ
99.99 Very High Positive 6 >99.99 Very High Positive
Reference Values:
<0.35 kU/L
FBNWG Bean Navy/White IgG

Reference Values:
BWRS Beckwith-Wiedemann Syndrome/Russell-Silver Syndrome,

35376 Molecular Analysis, Varies
Clinical Information: Beckwith-Wiedemann syndrome (BWS) is a disorder characterized by
prenatal and/or postnatal overgrowth, neonatal hypoglycemia, congenital malformations, and an
increased risk for embryonal tumors. Physical findings are variable and can include abdominal wall
defects, macroglossia, and hemihyperplasia. The predisposition for tumor development is associated
with specific tumor types such as adrenal carcinoma, nephroblastoma (Wilms tumor), hepatoblastoma,
and rhabdomyosarcoma. In infancy, BWS has a mortality rate of approximately 20%. Current data
suggest that the etiology of BWS is due to dysregulation of imprinted genes in the 11p15 region of
chromosome 11, including H19 (maternally expressed), LIT1 (official symbol KCNQ1OT1; paternally
expressed), IGF2 (paternally expressed), and CDKN1C (aliases p57 and KIP2; maternally expressed).
Expression of these genes is controlled by 2 imprinting centers (IC). Approximately 85% of BWS cases
appear to be sporadic, while 15% of cases are associated with an autosomal dominant inheritance
pattern. When a family history is present, the etiology is often due to inherited point alterations in
CDKN1C or an unknown cause. The etiology of sporadic cases includes: -Hypomethylation of
imprinting center 2 (IC2) (LIT1): approximately 50% to 60% -Paternal uniparental disomy of
chromosome 11: approximately 10% to 20% -Hypermethylation of imprinting center 1 (IC1) (H19):
approximately 2% to 7% -Unknown: approximately 10% to 20% -Point alteration in CDKN1C:
approximately 5% to 10% -Cytogenetic abnormality: approximately 1% to 2% -Differentially
methylated region 1 (DMR1) or DMR2 microdeletion: rare The clinical presentation of BWS is
dependent on which gene in the 11p15 region is involved. The risk for cancer has been shown to be
significantly higher in patients with abnormal methylation of IC1 (H19) versus IC2 (LIT1). In patients
with abnormal methylation of IC2 (LIT1), abdominal wall defects and overgrowth are seen at a higher
frequency. Russell-Silver syndrome (RSS) is a rare genetic condition with an incidence of
approximately 1 in 100,000. RSS is characterized by pre- and postnatal growth retardation with normal
head circumference, characteristic facies, fifth finger clinodactyly, and asymmetry of the face, body,
and/or limbs. Less commonly observed clinical features include cafe au lait spots, genitourinary
anomalies, motor, speech, cognitive delays, and hypoglycemia. Although clinical diagnostic criteria
have been developed, it has been demonstrated that many patients with molecularly confirmed RSS do
not meet strict clinical diagnostic criteria for RSS. Therefore, most groups recommend a relatively low
threshold for considering molecular testing in suspected cases of RSS. RSS is a genetically
heterogeneous condition that is associated with genetic and epigenetic alterations at chromosome 7 and
the chromosome 11p15.5 region. The majority of cases of RSS are sporadic, although familial cases
have been reported. The etiology of sporadic cases of RSS includes: -Hypomethylation of IC1 (H19):
approximately 30% to 50% -Maternal uniparental disomy (UPD) of chromosome 7: approximately 5%
to 10%* -11p15.5 duplications: rare -Chromosome 7 duplications: rare* *Note that this test does not
detect chromosome 7 UPD. However, testing is available; order UNIPD / Uniparental Disomy, Varies.
The clinical phenotype of RSS has been associated with the specific underlying molecular etiology.
Patients with hypomethylation of IC1 (H19) are more likely to exhibit "classic" RSS phenotype (ie,
severe intrauterine growth retardation, postnatal growth retardation, and asymmetry), while patients
with maternal UPD7 often show a milder clinical phenotype. Despite these general genotype-phenotype
correlations, many exceptions have been reported. Methylation abnormalities of IC1 (H19) and IC2
(LIT1) can be detected by methylation-sensitive multiple ligation-dependent probe amplification. While
testing can determine methylation status, it does not identify the mechanism responsible for the
methylation defect (such as paternal uniparental disomy or cytogenetic abnormalities).
Hypomethylation of IC2 (LIT1) is hypothesized to silence the expression of a number of maternally
expressed genes, including CDKN1C. Hypermethylation of IC1 is hypothesized to silence the
expression of H19, while also resulting in overexpression of IGF2. Absence of CDKN1C and H19
expression, in addition to overexpression of IGF2, is postulated to contribute to the clinical phenotype
of BWS. Hypomethylation of IC1 is hypothesized to result in overexpression of H19 and
underexpression of the IGF2, which is thought to contribute to the clinical phenotype of RSS.
Useful For: Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) or

Russell-Silver syndrome (RSS) Prenatal diagnosis if there is a high suspicion of BWS/RSS based on
ultrasound findings or in families at risk for BWS/RSS

Reference Values:
Clinical References: 1. DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP, Feinberg
AP: Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann Syndrome
with cancer and birth defects. Am J Hum Genet. 2002 Mar;70(3):604-611 2. Choufani S, Shuman C,
Weksberg R: Beckwith-Wiedemann Syndrome. Am J Med Genet C Semin Med Genet. 2010 Aug
15;154C(3):343-354 3. Wakeling EL: Silver-Russell syndrome. Arch Dis Child. 2011
Dec;96(12):1156-1161 4. Eggermann T, Begemann M, Binder G, Spengler S: Silver-Russell syndrome:
genetic basis and molecular genetic testing. Orphanet J Rare Dis. 2010 Jun 23;5:19 5. Priolo M, Sparago
A, Mammi C, Cerrato F, Lagana C, Riccio A: MS-MLPA is a specific and sensitive technique for
detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment. Eur J
Hum Genet. 2008 May;16(5):565-571
BECH Beech, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to beech Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
FBEFG Beef IgG

Reference Values:
BEEF Beef, IgE, Serum

Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease
and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to
identify allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm
sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of
allergic reactions to insect venom allergens, drugs, or chemical allergens.

Reference Values:

0 Negative

apply to all ages.
FBTRG Beet Root IgG

Reference Values:
BEETS Beets (Beetroot), IgE, Serum

Useful For: Establishing a diagnosis of an allergy to beets Defining the allergen responsible for

Reference Values:

0 Negative

apply to all ages.
FPHEN Benzene as Phenol, Occupational Exposure, Urine

Creatinine: >50 mg/dL
Phenol: mg/L
Phenol: mg/G creat
Normal (unexposed population):

less than 10 mg/L
Exposed:
Biological Exposure Index (BEI): 50 mg/g creatinine (End of Shift)
Toxic:
Not Established
FBEN Benzene, Occupational Exposure, Blood

90294
Reference Values:
Units: mg/L
Normal (unexposed population):

None detected
Exposed (end-of-shift):
Blood benzene concentrations of greater than 0.1 mg/L correlate with exposure to greater than 10 ppm
benzene in air.
Toxic:
Blood benzene concentrations greater than 0.90 mg/L have been observed in fatal cases of benzene
exposure.
BNZX Benzodiazepines Confirmation, Chain of Custody, Random,

608279 Urine
Clinical Information: Benzodiazepines are any of a group of compounds having a common
molecular structure and acting similarly as depressants of the central nervous system. As a class of drugs,
benzodiazepines are among the most commonly prescribed drugs in the western hemisphere because of
their efficacy, safety, low addiction potential, minimal side effects, and high public demand for sedative
and anxiolytic agents. Chain of custody is a record of the disposition of a specimen to document each
individual who collected, handled, and performed the analysis. When a specimen is submitted in this
Useful For: Detecting drug use involving benzodiazepines such as alprazolam, chlordiazepoxide,
clonazepam, diazepam, midazolam, oxazepam, temazepam, clobazam, flunitrazepam, flurazepam,
lorazepam, prazepam, triazolam, and zolpidem, in urine specimens handled through the chain-of-custody
process Providing chain of custody for when the results of testing could be used in a court of law. Its
opportunity for specimen tampering would be limited.
Interpretation: Benzodiazepines are extensively metabolized, and the parent compounds are not
detected in urine. This test screens for (and confirms) the presence of: -Alprazolam
-Alpha-hydroxyalprazolam (metabolite of alprazolam) -Chlordiazepoxide -Clonazepam
-7-Aminoclonazepam (metabolite of clonazepam) -Diazepam (separate prescribable drug and metabolite
of medzazepam) -Nordiazepam (metabolite of clorazepate, halazepam, prazepam, diazepam and
medazepam) -Midazolam -Alpha-hydroxy midazolam (metabolite of midazolam) -Oxazepam (separate
prescribable drug and metabolite of clorazepate, halazepam, prazepam, medazepam, temazepam, and
diazepam) -Temazepam (separate prescribable drug and metabolite of medazepam and diazepam)
-Clobazam -N-Desmethylclobazam (metabolite of clobazam) -Flunitrazepam -7-Aminoflunitrazepam
(metabolite of flunitrazepam) -Flurazepam -2-Hydroxy ethyl flurazepam (metabolite of flurazepam)
-Lorazepam -Prazepam -Triazolam -Alpha-hydroxy triazolam (metabolite of triazolam) -Zolpidem
-Zolpidem phenyl-4-carboxylic acid (metabolite of zolpidem) The clearance half-life of long-acting
benzodiazepines is more than 24 hours. It takes 5 to 7 half-lives to clear 98% of a drug dose. Therefore,
the presence of a long-acting benzodiazepine greater than the limit of quantification indicates exposure
within a 5 to 20-day interval preceding specimen collection. Following a dose of diazepam, the drug and
its metabolites appear in the urine within 30 minutes. Peak urine output is reached between 1 and 8 hours.
See Mayo Clinic Laboratories Drugs of Abuse Testing Guide for additional information including
metabolism, clearance (half-life), and approximate detection times.
Reference Values:
Negative
Cutoff concentrations by liquid chromatography- tandem mass spectroscopy:

Alpha-hydroxyalprazolam: 10 ng/mL
7-Aminoclonazepam: 10 ng/mL
Diazepam: 10 ng/mL
Midazolam: 10 ng/mL
Alpha-hydroxy midazolam: 10 ng/mL
Oxazepam: 10 ng/mL
Temazepam: 10 ng/mL
Clobazam: 10 ng/mL
N-Desmethylclobazam by LC-MS/MS: 10 ng/mL
7-Aminoflunitrazepam: 10 ng/mL
2-Hydroxy ethyl flurazepam: 10 ng/mL
Lorazepam: 10 ng/mL
Prazepam: 10 ng/mL
Triazolam: 10 ng/mL
Alpha-hydroxy triazolam: 10 ng/mL
Zolpidem: 10 ng/mL
Zolpidem phenyl-4-carboxylic acid: 10 ng/mL
Clinical References: 1. Gudin JA, Mogali S, Jones JD, Comer SD: Risks, management, and
monitoring of combination of opioid, benzodiazepines, and/or alcohol use. Postgrad Med. 2013
Jul;125(4):115-130. doi: 10.3810/pgm.2013.07.2684 2. Manchikanti L, Abdi S, Atluri S, et al:
American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid
prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician. 2012 Jul;15(3 Supp):S67-116
3. Barkin RL: In: Baselt RC, ed. Disposition of Toxic Drugs and Chemicals in Man. 8th ed. Biomedical
Publications; 2008 4. Langman LJ, Bechtel LK, Meier BM, Holstege C: Clinical toxicology. In: Rifai
N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th
ed. Elsevier; 2018:1328-1333
BNZU Benzodiazepines Confirmation, Random, Urine

608255 Clinical Information: Benzodiazepines are any of a group of compounds having a common
molecular structure and acting similarly as depressants of the central nervous system. As a class of
drugs, benzodiazepines are among the drugs most commonly prescribed in the western hemisphere
because of their efficacy, safety, low addiction potential, minimal side effects, and high public demand
for sedative and anxiolytic agents.
Useful For: Detecting drug use involving benzodiazepines such as alprazolam, chlordiazepoxide,
clonazepam, diazepam, midazolam, oxazepam, temazepam, clobazam, flunitrazepam, flurazepam,
lorazepam, prazepam, triazolam, and zolpidem
Interpretation: Benzodiazepines are extensively metabolized, and the parent compounds are not
detected in urine. This test screens for (and confirms) the presence of: -Alprazolam
-Alpha-hydroxyalprazolam (metabolite of alprazolam) -Chlordiazepoxide -Clonazepam
-7-Aminoclonazepam (metabolite of clonazepam) -Diazepam (separate prescribable drug and
metabolite of medzazepam) -Nordiazepam (metabolite of clorazepate, halazepam, prazepam, diazepam
and medazepam) -Midazolam -Alpha-hydroxy midazolam (metabolite of midazolam) -Oxazepam
(separate prescribable drug and metabolite of clorazepate, halazepam, prazepam, medazepam,
temazepam, and diazepam) -Temazepam (separate prescribable drug and metabolite of medazepam and
diazepam) -Clobazam -N-Desmethylclobazam (metabolite of clobazam) -Flunitrazepam
-7-Aminoflunitrazepam (metabolite of flunitrazepam) -Flurazepam -2-Hydroxy ethyl flurazepam
(metabolite of flurazepam) -Lorazepam -Prazepam -Triazolam -Alpha-hydroxy triazolam (metabolite of
triazolam) -Zolpidem -Zolpidem phenyl-4-carboxylic acid (metabolite of zolpidem) The clearance
half-life of long-acting benzodiazepines is more than 24 hours. It takes 5 to 7 half-lives to clear 98% of
a drug dose. Therefore, the presence of a long-acting benzodiazepine greater than the limit of
quantification indicates exposure within a 5 to 20-day interval preceding specimen collection.
Following a dose of diazepam, the drug and its metabolites appear in the urine within 30 minutes. Peak
urine output is reached between 1 and 8 hours. See Mayo Clinic Laboratories Drugs of Abuse Testing
Guide for additional information including metabolism, clearance (half-life), and approximate detection
times.
Reference Values:
Negative
Cutoff concentrations by liquid chromatography- tandem mass spectroscopy:

Diazepam: 10 ng/mL
Midazolam: 10 ng/mL
Oxazepam: 10 ng/mL
Temazepam: 10 ng/mL
Clobazam: 10 ng/mL
N-Desmethylclobazam by LC-MS/MS: 10 ng/mL
Lorazepam: 10 ng/mL
Prazepam: 10 ng/mL
Triazolam: 10 ng/mL
Zolpidem: 10 ng/mL
Clinical References: 1. Gudin JA, Mogali S, Jones JD, Comer SD: Risks, management, and
monitoring of combination of opioid, benzodiazepines, and/or alcohol use. Postgrad Med. 2013
Jul;125(4):115-130. doi: 10.3810/pgm.2013.07.2684 2. Manchikanti L, Abdi S, Atluri S, et al: American
Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic
non-cancer pain: Part 2--guidance. Pain Physician. 2012 Jul;15(3 Supp):S67-116 3. Barkin RL: In: Baselt
RC, ed. Disposition of Toxic Drugs and Chemicals in Man. 8th ed. Biomedical Publications; 2008 4.
Langman LJ, Bechtel LK, Meier BM, Holstege C: Clinical toxicology. In: Rifai N, Horvath AR, Wittwer
CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier;
2018:1328-1333
FCDU2 Benzodiazepines, Umbilical Cord Tissue

Units: ng/g
FBENZ Benztropine (Cogentin), Serum

Reference Range: 5.0 - 25.0 ng/mL
BEREP Ber-EP4 (Epithelial Cell Adhesion Molecule/EPCAM)

70364 Immunostain, Technical Component Only
Clinical Information: Epithelial cell adhesion molecule/EPCAM (Ber-EP4) is expressed on most
epithelial cells of the body, with the exception of squamous epithelium and mesothelium. It has been
used to distinguish basal cell carcinoma from squamous cell carcinoma of the skin, and to distinguish
pulmonary adenocarcinoma from mesothelioma.
Useful For: Aids in distinguishing basal cell carcinoma from squamous cell carcinoma of the skin
Aids in distinguishing pulmonary adenocarcinoma from mesothelioma
Clinical References: 1. Beer TW, Shepherd P, Theaker JM: Ber EP4 and Epithelial Membrane
Antigen Aid Distinction of Basal Cell, Squamous Cell and Basosquamous Carcinomas of the Skin.
Histopathology 2000;37:218-223 2. Ordonez NG: The Diagnostic Utility of Immunohistochemistry in
Distinguishing Between Epithelioid Mesotheliomas and Squamous Carcinomas of the Lung: A
Comparative Study. Modern Pathology 2006;19(3):417-428 3. Sheibani K, Shin SS, Kezirian J, et al:
Ber-EP4 Antibody as a Discriminant in the Differential Diagnosis of Malignant Mesothelioma Versus
Adenocarcinoma. American Journal of Surgical Pathology 1991;15(8):779-784
BBEET Berlin Beetle, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Berlin beetle Defining the allergen responsible
anaphylactic episode -To confirm sensitization prior to beginning immunotherapy

Reference Values:
0 Negative

apply to all ages.
BERG Bermuda Grass, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Bermuda grass Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
FBERY Beryllium, Blood

Reference Range: <1.0 ng/mL
BETV2 BET v2 (Profilin), IgE, Serum

609436 Clinical Information: Immunoglobulin E antibodies to the Bet v 2a profilin protein have been
reported in 10% to 38% of birch pollen-allergic patients. Birch pollen is highly allergenic and is a
significant cause of immediate hypersensitivity, affecting as much as 5% to 50% of the population of
Western Europe. The presence of antibodies to Bet v 2, may also indicate sensitivity to other profilin
containing pollens including ragweed pollen, mugwort pollen, and timothy grass pollen. The profilin
Bet v2 is related to, and cross-reactive with, antibodies to the potential peanut allergen profilin Ara h5.
As profilin proteins are present in many other foods, sensitivity to profilin Bet v2 may be associated in
broad allergen cross-reactivity among foods, including mango, peach, apple, hazelnut, celery, carrot,
paprika, anise, fennel, coriander, cumin, tomato, and potato. The most common manifestation of allergy
to food in profilin related allergic individuals is oral allergy syndrome. Profilins are generally not
resistant to heat and digestion. Individuals with birch pollen allergy and oral allergy syndrome are more
frequently allergic to apples and peaches than to other foods. In cases of allergic reaction associated
with oral allergy syndrome, rhinitis, itching, tingling, and other mild reactions on the oropharyngeal
mucosa were reported to be the most common complaints.
Useful For: Evaluation of patients suspected birch pollen allergy Evaluation of patients with
suspected peanut allergy Evaluation of patients with oral allergy syndrome to other pollens or
plant-based foods
Interpretation: Profilins are potentially cross-reactive allergenic proteins found in many plant
pollens and tissues. IgE antibodies to the profilin Bet v2, while associated with birch pollen sensitivity,
also represent a minor peanut allergen marker as it is cross-reactive with the peanut profilin Ara h5. The
presence of antibodies to profilin Bet v2 is typically associated with milder allergic reactions and oral
allergy syndrome.
Reference Values:
0 Negative
0/1 0.10-0.34 Borderline/Equivocal
6 > or =100 Strongly positive Concentrations > or =0.70 kU/L (Class 2 and above) will flag as
abnormally high.
Clinical References: 1. Anhoej C, Backer V, Nolte H: Diagnostic evaluation of grass- and

birch-allergic patients with oral allergy syndrome. Allergy. 2001 Jun;56(6):548-552. doi:
10.1034/j.1398-9995.2001.056006548.x 2. Sekerkova A, Polackova M: Detection of Bet v1, Bet v2 and
Bet v4 specific IgE antibodies in the sera of children and adult patients allergic to birch pollen:
evaluation of different IgE reactivity profiles depending on age and local sensitization. Int Arch Allergy
Immunol. 2011;154(4):278-85. doi: 10.1159/000321819 3. D'Amato G, Cecchi L, Bonini S, et al:
Allergenic pollen and pollen allergy in Europe. Allergy. 2007 Sep;62(9):976-990. doi:
10.1111/j.1398-9995.2007.01393.x 4. Cabanos C, Tandang-Silvas MR, Odijk V, et al: Expression,
purification, cross-reactivity and homology modeling of peanut profilin. Protein Expr Purif. 2010
Sep;73(1):36-45. doi: 10.1016/j.pep.2010.03.005 5. Bublin M, Breiteneder H: Cross-reactivity of peanut
allergens. Curr Allergy Asthma Rep. 2014 Apr;14(4):426. doi: 10.1007/s11882-014-0426-8 6. Chan ES,
Greenhawt MJ, Fleischer DM, Caubet JC: Managing cross-reactivity in those with peanut allergy. J
Allergy Clin Immunol Pract. 2019 Feb;7(2):381-386. doi: 10.1016/j.jaip.2018.11.012 7. Simberloff T,
Parambi R, Bartnikas LM, et al: Implementation of a standardized clinical assessment and management
plan (SCAMP) for food challenges. J Allergy Clin Immunol Pract. 2017 Mar-Apr;5(2):335-344.e3.
doi:10.1016/j.jaip.2016.05.021
WBSEQ Beta Globin Gene Sequencing, Varies

62128 Clinical Information: Beta-globin gene sequencing is useful in the evaluation of beta-globin chain
variants and beta thalassemia. It detects almost all beta-globin variants and the most common beta
thalassemia sequence variants, although prevalence is ethnicity dependent. Because these conditions are
often complex, this test should always be interpreted in the context of protein studies, such as hemoglobin
electrophoresis and red blood cell indices. The majority of beta-globin chain variants are clinically and
hematologically benign; however, some have important clinical consequences, such as erythrocytosis,
cyanosis/hypoxia, chronic hemolysis, or unexplained microcytosis. Most of the common clinically
significant hemoglobin (Hb) variants (ie, HbS, HbC, HbE, and others) are easily distinguished by
hemoglobin electrophoresis and do not require molecular analysis. In addition, they are frequently found
in complex hemoglobin disorders due to multiple genetic variants, and accurate classification requires
sequencing data within the context of protein data. In some instances, beta-globin sequencing is necessary
to identify or confirm the identity of rare variants, especially those associated with erythrocytosis and
chronic hemolytic anemia. Rare hyper-unstable variants (also termed dominant beta thalassemia
mutations) result in hemolytic anemia and do not create protein stable enough to be detectable by protein
methods, including stability studies. They are not always associated with elevated HbA2 or microcytosis
and, therefore, can be electrophoretically silent. These require a high degree of clinical suspicion as all
electrophoretic testing as well as stability studies cannot exclude this condition. Beta thalassemia is an
autosomal recessive condition characterized by decreased or absent synthesis of beta-globin chains due to
sequence variants in the beta-globin gene (HBB). No abnormal protein is present and diagnosis by
electrophoresis relies on hemoglobin fraction percentage alterations (ie, HbA2 or HbF elevations). Beta
thalassemia can be split into 3 broad classes (categorized by clinical features): 1. Beta thalassemia trait
(also called beta thalassemia minor and beta thalassemia carrier) (B[A]B[+] or B[A]B[0]) 2. Beta
thalassemia intermedia (B[+]B[+] or B[+]B[0]) 3. Beta thalassemia major (B[+]B[0] or B[0]B[0]) Beta
thalassemia trait is typically a harmless condition with varying degrees of microcytosis and hypochromia
and sometimes mild anemia. Transfusions are not required. Beta thalassemia intermedia is a clinical
distinction and is characterized by a more severe degree of anemia than beta thalassemia trait with few or
intermittent transfusions required. Later in life, these individuals are at risk for iron overload even in the
absence of chronic transfusion due to increased intestinal absorption of iron. Beta thalassemia major
typically comes to medical attention early in life due to severe anemia, hepatosplenomegaly, and failure to
thrive. Skeletal changes are also common due to expansion of the bone marrow. Without appropriate
treatment these patients have a shortened lifespan. The majority of beta thalassemia variations (>90%) are
point alterations, small deletions, or insertions, which are detected by beta-globin gene sequencing. The
remaining beta thalassemia sequence variants are either due to large genomic deletions of HBB or, very
rarely, trans-acting beta thalassemia variations located outside of the beta-globin gene cluster. Some rare
beta-chain variants can be clinically or electrophoretically indistinguishable from beta thalassemia and
cannot be confirmed without molecular analysis.
Useful For: Diagnosis of beta thalassemia intermedia or major Identification of a specific beta
thalassemia sequence variant (ie, unusually severe beta thalassemia trait) Evaluation of an abnormal
hemoglobin electrophoresis identifying a rare beta-globin variant Evaluation of chronic hemolytic anemia
of unknown etiology Evaluation of hereditary erythrocytosis with left-shifted p50 oxygen dissociation
results Preconception screening when there is a concern for a beta-hemoglobin disorder based on family
history
Interpretation: The alteration will be provided with the classification, if known. Further
interpretation requires correlation with protein studies and red blood cell indices.
Reference Values:
Clinical References: 1. Hoyer JD, Hoffman DR: The thalassemia and hemoglobinopathy
syndromes. In: McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Lippincott Williams and
Wilkins; 2002:866-895 2. Thein SL: The molecular basis of beta-thalassemia. Cold Spring Harb
Perspect Med. 2013 May 1;3(5):a011700 3. Hoyer JD, Kroft, SH: Color Atlas of Hemoglobin
Disorders: A Compendium Based on Proficiency Testing. CAP; 2003 4. Merchant S, Oliveira JL, Hoyer
JD, Viswanatha DS: Molecular diagnosis in hematopathology. In: Hsi E, Volume ed. Goldblum J, ed.
Hematopathology: A Volume in Foundations in Diagnostic Pathology Series. 2nd ed. Churchill
Livingstone; 2012
FBLGG Beta Lactoglobulin IgG

Reference Values:
AB2GP Beta-2 Glycoprotein 1 Antibodies, IgA, Serum

86180 Clinical Information: Beta-2 glycoprotein 1 (beta-2 GP1, also called apolipoprotein H) is a
326-amino acid polypeptide synthesized by hepatocytes, endothelial cells and trophoblast cells. It
contains 5 homologous domains of approximately 60 amino acids each.(1,2) Domain 5, located at the C
terminus, contains a hydrophobic core surrounded by 14 positively charged amino acid residues that
promote electrostatic interactions with plasma membranes via interactions with negatively charged
phospholipids. Complexes of beta-2 GP1 and phospholipid in vivo reveal epitopes that react with
natural autoantibodies.(3) Plasma from normal individuals contains low concentrations of IgG
autoantibodies to beta-2 GP1 antibodies that are of moderate affinity and react with an epitope on the
first domain near the N terminus. Pathologic levels of beta-2 GP1 antibodies occur in patients with
antiphospholipid syndrome (APS). APS is associated with a variety of clinical symptoms notably
thrombosis, pregnancy complications, unexplained cutaneous circulatory disturbances (livido reticularis
or pyoderma gangrenosum), thrombocytopenia or hemolytic anemia, and nonbacterial thrombotic
endocarditis. Beta-2 GP1 antibodies are found with increased frequency in patients with systemic
rheumatic diseases, especially systemic lupus erythematosus. Autoantibodies to beta-2 GP1 antibodies
are detected in the clinical laboratory by different types of assays including immunoassays and
functional coagulation assays. Immunoassays for beta-2 GP1 antibodies can be performed using either a
composite substrate comprised of beta-2 GP1 plus anionic phospholipid (eg, cardiolipin or
phosphatidylserine), or beta-2 GP1 alone. Antibodies detected by immunoassays that utilize composite
substrates are commonly referred to as phospholipid or cardiolipin antibodies. Antibodies detected
using beta-2 GP1 substrate without phospholipid (so called direct assays) are referred to simply as
"beta-2 GP1 antibodies." Some beta-2 GP1 antibodies are capable of inhibiting clot formation in
functional coagulation assays that contain low concentrations of phospholipid cofactors. Antibodies
detected by functional coagulation assays are commonly referred to as lupus anticoagulants. The
diagnosis of APS requires at least 1 clinical criteria and 1 laboratory criteria be met.(4) The clinical
criteria include vascular thrombosis (arterial or venous in any organ or tissue) and pregnancy morbidity
(unexplained fetal death, premature birth, severe preeclampsia, or placental insufficiency). Other
clinical manifestations, including heart valve disease, livedo reticularis, thrombocytopenia,
nephropathy, neurological symptoms, are often associated with APS, but are not included in the
diagnostic criteria. The laboratory criteria for diagnosis of APS are the presence of lupus anticoagulant,
the presence of IgG and/or IgM anticardiolipin antibody (>40 GPL, >40 MPL, or >99th percentile),
and/or the presence of IgG and/or IgM beta-2 GP1 antibody (>99th percentile). All antibodies must be
demonstrated on 2 or more occasions separated by at least 12 weeks. Direct assays for beta-2GP 1
antibodies have been reported to be somewhat more specific (but less sensitive) for disease diagnosis in
patients with APS.(5) Anticardiolipin and beta-2 GP1 antibodies of the IgA isotype are not part of the
laboratory criteria for APS due to lack of specificity.
Useful For: Evaluation of patients with suspected antiphospholipid syndrome by identification of

beta-2 GP1 IgA antibodies
Interpretation: Strongly positive results for IgG and IgM beta-2 glycoprotein 1 (beta-2 GP1)
antibodies (>40 U/mL for IgG and/or IgM) are diagnostic criterion for antiphospholipid syndrome (APS).
Lesser levels of beta-2 GP1 antibodies and antibodies of the IgA isotype may occur in patients with
clinical signs of APS, but the results are not considered diagnostic. Beta-2 GP1 antibodies must be
detected on 2 or more occasions at least 12 weeks apart to fulfill the laboratory diagnostic criteria for
APS. IgA beta-2 GP1 antibody result >15 U/mL with negative IgG and IgM beta-2 GP1 antibody results
are not diagnostic for APS. Detection of beta-2 GP1 antibodies is not affected by anticoagulant treatment.
Reference Values:
<15.0 U/mL (negative)
15.0-39.9 U/mL (weakly positive)
40.0-79.9 U/mL (positive)
> or =80.0 U/mL (strongly positive)
Results are expressed in arbitrary units.
Clinical References: 1. Caronti B, Calderaro C, Alessandri C, et al: Beta2-glycoprotein 1

(beta2-GP1) mRNA is expressed by several cell types involved in anti-phospholipid syndrome-related
tissue damage. Clin Exp Immunol 1999;115:214-219 2. Lozier J, Takahashi N, Putnam F: Complete
amino acid sequence of human plasma beta 2-glycoprotein 1. Proc Natl Acad Sci USA
1984;81:3640-3644 3. Kra-Oz Z, Lorber M, Shoenfeld Y, Scharff Y: Inhibitor(s) of natural
anti-cardiolipin autoantibodies. Clin Exp Immunol 1993;93:265-268 4. Wong RCW, Flavaloro EJ,
Adelstein S, et al: Consensus guidelines on anti-beta 2 glycoprotein I testing and reporting. Pathology
2008 Jan;40(1):58-63 5. Audrain MA, El-Kouri D, Hamidou MA, et al: Value of autoantibodies to
beta(2)-glycoprotein 1 in the diagnosis of antiphospholipid syndrome. Rheumatology (Oxford)
2002;41:550-553
B2GMG Beta-2 Glycoprotein 1 Antibodies, IgG and IgM, Serum

326-amino acid polypeptide synthesized by hepatocytes, endothelial cells, and trophoblast cells. It
phospholipids. Complexes of beta-2 GP1 and phospholipids in vivo reveal epitopes that react with natural
autoantibodies.(3) Plasma from normal individuals contains low concentrations of IgG autoantibodies to
beta-2 GP1 (beta-2 GP1 antibodies) that are of moderate affinity and react with an epitope on the first
domain near the N terminus. Pathologic levels of beta-2 GP1 antibodies occur in patients with
antiphospholipid syndrome (APS). APS is associated with a variety of clinical symptoms, notably,
thrombosis, pregnancy complications, unexplained cutaneous circulatory disturbances (livido reticularis
or pyoderma gangrenosum), thrombocytopenia or hemolytic anemia, and nonbacterial thrombotic
endocarditis. Beta-2 GP1 antibodies are found with increased frequency in patients with systemic
rheumatic diseases, especially systemic lupus erythematosus. Beta-2 GP1 antibodies are detected in the
clinical laboratory by different types of assays including immunoassays and functional coagulation assays.
Immunoassays for beta-2 GP1 antibodies can be performed using either a composite substrate comprised
of beta-2 GP1 plus anionic phospholipid (eg, cardiolipin or phosphatidylserine), or beta-2 GP1 alone.
Antibodies detected by immunoassays that utilize composite substrates are commonly referred to as
phospholipid or cardiolipin antibodies. Antibodies detected using beta-2 GP1 substrate without
phospholipid (so called direct assays) are referred to simply as beta-2 GP1 antibodies. Some beta-2 GP1
antibodies are capable of inhibiting clot formation in functional coagulation assays that contain low
concentrations of phospholipid cofactors. Antibodies detected by functional coagulation assays are
commonly referred to as lupus anticoagulants. The diagnosis of APS requires at least 1 clinical criteria
and 1 laboratory criteria be met.(4) The clinical criteria include vascular thrombosis (arterial or venous in
any organ or tissue) and pregnancy morbidity (unexplained fetal death, premature birth, severe
preeclampsia, or placental insufficiency). Other clinical manifestations, including heart valve disease,
livedo reticularis, thrombocytopenia, nephropathy, neurological symptoms, are often associated with APS
but are not included in the diagnostic criteria. The laboratory criteria for diagnosis of APS are the
presence of lupus anticoagulant, the presence of IgG and/or IgM anticardiolipin antibody (>40 GPL, >40
MPL, or >99th percentile), and/or the presence of IgG and/or IgM beta-2 GP1 antibody (>99th
percentile). All antibodies must be demonstrated on 2 or more occasions separated by at least 12 weeks.
Direct assays for beta-2 GP1 antibodies have been reported to be somewhat more specific (but less
sensitive) for disease diagnosis in patients with APS.(5) Anticardiolipin and beta-2 GP1 antibodies of the
IgA isotype are not part of the laboratory criteria for APS due to lack of specificity.

beta-2 glycoprotein 1 (beta-2 GP1) IgG and IgM antibodies
Interpretation: Strongly positive results for beta-2 glycoprotein 1 (beta-2 GP1) antibodies (>40
U/mL for IgG and/or IgM) are diagnostic criterion for antiphospholipid syndrome (APS). Lesser levels
of beta-2 GP1 antibodies and antibodies of the IgA isotype may occur in patients with clinical signs of
APS, but the results are not considered diagnostic. Beta-2 GP1 antibodies must be detected on 2 or more
occasions at least 12 weeks apart to fulfill the laboratory diagnostic criteria for APS. Detection of beta-2
GP1 antibodies is not affected by anticoagulant treatment.
Reference Values:
Results are expressed in arbitrary units and apply to IgG and IgM values.
Clinical References: 1. Caronti B, Calderaro C, Alessandri C, et al: Beta2-glycoprotein 1

(beta2-GP1) mRNA is expressed by several cell types involved in anti-phospholipid syndrome-related
tissue damage. Clin Exp Immunol 1999;115:214-219 2. Lozier J, Takahashi N, Putnam F: Complete
amino acid sequence of human plasma beta-2-glycoprotein 1. Proc Natl Acad Sci USA
1984;81:3640-3644 3. Kra-Oz Z, Lorber M, Shoenfeld Y, Scharff Y: Inhibitor(s) of natural
anti-cardiolipin autoantibodies. Clin Exp Immunol 1993;93:265-268 4. Wilson WW, Gharavi AE,
Koike T, et al: International consensus statement on preliminary classification criteria for definite
antiphospholipid syndrome. Arthritis Rheum 1999;42(7):1309-1311 5. Audrain MA, El-Kouri D,
Hamidou MA, et al: Value of autoantibodies to beta(2)-glycoprotein 1 in the diagnosis of
antiphospholipid syndrome. Rheumatology (Oxford) 2002;41:550-553
GB2GP Beta-2 Glycoprotein 1 Antibodies, IgG, Serum

phospholipids. Complexes of beta 2 GP1 and phospholipid in vivo reveal epitopes that react with
autoantibodies to beta-2 GP1 (beta-2 GP1 antibodies) that are of moderate affinity and react with an
epitope on the first domain near the N terminus. Pathologic levels of beta 2 GP1 antibodies occur in
patients with antiphospholipid syndrome (APS). APS is associated with a variety of clinical symptoms
notably thrombosis, pregnancy complications, unexplained cutaneous circulatory disturbances (livido
reticularis or pyoderma gangrenosum), thrombocytopenia or hemolytic anemia, and nonbacterial
thrombotic endocarditis. Beta 2 GP1 antibodies are found with increased frequency in patients with
systemic rheumatic diseases, especially systemic lupus erythematosus. Autoantibodies to beta-2 GP1
are detected in the clinical laboratory by different types of assays including immunoassays and
functional coagulation assays. Immunoassays for beta-2 GP1 antibodies can be performed using either a
composite substrate comprised of beta-2 GP1 plus anionic phospholipid (eg, cardiolipin or
using beta-2 GP1 substrate without phospholipid (so-called direct assays) are referred to simply as
nephropathy, neurological symptoms, are often associated with APS but are not included in the
the presence of IgG and/or IgM anticardiolipin antibody (>40 GPL, >MPL, or >99th percentile), and/or
the presence of IgG and/or IgM beta GP1 antibody (>99th percentile). All antibodies must be
demonstrated on 2 or more occasions separated by at least 12 weeks. Direct assays for beta-2 GP1
patients with APS.(5) Anticardiolipin and beta-2 GP1 antibodies of the IgA isotype are not part of the

beta-2 GP1 IgG antibodies
Interpretation: Strongly positive results for beta 2 glycoprotein 1 (beta 2 GP1) antibodies (>40 U/mL
for IgG and/or IgM) are diagnostic criterion for antiphospholipid syndrome (APS). Lesser levels of IgG
and IgM beta 2 GP1 antibodies and antibodies of the IgA isotype may occur in patients with clinical signs
of APS, but the results are not considered diagnostic. Beta 2 GP1 antibodies must be detected on 2 or
more occasions at least 12 weeks apart to fulfill the laboratory diagnostic criteria for APS. Detection of
beta 2 GP1 antibodies is not affected by anticoagulant treatment.
Reference Values:
Clinical References: 1. Caronti B, Calderaro C, Alessandri C, et al: Beta 2 glycoprotein 1 (beta 2

GP1) mRNA is expressed by several cell types involved in anti-phospholipid syndrome-related tissue
damage. Clin Exp Immunol 1999;115:214-219 2. Lozier J, Takahashi N, Putnam F: Complete amino acid
sequence of human plasma beta 2 glycoprotein 1. Proc Natl Acad Sci USA 1984;81:3640-3644 3. Kra-Oz
Z, Lorber M, Shoenfeld Y, Scharff Y: Inhibitor(s) of natural anti-cardiolipin autoantibodies. Clin Exp
Immunol 1993;93:265-268 4. Wong RCW, Flavaloro EJ, Adelstein S, et al: Consensus guidelines on
anti-beta 2 glycoprotein I testing and reporting. Pathology 2008 Jan;40(1):58-63 5. Audrain Ma, El-Kouri
D, Hamidou MA, et al: Value of autoantibodies to beta(2)-glycoprotein 1 in the diagnosis of
MB2GP Beta-2 Glycoprotein 1 Antibodies, IgM, Serum
phospholipids. Complexes of beta 2 GP1 and phospholipid in vivo reveal epitopes that react with
autoantibodies to beta-2 GP1 (beta-2 GP1 antibodies) that are of moderate affinity and react with an
epitope on the first domain near the N terminus. Pathologic levels of beta 2 GP1 antibodies occur in
patients with antiphospholipid syndrome (APS). APS is associated with a variety of clinical symptoms,
notably, thrombosis, pregnancy complications, unexplained cutaneous circulatory disturbances (livido
reticularis or pyoderma gangrenosum), thrombocytopenia or hemolytic anemia, and nonbacterial
thrombotic endocarditis. Beta 2 GP1 antibodies are found with increased frequency in patients with
systemic rheumatic diseases, especially systemic lupus erythematosus. Autoantibodies to beta-2 GP1
antibodies are detected in the clinical laboratory by different types of assays including immunoassays
and functional coagulation assays. Immunoassays for beta-2 GP1 antibodies can be performed using
either a composite substrate comprised of beta-2 GP1 plus anionic phospholipid (eg, cardiolipin or
using beta-2 GP1 substrate without phospholipid (so called direct assays) are referred to simply as
nephropathy, neurological symptoms, are often associated with APS but are not included in the
the presence of IgG and/or IgM anticardiolipin antibody (>40 GPL, >40 MPL, or >99th percentile),
and/or the presence of IgG and/or IgM beta-2 GP1 antibody (>99th percentile). All antibodies must be
demonstrated on 2 or more occasions separated by at least 12 weeks. Direct assays for beta 2 GP1
patients with APS.(5) Anticardiolipin and beta 2 GP1 antibodies of the IgA isotype are not part of the

beta-2 GP1 IgM antibodies
Interpretation: Strongly positive results for beta-2 glycoprotein 1 (beta-2 GPI) antibodies (>40
U/mL for IgG and/or IgM) are diagnostic criterion for antiphospholipid syndrome (APS). Lesser levels
of beta-2 GP1 antibodies and antibodies of the IgA isotype may occur in patients with clinical signs of
APS, but the results are not considered diagnostic. Beta-2 GP1 antibodies must be detected on 2 or more
occasions at least 12 weeks apart to fulfill the laboratory diagnostic criteria for APS. Detection of beta-2
GP1 antibodies is not affected by anticoagulant treatment.
Reference Values:
Clinical References: 1. Caronti B, Calderaro C, Alessandri C, et al: Beta 2 glycoprotein 1 (beta 2

GP1) mRNA is expressed by several cell types involved in anti-phospholipid syndrome-related tissue
damage. Clin Exp Immunol 1999;115:214-219 2. Lozier J, Takahashi N, Putnam F: Complete amino
acid sequence of human plasma beta 2 glycoprotein 1. Proc Natl Acad Sci USA 1984;81:3640-3644 3.
Kra-Oz Z, Lorber M, Shoenfeld Y, et al: Inhibitor(s) of natural anti-cardiolipin autoantibodies. Clin Exp
Immunol 1993;93:265-268 4. Wong RCW, Flavaloro EJ, Adelstein S, et al: Consensus guidelines on
anti-beta 2 glycoprotein I testing and reporting. Pathology 2008 Jan;40(1):58-63 5. Audrain Ma,
El-Kouri D, Hamidou MA, et al: Value of autoantibodies to beta(2)-glycoprotein 1 in the diagnosis of
B2MU Beta-2 Microglobulin, Random, Urine

602026 Clinical Information: Beta-2 microglobulin is a low-molecular-weight protein that forms the light
chain component of class I histocompatibility (HLA: human leukocyte antigen) antigens. Increased urine
levels are seen in proximal tubular renal damage due to a variety of causes, including cadmium, mercury,
lithium, or aminoglycoside toxicity; pyelonephritis; and Balkan nephropathy, a chronic interstitial
nephritis of unknown etiology.
Useful For: Evaluation of renal tubular damage Monitoring exposure to cadmium and mercury
Interpretation: Increased excretion is consistent with renal tubular damage. Beta-2 microglobulin
excretion is increased 100 to 1000 times normal levels in cadmium-exposed workers.
Reference Values:
< or =300 mcg/L
Clinical References: 1. Ikeda M, Ezaki T, Tsukahara T, et al: Threshold levels of urinary cadmium
in relation to increases in urinary beta2-microglobulin among general Japanese populations. Toxicol Lett.
2003 Feb 3;137(3):135-141 2. Moriguchi J, Ezaki T, Tsukahara T, et al: Comparative evaluation of four
urinary tubular dysfunction markers, with special references to the effects of aging and correction for
creatinine concentration. Toxicol Lett. 2003 Aug 28;143(3):279-290 3. Stefanovic V, Cukuranovic R,
Mitic-Zlatkovic M, Hall PW: Increased urinary albumin excretion in children from families with Balkan
nephropathy. Pediatr Nephrol. 2002 Nov;17(11):913-916
BETA2 Beta-2 Transferrin: Detection of Spinal Fluid in Other Body

80351 Fluid
Clinical Information: The diagnosis of cerebrospinal fluid (CSF) rhinorrhea or otorrhea (leakage of
CSF into the nose or ear canal, usually as a result of head trauma, tumor, congenital malformation, or
surgery) is often difficult to confirm. Traditional chemical analyses (eg, glucose, protein, specific gravity)
are unreliable. Radiographic studies, especially those involving the injection of dyes or radiographic
compounds, are costly and may introduce additional risks to the patient. Transferrin that migrates in the
beta-1 electrophoretic fraction (beta-1 transferrin) is found in most body fluids. Beta-2 transferrin is a
CSF-specific variant of transferrin and is used as an endogenous marker of CSF leakage. Beta-2
transferrin is formed by loss of sialic acid due to the presence of neuraminidase in the central nervous
system. Beta-2 transferrin has also been called CSF-specific transferrin and tau protein. Prompt diagnosis
and localization facilitates appropriate decisions and decreases the risk of meningitis.
Useful For: Detection of spinal fluid in body fluids, such as ear or nasal fluid
Interpretation: The cerebrospinal fluid (CSF) variant of transferrin is identified by its unique
electrophoretic migration. If beta-1 and beta-2 transferrin are detected in drainage fluids, the specimen is
presumed to be contaminated with CSF. The presence of beta-2 transferrin band is detectable with as little
as 2.5% spinal fluid contamination of body fluid.
Reference Values:
Negative, no beta-2 transferrin (spinal fluid) detected
Clinical References: 1. Oberascher G: Cerebrospinal fluid otorrhea--new trends in diagnosis. Am J

Otol. 1988;9(2):102-108 2. Normansell DE, Stacy EK, Booker CF, et al: Detection of beta-2 transferrin in
otorrhea and rhinorrhea in a routine clinical laboratory setting. Clin Diag Lab Immunol. 1994
Jan;1(1):68-70. doi: 10.1128/cdli.1.1.68-70.1994 3. Sanders EL, Clark RJ, Katzmann JA: Cerebrospinal
fluid leakage: agarose gel electrophoresis detection of beta(2)-transferrin and nephelometric quantification
of beta-trace protein. Clin Chem. 2004 Dec;50(12):2401-2403. doi: 10.1373/clinchem.2004.040246 4.
McCudden CR, Senior BA, Hainsworth S, et al: Evaluation of high resolution gel beta (2)-transferrin for
detection of cerebrospinal fluid leak. Clin Chem Lab Med. 2013 Feb;51(2):311-315. doi:
10.1515/cclm-2012-0408 5. O'Cearbhaill RM, Kavanagh EC: Beta-2 Transferrin and IR. J Vasc Interv
Radiol. 2018 Mar;29(3):439. doi: 10.1016/j.jvir.2017.10.002 6. Zervos TM, Macki M, Cook B, Schultz
LR, Rock JP, Craig JR: Beta-2 transferrin is detectable for 14 days whether refrigerated or stored at room
temperature. Int Forum Allergy Rhinol. 2018 Sep;8(9):1052-1055. doi: 10.1002/alr.22136
B2MC Beta-2-Microglobulin (Beta-2-M), Spinal Fluid

60546 Clinical Information: Beta-2-microglobulin (beta-2-M) is a small membrane protein (11,800 Da)
associated with the heavy chains of class I major histocompatibility complex proteins and is, therefore,
on the surface of all nucleated cells. The small size allows beta-2-M to pass through the glomerular
membrane, but it is almost completely reabsorbed in the proximal tubules. Increased beta-2-M levels in
the cerebrospinal fluid (CSF) have been shown to be of diagnostic use in non-Hodgkin lymphoma with
central nervous system involvement. Elevated CSF:serum ratios seen in patients with aseptic
meningoencephalitis suggest the possibility of neurologic processes including those associated with
HIV infection and acute lymphoblastic leukemia. Beta-2-M measurement in multiple sclerosis seems to
be of indeterminate usefulness.
Useful For: Evaluation of central nervous system inflammation and B-cell proliferative diseases
Interpretation: Elevations of cerebrospinal fluid beta-2-microgobulin levels may be seen in a
number of diseases including malignancies, autoimmune disease, and neurological disorders.
Reference Values:
0.70-1.80 mcg/mL
Clinical References: 1. Koch TR, Lichtenfeld KM, Wiernik PH: Detection of central nervous
system metastasis with cerebrospinal fluid beta-2-microglobulin. Cancer. 1983 Jul;52(1):101-104 2.
Mavligit GM, Stuckey SE, Cabanillas FF, et al: Diagnosis of leukemia or lymphoma in the central
nervous system by beta-2-microglobulin determination. N Engl J Med. 1980 Sep 25;303(13):718-722 3.
Jeffery GM, Frampton CM, Legge HM, Hart DN: Cerebrospinal fluid beta 2-microglobulin levels in
meningeal involvement by malignancy. Pathology. 1990 Jan;22(1):20-23 4. Us O, Lolli F, Baig S, Link
H: Intrathecal synthesis of beta-2-microglobulin in multiple sclerosis and aseptic meningo-encephalitis.
Acta Neurol Scand. 1989 Dec;80(6):598-602 5. Elovaara I, Livanainen M, Poutianen E, et al: CSF and
serum beta-2-microglobulin in HIV infection related to neurological dysfunction. Acta Neurol Scand.
1989 Feb;79(2):81-87 6. Dolan MJ, Lucey DR, Hendrix CW, Melcher GP, Spencer GA, Boswell RN:
Early markers of HIV infection and subclinical disease progression. Vaccine. 1993;11(5):548-551 7.
Brew BJ, Bhalla RB, Fleisher M, et al: Cerebrospinal fluid beta 2 microglobulin in patients infected
with human immunodeficiency virus. Neurology. 1989 Jun;39(6):830-834 8. Musto P, Tomasi P,
Cascavilla N, et al: Significance and limits of cerebrospinal fluid beta-2-microglobulin measurement in
course of acute lymphoblastic leukemia. Am J Hematol. 1988 Aug;28(4):213-218 9. Lucey DR,
McGuire SA, Clerici M, et al: Comparison of spinal fluid beta 2-microglobulin levels with CD4+ T cell
count, in vitro T helper cell function, and spinal fluid IgG parameters in 163 neurologically normal
adults infected with the human immunodeficiency virus type l. J Infect Dis. 1991 May;163(5):971-975
10. Bjerrum OW, Bach FW, Zeeberg I: Increased level of cerebrospinal fluid beta 2-microglobulin is
related to neurologic impairment in multiple sclerosis. Acta Neurol Scand. 1988 Jul;78(1):72-75 11.
Dietzen DJ, Willrich MAV: Amino acids, peptides, and proteins. In: Rifai N, Chiu RWK, Young I,
Burnham CAD, eds. Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier; 2023:chap 31
B2M Beta-2-Microglobulin, Serum

9234 Clinical Information: Beta-2-microglobulin (beta-2-M) is a small membrane protein (11,800 Da)
associated with the heavy chains of class I major histocompatibility complex proteins and is, therefore,
on the surface of all nucleated cells. The small size allows beta-2-M to pass through the glomerular
membrane, but it is almost completely reabsorbed in the proximal tubules. Serum beta-2-M levels are
elevated in diseases associated with increased cell turnover. Levels are also elevated in several benign
conditions such as chronic inflammation, liver disease, kidney dysfunction, some acute viral infections,
and a number of malignancies, especially hematologic malignancies associated with the B-lymphocyte
lineage. In multiple myeloma, beta-2-M is a powerful prognostic factor, and values less than4 mcg/mL
are considered a good prognostic factor. In renal tubular disease, serum levels are low and urine levels
are high. Although urine beta-2-M has been used to assess tubular dysfunction, it is not stable in urine
below pH 5.5. See Multiple Myeloma: Laboratory Screening
Useful For: Prognosis assessment of multiple myeloma Evaluation of renal tubular disorders
Interpretation: A serum beta-2-microglobulin (beta-2-M) value of less than 4 mcg/mL is a good
prognostic factor in patients with multiple myeloma. In a study of pretreatment serum beta-2-M levels in
100 patients with myeloma, it was reported that the median survival of patients with values greater than 4
mcg/mL was 12 months, whereas median survival for patients with values less than 4 mcg/mL was 43
months.
Reference Values:
1.21-2.70 mcg/mL
Clinical References: 1. Bataille R, Magub M, Grenier J, Donnadio D, Sany J: Serum

beta-2-microglobulin in multiple myeloma: Relation to presenting features and clinical status. Eur J
Cancer Clin Oncol. 1982 Jan;18(1):59-66 2. Garewal H, Durie BG, Kyle RA, Finley P, Bower B,
Serokman R: Serum beta-2-microglobulin in the initial staging and subsequent monitoring of monoclonal
plasma cell disorders. J Clin Oncol. 1984 Jan;2(1):51-57 3. Norfolk D, Child JA, Cooper EH, Kerruish S,
Ward AM: Serum beta-2-microglobulin in myelomatosis: potential value in stratification and monitoring.
Br J Cancer. 1980 Oct;42(4):510-550 4. Dolan MJ, Lucey DR, Hendrix CW, Melcher GP, Spencer GA,
Boswell RN: Early markers of HIV infection and subclinical disease progression. Vaccine.
1993;11(5):548-551 5. Karlsson FA, Wibell L, Evrin PE: Beta-2-microglobulin in clinical medicine.
Scand J Clin Lab Invest. 1986;154:27-37 6. Greipp PR, Katzmann JA, O'Fallon WM, Kyle RA: Value of
beta-2-microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly
diagnosed myeloma. Blood. 1988 Jul;72(1):219-223 7. Dietzen DJ, Willrich MAV: Amino acids,
peptides, and proteins. In: Rifai N, Chiu RWK, Young I, Burnham CAD, eds. Tietz Textbook of
Laboratory Medicine. 7th ed. Elsevier; 2023:chap 31
BAMY Beta-Amyloid Immunostain, Technical Component Only

70634 Clinical Information: Beta amyloid is a component of senile and diffuse plaques and neurofibrillary
tangles, a characteristic of Alzheimer disease. Beta amyloid is also a component of vascular amyloid in
the brain of dementia patients.
Useful For: Identification of senile plaques in neurodegenerative disease

Interpretation: This test does not include pathologist interpretation; only technical performance of the
stain is performed. If an interpretation is required order PATHC / Pathology Consultation for a full
diagnostic evaluation or second opinion of the case. The positive and negative controls are verified as
showing appropriate immunoreactivity and documentation is retained at Mayo Clinic Rochester. If a
available upon request. Contact 855-516-8404. Interpretation of this test should be performed in the
Clinical References: 1. Hubin E, Van Nuland NA, Broersen K, Pauwels K: Transient dynamics of
Abeta contribute to toxicity in Alzheimer's disease. Cell Mol Life Sci 2014 Sep;71(18):3507-3521 2.
Bloom GS: Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA
Neurol 2014 Apr;71(4):505-508 3. Skaper SD: Alzheimer's disease and amyloid: culprit or coincidence?
Int Rev Neurobiol 2012;102:277-316
CTNNB Beta-Catenin (CTNNB1) Mutation Analysis, Tumor
92360 Clinical Information: Desmoid-type fibromatosis is a locally invasive soft tissue tumor. The
histological diagnosis of desmoid-type fibromatosis is challenging. Mutations in exon 3 of the
beta-catenin (BCAT also known as CTNNB1) gene have been identified in 50% to 87% of
desmoid-type fibromatosis, including T41A (121 A->G), S45P (133 T->C), and S45F (134 C->T), but
not in other soft tissue tumors. Patients harboring beta-catenin mutations may have a higher recurrence
rate compared to the patients with wild-type beta-catenin. Next-generation sequencing has recently
emerged as an accurate, cost-effective method to identify alterations across numerous genes. This test
uses formalin-fixed paraffin-embedded tissue or cytology slides to assess for common somatic
mutations in the beta-catenin gene known to be associated with desmoid-type fibromatosis. The results
of this test can be useful for supporting a diagnosis of desmoid-type fibromatosis and predicting
prognosis.
Useful For: Distinguishing desmoid-type fibromatosis from other soft tissue tumors by assessing
gene targets with in the BCAT (CTNNB1) gene This test is not useful for hematological malignancies.

Reference Values:
Clinical References: 1. Lazar AJ, Tuvin D, Hajibashi S, et al: Specific mutations in the
beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol
2008;173:1518-1527 2. Amary MF, Pauwels P, Meulemans E, et al: Detection of beta-catenin mutations
in paraffin-embedded sporadic desmoid-type fibromatosis by mutation-specific restriction enzyme
digestion (MSRED): an ancillary diagnostic tool. Am J Surg Pathol 2007;31:1299-1309 3. Domont J,
Salas S, Lacroix L, et al: High frequency of beta-catenin heterozygous mutations in extra-abdominal
fibromatosis: a potential molecular tool for disease management. Br J Cancer 2010;102:1032-1036
BCATN Beta-Catenin Immunostain, Technical Component Only

70361 Clinical Information: Beta-catenin is involved in cellular cohesion through binding to the
cytoplasmic tail of E-cadherin, and in intracellular signaling as a component of the Wnt pathway. In
normal cells, B-catenin levels are regulated by the adenomatous polyposis coli (APC) protein, which
promotes normal degradation of the protein. Alterations in either B-catenin or APC can result in
accumulation of the protein and abnormal localization in the nucleus. In the nucleus, B-catenin acts as a
cofactor in the upregulation of oncogenes including cyclin D1 and cmyc. In normal tissues, staining for
B-catenin is limited to the membrane. Aberrant nuclear staining can be used diagnostically in selected
tumors of the soft tissue (fibromatoses, endometrial stromal sarcoma), pancreas, liver and lung.
Useful For: Identification of aberrant nuclear staining pattern observed in some tumors
Clinical References: 1. Klymkowsky MW: Beta-catenin and its regulatory network. Hum Pathol.
2005 Mar;36(3):225-227 2. Bell DA: Origins and molecular pathology of ovarian cancer. Mod Pathol.
2005 Feb;18(Suppl 2):S19-32 3. Smith ME, Pignatelli M: The molecular histology of neoplasia: the role
of the cadherin/catenin complex. Histopathology. 1997 Aug;31(2):107-111
CTX Beta-CrossLaps, Serum
83175 Clinical Information: Human bone is continuously remodeled through a process of bone formation
and resorption. Approximately 90% of the organic matrix of bone is type I collagen, a helical protein that
is crosslinked at the N- and C-terminal ends of the molecule. During bone resorption, osteoclasts secrete a
mixture of acid and neutral proteases that degrade the collagen fibrils into molecular fragments including
C-terminal telopeptide (CTx). As bone ages, the alpha form of aspartic acid present in CTx converts to the
beta form. Beta-CTx is released into the bloodstream during bone resorption and serves as a specific
marker for the degradation of mature type I collagen. Elevated serum concentrations of beta-CTx have
been reported in patients with increased bone resorption. Bone turnover markers are physiologically
elevated during childhood, growth, and fracture healing. The elevations in bone resorption markers and
bone formation markers are typically balanced in these circumstances and are of no diagnostic value. By
contrast, bone turnover markers may be useful when the bone remodeling process is unbalanced.
Abnormalities in the process of bone remodeling can result in changes in skeletal mass and shape. Many
diseases, in particular hyperthyroidism, all forms of hyperparathyroidism, most forms of osteomalacia and
rickets (even if not associated with hyperparathyroidism), hypercalcemia of malignancy, Paget disease,
multiple myeloma, and bone metastases, as well as various congenital diseases of bone formation and
remodeling, can result in accelerated and unbalanced bone turnover. Unbalanced bone turnover is also
found in age-related and postmenopausal osteopenia and osteoporosis. Disease-associated bone turnover
abnormalities should normalize in response to effective therapeutic interventions, which can be monitored
by measurement of serum and urine bone resorption markers.
Useful For: Monitoring antiresorptive therapies (eg, bisphosphonates and hormone replacement
therapy) in postmenopausal women treated for osteoporosis and individuals diagnosed with osteopenia An
adjunct in the diagnosis of medical conditions associated with increased bone turnover
Interpretation: Elevated levels of beta-C-terminal telopeptide (CTx) indicate increased bone

resorption. Increased levels are associated with osteoporosis, osteopenia, Paget disease, hyperthyroidism,
and hyperparathyroidism. In patients taking antiresorptive agents (bisphosphonates or hormone
replacement therapy), a decrease of 25% or more from baseline beta-CTx levels (ie, prior to the start of
therapy) 3 to 6 months after initiation of therapy indicates an adequate therapeutic response.
Reference Values:
Males
<5 years: 242-1292 pg/mL
5-9 years: 351-1532 pg/mL
10-15 years: 447-2457 pg/mL
16-17 years: 478-1666 pg/mL
18-30 years: 120-946 pg/mL
31-50 years: 93-630 pg/mL
51-70 years: 35-836 pg/mL
>70 years: not established
Females
<5 years: 347-1508 pg/mL
5-9 years: 383-1556 pg/mL
10-15 years: 311-1776 pg/mL
16-17 years: 146-1266 pg/mL
Premenopausal: 25-573 pg/mL
Postmenopausal: 104-1008 pg/mL
Clinical References: 1. Christgau S, Bitsch-Jensen O, Hanover Bjarnason N, et al: Serum CrossLaps

for monitoring the response in individuals undergoing antiresorptive therapy. Bone. 2000
May;26(5):505-511 2. Garnero P, Borel O, Delmas PD: Evaluation of a fully automated serum assay for
C-terminal cross-linking telopeptide of type I collagen in osteoporosis. Clin Chem. 2001
Apr;47(4):694-702 3. Fraser W: Bone and Mineral Metabolism. In Rifai N, Horvath AR, Wittwer CT,
eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier;2018;1422-1491 4.
Delmas PD, Eastell R, Garnero P, et al: The use of biochemical markers of bone turnover in osteoporosis.
Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporo Int.
2000;11:S2-S17
BGAW Beta-Galactosidase, Blood

60987 Clinical Information: Beta-galactosidase is a lysosomal enzyme responsible for catalyzing the
breakdown of gangliosides. Isolated deficiency of this enzyme is expressed clinically as 2 different
autosomal recessive diseases, GM1 gangliosidosis and Morquio syndrome B (mucopolysaccharidosis
IVB [MPS IVB] or Morquio B). Galactosialidosis (GS) is associated with a combined deficiency of
beta-galactosidase and neuraminidase secondary to a defect in protective protein cathepsin A.
Enzymatic testing is not reliable for carrier detection of these conditions. In GM1 gangliosidosis,
reduced or absent beta-galactosidase activity leads to the accumulation of GM1 gangliosides,
oligosaccharides, and keratan sulfate. The disorder can be classified into 3 subtypes that vary with
respect to age of onset and clinical presentation. Type 1, or infantile onset, typically presents between
birth and 6 months of age with a very rapid progression of hypotonia, dysostosis multiplex,
hepatosplenomegaly, central nervous system degeneration, and death usually by 1 to 2 years of
age..Type 2 is generally classified as late infantile or juvenile with onset between 7 months and 3 years
of age presenting with developmental delays and a slower progression. Type 3 is an adult or chronic
variant with onset between 3 and 30 years of age and is typically characterized by slowly progressive
dementia with parkinsonian features and dystonia. The incidence has been estimated to be 1 in 100,000
to 200,000 live births. In Morquio B, reduced or absent beta-galactosidase activity leads to the
accumulation of glycosaminoglycans, particularly keratan sulfate, in lysosomes and interferes with
normal functioning of cells, tissues, and organs. Morquio B typically manifests as a systemic skeletal
disorder with variable severity ranging from early severe disease to a later onset attenuated form.
Virtually all patients have dysostosis multiplex and short stature along with other symptoms that may
include coarse facies, hepatosplenomegaly, hoarse voice, stiff joints, cardiac disease, but no
neurological involvement. Galactosialidosis is an autosomal recessive lysosomal storage disease caused
by variants in the cathepsin A gene, CTSA, resulting in a combined deficiency of the enzymes
beta-galactosidase and neuraminidase. The disorder can be classified into 3 subtypes that vary with
respect to age of onset and clinical presentation. Typical clinical presentation includes coarse facial
features, cherry-red spots, and skeletal dysplasia. The early infantile form is associated with fetal
hydrops, visceromegaly, skeletal dysplasia, and early death, while the late infantile form is
characterized by short stature, dysostosis multiplex, coarse facial features, corneal clouding,
hepatosplenomegaly, and/or heart valve problems. Individuals of Japanese ancestry make up the
majority of patients with the juvenile/adult form of GS and typically develop symptoms after 4 years of
age. These include neurologic degeneration, ataxia, and angiokeratomas. A diagnostic workup in an
individual with GM1 gangliosidosis, Morquio B, or GS typically demonstrates decreased
beta-galactosidase enzyme activity in leukocytes or fibroblasts; however, additional testing and
consideration of the patient's clinical findings are necessary to differentiate between these conditions.
Follow-up testing may include LSDS / Lysosomal Storage Disorders Screen, Random, Urine, which
analyzes urine mucopolysaccharides, oligosaccharides, ceramide trihexosides, and sulfatides. The LSDS
test can help differentiate between the 3 conditions to guide physicians in choosing the best
confirmatory molecular testing option. See Lysosomal Storage Disorders Diagnostic Algorithm, Part 1 .
Useful For: Diagnosis of GM1 gangliosidosis, Morquio syndrome B, and galactosialidosis using
whole blood specimens This test is not useful for carrier detection.
Interpretation: Results below 5.0 nmol/hour/mL in properly submitted specimens are consistent
with beta-galactosidase deficiency (GM1 gangliosidosis, Morquio syndrome B, or galactosialidosis).
Further differentiation between GM1, Morquio syndrome B, and galactosialidosis is dependent on the
patient's clinical findings and results of additional biochemical testing. Normal results (> or =5.0
nmol/h/mL) are not consistent with beta-galactosidase deficiency.
Reference Values:
> or =5.0 nmol/hour/mL
Clinical References: 1. Suzuki Y, Nanba E, Matsuda J, et al: Beta-galactosidase deficiency

(beta-galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Valle D, Antonarakis S, Ballabio
A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease.
McGraw-Hill; 2019. Accessed January 5, 2022. Available at
https://ommbid.mhmedical.com/content.aspx?sectionid=225547263 2. Regier DS, Tifft CJ:
GLB1-related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet].
University of Washington, Seattle; 2013. Updated August 29, 2019. Accessed January 5, 2022.
Available at www.ncbi.nlm.nih.gov/books/NBK164500 3. d'Azzo A, Andria G, Bonten E, Annunziata
I: Galactosialidosis. In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online
Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed January 5, 2022.
Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225547663 4. Arash-Kaps L,
Komlosi K, Seegraber M, et.at: The clinical and molecular spectrum of GM1 gangliosidosis. Pediatr.
2019 Dec;215:152-157.e3. doi: 10.1016/j.jpeds.2019.08.016
BGABS Beta-Galactosidase, Blood Spot

breakdown of gangliosides. The deficiency of this enzyme can be seen in the following conditions: GM1
gangliosidosis, Morquio syndrome B, and galactosialidosis. Enzymatic testing is not reliable for carrier
detection of these conditions. GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder
caused by reduced or absent beta-galactosidase activity. Absent or reduced activity leads to the
accumulation of GM1 gangliosides, oligosaccharides, and keratan sulfate. The disorder can be classified
into 3 subtypes that vary with respect to age of onset and clinical presentation. Type 1, or infantile onset,
typically presents between birth and 6 months of age with a very rapid progression of hypotonia,
dysostosis multiplex, hepatosplenomegaly, central nervous system degeneration, and death usually by 1 to
2 years of age. Type 2 is generally classified as late infantile or juvenile with onset between 7 months and
3 years of age, presenting with developmental delays, and a having a slower progression. Type 3 is an
adult or chronic variant with onset between 3 and 30 years of age and is typically characterized by slowly
progressive dementia with parkinsonian features and dystonia. The incidence has been estimated to be 1
in 100,000 to 200,000 live births. Mucopolysaccharidosis type IVB (MPS IVB or Morquio syndrome B)
is an autosomal recessive lysosomal storage disorder caused by reduced or absent beta-galactosidase
activity leading to the accumulation of glycosaminoglycans, particularly keratan sulfate, in lysosomes and
interferes with normal functioning of cells, tissues, and organs. MPS IVB typically manifests as a
systemic skeletal disorder with variable severity ranging from early severe disease to a later onset
attenuated form. Virtually all patients have dysostosis multiplex and short stature along with other
symptoms that may include coarse facies, hepatosplenomegaly, hoarse voice, stiff joints, cardiac disease,
but no neurological involvement. Galactosialidosis (GS) is an autosomal recessive lysosomal storage
disease associated with a combined deficiency of beta-galactosidase and neuraminidase secondary to a
defect in the cathepsin A protein. The disorder can be classified into 3 subtypes that vary with respect to
age of onset and clinical presentation. Typical clinical presentation is coarse facial features, cherry-red
spots, and skeletal dysplasia. The early infantile form is associated with fetal hydrops, skeletal dysplasia,
and early death, while the late infantile form is characterized by short stature, dysostosis multiplex, coarse
facial features, corneal clouding, hepatosplenomegaly, and heart valve problems. Individuals of Japanese
ancestry makeup the majority of patients with the juvenile/adult form of GS and typically develop
symptoms after 4 years of age. These include neurologic degeneration, ataxia, and angiokeratomas. A
diagnostic workup in an individual with GM1 gangliosidosis, Morquio B, or galactosialidosis typically
demonstrates decreased beta-galactosidase enzyme activity in leukocytes or fibroblasts; however,
additional testing and consideration of the patient's clinical findings are necessary to differentiate between
these conditions. Follow-up testing may include LSDS / Lysosomal Storage Disorders Screen, Random,
Urine, which analyzes urine mucopolysaccharides, oligosaccharides, ceramide trihexosides, and
sulfatides. The LSDS test can help differentiate between the 3 conditions to guide physicians in choosing
the best confirmatory molecular testing option. See Lysosomal Storage Disorders Diagnostic Algorithm,
Part 1
Useful For: Diagnosis of beta-galactosidase deficiency (GM1 gangliosidosis, Morquio syndrome B,

and galactosialidosis) using blood spot specimens This test is not useful for carrier detection.
Interpretation: Properly submitted specimens with results less than 5.0 nmol/h/mL are consistent with
beta-galactosidase deficiency (GM1 gangliosidosis, Morquio syndrome B, or galactosialidosis). Further
differentiation between GM1, Morquio syndrome B, and galactosialidosis is dependent on the patient's
clinical findings and results of additional biochemical testing. Normal results (> or =5.0 nmol/hour/mL)
are not consistent with beta-galactosidase deficiency.
Reference Values:
> or =5.0 nmol/hour/mL
Clinical References: 1. Suzuki Y, Nanba E, Matsuda J, et al: Beta-galactosidase deficiency

(beta-galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Valle D, Antonarakis S, Ballabio
A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease.
https://ommbid.mhmedical.com/content.aspx?sectionid=225547263 2. Regier DS, Tifft CJ:
GLB1-related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Updated 29
Aug 2019. Accessed January 5, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK164500/ 3.
d'Azzo A, Andria G, Bonten E, Annunziata I: Galactosialidosis. In: Valle D, Antonarakis S, Ballabio A,
Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease.
https://ommbid.mhmedical.com/content.aspx?sectionid=225547663 4. Arash-Kaps L, Komlosi K,
Seegraber M, et.at: The clinical and molecular spectrum of GM1 gangliosidosis. Pediatr. 2019
Dec;215:152-157.e3. doi: 10.1016/j.jpeds.2019.08.016
BGA Beta-Galactosidase, Leukocytes

hydrolysis of gangliosides. Isolated deficiency of this enzyme can be expressed clinically as 2 different
diseases, GM1 gangliosidosis (GM1) and Morquio syndrome B (MPS IVB: mucopolysaccharidosis
IVB), or in some patients as a disease that combines the skeletal features of MPS IVB and neurologic
features of GM1. Galactosialidosis is also associated with a deficiency of beta-galactosidase but in
conjunction with neuraminidase secondary to a defect in protective protein cathepsin A (CTSA).
Enzymatic testing is not reliable for carrier detection of these conditions. GM1 gangliosidosis is
autosomal recessive and absent or reduced beta-galactosidase enzyme activity leads to the accumulation
of GM1 gangliosides, oligosaccharides, and keratan sulfate. The disorder can be classified into 3
subtypes that vary with respect to age of onset and clinical presentation. Type 1, or infantile onset,
typically presents between birth and 6 months with a very rapid progression of hypotonia, dysostosis
multiplex, hepatosplenomegaly, central nervous system degeneration, and death usually by 1 to 2 years.
Type 2 is generally classified as late infantile or juvenile with onset between 7 months and 3 years,
presenting with developmental delays or regression and a slower clinical course. Type 3 is an adult or
chronic variant with onset between 3 and 30 years and is typically characterized by slowly progressive
dementia with parkinsonian features and dystonia. In MPS IVB, reduced or absent beta-galactosidase
activity leads to the accumulation of glycosaminoglycans (GAG), specifically keratan sulfate, in cells,
tissues, and organs interfering with their normal function. MPS IVB typically manifests as a systemic
skeletal disorder with variable severity ranging from early severe disease to a later onset attenuated
form. Virtually all patients have dysostosis multiplex and short stature along with other symptoms that
may include coarse facies, hepatosplenomegaly, hoarse voice, stiff joints, and cardiac disease but no
neurological involvement. Galactosialidosis (GS) is an autosomal recessive lysosomal storage disease
caused by variants in CTSA resulting in a combined deficiency of the enzymes beta-galactosidase and
neuraminidase. The disorder can be classified into 3 subtypes that vary with respect to age of onset and
clinical presentation. Typical clinical presentation includes coarse facial features, cherry-red spots, and
skeletal dysplasia. The early infantile form is associated with fetal hydrops, visceromegaly, skeletal
dysplasia, and early death. The late infantile form typically presents with short stature, dysostosis
multiplex, coarse facial features, hepatosplenomegaly, and/or heart valve problems. The majority of
individuals with the juvenile/adult form of GS are of Japanese ancestry and develop symptoms after 4
years of age, which include neurologic degeneration, ataxia, and angiokeratomas. Patients with
mucolipidosis II/III (I-cell disease) may also demonstrate deficiency of beta-galactosidase in leukocytes,
in addition to deficiency of other hydrolases. I-cell disease is an autosomal recessive lysosomal storage
disorder resulting in impaired transport and phosphorylation of newly synthesized lysosomal proteins to
the lysosome due to deficiency of N-acetylglucosamine 1-phosphotransferase (GlcNAc). Characteristic
clinical features include short stature, skeletal and cardiac abnormalities, and developmental delay.
Measurement of beta-galactosidase activity is not the preferred diagnostic test for I-cell disease but may
be included in the testing strategy. A diagnostic workup in an individual with GM1 gangliosidosis, MPS
IVB, or GS typically demonstrates decreased beta-galactosidase enzyme activity in leukocytes or
fibroblasts; however, additional testing and consideration of the patient's clinical findings are necessary
to differentiate between these conditions. Follow-up testing may include LSDS / Lysosomal Storage
Disorders Screen, Random, Urine, which analyzes mucopolysaccharides, oligosaccharides, ceramide
trihexosides, and sulfatides to help differentiate between the 3 conditions and guide physicians in
choosing the best confirmatory molecular testing option, which may include LSDGP / Lysosomal
Storage Disease Gene Panel, Varies.
Useful For: Aiding in the diagnosis of GM1 gangliosidosis, Morquio B disease, and galactosialidosis
This test is not suitable for carrier detection.
Interpretation: Very-low enzyme activity levels are consistent with GM1 gangliosidosis and Morquio
B disease. Clinical findings must be used to differentiate between those 2 diseases. The deficiency of
beta-galactosidase combined with neuraminidase deficiency is characteristic of galactosialidosis.
Reference Values:
> or =1.56 nmol/min/mg
Clinical References: 1. Suzuki Y, Nanba E, Matsuda J, Higaki K, Oshima A: Beta-galactosidase

deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Valle DL, Antonarakis
S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited
Disease. McGraw-Hill; 2019. Accessed March 01, 2022. Available at
https://ommbid.mhmedical.com/content.aspx?sectionid=225547263 2. d'Azzo A, Andria G, Bonten E,
Annunziata I: Galactosialidosis. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, et al,
eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed
March 01, 2022. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225547663 3.
Caciotti A, Garman SC, Rivera-Colon Y, et al: GM1 gangliosidosis and Morquio B disease: an update on
genetic alterations and clinical findings. Biochim Biophys Acta. 2011 Jul;1812(7):782-790. doi:
10.1016/j.bbadis.2011.03.018 4. Kingma SDK, Ceulemans B, Kenis S, Jonckheere AI: Are GMI
gangliosidosis and Morquio type B two different disorders or part of one phenotypic spectrum?. JIMD
Rep. 2021 Mar;59(1):90-103. doi: 10.1002/jmd2.12204
WBDDR Beta-Globin Cluster Locus Deletion/Duplication, Blood

48052 Clinical Information: Large deletions involving the beta-globin cluster locus on chromosome 11
manifest with widely variable clinical phenotypes. Up to 10% of beta thalassemia cases (dependent on
ethnicity) are caused by large deletions in the beta-globin cluster. Other thalassemias, including delta-beta
thalassemia, gamma-delta-beta thalassemia, and epsilon-gamma-delta-beta thalassemia, also result from
functional loss of genes or the locus control region (LCR) that controls globin gene expression. In
addition, hereditary persistence of fetal hemoglobin (HPFH) is caused by deletions of variable size along
the beta-globin cluster locus. Most, but not all, of the large deletion beta-globin cluster disorders are
associated with variably elevated hemoglobin (Hb) F percentages that persist after 2 years of age. In
addition, most manifest in microcytosis. A notable exception is HPFH, which can have normal to minimal
decreased mean corpuscular volume (MCV) values. The correct classification of these deletions is
important as they confer variable predicted phenotypes and some are more protective than others when
found in combination with a second beta-globin variant, such as HbS or beta thalassemia. In addition,
identification of these deletions can explain lifelong microcytosis in the setting of normal iron studies and
negative alpha thalassemia molecular results.
Useful For: Determining the etiology of hereditary persistence of fetal hemoglobin (HPFH) or
delta-beta thalassemia Diagnosing less common causes of beta-thalassemia; these large deletional beta
thalassemia alterations result in elevated hemoglobin (Hb) A2 and usually have slightly elevated HbF
levels Distinguishing homozygous HbS disease from a compound heterozygous HbS/large beta-globin
cluster deletion disorder (ie, HbS/beta zero thalassemia, HbS/delta beta zero thalassemia, HbS/HPFH,
HbS/gamma-delta-beta-thalassemia) Diagnosing complex thalassemias where the beta-globin gene and 1
or more of the other genes in the beta-globin cluster have been deleted Evaluating and classifying
unexplained increased HbF percentages Evaluating microcytic neonatal anemia Evaluating unexplained
long standing microcytosis in the setting of normal iron studies and negative alpha thalassemia
testing/normal Hb A2 percentages Confirming gene fusion hemoglobin variants such as Hb Lepore and
Hb P-Nilotic Confirming homozygosity vs hemizygosity of alterations in the beta-like genes (HBB, HBD,
HBG1, HBG2) This test is not useful for diagnosis or confirmation of alpha thalassemia, the most
common beta thalassemias, or hemoglobin variants. It also does not detect nondeletional hereditary
persistence of fetal hemoglobin.
Interpretation: The alterations will be provided with the classification, if known. Further
Reference Values:
Clinical References: 1. Hein MS, Oliveira JL, Swanson KC, et al: Large deletions involving the
beta globin gene complex: genotype-phenotype correlation of 119 cases. Blood. 2015;126:3374 2. Kipp
BR, Roellinger SE, Lundquist PA, et al: Development and clinical implementation of a combination
deletion PCR and multiplex ligation-dependent probe amplification assay for detecting deletions
involving the human alpha-globin gene cluster. J Mol Diagn. 2011 Sep;13(5):549-557. doi:
10.1016/j.jmoldx.2011.04.001 3. Rund D, Rachmilewitz E: Beta-thalassemia. N Engl J Med.
2005;353:1135-1146 4. Nussbaum R, McInnes R, Willard H: Principles of molecular disease: Lessons
from the hemoglobinopathies. In: Thompson and Thompson Genetics in Medicine. 7th ed. Saunders
Elsevier; 2007:323-342 5. Wood WG: Hereditary persistence of fetal hemoglobin and delta beta
thalassemia. In: Disorders of Hemoglobin, 1st ed. Cambridge University Press, 2001;356-388
WBDD Beta-Globin Cluster Locus, Deletion/Duplication, Varies

65200 Clinical Information: Large deletions involving the beta-globin cluster locus on chromosome 11
manifest with widely variable clinical phenotypes. Up to 10% of beta-thalassemia cases (dependent on
ethnicity) are caused by large deletions in the beta-globin cluster. Other thalassemias including
delta-beta thalassemia, gamma-delta-beta-thalassemia, and epsilon-gamma-delta-beta-thalassemia, also
result from functional loss of genes or the locus control region (LCR) that controls globin gene
expression. In addition, hereditary persistence of fetal hemoglobin (HPFH) is caused by deletions of
variable size along the beta-globin cluster locus. Most, but not all, of the large deletion beta-globin
cluster disorders are associated with variably elevated hemoglobin F percentages that persist after 2
years of age. In addition, most manifest in microcytosis. A notable exception is HPFH, which can have
normal to minimal decreased mean corpuscular volume (MCV) values. The correct classification of
these deletions is important as they confer variable predicted phenotypes and some are more protective
than others when found in combination with a second beta-globin variant, such as HbS or beta
thalassemia. In addition, identification of these deletions can explain lifelong microcytosis in the setting
of normal iron studies and negative alpha thalassemia molecular results.
Useful For: Determining the etiology of hereditary persistence of fetal hemoglobin (HPFH) or
delta-beta thalassemia Diagnosing less common causes of beta thalassemia; these large deletional beta
thalassemia variants result in elevated hemoglobin (Hb) A2 and usually have slightly elevated HbF
levels Distinguishing homozygous Hb S disease from a compound heterozygous HbS/large beta-globin
cluster deletion disorder (ie, HbS/beta zero thalassemia, Hb S/delta-beta zero thalassemia, HbS/HPFH,
HbS/gamma-delta-beta thalassemia) Diagnosing complex thalassemias where the beta-globin gene and
one or more of the other genes in the beta-globin cluster have been deleted Evaluating and classifying
unexplained increased HbF percentages Evaluating microcytic neonatal anemia Evaluating unexplained
long standing microcytosis in the setting of normal iron studies and negative alpha thalassemia
testing/normal HbA2 percentages Confirming gene fusion hemoglobin variants such as Hb Lepore and
Hb P-Nilotic Confirming homozygosity vs hemizygosity of variants in the beta-like genes (HBB, HBD,
HBG1, HBG2) This test is not useful for diagnosis or confirmation of alpha thalassemia, the most
common beta thalassemias, or hemoglobin variants. It also does not detect nondeletional HPFH.
Interpretation: The alterations will be provided with the classification, if known. Further
Reference Values:
Clinical References: 1. Hein MS, Oliveira JL, Swanson KC, et al: Large Deletions Involving the
Beta Globin Gene Complex: Genotype-Phenotype Correlation of 119 cases. Blood. 2015;126:3374 2.
Kipp BR, Roellinger SE, Lundquist PA, Highsmith WE, Dawson DB: Development and clinical
implementation of a combination deletion PCR and multiplex ligation-dependent probe amplification
assay for detecting deletions involving the human alpha-globin gene cluster. J Mol Diagn. 2011
Sep;13(5):549-57. doi: 10.1016/j.jmoldx.2011.04.001 3. Rund D, Rachmilewitz E: Beta-thalassemia. N
Engl J Med. 2005 Sep;353(11):1135-1146 4. Nussbaum R, McInnes R, Willard H: Principles of molecular
disease: Lessons from the hemoglobinopathies. In: Thompson and Thompson Genetics in Medicine. 7th
ed. Saunders Elsevier; 2007:323-342 5. Wood WG: Hereditary persistence of fetal hemoglobin and delta
beta thalassemia. In: Disorders of Hemoglobin. Cambridge University Press; 2001:356-388
WBSQR Beta-Globin Gene Sequencing, Blood

47959 Clinical Information: Beta-globin gene sequencing is useful in the evaluation of beta-globin chain
variants and beta thalassemia. It detects almost all beta-globin variants and the most common beta
thalassemia sequence variants, although prevalence is ethnicity dependent. Because these conditions are
often complex, this test should always be interpreted in the context of protein studies, such as hemoglobin
electrophoresis and red blood cell indices. The majority of beta-globin chain variants are clinically and
hematologically benign; however, some have important clinical consequences, such as erythrocytosis,
cyanosis/hypoxia, chronic hemolysis, or unexplained microcytosis. Most of the common clinically
significant hemoglobin (Hb) variants (ie, HbS, HbC, HbE, and others) are easily distinguished by
hemoglobin electrophoresis and do not require molecular analysis. In addition, they are frequently found
in complex hemoglobin disorders due to multiple genetic variants, and accurate classification requires
sequencing data within the context of protein data. In some instances, beta-globin sequencing is necessary
to identify or confirm the identity of rare variants, especially those associated with erythrocytosis and
chronic hemolytic anemia. Rare hyper-unstable variants (also termed dominant beta thalassemia
mutations) result in hemolytic anemia and do not create protein stable enough to be detectable by protein
methods, including stability studies. They are not always associated with elevated HbA2 or microcytosis
and, therefore, can be electrophoretically silent. These require a high degree of clinical suspicion as all
electrophoretic testing as well as stability studies cannot exclude this condition. Beta thalassemia is an
autosomal recessive condition characterized by decreased or absent synthesis of beta-globin chains due to
alterations in the beta-globin gene (HBB). No abnormal protein is present and diagnosis by
electrophoresis relies on hemoglobin fraction percentage alterations (ie, HbA2 or HbF elevations).
Beta-thalassemia can be split into 3 broad classes (categorized by clinical features): 1. Beta thalassemia
trait (also called beta thalassemia minor and beta thalassemia carrier) (B[A]B[+] or B[A]B[0]). 2. Beta
thalassemia intermedia (B[+]B[+] or B[+]B[0]) 3. Beta thalassemia major (B[+]B[0] or B[0]B[0]) Beta
thalassemia trait is typically a harmless condition with varying degrees of microcytosis and hypochromia
and sometimes mild anemia. Transfusions are not required. Beta thalassemia intermedia is a clinical
distinction and is characterized by a more severe degree of anemia than beta thalassemia trait with few or
intermittent transfusions required. Later in life, these individuals are at risk for iron overload even in the
absence of chronic transfusion due to increased intestinal absorption of iron. Beta thalassemia major
typically comes to medical attention early in life due to severe anemia, hepatosplenomegaly, and failure to
thrive. Skeletal changes are also common due to expansion of the bone marrow. Without appropriate
treatment these patients have a shortened lifespan. The majority of beta thalassemia variations (>90%) are
point alterations, small deletions, or insertions, which are detected by beta-globin gene sequencing. The
remaining beta thalassemia sequence variants are either due to large genomic deletions of HBB or, very
rarely, trans-acting beta thalassemia variations located outside of the beta-globin gene cluster. Some rare
beta-chain variants can be clinically or electrophoretically indistinguishable from beta thalassemia and
cannot be confirmed without molecular analysis.
Useful For: Evaluates for the following in an algorithmic process for the HAEV1 / Hemolytic
Anemia Evaluation, Blood; HBEL1 / Hemoglobin Electrophoresis Evaluation, Blood; MEV1 /
Methemoglobinemia Evaluation, Blood; REVE1 / Erythrocytosis Evaluation, Whole Blood; THEV1 /
Thalassemia and Hemoglobinopathy Evaluation, Blood and Serum: -Diagnosis of beta thalassemia
intermedia or major -Identification of a specific beta thalassemia sequence variant (ie, unusually severe
beta thalassemia trait) -Evaluation of an abnormal hemoglobin electrophoresis identifying a rare
beta-globin variant -Evaluation of chronic hemolytic anemia of unknown etiology -Evaluation of
hereditary erythrocytosis with left-shifted p50 oxygen dissociation results -Preconception screening
when there is a concern for a beta-hemoglobin disorder based on family history
Interpretation: The alteration will be provided with the classification, if known. Further
Reference Values:
Clinical References: 1. Hoyer JD, Hoffman DR: The thalassemia and hemoglobinopathy
syndromes. In: McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Lippincott Williams and
Wilkins; 2002;866-895 2. Thein SL: The molecular basis of beta-thalassemia. Cold Spring Harb
Perspect Med. 2013 May 1;1;3(5):a011700 3. Hoyer JD, Kroft, SH: Color Atlas of Hemoglobin
Disorders: A Compendium Based on Proficiency Testing. CAP; 2003 4. Merchant S, Oliveira JL, Hoyer
JD, Viswanatha DS: Molecular diagnosis in hematopathology. In: Goldblum J, His E, eds.
Hematopathology: A Volume in Foundations in Diagnostic Pathology Series. 2nd ed. Churchill
Livingstone; 2012
GBAW Beta-Glucosidase, Leukocytes

606273 Clinical Information: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder
caused by reduced or absent acid beta-glucosidase (glucocerebrosidase) enzyme activity resulting in
accumulation of glucosylceramide (glucocerebroside) and glucopsychosine (glucosylsphingosine) in the
lysosomes. This interferes with the normal functioning of cells and leads to clinical abnormalities
characteristic of the disease. While clinical features and severity of symptoms are widely variable
within Gaucher disease, common features include abnormal blood parameters such as decreased red
blood cells (anemia) and/or platelets (thrombocytopenia), bone disease, and hepatosplenomegaly. Three
clinical subtypes have been identified based on the presence and progression of central nervous system
(CNS) involvement. Type 1 is the most common type, representing 95% of all cases, and is generally
characterized by bone disease, hepatosplenomegaly, anemia and thrombocytopenia, coagulation
abnormalities, lung disease, and no CNS involvement. Type 2 or acute neuronopathic (GD2), typically
has a very severe progression with onset in the first 2 years of life including neurologic disease,
hepatosplenomegaly, and lung disease, with death usually between 2 and 4 years due to lung failure.
Individuals with type 3 or chronic neuronopathic (GD3) may have onset prior to 2 years of age, but the
progression is not as severe, and they may survive into the third and fourth decade. Finally, within the
spectrum, there is a perinatal lethal form associated with skin abnormalities and nonimmune hydrops
fetalis and a cardiovascular form presenting with calcification of the aortic and mitral valves, mild
splenomegaly, and corneal opacities. Treatment is available in the form of enzyme replacement therapy
(ERT), substrate reduction therapy, and chaperone therapy for types 1 and 3. Individuals with type 3
may benefit from bone marrow transplantation. Currently, only supportive therapy is available for type
2. Emerging therapies currently listed at Clinicaltrials.gov include gene therapy and in utero ERT. The
incidence of type 1 ranges from 1 in 20,000 to 200,000 in the general population, but it is much more
frequent among Ashkenazi Jewish population with an incidence between 1 in 400 and 900. Types 2 and
3 both have an incidence of approximately 1 in 100,000 in the general population. A diagnostic workup
for Gaucher disease may demonstrate the characteristic finding of "Gaucher cells" on bone marrow
examination. Significantly reduced or absent enzyme activity of acid beta-glucosidase along with
elevation of the biomarker, glucopsychosine (GPSY / Glucopsychosine, Blood Spot; GPSYP /
Glucopsychosine, Plasma; GPSYW / Glucopsychosine, Blood) is diagnostic. Molecular analysis of the
GBA gene allows for detection of disease-causing variants in affected patients (GBAZ / Gaucher
Disease, Full Gene Analysis, Varies or CGPH / Custom Gene Panel, Hereditary, Next-Generation
Sequencing, Varies [specify GBA Gene List ID IEMCP-M4F13T]).
Useful For: Diagnosis of Gaucher disease This test is not intended for carrier detection.
Interpretation: Individuals affected with Gaucher disease will have enzyme levels less than 3.53
nmol/h/mg protein. In our experience some carriers will also have less than 3.53 nmol/h/mg protein
activity.
Reference Values:
Note: Results from this assay do not reflect carrier status because of individual variation of
beta-glucosidase enzyme levels.
Clinical References: 1. Martins AM, Valadares ER, Porta G, et al: Recommendations on diagnosis,
treatment, and monitoring for Gaucher disease. J Pediatr. 2009 Oct;155(4 Suppl):S10-S18 2. Daykin EC,
Ryan E, Sidransky E: Diagnosing neuronopathic Gaucher disease: New considerations and challenges in
assigning Gaucher phenotypes. Mol Genet Metab. 2021 Feb;132(2):49-58. doi:
10.1016/j.ymgme.2021.01.002 3. Pastores GM, Hughes DA: Gaucher disease. In: Adam MP, Ardinger
June 21, 2018. Accessed March 1, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1269/ 4.
Weinreb NJ, Andersson HC, Banikazemi M, et al: Prevalence of type 1 Gaucher disease in the United
States. Arch Intern Med. 2008 Feb;168:326-328 5. Elliott S, Buroker N, Cournoyer JJ, et al: Pilot study of
newborn screening for six lysosomal storage diseases using tandem mass spectrometry. Mol Genet Metab.
2016 Aug;118(4):304-309
BHCG Beta-Human Chorionic Gonadotropin, Quantitative, Serum

61718 Clinical Information: Human chorionic gonadotropin (hCG) is a glycoprotein hormone (molecular
weight: MW approximately 36,000 Dalton: Da) consisting of 2 noncovalently bound subunits. The alpha
subunit (92-amino acids; "naked" protein MW 10,205 Da) is essentially identical to that of luteinizing
hormone (LH), follicle-stimulating hormone, and thyrotropin (previously known as thyroid-stimulating
hormone: TSH). The alpha subunit is essential for receptor transactivation. The different beta subunits of
the above hormones are transcribed from separate genes, show less homology, and convey the
receptor-specificity of the dimeric hormones. The chorionic gonadotropin, beta gene (coding for a
145-amino acid, "naked" protein MW 15,531 Da, glycosylated subunit MW approximately 22,500 Da) is
highly homologous to the beta subunit of LH and acts through the same receptor. However, while LH is a
classical tropic pituitary hormone, hCG does not usually circulate in significant concentrations. In
pregnant primates (including humans) it is synthesized in the placenta and maintains the corpus luteum
and, hence, progesterone production, during the first trimester. Thereafter, the placenta produces steroid
hormones, diminishing the role of hCG. hCG concentrations fall, leveling off around week 20,
significantly above prepregnancy levels. After delivery, miscarriage, or pregnancy termination, hCG falls
with a half-life of 24 to 36 hours, until prepregnancy levels are reached. Outside of pregnancy, hCG may
be secreted by abnormal germ cell, placental, or embryonal tissues, in particular seminomatous and
nonseminomatous testicular tumors; ovarian germ cell tumors; gestational trophoblastic disease (GTD:
hydatidiform mole and choriocarcinoma); and benign or malignant nontesticular teratomas. Rarely, other
tumors including hepatic, neuroendocrine, breast, ovarian, pancreatic, cervical, and gastric cancers may
secrete hCG, usually in relatively modest quantities. During pathological hCG production, the highly
coordinated secretion of alpha and beta subunits of hCG may be disturbed. In addition to secreting intact
hCG, tumors may produce disproportionate quantities of free alpha-subunits or, more commonly, free
beta-subunits. Assays that detect both intact hCG and free beta-hCG, including this assay, tend to be more
sensitive in detecting hCG-producing tumors. With successful treatment of hCG-producing tumors, hCG
levels should fall with a half-life of 24 to 36 hours, and eventually return to the reference range.
Useful For: Monitoring patients for retained products of conception Aiding in the diagnosis of
gestational trophoblastic disease (GTD), testicular tumors, ovarian germ cell tumors, teratomas, and,
rarely, other human chorionic gonadotropin (hCG)-secreting tumors Serial measurement of hCG
following treatment for: -Monitoring therapeutic response in GTD or in hCG-secreting tumors
-Detecting persistent or recurrent GTD or hCG-secreting tumors This test is not intended to detect or
monitor pregnancy.
Interpretation: After delivery, miscarriage, or pregnancy termination, human chorionic

gonadotropin (hCG) falls with a half-life of 24 to 36 hours, until prepregnancy levels are reached. An
absent or significantly slower decline is seen in patients with retained products of conception.
Gestational trophoblastic disease (GTD) is associated with very considerable elevations of hCG, usually
above 2 multiples of the medians for gestational age persisting or even rising beyond the first trimester.
Serum hCG levels are elevated in approximately 40% to 50% of patients with nonseminomatous
testicular cancer and 20% to 40% of patients with seminoma. Markedly elevated levels of hCG (>5000
IU/L) are uncommon in patients with pure seminoma and indicate the presence of a mixed testicular
cancer. Ovarian germ cell tumors (approximately 10% of ovarian tumors) display elevated hCG levels
in 20% to 50% of cases. Teratomas in children may overproduce hCG, even when benign, resulting in
precocious pseudopuberty. Levels may be elevated to similar levels as seen in testicular cancer. Among
nonreproductive tumors, hepatobiliary tumors (hepatoblastomas, hepatocellular carcinomas, and
cholangiocarcinomas) and neuroendocrine tumors (eg, islet cell tumors and carcinoids) are those most
commonly associated with hCG production. Many hCG-producing tumors also produce other
embryonic proteins or antigens, in particular alpha fetoprotein (AFP). AFP should, therefore, also be
measured in the diagnostic workup of such neoplasms. Complete therapeutic response in hCG-secreting
tumors is characterized by a decline in hCG levels with an apparent half-life of 24 to 36 hours and
eventual return to concentrations within the reference range. GTD and some tumors may produce
hyperglycoslated hCG with a longer half-life, but an apparent half-life of more than 3 days suggests the
presence of residual hCG-producing tumor tissue. A rise in hCG levels above the reference range in
patients with hCG-producing tumors that had previously been treated successfully, suggests possible
local or distant metastatic recurrence.
Reference Values:
Children(1,2)
Males
Birth-3 months: < or =50 IU/L*
>3 months-<18 years: <1.4 IU/L
Females
Birth-3 months: < or =50 IU/L*
>3 months-<18 years: <1.0 IU/L
*Human chorionic gonadotropin (hCG), produced in the placenta, partially passes the placental barrier.
Newborn serum beta-hCG concentrations are approximately 1/400th of the corresponding maternal
serum concentrations, resulting in neonate beta-hCG levels of 10-50 IU/L at birth. Clearance half-life is
approximately 2-3 days. Therefore, by 3 months of age, levels comparable to adults should be reached.
Adults (97.5th percentile)

Males: <1.4 IU/L
Females
Premenopausal, nonpregnant: <1.0 IU/L
Postmenopausal: <7.0 IU/L
Pediatric reference values based on:
1. Chen RJ, Huang SC, Chow SN, Hsieh CY: Human chorionic gonadotropin pattern in maternal
circulation. Amniotic fluid and fetal circulation in late pregnancy. J Reprod Med. 1993;38:151-154
2. Schneider DT, Calaminus G, Gobel U: Diagnostic value of alpha 1-fetoprotein and beta-human
chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol. 2001;18:11-26
Clinical References: 1. Cole LA, Khanlian SA, Muller CY: Detection of perimenopause or
postmenopause human chorionic gonadotropin: an unnecessary source of alarm. Am J Obstet Gynecol.
2008;198:275.e1-275.e7 2. Schneider DT, Calaminus G, Gobel U: Diagnostic value of alpha 1-fetoprotein
and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol.
2001;18(1):11-26 3. Cole LA, Butler S: Detection of hCG in trophoblastic disease. The USA hCG
reference service experience. J Reprod Med. 2002;40(6):433-444 4. von Eyben FE: Laboratory markers
and germ cell tumors. Crit Rev Clin Lab Sci .2003;40(4):377-427 5. Sturgeon CM, Duffy MJ, Stenman
UH: National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor
markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008; 54(12):e11-79
BHSF Beta-Human Chorionic Gonadotropin, Quantitative, Spinal Fluid

8877 Clinical Information: Human chorionic gonadotropin (hCG) is synthesized during pregnancy by
syncytiotrophoblast cells. hCG may also be produced by neoplastic cells of testicular tumors (seminomas
or nonseminomas), ovarian germ cell tumors, gestational trophoblastic disease, choriocarcinoma and
various nontrophoblastic tumors including breast, ovarian, pancreatic, cervical, gastric, and hepatic
cancers. Measurement of hCG is used as an adjunct in the diagnosis of germ cell tumors. The presence of
hCG in cerebrospinal fluid (CSF) is suggestive of tumor presence. Pure germinomas are associated with
low hCG concentrations in both serum and CSF. A subset of nongerminomatous germ cell tumors
contains syncytiotrophoblastic giant cells. These tumors are associated with moderately increased hCG
concentrations (<1000 IU/L) in the serum and/or CSF, and the survival rate in patients suffering these
tumors is worse than that of patients with pure germinomas. In contrast, choriocarcinomas, another subset
of nongerminomatous germ cell tumors, are associated with very high hCG concentrations (>1000 IU/L)
in both serum and CSF. Quantification of the hCG in CSF can be important in guiding treatment and
monitoring response to treatment of these tumors. The combination of the specific antibodies used in the
Roche Beta hCG immunoassay recognize the holo-hormone, "nicked" forms of hCG, the beta-core
fragment, and the free beta-subunit.
Useful For: Aiding in the diagnosis of brain metastases of testicular cancer or extragonadal
intracerebral germ cell tumors
Interpretation: Elevated levels of human chorionic gonadotropin in spinal fluid indicate the probable
presence of central nervous system metastases or recurrence of tumor in patients with germ cell tumors,
including patients with testicular cancer or choriocarcinoma.
Reference Values:
<1.0 IU/L
Clinical References: 1. Tian C, Shi Q, Xiao G, et al: CSF and serum hCG in patients without
gestational and neoplastic hCG-secretion. Scand J Clin Lab Invest. 2011 Jul;71(4):264-268 2. Tian C, Shi
Q, Pu C, et al: Re-evaluation of the significance of cerebrospinal fluid human chorionic gonadotropin in
detecting intracranial ectopic germinomas. J Clin Neurosci. 2011 Feb;18(2):223-226 3. Gonzalez-Sanchez
V, Moreno-Perez O, Sanchez Pellicer P, et al: Validation of the human chorionic gonadotropin
immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas. Ann
Clin Biochem. 2011 Sep;48(Pt 5):433-437
BHYD Beta-Hydroxybutyrate, Serum

9251 Clinical Information: Beta-hydroxybutyrate (BHB) is 1 of 3 sources of ketone bodies. Its relative
proportion in the blood (78%) is greater than the other 2 ketone bodies, acetoacetate (20%) and acetone
(2%). During carbohydrate deprivation (starvation, digestive disturbances, frequent vomiting), decreased
carbohydrate utilization (diabetes mellitus), glycogen storage diseases, and alkalosis, acetoacetate
production increases. The increase may exceed the metabolic capacity of the peripheral tissues. As
acetoacetate accumulates in the blood, a small amount is converted to acetone by spontaneous
decarboxylation. The remaining and greater portion of acetoacetate is converted to BHB.
Useful For: Monitoring therapy for diabetic ketoacidosis Investigating the differential diagnosis of
any patient presenting to the emergency room with hypoglycemia, acidosis, suspected alcohol ingestion,
or an unexplained increase in the anion gap In pediatric patients, the presence or absence of
ketonemia/uria is an essential component in the differential diagnosis of inborn errors of metabolism
Serum beta-hydroxybutyrate is a key parameter monitored during controlled 24-hour fasts
Interpretation: The beta-hydroxybutyrate (BHB)/acetoacetate ratio is typically between 3:1 and 7:1
in severe ketotic states. Serum BHB increases in response to fasting, but should not exceed 0.4 mmol/L
following an overnight fast (up to 12 hours). In pediatric patients, a hypo- or hyper-ketotic state (with or
without hypoglycemia) may suggest specific groups of metabolic disorders.
Reference Values:
<0.4 mmol/L

Philadelphia, WB Saunders Co. 1999 2. Vassault A, Bonnefont JP, Specola N, et al: Lactate, pyruvate,
and ketone bodies. In Techniques in Diagnostic Human Biochemical Genetics - A Laboratory Manual.
Edited by F Hommes. New York, Wiley-Liss, 1991 3. Bonnefont JP, Specola NB, Vassault A, et al: The
fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur
J Pediatr 1990;150:80-85
BLACT Beta-Lactamase
8118 Clinical Information: Various bacteria produce a class of enzymes called beta-lactamases, which
may be mediated by genes on plasmids or chromosomes. Production of beta-lactamase may be
constitutive or induced by exposure to antimicrobials. Beta-lactamases hydrolyze (and thereby
inactivate) the beta-lactam rings of a variety of susceptible penicillins and cephalosporins.
Beta-lactamases are classified by their preferred antimicrobial substrate and the effect of various
inhibitors (such as clavulanic acid) on them. Some antimicrobials, such as cefazolin and cloxacillin are
resistant to such hydrolysis (at least for staphylococcal beta-lactamases). Beta-lactamase producing
strains of the following are resistant to many types of penicillin: Staphylococcus species, Hemophilus
influenzae, Neisseria gonorrhoeae, Bacteroides species, Enterococcus species, and Moraxella
catarrhalis. The above organisms, when isolated from critical specimens such as blood or spinal fluid,
should always be tested for beta-lactamase production. Addition of a beta-lactamase inhibitor to a
beta-lactam (such as sulbactam plus ampicillin) restores the activity of the antimicrobials.
Useful For: Predicting the resistance of beta-lactamase producing isolates to hydrolysis-susceptible

beta-lactam antimicrobials
Interpretation: A positive test indicates production of beta-lactamase.

Reference Values:
Negative (reported as positive or negative)
Clinical References: Livermore DM, Williams JD: Beta-lactams: mode of action and mechanisms
of bacterial resistance. In Antibiotics in Laboratory Medicine. Fourth edition. Edited by V Lorian.
Baltimore, MD, Williams and Wilkins, 1996, pp 502-578
BLAC Beta-Lactoglobulin, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to beta-lactoglobulin Defining the allergen


Reference Values:
0 Negative

apply to all ages.
HCO3 Bicarbonate, Serum

876 Clinical Information: Bicarbonate is the second largest fraction of the anions in plasma. Included in
this fraction are the bicarbonate (HCO3[-]) and carbonate (CO3[-2]) ions, carbon dioxide in physical
solution, as well as the carbamino compounds. At the physiological pH of blood, the concentration of
carbonate is 1/1000 that of bicarbonate. The carbamino compounds are also present in such low quantities
that they are generally not mentioned specifically. The bicarbonate content of serum or plasma is a
significant indicator of electrolyte dispersion and anion deficit. Together with pH determination,
bicarbonate measurements are used in the diagnosis and treatment of numerous potentially serious
disorders associated with acid-base imbalance in the respiratory and metabolic systems. Some of these
conditions are diarrhea, renal tubular acidosis, carbonic anhydrase inhibitors, hyperkalemic acidosis, renal
failure, and ketoacidosis.
Useful For: Diagnosis and treatment of acid-base imbalance in respiratory and metabolic systems
Interpretation: Alterations of bicarbonate (HCO3) and carbon dioxide (CO2) dissolved in plasma are
characteristic of acid-base imbalance. The nature of the imbalance cannot, however, be inferred from the
bicarbonate value itself, and the determination of bicarbonate is rarely ordered alone. Its value has
significance in the context of other electrolytes determined with it and in screening for electrolyte
imbalance.
Reference Values:
Males
12-24 months: 17-25 mmol/L
Females
Reference values have not been established for patients that are <12 months of age.
Clinical References: Tietz Textbook of Clinical Chemistry, Edited by Burtis and Ashwood.
Philadelphia, PA, WB Saunders Company, 1994.
FBIUR Bicarbonate, Urine

Normally: None Detected
BAPS Bile Acid Profile, Serum

62538 Clinical Information: Bile acids are formed in the liver from cholesterol, conjugated primarily to
glycine and taurine, stored and concentrated in the gallbladder, and secreted into the intestine after the
ingestion of a meal. In the intestinal lumen, the bile acids serve to emulsify ingested fats and thereby
promote digestion. During the absorptive phase of digestion, approximately 90% of the bile acids are
reabsorbed. The efficiency of the hepatic clearance of bile acids from portal blood maintains serum
concentrations at low levels in normal persons. An elevated fasting level, due to impaired hepatic
clearance, is a sensitive indicator of liver disease. Following meals, serum bile acid levels have been
shown to increase only slightly in normal persons, but markedly in patients with various liver diseases,
including cirrhosis, hepatitis, cholestasis, portal-vein thrombosis, Budd-Chiari syndrome, cholangitis,
Wilson disease, and hemochromatosis. No increase in bile acids will be noted in patients with intestinal
malabsorption. Metabolic hepatic disorders involving organic anions (eg, Gilbert disease, Crigler-Najjar
syndrome, and Dubin-Johnson syndrome) do not cause abnormal serum bile acid concentrations. The
concentration of bile acids in serum is influenced by many different liver diseases due to the inability of
the liver to efficiently extract circulating bile acids from portal blood. In addition, bile acid levels are
altered in several biochemical genetic conditions, such as peroxisomal biogenesis disorders like
Zellweger syndrome and disorders of bile acid synthesis such as D-bifunctional protein deficiency and
alpha methyl-CoA racemase deficiency, due to the loss of specific enzymes important for bile acid
metabolism. This analysis includes a quantitative characterization of primary and secondary bile acids
as well as 2 bile acid precursor species for the assessment of bile acid metabolism.
Useful For: Evaluating the enterohepatic cycle consisting of the biliary system, intestine, portal
circulation, and hepatocytes Supporting researchers in need of free and conjugated values of all 20 bile
acid species as well as total bile acid
Interpretation: Total bile acids are metabolized in the liver and can serve as a marker for normal
liver function. Increases in serum C27 bile acids are seen in patients with peroxisomal biogenesis
disorders such as Zellweger syndrome or single enzyme defects of bile acid synthesis such as
D-bifunctional protein deficiency and alpha methyl CoA racemaces. Totals of the free and conjugated
bile acid species for all 20 bile acids in addition to total bile acids will be reported. No interpretive
report will be provided.
Reference Values:
Chenodeoxycholic acid: < or =2.26 nmol/mL Cholic acid: < or =2.74 nmol/mL Deoxycholic acid: < or
=2.84 nmol/mL Dihydroxycholestanoic acid: < or =0.07 nmol/mL Glycochenodeoxycholic acid: < or
=5.14 nmol/mL Glycocholic acid: < or =2.17 nmol/mL Glycodeoxycholic acid: < or =3.88 nmol/mL
Glycohyodeoxycholic acid: < or =0.01 nmol/mL Glycolithocholic acid: < or =0.11 nmol/mL
Glycoursodeoxycholic acid: < or =1.00 nmol/mL Hyodeoxycholic acid: < or =0.12 nmol/mL Lithocholic
acid: < or =0.09 nmol/mL Taurochenodeoxycholic acid: < or =0.80 nmol/mL Taurocholic acid: < or
=0.31 nmol/mL Taurodeoxycholic acid: < or =0.78 nmol/mL Taurohyodeoxycholic acid: < or =0.02
nmol/mL Taurolithocholic acid: < or =0.04 nmol/mL Tauroursodeoxycholic acid: < or =0.05 nmol/mL
Trihydroxycholestanoic acid: < or =1.73 nmol/mL Ursodeoxycholic acid: < or =0.64 nmol/mL Total bile
acids: < or =19.00 nmol/mL
Clinical References: 1. Sundaram SS, Bove KE, Lovell MA, Sokol RJ: Mechanisms of disease:
inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008 Aug;5(8):456-468 2.
Wanders RJA, Rizzo WB: Inborn errors of peroxisome biogenesis and function. In: Sarafoglou K,
Hoffmann GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. McGraw-Hill
Medical Division, 2nd ed. 2017:427-446: 3. Ducroq DH, Morton MS, Shadi N, et al: Analysis of serum
bile acids by isotope dilution-mass spectrometry to assess the performance of routine total bile acid
methods. Ann Clin Biochem. 2010 Nov;47(Pt 6):535-540 4. Fischler B, Eggersten G, Bjorkhem I:
Genetic defects in synthesis and transport of bile acids. In: Sarafoglou K, Hoffmann GF, Roth KS, eds.
Pediatric Endocrinology and Inborn Errors of Metabolism. McGraw-Hill Medical Division; 2017:447-460
BAIPD Bile Acids for Peroxisomal Disorders, Serum

syndrome, and Dubin-Johnson syndrome) do not cause abnormal serum bile acid concentrations. This bile
acid test for peroxisomal disorders measures concentrations of C27 bile acids, which are diagnostic
markers for peroxisomal biogenesis disorders such as Zellweger syndrome and single enzyme defects of
bile acid synthesis such as D-bifunctional protein deficiency and alpha methyl-CoA racemase deficiency.
Elevated levels of C27 bile acids may enable diagnosis of peroxisomal biogenesis disorders and bile acid
synthesis defects in children with liver cholestasis. Treatment for peroxisomal biogenesis disorders and
bile acid synthesis defects with cholic acid is available. Measurement of C27 bile acids before and during
treatment with bile acid therapy such as cholic acid can assist with monitoring of treatment efficacy.
Useful For: Biomarker for peroxisomal biogenesis disorders such as Zellweger syndrome and single
enzyme defects of bile acid synthesis including D-bifunctional protein deficiency and alpha methyl CoA
racemaces Monitoring patients receiving bile acid therapy such as cholic acid for liver disease due to
peroxisomal biogenesis disorders or single enzyme defects in bile acid synthesis
Interpretation: Increases in serum C27 bile acids are seen in patients with peroxisomal biogenesis
disorders such as Zellweger syndrome or single enzyme defects of bile acid synthesis such as
D-bifunctional protein deficiency and alpha methyl CoA racemaces. Total bile acids are metabolized in
the liver and can serve as a marker for normal liver function. The values of 2 bile acid precursors,
dihydroxycholestanoic acid and trihydroxycholestanoic acid, will be reported, along with total cholic acid,
total chenodeoxycholic acid, total ursodeoxycholic acid, and total bile acids. No interpretive report will be
provided.
Reference Values:
Dihydroxycholestanoic acid < or =0.10
Trihydroxycholestanoic acid < or =1.30
Total cholic acid < or =5.00
Total chenodeoxycholic acid < or =6.00
Total ursodeoxycholic acid < or =2.00
Total bile acids < or =19.00
Clinical References: 1. Johnson DW, ten Brink HJ, Schuit RC, Jakobs C: Rapid and quantitative
analysis of unconjugated C(27) bile acids in plasma and blood samples by tandem mass spectrometry. J
Lipid Res. 2001 Jan;42(1):9-16 2. Bootsma AH, Overmars H, Van Rooij A, et al: Rapid analysis of
conjugated bile acids in plasma using electrospray tandem mass spectrometry: application for selective
screening of peroxisomal disorders. J Inherit Metab Dis. 1999 May;22(3):307-310 3. Ferdinandusse S,
Jimenez-Sanchez G, Koster J, et al: A novel bile acid biosynthesis defect due to a deficiency of
peroxisomal ABCD3. Hum Mol Genet. 2015 Jan 15;24(2):361-370 4. Heubi JE, Setchell KDR, Bove
KE: Inborn errors of bile acid metabolism. Clin Liver Dis. 2018 Nov;22(4):671-687. doi:
10.1016/j.cld.2018.06.006 5. Sundaram SS, Bove KE, Lovell MA, Sokol RJ: Mechanisms of disease:
inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008 Aug;5(8):456-468 6.
Wanders RJA, Rizzo WB: Inborn errors of peroxisome biogenesis and function. In: Sarafoglou K,
Hoffmann GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed.
McGraw-Hill Medical Division; 2017:427-446 7. Fischler B, Eggersten G, Bjorkhem I: Genetic Defects
in Synthesis and Transport of Bile Acids. In: Sarafoglou K, Hoffmann GF, Roth KS, eds. Pediatric
Endocrinology and Inborn Errors of Metabolism. McGraw-Hill Medical Division; 2017:447-460
BA48F Bile Acids, Bowel Dysfunction, 48 Hour, Feces

607368 Clinical Information: Bile acids are natural products of cholesterol synthesis that aid in the
emulsification and absorption of dietary fats in the small intestine. The majority of bile acids are
reabsorbed in the ileum of the healthy individual, with only 5% excreted in feces.(1) Primary bile acids
cholic acid (CA) and chenodeoxycholic acid (CDCA) are deconjugated and dehydroxylated via
intestinal bacteria into secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA),
respectively.(2) The sum of CA, CDCA, DCA, LCA, and ursodeoxycholic acid (UDCA) compose the
majority of bile acids in the feces. Impaired absorption of bile acids in the terminal ileum leads to
excess bile acids in the colon that can cause diarrhea from chloride and water secretion; a condition
called bile acid malabsorption (BAM). Irritable bowel syndrome (IBS) is a nonspecific multifactorial
disorder involving the large intestine. IBS is characterized by cramping, bloating, diarrhea, and
constipation and classified as either IBS-D (diarrhea) or IBS-C (constipation) by the Rome III
criteria.(3) Up to 50% of IBS-D patients have accelerated colonic transit time; the mechanism of IBS-D
pathophysiology is varied with more than 25% having BAM.(1,4) Several methods have been
developed for detection of BAM, but are not widely available in clinical practice.(5) Therefore, patients
are often placed on trials of bile acids sequestrants to determine if symptoms improve. Quantitation of
fecal bile acids aids in screening for IBS-D and identification of patients with chronic diarrhea who may
benefit from bile acid sequestrant therapy.
Useful For: Aids to evaluate patients suspected of having irritable bowel syndrome-diarrhea (IBS-D)
symptoms due to bile acid malabsorption
Interpretation: Elevated total fecal bile acid or percent cholic acid plus chenodeoxycholic acid is
consistent with the diagnosis of bile acid malabsorption. Pharmacological treatment with bile acid
sequestrants has been shown to improve symptoms in some patients.
Reference Values:
> or = to 18 years:
Sum of cholic acid and chenodeoxycholic acid < or =9.7%
Total bile acids < or =2619 mcmoles/48 hours
Reference values have not been established for patients who are <18 years of age
Clinical References: 1. Vijayvargiya P, Camilleri M, Chedid V, et al: Analysis of fecal primary bile
acids detects increased stool weight and colonic transit in patients with chronic functional diarrhea. Clin
Gastroenterol Hepatol. 2019;17(5):922-929.e2 2. Vijayvargiya P, Camilleri M, Current practice in the
diagnosis of bile acid diarrhea. Gastroenterology. 2019;156:(5):1233-1238 3. Wedlake L, A'Hern R,
Russell D, et al: Systematic review: The prevalence of idiopathic bile acid malabsorption as diagnosed by
SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol
Ther. 2009;30:707-717 4. Shin A, Camilleri M, Vijayvargiya P, et al: Bowel functions, fecal
unconjugated primary and secondary bile acids, and colonic transit in patients with irritable bowel
syndrome. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1270-1275 5. Longstreth GF, Thompson WG,
Chey WD, et al: Functional bowel disorders. Gastroenterology. 2006;130:1480-1491 6. Camilleri M,
McKinzie S, Busciglio I, et al: Prospective study of motor, sensory, psychologic, and autonomic functions
in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2008;6:772-781 7. Vijayvargiya P,
Camilleri M, Shin A, Saenger A: Methods for diagnosis of bile acid malabsorption in clinical practice.
Clin Gastroenterol Hepatol. 2013 Oct;11(10):1232-1239
BAFS Bile Acids, Fractionated and Total, Serum

syndrome, and Dubin-Johnson syndrome) do not cause abnormal serum bile acid concentrations.
Useful For: Measuring tauro- and glycol-conjugated and unconjugated bile acid constituents in serum
Monitoring patients receiving bile acid therapy, such as cholic acid, deoxycholic acid, or ursodeoxycholic
acid Aiding in the evaluation of liver function; evaluation of liver function changes before the formation
of more advanced clinical signs of illness such as icterus Determining hepatic dysfunction as a result of
chemical and environmental injury Indicating hepatic histological improvement in chronic hepatitis C
patients responding to interferon treatment Indicating intrahepatic cholestasis of pregnancy This assay is
not useful for the diagnosis of peroxisomal biogenesis disorders or inborn errors of bile acid metabolism.
Interpretation: Total bile acids are metabolized in the liver and can serve as a marker for normal liver
function. Increases in serum bile acids are seen in patients with acute hepatitis, chronic hepatitis, liver
sclerosis, liver cancer, and intrahepatic cholestasis of pregnancy.
Reference Values:
Total cholic acid: < or =5.00 nmol/mL Total chenodeoxycholic acid: < or =6.00 nmol/mL Total
deoxycholic acid: < or =6.00 nmol/mL Total ursodeoxycholic acid: < or =2.00 nmol/mL Total bile acids:
< or =19.00 nmol/mL
Clinical References: 1. Marschall HU: Management of intrahepatic cholestasis of pregnancy. Expert

Rev Gastroenterol Hepatol. 2015;9(10):1273-1279 2. Ducroq DH, Morton MS, Shadi N, et al: Analysis of
serum bile acids by isotope dilution-mass spectrometry to assess the performance of routine total bile acid
methods. Ann Clin Biochem. 2010 Nov;47(Pt 6):535-540 3. Piechota J, Jelski W: Intrahepatic cholestasis
in pregnancy: Review of the literature. J Clin Med. 2020 May 6;9(5):1361. doi: 10.3390/jcm9051361.
BILEA Bile Acids, Total, Serum
shown to increase only slightly in normal persons but markedly in patients with various liver diseases,
syndrome, and Dubin-Johnson syndrome) do not cause abnormal serum bile acid concentrations.
Significant increases in total bile acids in nonfasting pregnant females can aid in the diagnosis of
cholestasis. Other factors, such as complete medical history, physical exam, and liver function tests
should also be considered.
Useful For: An aid in the evaluation of liver function Evaluation of liver function changes before the
formation of more advanced clinical signs of illness such as icterus An aid in the determination of
hepatic dysfunction as a result of chemical and environmental injury An indicator of hepatic histological
improvement in chronic hepatitis C patients responding to interferon treatment An indicator for
intrahepatic cholestasis of pregnancy
Interpretation: Total bile acids are metabolized in the liver and can serve as a marker for normal
liver function. Increases in serum bile acids are seen in patients with acute hepatitis, chronic hepatitis,
liver sclerosis, and liver cancer.
Reference Values:
< or =10 mcmol/L
Reference interval applies to fasting total bile acid concentrations.
Clinical References: 1. Sawkat Anwer M, Meyer DJ: Bile Acids in the diagnosis, pathology, and
therapy of hepatobiliary diseases. Vet Clin North Am Small Anim Pract. 1995 March;25(2):503-517 2.
Javitt NB: Diagnostic value of serum bile acids. Clin Gastroenterol. 1977;6:219-226 3. Osuga T,
Mitamura K, Mashige F, et al: Evaluation of fluorimetrically estimated serum bile acid in liver disease.
Clin Chim Acta. 1977;75:81-90 4. Shima T, Tada H, Morimoto M, et al: Serum total bile acid level as a
sensitive indicator of hepatic histological improvement in chronic hepatitis C patients responding to
interferon treatment. J Gastroenterol Hepatol. 2000 March;15(30):294-299 5. Lebovics E, Seif F, Kim
D, et al: Pruritus in chronic hepatitis C: Association with high serum bile acids, advanced pathology,
and bile duct abnormalities. Dig Dis Sci. 1997 May;42(5):1094-1099 6. Korman MG, Hofmann AF,
Summerskill WHJ: Assessment of activity in chronic active liver disease. Serum bile acids compared
with conventional tests and histology. NEJM 1974 June 20;290:1399-1402 7. Manzotti C, Casazza G,
Stimac T, Nikolova D, Gluud C. Total serum bile acids or serum bile acid profile, or both, for the
diagnosis of intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2019 Jul
5;7(7):CD012546. doi: 10.1002/14651858.CD012546.pub2
FBAC Bile Acids, Urine

75012 Clinical Information: Diagnostic testing in pediatric and adult patients presenting with conditions
of cholestatic liver disease, neurological disease, or fat-soluble vitamin malabsorption of unknown
etiology. Urine FAB-MS analysis provides a rapid and cost-effective means of diagnosing the most
common of the genetic defects in the metabolism of cholesterol to the primary bile acids. Mass
spectrometry testing may be used to monitor the biochemical response to primary bile acid therapy and
to help in decisions on dose adjustments, where compliance should lead to a reduction in levels of
atypical bile acids.
BILID Bilirubin Direct, Serum
81787 Clinical Information: Approximately 85% of the total bilirubin produced is derived from the heme
moiety of hemoglobin while the remaining 15% is produced from the RBC precursors destroyed in the
bone marrow and from the catabolism of other heme-containing proteins. After production in peripheral
tissues, bilirubin is rapidly taken up by hepatocytes where it is conjugated with glucuronic acid to produce
mono- and diglucuronide, which are excreted in the bile. Direct bilirubin is a measurement of conjugated
bilirubin. Jaundice can occur as a result of problems at each step in the metabolic pathway. Disorders may
be classified as those due to: increased bilirubin production (eg, hemolysis and ineffective erythropoiesis),
decreased bilirubin excretion (eg, obstruction and hepatitis), and abnormal bilirubin metabolism (eg,
hereditary and neonatal jaundice). Inherited disorders in which direct bilirubinemia occurs include
Dubin-Johnson syndrome and Rotor syndrome. Jaundice of the newborn where direct bilirubin is elevated
includes idiopathic neonatal hepatitis and biliary atresia. The most commonly occurring form of jaundice
of the newborn, physiological jaundice, results in unconjugated (indirect) hyperbilirubinemia. Elevated
unconjugated bilirubin in the neonatal period may result in brain damage (kernicterus). Treatment options
are phototherapy and, if severe, exchange transfusion. The increased production of bilirubin that
accompanies the premature breakdown of erythrocytes and ineffective erythropoiesis results in
hyperbilirubinemia in the absence of any liver abnormality. In hepatobiliary diseases of various causes,
bilirubin uptake, storage, and excretion are impaired to varying degrees. Thus, both conjugated and
unconjugated bilirubin is retained and a wide range of abnormal serum concentrations of each form of
bilirubin may be observed. Both conjugated and unconjugated bilirubin are increased in hepatocellular
diseases such as hepatitis and space-occupying lesions of the liver, and obstructive lesions such as
carcinoma of the head of the pancreas, common bile duct, or ampulla of Vater.
Useful For: Evaluation of jaundice and liver functions

Interpretation: Direct bilirubin levels must be assessed in conjunction with total and indirect levels
and the clinical setting.
Reference Values:
> or =12 months: 0.0-0.3 mg/dL

Philadelphia, PA, WB Saunders Company, 1994 2. Roche/Hitachi Modular Analytics Reference Guide,
Vol 7
BFBL Bilirubin, Body Fluid

606895 Clinical Information: Peritoneal fluid: Bilirubin is typically measured in peritoneal fluid of patients
with suspected bile duct leak or gallbladder perforation as a screening test prior to imaging or
cholescintigraphy. If the value is higher than that of serum and is greater than 6 mg/dL, and the ascitic
fluid amylase is not elevated (indicating upper intestinal perforation), it can be assumed that the
gallbladder has perforated into the peritoneum (choleperitoneum) and/or bowel or biliary perforation has
occurred.(1) Furthermore, biliary leakage after laparoscopic cholecystectomy is the most common
post-operative complication.(2) While endoscopy is a beneficial first-line treatment for the management
of bile leaks there often are logistical issues which hinder the procedure from being performed rapidly.
Post-cholecystectomy patients generally have a drain in place (particularly a Jackson Pratt or JP drain)
and may undergo bilirubin testing on the drain fluid as an objective assessment of a bile leak. A body
fluid/serum bilirubin ratio of greater than 5 in a JP drain fluid is highly sensitive and specific for bile
leak.(3) Pleural fluid: Measurement of bilirubin in pleural fluid has been investigated to aid in the
differentiation of transudative and exudative effusions in pursuit of more specific biomarkers than
traditional light criteria measuring total protein and lactate dehydrogenase. Bilirubin values tend to be
higher in exudates than in transudates, although there is some overlap between groups which limits the
usefulness of its measure.(4) Other fluids: Determination of body fluid bilirubin concentration can aid in
the distinction between a transudative and an exudative fluid or identify the presence of bile in other fluid
compartments.
Useful For: Evaluation of peritoneal fluid or abdominal drain fluid as a screening test for bile
leakage May aid in the distinction between a transudative and an exudative pleural effusion
Interpretation: Bilirubin may be measured in other fluids although the decision limits are not well
defined in fluids other than pleural fluid. Fluid to serum bilirubin ratios are expected to be less than or
equal to 1.0 and should be interpreted in conjunction with other clinical findings.
Reference Values:
Clinical References: 1. Runyon BA: Ascitic fluid bilirubin concentration as a key to

choleperitoneum. J Clin Gastroenterol. 1987 Oct;9(5):543-545 2. Koch M, Garden OJ, Padbury R, et al:
Bile leakage after hepatobiliary and pancreatic surgery: a definition and grading of severity by the
International Study Group of Liver Surgery. Surgery 2011. May;149(5):680-688. doi:
10.1016/j.surg.2010.12.002 3. Darwin P, Goldberg E, Uradomo L: Jackson Pratt drain fluid-to-serum
bilirubin concentration ratio for the diagnosis of bile leaks. Gastrointest Endosc. 2010 Jan;71(1):99-104.
doi: 10.1016/j.gie.2009.08.015 4. Metintas M, Alatas O, Alatas F, Colak O, Ozdemir N, Erginel S:
Comparative analysis of biochemical parameters for differentiation of pleural exudates from transudates
Light's criteria, cholesterol, bilirubin, albumin gradient, alkaline phosphatase, creatine kinase, and uric
acid. Clin Chim Acta. 1997 Aug 29;264(2):149-162. doi: 10.1016/s0009-8981(97)00091-0
BILUR Bilirubin, Random, Urine

609779 Clinical Information: Bilirubin is primarily derived from metabolism of hemoglobin. Only
conjugated bilirubin is excreted into the urine and normally only trace amounts can be detected in urine.
Elevated urinary bilirubin occurs in patients with obstructive jaundice or jaundice due to hepatocellular
disease or injury. However, urine bilirubin is relatively insensitive for detection of liver disease.
Hyperbilirubinemia due to hemolysis is principally due to unconjugated bilirubin, and therefore does
not result in increased urinary bilirubin.
Useful For: Limited use in screening of patients for liver disease

Interpretation: Elevated urinary bilirubin is suggestive of hepatocellular disease or post-hepatic
biliary obstruction.
Reference Values:
Negative
Clinical References: 1. Brunzel NA: Fundamentals of Urine and Body Fluid Analysis. 4th ed.
Saunders; 2017 2. Hoilat GJ, John S: Bilirubinuria. In: StatPearls [Internet]. StatPearls Publishing;
2020. Accessed February 12, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK557439/
BILI3 Bilirubin, Serum

8452 Clinical Information: Bilirubin is one of the most commonly used tests to assess liver function.
Approximately 85% of the total bilirubin produced is derived from the heme moiety of hemoglobin,
while the remaining 15% is produced from RBC precursors destroyed in the bone marrow and from the
catabolism of other heme-containing proteins. After production in peripheral tissues, bilirubin is rapidly
taken up by hepatocytes where it is conjugated with glucuronic acid to produce bilirubin mono- and
diglucuronide, which are then excreted in the bile. A number of inherited and acquired diseases affect 1
or more of the steps involved in the production, uptake, storage, metabolism, and excretion of bilirubin.
Bilirubinemia is frequently a direct result of these disturbances. The most commonly occurring form of
unconjugated hyperbilirubinemia is that seen in newborns and referred to as physiological jaundice. The
increased production of bilirubin, that accompanies the premature breakdown of erythrocytes and
ineffective erythropoiesis, results in hyperbilirubinemia in the absence of any liver abnormality. The
rare genetic disorders, Crigler-Najjar syndromes type I and type II, are caused by a low or absent
activity of bilirubin UDP-glucuronyl-transferase. In type I, the enzyme activity is totally absent, the
excretion rate of bilirubin is greatly reduced and the serum concentration of unconjugated bilirubin is
greatly increased. Patients with this disease may die in infancy owing to the development of kernicterus.
In hepatobiliary diseases of various causes, bilirubin uptake, storage, and excretion are impaired to
varying degrees. Thus, both conjugated and unconjugated bilirubin are retained and a wide range of
abnormal serum concentrations of each form of bilirubin may be observed. Both conjugated and
unconjugated bilirubins are increased in hepatitis and space-occupying lesions of the liver; and
obstructive lesions such as carcinoma of the head of the pancreas, common bile duct, or ampulla of
Vater.
Useful For: Assessing liver function Evaluating a wide range of diseases affecting the production,
uptake, storage, metabolism, or excretion of bilirubin Monitoring the efficacy of neonatal phototherapy
Interpretation: The level of bilirubinemia that results in kernicterus in a given infant is unknown. In
preterm infants, the risk of a handicap increases by 30% for each 2.9 mg/dL increase of maximal total
bilirubin concentration. While central nervous system damage is rare when total serum bilirubin (TSB) is
less than 20 mg/dL, premature infants may be affected at lower levels. The decision to institute therapy is
based on a number of factors including TSB, age, clinical history, physical examination, and coexisting
conditions. Phototherapy typically is discontinued when TSB level reaches 14 to 15 mg/dL. Physiologic
jaundice should resolve in 5 to 10 days in full-term infants and by 14 days in preterm infants. When any
portion of the biliary tree becomes blocked, bilirubin levels will increase.
Reference Values:
Direct Bilirubin
> or =12 months: 0.0-0.3 mg/dL
Total Bilirubin
0-6 days: Refer to www.bilitool.org for information on age-specific (postnatal hour of life) serum
bilirubin values.
7-14 days: <15.0 mg/dL
15 days to 17 years: < or =1.0 mg/dL
> or =18 years: < or =1.2 mg/ dL
Clinical References: 1. Tietz Textbook of Clinical Chemistry, Second edition. Edited by CA Burtis,
ER Ashwood. Philadelphia, WB Saunders Company, 1994 2. Scharschmidt BF, Blanckaert N, Farina FA,
et al: Measurement of serum bilirubin and its mono- and diconjugates: Applications to patients with
hepatobiliary disease. Gut 1982;23:643-649 3. American Academy of Pediatrics Provisional Committee
on Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice Parameter: Management of
hyperbilirubinemia in the healthy term newborn. Pediatrics 1994;94:558-565
BILIT Bilirubin, Total, Serum

81785 Clinical Information: Bilirubin is one of the most commonly used tests to assess liver function.
Approximately 85% of the total bilirubin produced is derived from the heme moiety of hemoglobin, while
the remaining 15% is produced from the red blood cell precursors destroyed in the bone marrow and from
the catabolism of other heme-containing proteins. After production in peripheral tissues, bilirubin is
rapidly taken up by hepatocytes where it is conjugated with glucuronic acid to produce mono- and
diglucuronide, which are excreted in the bile. A number of inherited and acquired diseases affect 1 or
more of the steps involved in the production, uptake, storage, metabolism, and excretion of bilirubin.
Bilirubinemia is a frequent and direct result of these disturbances. Jaundice can occur as a result of
problems at each step in the metabolic pathway. Disorders may be classified as those due to: increased
bilirubin production (eg, hemolysis and ineffective erythropoiesis), decreased bilirubin excretion (eg,
obstruction and hepatitis), and abnormal bilirubin metabolism (eg, hereditary and neonatal jaundice). The
most commonly occurring form of unconjugated hyperbilirubinemia is that seen in newborns and referred
to as physiological jaundice. Elevated unconjugated bilirubin in the neonatal period may result in brain
damage (kernicterus). Treatment options are phototherapy and, if severe, exchange transfusion. The rare
genetic disorders, Crigler-Najjar syndromes type I and type II, are caused by a low or absent activity of
bilirubin UDP-glucuronyl-transferase. In type I, the enzyme activity is totally absent, the excretion rate of
bilirubin is greatly reduced and the serum concentration of unconjugated bilirubin is greatly increased.
Patients with this disease may die in infancy owing to the development of kernicterus. The increased
production of bilirubin, that accompanies the premature breakdown of erythrocytes and ineffective
erythropoiesis, results in hyperbilirubinemia in the absence of any liver abnormality. In hepatobiliary
diseases of various causes, bilirubin uptake, storage, and excretion are impaired to varying degrees. Thus,
both conjugated and unconjugated bilirubin is retained and a wide range of abnormal serum
concentrations of each form of bilirubin may be observed. Both conjugated and unconjugated bilirubin are
increased in hepatitis and space-occupying lesions of the liver; and obstructive lesions such as carcinoma
of the head of the pancreas, common bile duct, or ampulla of Vater.
Useful For: Assessing liver function Evaluating a wide range of diseases affecting the production,
uptake, storage, metabolism, or excretion of bilirubin Monitoring the efficacy of neonatal phototherapy
Interpretation: The level of bilirubinemia that results in kernicterus in a given infant is unknown.
While central nervous system damage is rare when total serum bilirubin (TSB) is less than 20 mg/dL,
premature infants may be affected at lower levels. The decision to institute therapy is based on a number
of factors including TSB, age, clinical history, physical examination and coexisting conditions.
Phototherapy typically is discontinued when TSB level reaches 14 to 15 mg/dL. Physiologic jaundice
should resolve in 5 to 10 days in full-term infants and by 14 days in preterm infants. In preterm infants,
the risk of a handicap increases by 30% for each 2.9 mg/dL increase of maximal total bilirubin
concentration. When any portion of the biliary tree becomes blocked, bilirubin levels will increase.
Reference Values:
0-6 days: Refer to www.bilitool.org for information on age-specific (postnatal hour of life) serum
bilirubin values.
7-14 days: <15.0 mg/dL
> or =18 years: < or =1.2 mg/ dL

Philadelphia, WB Saunders Company, 1994 2. Scharschmidt BF, Blanckaert N, Farina FA, et al:
Measurement of serum bilirubin and its mono- and diconjugates: Applications to patients with
hepatobiliary disease. Gut 1982;23:643-649 3. American Academy of Pediatrics Provisional Committee
on Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: Management of
hyperbilirubinemia in the healthy term newborn. Pediatrics 1994;94:558-565
BIOTN Biotin, Serum

606867 Clinical Information: Biotin is a water soluble B complex vitamin (vitamin B7 or vitamin H) that
is an essential cofactor for the synthesis of fatty acids, catabolism of branched chained amino acids, and
for gluconeogenesis. It is usually found at relatively low endogenous concentrations in patients on a
normal diet. However, biotin can be found in over-the-counter multi-vitamins, prenatal vitamins, and
dietary supplements marketed for hair, skin, and nail growth. Additionally, treatment of certain
progressive multiple sclerosis patients with high doses of biotin has been reported to be beneficial.
Biotin supplementation from either over-the-counter or prescription sources can result in extremely
elevated circulating biotin. Some immunoassays in the clinical laboratory use chemistry that utilizes the
high affinity and avidity that biotin has for binding avidin (or streptavidin). As a result, high serum
biotin concentrations can yield inaccurate laboratory results in laboratory assays that utilize this
biotin-streptavidin chemistry. Specifically, specimens with high biotin can yield falsely decreased
results when the testing methodology utilizes sandwich-based methods or falsely increased results when
the methodology utilizes competitive binding methods. Each clinical laboratory method that utilizes
biotin-streptavidin chemistry has a defined biotin concentration limit above which serum biotin can
interfere with assay results. This test measures free biotin concentrations in serum and can be used to
determine whether a patient has high biotin concentrations that are likely from biotin
supplementation/treatment.
Useful For: Measurement of biotin in serum Assessment of biotin concentrations in individuals

taking biotin supplements Investigation of unexpected results from immunoassays that utilize
biotin-streptavidin detection methods This test is not useful as a screen for biotinidase deficiency.
Interpretation: Biotin results that are significantly higher than the reference interval indicate biotin
supplementation.
Reference Values:
> or =18 years: < or =0.3 ng/mL
Clinical References: 1. Elston MS, Sehgal S, Du Toit S, Yarndley T, Conaglen JV: Factitious
Gravesâ€™ disease due to biotin immunoassay interference-a case and review of the literature. J Clin
Endocrinol Metab. 2016 Sep;101(9):3251-3255 2. Grimsey P, Frey N, Bendig G, et al: Population
pharmacokinetics of exogenous biotin and the relationship between biotin serum levels and in vitro
immunoassay interference. Int J Pharmacokinet. 2017 Sep 14;2:247-256 3. Katzman BM, Lueke AJ,
Donato LJ, Jaffe AS, Baumann NA: Prevalence of biotin supplement usage in outpatients and plasma
biotin concentrations in patients presenting to the emergency department. Clin Biochem. 2018
Sep;60:11-16
BTDZ Biotinidase Deficiency, BTD Full Gene Analysis, Varies

35375 Clinical Information: Biotinidase deficiency is an inherited metabolic disease caused by reduced
levels of biotinidase, an enzyme that recycles biotin by releasing it from its metabolic product, biocytin,
or exogenous dietary proteins. Biotin is a vitamin that serves as a coenzyme for 4 carboxylases that are
essential for amino acid catabolism, gluconeogenesis, and fatty acid synthesis. Depletion of free biotin
reduces carboxylase activity, resulting in secondary carboxylase deficiency. Depending on the amount of
residual biotinidase activity, individuals can have either profound or partial biotinidase deficiency. Age of
onset and clinical phenotype vary among individuals. Profound biotinidase deficiency occurs in
approximately 1 in 137,000 live births and partial biotinidase deficiency occurs in approximately 1 in
110,000 live births, resulting in a combined incidence of about 1 in 61,000. Untreated profound
biotinidase deficiency (<10% of normal biotinidase activity) manifests within the first decade of life as
seizures, hypotonia, neurosensory hearing loss, respiratory problems, and cutaneous symptoms including
skin rash, alopecia, and recurrent viral or fungal infections. Among children and adolescents with
profound biotinidase deficiency, clinical features include ataxia, sensorineural hearing loss,
developmental delay, and eye problems such as optic neuropathy leading to blindness. Partial biotinidase
deficiency (10%-30% of normal biotinidase activity) is associated with a milder clinical presentation,
which may include cutaneous symptoms without neurologic involvement. Treatment with biotin has been
successful in both preventing and reversing the clinical features associated with biotinidase deficiency. As
a result, biotinidase deficiency is included in most newborn screening programs in order to prevent
disease. Biotinidase deficiency exhibits a similar clinical presentation to carboxylase and holocarboxylase
synthetase deficiency. Therefore, measurement of the biotinidase enzyme is required to differentiate
between these diseases and ensure proper diagnosis. Newborn screening for biotinidase deficiency
involves direct analysis of the biotinidase enzyme from blood spots obtained shortly after birth. This
enables early identification of potentially affected individuals and quick follow-up with confirmatory
biochemical and molecular testing. Biotinidase deficiency is inherited in an autosomal recessive manner,
caused by mutations in the biotinidase gene (BTD). The carrier frequency for biotinidase deficiency in the
general population is about 1:120. Several common mutations in the BTD gene have been identified,
accounting for about 60% of affected individuals. Sequencing of the entire BTD gene detects other, less
common, disease-causing mutations. While genotype-phenotype correlations are not well established, it
appears that certain mutations are associated with profound biotinidase deficiency, while others are
associated with partial deficiency. The recommended first-tier test to screen for biotinidase deficiency is a
biochemical test that measures biotinidase enzyme activity, either newborn screening or BIOTS /
Biotinidase, Serum. Molecular tests form the basis of confirmatory or carrier testing. Individuals with
decreased enzyme activity are more likely to have 2 identifiable mutations in the BTD gene by molecular
genetic testing.
Useful For: Second-tier test for confirming biotinidase deficiency (indicated by biochemical testing or
newborn screening) Carrier testing of individuals with a family history of biotinidase deficiency, but
disease-causing mutations have not been identified in an affected individual
Reference Values:
May;17(5):405-424 2. Kaye CI, Committee on Genetics, Accurso F, et al: Newborn screening fact
sheets. Pediatrics 2006 Sep;118(3):e934-963 3. Moslinger D, Muhl A, Suormala T, et al: Molecular
characterization and neuropsychological outcome of 21 patients with profound biotinidase deficiency
detected by newborn screening and family studies. Eur J Pediatr 2003 Dec;162 Suppl 1:S46-49 Epub
2003 Nov 20 4. Nyhan WL, Barshop B, Ozand PT: Multiple carboxylase deficiency/biotinidase
deficiency. In Altas of Metabolic Diseases. Second edition. New York, Oxford University Press, 2005
pp 42-48 5. Wolf B, Jensen KP, Barshop B, et al: Biotinidase deficiency: novel mutations and their
biochemical and clinical correlates. Hum Mutat 2005 Apr;25(4):413
BIOTS Biotinidase, Serum

88205 Clinical Information: Biotinidase deficiency is an autosomal recessive disorder caused by variants
in the biotinidase gene (BTD). Age of onset and clinical phenotype vary among individuals depending
on the amount of residual biotinidase activity. Profound biotinidase deficiency occurs in approximately
1 in 137,000 live births and partial biotinidase deficiency occurs in approximately 1 in 110,000 live
births, resulting in a combined incidence of about 1 in 61,000. The carrier frequency for biotinidase
deficiency within the general population is about 1 in 120. Â Untreated profound biotinidase deficiency
typically manifests within the first decade of life as seizures, ataxia, developmental delay, hypotonia,
sensorineural hearing loss, vision problems, skin rash, and alopecia. Partial biotinidase deficiency is
associated with a milder clinical presentation and may include cutaneous symptoms without neurologic
involvement. Certain organic acidurias, such as holocarboxylase synthase deficiency, isolated
carboxylase synthase deficiency, and 3-methylcrotonylglycinuria, present similarly to biotinidase
deficiency. Serum biotinidase levels can help rule out these disorders. Â Treatment with biotin is
successful in preventing the clinical features associated with biotinidase deficiency. In symptomatic
patients, treatment will reverse many of the clinical features except developmental delay, vision, and
hearing complications. As a result, biotinidase deficiency is included in most newborn screening
programs. This enables early identification and treatment of presymptomatic patients. Â Molecular
tests are useful for confirmation of diagnosis or carrier testing. When biotinidase enzyme activity is
deficient, sequencing of the entire BTD gene (BTDZ / Biotinidase Deficiency, BTD Full Gene
Analysis, Varies) allows for detection of disease-causing variants in affected patients. Identification of
familial variants allows for testing of at-risk family members (FMTT / Familial Mutation, Targeted
Testing, Varies). Â While genotype-phenotype correlations are not well established, it appears that
certain genetic variants are associated with profound biotinidase deficiency, while others are associated
with partial deficiency.
Useful For: Preferred test for the diagnosis of biotinidase deficiency Follow-up testing for certain
organic acidurias
Interpretation: An interpretive report is provided. Values below 3.5 U/L are occasionally seen in
specimens from unaffected patients.
Reference Values:
3.5-13.8 U/L
Clinical References: 1. Zempleni J, Barshop BA, Cordonier EL, et al: Disorders of biotin
metabolism. In: Valle D, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online
Metabolic and Molecular Bases of Inherited Diseases. McGraw-Hill; Accessed August 24, 2021.
Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225548571 2. Wolf B. Biotinidase
deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of
Washington, Seattle; 2000. Updated June 09, 2016. Accessed August 24, 2021. Available at:
FBFPI Bird Fancier's Precipitin Panel I

Canary Droppings Negative
Chicken Serum Negative
Cockatiel Droppings Negative
Finch Droppings Negative
Parakeet Droppings Negative
Parakeet Serum Negative
Parrot Droppings Negative

Parrot Serum Negative
Pigeon/Dove Droppings Negative
Pigeon/Dove Serum Negative The gel diffusion method was used to test this
patient's serum for the presence of precipitating antibodies
(IgG) to the antigens indicated. These antibodies are
serological markers for exposure and immunological
sensitization. The clinical significance varies, depending on
the history and symptoms.
BHDZ Birt-Hogg-Dube Syndrome, FLCN, Full Gene Analysis, Varies

614584 Clinical Information: Germline variants in the FLCN gene are associated with Birt-Hogg-Dube
(BHD) syndrome. BHD syndrome is characterized by cutaneous manifestations (fibrofolliculomas,
trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of
pneumothorax, and various types of renal tumors. BHD syndrome is inherited in an autosomal dominant
manner and the penetrance is considered to be very high.(1-6) While there is no consensus on clinical
surveillance of BHD syndrome, many recommendations have been put forth for the individual
manifestations of the condition by different groups, such as the National Cancer Institute.(4-6)
Useful For: Evaluation for patients with a personal or family history suggestive of Birt-Hogg-Dube
(BHD) syndrome Establishing a diagnosis of BHD syndrome allowing for targeted cancer surveillance
based on associated risks Identifying variants within genes known to be associated with increased risk for
BHD syndrome allowing for predictive testing of at-risk family members
significance.
Reference Values:
Clinical References: 1. Sattler EC, Steinlein OK: Birt-Hogg-Dube syndrome. In: Adam MP,
Ardinger HH, Pagon RA, et al, eds. GeneReviews. [Internet]. University of Washington, Seattle; 2006.
Updated January 30, 2020. Accessed July 6, 2021. Available at: www.ncbi.nlm.nih.gov/books/NBK1522/
2. Houweling AC, Gijezen LM, Joneker MA, et al: Renal cancer and pneumothorax risk in
Birt-Hogg-Dube syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J
Cancer. 2011 Dec 6;105(12):1912-1919 3. Schmidt LS, Nickerson ML, Warren MB, et al: Germline
BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube
Syndrome. Am J Hum Genet. 2005 Jun;76(6):1023-1033 4. Stamatakis L, Metwalli AR, Middelton LA,
Linehan WM: Diagnosis and management of BHD-associated kidney cancer. Fam Cancer. 2013
Sep;12(3):397-402 5. Farrant PBJ, Emerson R: Letter: hyfrecation and curettage as a treatment for
fibrofolliculomas in Birt-Hogg-Dube syndrome. Dermatol Surg. 2007 Oct;33(10):1287-1288 6. Kim D,
Wysong A, Teng JM, Rahman Z: Laser-assisted delivery of topical rapamycin: mTOR inhibition for
Birt-Hogg-Dube syndrome. Dermatol Surg. 2019 Dec;45(12):1713-1715 7. Richards S, Aziz N, Bale S, et
al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation
of the American College of Medical Genetics and Genomics and the Association for Molecular
Pathology. Genet Med. 2015 May;17(5):405-424
BIWB Bismuth, Blood

64274 Clinical Information: Bismuth is used in the production of alloys, pigments, and chemical
additives. Various compounds have also been used as therapeutic agents, astringents, antacids.(1)
Bismuth subsalicylate (Pepto-Bismol) is one example commonly used for indigestion and diarrhea. In
unexposed individuals, bismuth blood concentrations were typically less than 0.02 mcg/L compared to
peptic ulcer patients taking bismuth medications where the concentrations ranged from 4 to 30
mcg/L.(2-4) Elimination from the body takes place primarily by the urinary and fecal routes, but the
exact proportion contributed by each route is still unknown. Elimination from blood displays
multicompartment pharmacokinetics with half-lives of 8 to 16 hours (early) and 5 to 11 days (late).(1) A
number of toxic effects have been attributed to bismuth compounds in humans including: nephropathy,
encephalopathy, osteoarthropathy, gingivitis, stomatitis, and colitis. Common early symptoms include
salivation, mucosal swelling, discoloration of the tongue, gums, abdominal pain, and nausea.(1)
Useful For: Determining bismuth toxicity

Interpretation: Normal blood concentrations for unexposed individuals are less than 1 ng/mL and
the therapeutic range is 4 to 30 ng/mL.(2-4)
Reference Values:
<1 ng/mL (unexposed)
4-30 ng/mL (therapeutic)
Clinical References: 1. Baselt R: Disposition of Toxic Drugs and Chemicals In Man. 10th ed.
Biomedical Publications; 2014 2. Heitland P, Koster HD: Biomonitoring of 37 trace elements in blood
samples from inhabitants of northern Germany by ICP-MS. J Trace Elem Med Biol.
2006;20(4):253-262 3. Serfontein WJ, Mekel R, Bank S, Barbezat G, Novis B: Bismuth toxicity in
man-I. Bismuth blood and urine levels in patients after administration of a bismuth protein complex
(Bicitropeptide). Res Commun Chem Pathol Pharmacol. 1979 Nov;26(2):383-389 4. Serfontein WJ,
Mekel R: Bismuth toxicity in man II. Review of bismuth blood and urine levels in patients after
administration of therapeutic bismuth formulations in relation to the problem of bismuth toxicity in
man. Res Commun Chem Pathol Pharmacol. 1979 Nov;26(2):391-411 5. Roberts NB, Taylor A, Sodi
R: Vitamins and trace elements. Rifai N, Horvath AR, Wittwer CT, eds: Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:chap 37
BIVAL Bivalirudin, Ecarin, Plasma

614120 Clinical Information: Bivalirudin, a parenteral anticoagulant that directly inhibits thrombin (direct
thrombin inhibitor, DTI) factor IIa. It is indicated for use in patients with unstable angina undergoing
percutaneous coronary intervention (PCI), in those undergoing PCI with provisional use of glycoprotein
IIb/IIIa inhibitor (GPI), or in those with, or at risk of, heparin- induced thrombocytopenia (HIT) or HIT
and thrombosis syndrome (HITTS) undergoing PCI. In these indications it is intended for use with
aspirin. Frequently, bivalirudin is used for prevention of treatment of thrombosis in patients with HIT
with or without thrombosis and with renal and/or hepatic dysfunction. Bivalirudin is administered via
continuous intravenous infusion, is removed by a combination of proteolytic cleavage by thrombin and
renal clearance mechanisms, and can inhibit both soluble and clot-bound thrombin. Bivalirudin's effect
is typically monitored using the activated partial thromboplastin time (aPTT) test with a target aPTT
ratio of 1.5 to 2.5 times the patientâ€™s baseline value. However, in instances where patients have a
prolonged baseline aPTT (eg, lupus anticoagulants and factor XII deficiency), aPTT monitoring of
bivalirudin is not reliable and direct measurement of the effect of bivalirudin on factor IIa may be more
reliable. For HIT, monitoring every 2 to 4 hours until in range and then once daily; for PCI, monitoring
is unnecessary unless renal failure is present. Internal laboratory validation demonstrates that plasma
concentrations of bivalirudin from 0.25 to 2.00 mcg/mL correspond to an aPTT ratio of 1.5 to 3.0.
Correlation of bivalirudin drug concentrations with aPTT ratios may vary with different aPTT reagents.
Useful For: Monitoring of bivalirudin therapy for patients with prolonged baseline activated partial
thromboplastin time
Interpretation: Therapeutic reference ranges have not been established. See Clinical Information for
activated partial thromboplastin time correlative information.
Reference Values:
<0.10 mcg/mL
Clinical References: 1. Linkins LA, Dans AL, Moores LK, et al: Treatment and prevention of
heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012
Feb;141(2 Suppl):e495S-e530s 2. Love JE, Ferrell C, Chandler WL: Monitoring direct thrombin
inhibitors with a plasma diluted thrombin time. Thromb Haemost. 2007 Jul;98(1):234-242 3. Van Cott
EM, Roberts AJ, Dager WE: Laboratory Monitoring of Parenteral Direct Thrombin Inhibitors. Semin
Thromb Hemost. 2017 Apr;43(3):270-276 4. Gosselin RC, Douxfils J: Ecarin based coagulation testing.
Am J Hematol. 2020 Apr;95(6). doi: 10.1002/ajh.25852 5. Gosselin RC, King JH, Janatpour KA, Dager
WE, Larkin EC, Owings JT: Comparing direct thrombin inhibitors using aPTT, ecarin clotting times, and
thrombin inhibitor management testing. Ann Pharmacother. 2004 Sep;38(9):1383-1388.
doi:10.1345/aph.1D565 6. Beyer JT, Lind SE, Fisher S, Trujillo TC, Wempe MF, Kiser TH: Evaluation of
intravenous direct thrombin inhibitor monitoring tests: Correlation with plasma concentrations and
clinical outcomes in hospitalized patients. J Thromb Thrombolysis. 2020 Feb;49(2):259-267. doi:
10.1007/s11239-019-01961-3
PBKQN BK Virus DNA Detection and Quantification, Plasma

614567 Clinical Information: BK virus (BKV) is a circular, double-stranded DNA virus with an
approximately 5 kilobase-size genome in the polyomavirus family, of which 13 members of the family are
known, including the JC virus (JCV) and SV40. BKV shares about 75% of its DNA sequence with JCV.
Nearly 80% of the adult population worldwide have antibodies to both viruses, indicating previous
infection or exposure to these viruses. Initial infection with BKV is usually acquired in childhood, mostly
asymptomatic or manifesting as a mild flu-like illness. After primary infection, BKV establishes latency
in the kidney and bladder of the infected individual. In the setting of immunosuppression, the virus
reactivates and begins to replicate, triggering renal tubular cell lysis and viruria. As the reactivation
progresses, the virus multiplies and crosses into the bloodstream, causing viremia and invading the kidney
graft. In patients with kidney transplants, reactivation of BKV typically reaches peak incidence at 3
months posttransplantation with BK viral replication in the kidney graft, causing BKV-associated
nephropathy (BKVAN), which manifests as kidney dysfunction that may result in eventual loss of the
transplanted kidney. Reactivation of BKV in the bladder can lead to hemorrhagic cystitis. Currently, there
are no FDA-approved antiviral agents or treatments for BKVAN or BKV-associated hemorrhagic cystitis,
and the main treatment is to decrease the immunosuppression, with the risk of acute rejection of the
kidney graft. After BK reactivation, the virus is first detectable in the urine, with viremia developing
several weeks later. Quantitative BKV DNA in the plasma is the most widely used and preferred test for
the laboratory diagnosis of BKVAN and BKV-associated hemorrhagic cystitis, as BKV viremia has
higher positive predictive value (50%-60%) than BKV viruria for the diagnosis of BKVAN. Serial
monitoring of BKV DNA level in plasma is recommended to guide optimal immunosuppressant dosing
regimen. In those with BKVAN, clearance of BK viremia is a sign of resolution of the nephropathy.
Useful For: Detection and serial monitoring of BV virus-associated nephropathy in kidney transplant
recipients using plasma specimens Detection and serial monitoring of BV virus-associated hemorrhagic
cystitis in organ transplant recipients
Interpretation: The quantification range of this assay is 22 to 100,000,000 IU/mL (1.34 log to 8.00
log IU/mL), with a limit of detection (95% detection rate) at 22 IU/mL. An "Undetected" test result
indicates the absence of BK virus (BKV) DNA in the plasma. A test result of "<22 IU/mL (<1.34 log
IU/mL)" indicates that BKV DNA is detected in the plasma, but the assay cannot accurately quantify
the BKV DNA present below this level. A quantitative value (reported in IU/mL and log IU/mL)
indicates the level of BKV DNA (ie, viral load) present in the plasma. A test result of ">100,000,000
IU/mL (>8.00 log IU/mL)" indicates that BKV DNA level present in plasma is above 100,000,000
IU/mL (8.00 log IU/mL), and the assay cannot accurately quantify BKV DNA present above this level.
An "Inconclusive" result indicates that the presence or absence of BKV DNA in the plasma specimen
could not be determined with certainty after repeat testing in the laboratory, possibly due to polymerase
chain reaction inhibition or presence of interfering substance. Submission of a new specimen for testing
is recommended if clinically indicated.
Reference Values:
Undetected
Clinical References: 1. Bechert CJ, Schnadig VJ, Payne DA, Dong J: Monitoring of BK viral load
in renal allograft recipients by real time PCR assays. Am J Clin Pathol. 2010 Feb;133(2):242-250. doi:
10.1309/AJCP63VDFCKCRUUL 2. Hirsch HH, Randhawa P, AST Infectious Diseases Community of
Practice: BK polyomavirus in solid organ transplantation. Am J Transplant. 2013 Mar;13 Suppl
4:179-188. doi: 10.1111/ajt.12110 3. Hirsch HH, Randhawa PS, AST Infectious Diseases Community
of Practice: BK polyomavirus in solid organ transplantation-Guidelines from the American Society of
Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13528.
doi: 10.1111/ctr.13528 4. Muhsin SA, Wojciechowski D: BK virus in transplant recipients: current
perspectives. Transplant Research and Risk Management. 2019:11:47-58. doi: 10.2147/TRRM.S188021
UBKQN BK Virus DNA Detection and Quantification, Random, Urine

614568 Clinical Information: BK virus (BKV) is a circular, double-stranded DNA virus with an
approximately 5 kilobase-size genome in the polyomavirus family, of which 13 members of the family
are known, including the JC virus (JCV) and SV40. BKV shares about 75% of its DNA sequence with
JCV. Nearly 80% of the adult population worldwide have antibodies to both viruses, indicating previous
infection or exposure to these viruses. Initial infection with BKV is usually acquired in childhood,
mostly asymptomatic or manifesting as a mild flu-like illness. After primary infection, BKV establishes
latency in the kidney and bladder of the infected individual. In the setting of immunosuppression, the
virus reactivates and begins to replicate, triggering renal tubular cell lysis and viruria. As the
reactivation progresses, the virus multiplies and crosses into the bloodstream, causing viremia and
invading the kidney graft. In patients with kidney transplants, reactivation of BKV typically reaches
peak incidence at 3 months post-transplantation with BK viral replication in the kidney graft, causing
BKV-associated nephropathy (BKVAN), which manifests as kidney dysfunction that may result in
eventual loss of the transplanted kidney. Reactivation of BKV in the bladder can lead to hemorrhagic
cystitis. Currently, there are no FDA-approved antiviral agents or treatments for BKVAN or
BKV-associated hemorrhagic cystitis, and the main treatment is to decrease the immunosuppression
with risk of acute rejection of the kidney graft. After BK reactivation, the virus is first detectable in the
urine, with viremia developing several weeks later. Quantitative BKV DNA in the plasma is the most
widely used and preferred test for the laboratory diagnosis of BKVAN and BKV-associated
hemorrhagic cystitis, as BKV viremia has higher positive predictive value (50%-60%) than BKV viruria
for the diagnosis of BKVAN. Serial monitoring of BKV DNA level in plasma is recommended to guide
optimal immunosuppressant dosing regimen. In those with BKVAN, clearance of BK viremia is a sign
of resolution of the nephropathy.
Useful For: Detection and serial monitoring of BK virus- (BKV) associated nephropathy in kidney
transplant recipients using random urine specimens Detection and serial monitoring of BKV-associated
hemorrhagic cystitis in organ transplant recipients
log IU/mL), with a limit of detection (95% detection rate) at 12 IU/mL. An "Undetected" test result
indicates the absence of BK virus (BKV) DNA in the urine. A test result of "<200 IU/mL (<2.30 log
IU/mL)" indicates that BKV DNA is detected in the urine, but the assay cannot accurately quantify the
BKV DNA present below this level. A quantitative value (reported in IU/mL and log IU/mL) indicates the
level of BKV DNA (ie, viral load) present in the urine. A test result of ">100,000,000 IU/mL (>8.00 log
IU/mL)" indicates that BKV DNA level present in urine is above 100,000,000 IU/mL (8.00 log IU/mL),
and the assay cannot accurately quantify BKV DNA present above this level. An "Inconclusive" result
indicates that the presence or absence of BKV DNA in the urine specimen could not be determined with
certainty after repeat testing in the laboratory, possibly due to polymerase chain reaction inhibition or
presence of interfering substance. Submission of a new specimen for testing is recommended if clinically
indicated.
Clinical References: 1. Bechert CJ, Schnadig VJ, Payne DA, Dong J: Monitoring of BK viral load
in renal allograft recipients by real time PCR assays. Am J Clin Pathol. 2010 Feb;133(2):242-250. doi:
10.1309/AJCP63VDFCKCRUUL 2. Hirsch HH, Randhawa P, AST Infectious Diseases Community of
Practice: BK polyomavirus in solid organ transplantation. Am J Transplant. 2013 Mar;13(Suppl
4):179-188. doi: 10.1111/ajt.12110 3. Hirsch HH, Randhawa PS, AST Infectious Diseases Community of
Practice: BK polyomavirus in solid organ transplantation-Guidelines from the American Society of
Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13528. doi:
10.1111/ctr.13528 4. Muhsin SA, Wojciechowski D: BK virus in transplant recipients: current
perspectives. Transplant Research and Risk Management. 2019:11:47-58. doi: 10.2147/TRRM.S188021
BLPEP Black/White Pepper, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to black or white pepper Defining the allergen

Reference Values:
0 Negative

apply to all ages.
BLACK Blackberry, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to blackberry Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
BLAST Blastomyces Antibody, Enzyme Immunoassay, Serum
35793 Clinical Information: Blastomyces dermatitidis, an adimorphic fungus, is endemic throughout the
Midwestern, south-central, and southeastern Unites States, particularly in regions around the Ohio and
Mississippi river valley, the Great Lakes and the Saint Lawrence River. It is also found in regions of
Canada. Blastomyces is an environmental fungus, preferring moist soil and decomposing organic matter,
which produces fungal spores that are released and inhaled by animals or humans. At body temperature,
the spores mature into yeast, which can stay in the lungs or disseminate through the bloodstream to other
parts of the body. Recently, through phylogenetic analysis, Blastomyces dermatitidis has been separated
into two distinct species; B. dermatitidis and Blastomyces gilchristii, both able to cause blastomycosis in
infected patients. Interestingly, B. dermatitidis infections are associated more frequently with
dissemination, particularly in elderly patients, smokers and immunocompromised hosts, while B.
gilchristii has primarily been associated with pulmonary and constitutional symptoms. Approximately
50% of patients infected with Blastomyces will develop symptoms, which are frequently non-specific and,
include fever, cough, night sweats, myalgia or arthralgia, weight loss, chest pain and fatigue. Typically
symptoms appear anywhere from 3 weeks to 3 months following infection. Diagnosis of blastomycosis
relies on a combination of assays, including culture and molecular testing on appropriate specimens and
serologic evaluation for both antibodies to and antigen released from Blastomyces. Although culture
remains the gold standard method and is highly specific, the organism can take several days to weeks to
grow, and sensitivity is diminished in cases of acute or localized disease. Similarly, molecular testing
offers high specificity and a rapid turnaround time, however, sensitivity is imperfect. Detection of an
antibody response to Blastomyces offers high specificity, however, results may be falsely negative in
acutely infected patients and in immunosuppressed patients.
Useful For: Aiding in the diagnosis of blastomycosis

Interpretation: A positive result indicates that IgG and/or IgM antibodies to Blastomyces were
detected. The presence of antibodies is presumptive evidence that the patient was or is currently infected
with (or was exposed to) Blastomyces. A negative result indicates that antibodies to Blastomyces were not
detected. The absence of antibodies is presumptive evidence that the patient was not infected with
Blastomyces. However, the specimen may have been obtained before antibodies were detectable or the
patient may be immunosuppressed. If infection is suspected, another specimen should be collected 7 to 14
days later and submitted for testing. Specimens testing positive or equivocal will be submitted for further
testing by another conventional serologic test (eg, SBL / Blastomyces Antibody by Immunodiffusion,
Serum).
Reference Values:
Negative
Clinical References: Kaufman L, Kovacs JA, Reiss E: Clinical immunomycology. In: Rose NR, De
Macario EC, Folds JD, et al, eds. Manual of Clinical and Laboratory Immunology. ASM Press;
1997:588-589
FBAI Blastomyces Antibody, Immunodiffusion

75757 Clinical Information: Blastomycosis, caused by the fungus blastomyces dermatitidis, occurs most
commonly in men ages 20-69 years. Infection may be transient or lead to chronic, progressive pulmonary
disease.
Interpretation: A positive result is diagnostic of active or recent blastomycosis and is found in

approximately 80% of proven cases of blastomycosis.
Reference Values:
Negative
UBLAS Blastomyces Antigen, Quantitative, Enzyme Immunoassay,
607746 Random, Urine
Clinical Information: Blastomyces dermatitidis is endemic throughout the Midwestern, south
central, and Southeastern United States, particularly in regions around the Ohio and Mississippi river
valleys, the Great Lakes, and the Saint Lawrence River. It is also found in regions of Canada.
Blastomyces species are dimorphic fungi, preferring moist soil and decomposing organic matter, which
produces fungal spores that are released and inhaled by humans. At body temperature, spores mature
into yeast, which may remain in the lungs or disseminate through the bloodstream to other parts of the
body. Through phylogenetic analysis, B. dermatitidis has been separated into 2 distinct species: B
dermatitidis and Blastomyces gilchristii, both able to cause blastomycosis. B dermatitidis infections are
frequently associated with dissemination, particularly in older patients, smokers, and
immunocompromised hosts, while B gilchristii has primarily been associated with pulmonary and
constitutional symptoms. Additional species of Blastomyces have recently been discovered and
characterized, however the performance characteristics of this assay for these species are unknown.
Approximately half of patients infected with Blastomyces will develop symptoms, which are frequently
nonspecific, including fever, cough, night sweats, myalgia or arthralgia, weight loss, dyspnea, chest
pain, and fatigue. Symptoms may appear anywhere from 3 weeks to 3 months following infection.
Diagnosis of blastomycosis relies on a combination of assays, including culture and molecular testing
performed on appropriate specimens, and serologic evaluation for both antibodies to and antigen
released from Blastomyces. Although culture remains the gold standard method and is highly specific,
the organism can take several days to weeks to grow and sensitivity is diminished in cases of acute or
localized disease. Similarly, molecular testing offers high specificity and a rapid turnaround time,
however sensitivity is imperfect. Detection of an antibody response to Blastomyces offers high
specificity, however results may be falsely negative in patients who are acutely ill or are
immunosuppressed.
Useful For: Diagnosis of infection with Blastomyces dermatitidis Monitor antigen levels following
initiation of antifungal treatment
Interpretation: Not Detected: No Blastomyces antigen detected. False negative results may occur.
Repeat testing on a new specimen should be considered if clinically indicated. Detected: Blastomyces
antigen detected, below the limit of quantification (<1.3 ng/mL). Results should be correlated with
clinical presentation, exposure history, and other diagnostic procedures, including culture, serology,
histopathology, and radiographic findings, for the diagnosis of blastomycosis. False-positive results may
occur in patients with other fungal infections, including Histoplasma. Detected: Blastomyces antigen
detected. The reportable range of this assay is 1.3 to 20.0 ng/mL. Results should be correlated with
clinical presentation, exposure history, and other diagnostic procedures, including culture, serology,
occur in patients with other fungal infections, including Histoplasma. Detected: Blastomyces antigen
detected, above the limit of quantification (>20.0 ng/mL). Results should be correlated with clinical
presentation, exposure history, and other diagnostic procedures, including culture, serology,
occur in patients with other fungal infections, including Histoplasma.
Reference Values:
BLASTOMYCES ANTIGEN RESULT
Not detected
BLASTOMYCES ANTIGEN VALUE

Not detected: 0.0 ng/mL
Detected: <1.3 ng/mL
Detected: 1.3-20.0 ng/mL
Detected: >20.0 ng/mL
Clinical References: 1. McBride JA, Gauthier GM, Klein BS: Clinical manifestations and
treatment of Blastomycosis. Clin Chest Med. 2017 Sep;38(3):435-449 2. Saccente M, Woods GL:
Clinical and laboratory update on Blastomycosis. Clin Microbiol Rev. 2010 Apr;23(2):367-381. doi:
10.1128/CMR.00056-09
ALBLD Bleeding Diathesis Profile, Limited, Plasma

603305 Clinical Information: Bleeding problems may be associated with a wide variety of coagulation
abnormalities or may be due to problems not associated with coagulation (trauma and surgery as obvious
examples). A partial listing of causes follows. -Deficiency or functional abnormality (congenital or
acquired) of any of the following coagulation proteins: fibrinogen (factor I), factor II (prothrombin),
factor V, factor VII, factor VIII (hemophilia A), factor IX (hemophilia B), factor X, factor XI (hemophilia
C; bleeding severity notÂ always proportionate to factor level), factor XIII (fibrin-stabilizing factor), von
Willebrand factor (VWF antigen and activity), and alpha-2 plasmin inhibitor and plasminogen activator
inhibitor (PAI-I; severe deficiency in rare cases). Neither alpha-2 plasmin inhibitor nor PAI-I are included
as a routine bleeding diathesis assay component, but either can be performed if indicated or requested.
-Deficiency (thrombocytopenia) or functional abnormality of platelets such as congenital (Glanzmann
thrombasthenia, Bernard-Soulier syndrome, storage pool disorders, etc) and acquired (myeloproliferative
disorders, uremia, drugs, etc) disorders. Platelet function abnormalities cannot be studied on mailed-in
specimens. -Specific factor inhibitors (most commonly directed against factor VIII); factor inhibitors
occur in 10% to15% of the hemophilia population and are more commonly associated with severe
deficiencies of factor VIII or IX (antigen <1%). The inhibitor appears in response to transfusion therapy
with factor concentrates with no correlation of occurrence and amount of therapy. Factor VIII inhibitors
may occur spontaneously in the postpartum patient, with certain malignancies, in association with
autoimmune disorders (eg, rheumatoid arthritis, systemic lupus erythematosus), in the elderly, and for no
apparent reason. -Other acquired causes of increased bleeding include paraproteinemia; other
factor-specific inhibitors, including those against factor V, factor XI; or virtually any of the coagulation
proteins. -Acute disseminated intravascular coagulation/intravascular coagulation and fibrinolysis
(DIC/ICF), which is a fairly common cause of bleeding. Bleeding can also occur in patients with chronic
ICF.
Useful For: Detection of the more common potential causes of abnormal bleeding (eg, factor
deficiencies/hemophilia, von Willebrand disease, factor-specific inhibitors) and a simple screen to
evaluate for an inhibitor or severe deficiency of factor XIII (rare) This test is not useful for assessing
platelet function (eg, congenital or acquired disorders such as Glanzmann thrombasthenia,
Bernard-Soulier syndrome, storage pool disease, myeloproliferative disease, associated platelet
dysfunction), which requires fresh platelets

Reference Values:
Clinical References: Boender J, Kruip MJ, Leebeek FW: A Diagnostic Approach to Mild Bleeding
Disorders. J Thromb Haemost 2016;Aug;14(8):1507-1516 doi: 10.1111/jth.13368.
BTROP Blomia tropicalis, IgE, Serum

Useful For: Aiding in the diagnosis of an allergic disease and defining the allergens responsible for
eliciting signs and symptoms Identifying allergens that may be responsible for allergic disease and/or
anaphylactic episode, confirming sensitization to particular allergens prior to beginning immunotherapy,
and investigating the specificity of allergic reactions to insect venom allergens, drugs, or chemical
allergens

Reference Values:
0 Negative

apply to all ages.
Management by Laboratory Methods. 21st edition. Edited by RA McPherson, MR Pincus. WB
Saunders Company, New York, 2007, Part VI, pp 961-971
BUN Blood Urea Nitrogen (BUN), Serum

81793 Clinical Information: Urea is the final degradation product of protein and amino acid metabolism.
In protein catabolism, the proteins are broken down to amino acids and deaminated. The ammonia
formed in this process is synthesized to urea in the liver. This is the most important catabolic pathway
for eliminating excess nitrogen in the human body. Increased blood urea nitrogen (BUN) may be due to
prerenal causes (cardiac decompensation, water depletion due to decreased intake and excessive loss,
increased protein catabolism, and high protein diet), renal causes (acute glomerulonephritis, chronic
nephritis, polycystic kidney disease, nephrosclerosis, and tubular necrosis), and postrenal causes (eg, all
types of obstruction of the urinary tract, such as stones, enlarged prostate gland, tumors). The
determination of serum BUN currently is the most widely used screening test for the evaluation of
kidney function. The test is frequently requested along with the serum creatinine test since simultaneous
determination of these 2 compounds appears to aid in the differential diagnosis of prerenal, renal and
postrenal hyperuremia.
Useful For: Screening test for evaluation of kidney function

Reference Values:
Males
Females
Clinical References: Lamb EJ, Jones GRD: Kidney function tests. In: Rifai N, Horvath AR, Wittwer
BWOR Blood Worm, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to blood worm Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
MUSS Blue Mussel, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to blue mussel Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
FBLUG Blueberry IgG

Reference Values:
BLUE Blueberry, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to blueberry Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
BOB1 BOB-1 Immunostain, Technical Component Only

70365 Clinical Information: BOB-1 is a transcriptional co-activator that interacts with the transcription
factors OCT-1 or OCT-2 in regulating transcription of immunoglobulin genes. In normal tonsil, the
germinal center B cells all express BOB-1, while only scattered cells in the mantle zone express this
protein. Expression of BOB-1, OCT-2, and PU.1 transcription factors are often down-regulated in classic
Hodgkin lymphomas, in contrast to many cases of diffuse large B-cell lymphoma.

Interpretation: This test does not include pathologist interpretation only technical performance of the
stain. If interpretation is required order PATHC / Pathology Consultation for a full diagnostic evaluation
or second opinion of the case. The positive and negative controls are verified as showing appropriate
included on the slide, a scanned image of the relevant quality control tissue is available upon request.
Contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's
clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Herbeck R, Teodorescu Brinzeu D, Giubelan M, et al: B-cell transcription
factors Pax-5, Oct-2, BOB.1, Bcl-6, and MUM1 are useful markers for the diagnosis of nodular
lymphocyte predominant Hodgkin lymphoma. Rom J Morphol Embryol. 2011;52(1):69-74 2. Advani AS,
Lim K, Gibson S, et al: OCT-2 expression and OCT-2/BOB.1 co-expression predict prognosis in patients
with newly diagnosed acute myeloid leukemia. Leuk Lymphoma. 2010 Apr;51(4):606-612. doi:
10.3109/10428191003592735 3. Hoeller S, Zihler D, Zlobec I, et al: BOB.1, CD79a and cyclin E are the
most appropriate markers to discriminate classical Hodgkin's lymphoma from primary mediastinal large
B-cell lymphoma. Histopathology. 2010 Jan;56(2):217-228. doi: 10.1111/j.1365-2559.2009.03462.x
BAP Bone Alkaline Phosphatase, Serum

82985 Clinical Information: Bone alkaline phosphatase (BAP) is the bone-specific isoform of alkaline
phosphatase. A glycoprotein that is found on the surface of osteoblasts, BAP reflects the biosynthetic
activity of these bone-forming cells. BAP has been shown to be a sensitive and reliable indicator of
bone metabolism.(1) Normal bone is constantly undergoing remodeling in which bone degradation or
resorption is balanced by bone formation. This process is necessary for maintaining bone health. If the
process becomes uncoupled and the rate of resorption exceeds the rate of formation, the resulting bone
loss can lead to osteoporosis and, consequently, a higher susceptibility to fractures. Osteoporosis is a
metabolic bone disease characterized by low bone mass and abnormal bone microarchitecture. It can
result from a number of clinical conditions including states of high bone turnover, endocrine disorders
(primary and secondary hyperparathyroidism and thyrotoxicosis), osteomalacia, kidney failure,
gastrointestinal diseases, long-term corticosteroid therapy, multiple myeloma, and cancer metastatic to
the bones.(2) Paget disease is another common metabolic bone disease caused by excessive rates of
bone remodeling resulting in local lesions of abnormal bone matrix. These lesions can result in fractures
or neurological involvement. Antiresorptive therapies are used to restore the normal bone structure.
Useful For: Diagnosis and assessment of severity of metabolic bone disease including Paget disease,
osteomalacia, and other states of high bone turnover Monitoring efficacy of antiresorptive therapies
including postmenopausal osteoporosis treatment The assay is not intended as a screening test for
osteoporosis. Measurements of bone turnover markers are not useful for the diagnosis of osteoporosis;
diagnosis of osteoporosis should be made on the basis of bone density.
Interpretation: Bone alkaline phosphatase (BAP) concentration is high in Paget disease and
osteomalacia.(3) Antiresorptive therapies lower BAP from baseline measurements in Paget disease,
osteomalacia, and osteoporosis. Several studies have shown that antiresorptive therapies for
management of osteoporosis patients should result in at least a 25% decrease in BAP within 3 to 6
months of initiating therapy.(4,5) BAP also decreases following antiresorptive therapy in Paget
disease.(6) When used as a marker for monitoring purposes, it is important to determine the critical
difference (or least significant change). The critical difference is defined as the difference between 2
determinations that may be considered to have clinical significance. The critical difference for this
method was calculated to be 25% with a 95% confidence level.(1)
Reference Values:
Males
<2 years: 25-221 mcg/L
2-9 years: 27-148 mcg/L
10-13 years: 35-169 mcg/L
14-17 years: 13-111 mcg/L
Adults: < or =20 mcg/L
Females
<2 years: 28-187 mcg/L
2-9 years: 31-152 mcg/L
10-13 years: 19-177 mcg/L
14-17 years: 7-41 mcg/L
Adults
Premenopausal: < or =14 mcg/L
Postmenopausal: < or =22 mcg/L
Clinical References: 1. Kress BC: Bone alkaline phosphatase: methods of quantitation and clinical
utility. J Clin Ligand Assay. 1998;21(2):139-148 2. Kuo TR, Chen CH: Bone biomarker for the clinical
assessment of osteoporosis: recent developments and future perspectives. Biomark Res. 2017 May;5:18.
doi: 10.1186/s40364-017-0097-4 3. Sharma U, Pal D, Prasad R: Alkaline phosphatase: an overview.
Indian J Clin Biochem. 2014 Jul;29(3):269â€“278. doi: 10.1007/s12291-013-0408-y 4. Kress BC,
Mizrahi IA, Armour KW, et al: Use of bone alkaline phosphatase to monitor alendronate therapy in
individual postmenopausal osteoporotic women. Clin Chem. 1999 Jul;45(7):1009-1017 5. Garnero P,
Darte C, Delmas PD: A model to monitor the efficacy of alendronate treatment in women with
osteoporosis using a biochemical marker of bone turnover. Bone. 1999 Jun;24(6):603-609 6. Raisz L,
Smith JA, Trahiotism M, et al: Short-term risedronate treatment in postmenopausal women: Effects on
biochemical markers of bone turnover. Osteoporos Int. 2000;11:615-620
BHISI Bone Histomorphometry, Consultant Interpretation, Slides Only

70314 Clinical Information: Bone histomorphometry is a very sophisticated procedure utilizing full
thickness bone biopsy. Techniques such as 2-time interval labeling with tetracycline permit the direct
measurement of the rate of bone formation. The information derived is useful in the diagnosis of
metabolic bone diseases including renal osteodystrophy, osteomalacia, and osteoporosis. Other obtainable
information relate to disorders such as aluminum toxicity and iron abnormalities.
Useful For: Identifying undetermined metabolic bone disease in submitted slide specimens Diagnosing
renal osteodystrophy Diagnosing osteomalacia Diagnosing osteoporosis Diagnosing Paget disease
Assessing the effects of therapy Identifying disorders of the hematopoietic system Diagnosing aluminum
toxicity Identifying the presence of iron in the bone
Interpretation: Clinical endocrinologists trained in histomorphometric techniques review and interpret

the histological appearance. A pathologist interprets the bone marrow from a hematoxylin and
eosin-stained slide. No histomorphometric values are given.
Reference Values:
The laboratory will provide an interpretive report.
Clinical References: Recker RR: Bone Histomorphometry: Techniques and Interpretation. Boca
Raton, FL, CRC Press, 1983
BHISC Bone Histomorphometry, Gross Microscopic Exam

70312 Clinical Information: Bone histomorphometry is a very sophisticated procedure utilizing
full-thickness bone biopsy. Techniques such as 2-time interval labeling with tetracycline permit the direct
measurement of the rate of bone formation. The information derived is useful in the diagnosis of
metabolic bone diseases, including renal osteodystrophy, osteomalacia, and osteoporosis, and other
disorders such as aluminum toxicity and iron abnormalities.
Useful For: Undetermined metabolic bone disease in wet tissue specimens Renal osteodystrophy
Osteomalacia Osteoporosis Paget disease Assessing effects of therapy Identification of some disorders of
the hematopoietic system Aluminum toxicity Presence of iron in the bone
Interpretation: Computer-generated histomorphometric values are given for adequate specimens.

Normal histomorphometric values for iliac crest are provided (female only). An interpretive report will be
provided.
Reference Values:
The laboratory will provide a quantitative and an interpretive report.
Clinical References: Recker RR: Bone Histomorphometry: Techniques and Interpretation. Boca
Raton, FL, CRC Press, 1983
BMAPC Bone Marrow Aspirate (Bill Only)
BMBPC Bone Marrow Biopsy (Bill Only)

BMCPC Bone Marrow Clot (Bill Only)

BPRP Bordetella pertussis and Bordetella parapertussis, Molecular

80910 Detection, PCR, Varies
Clinical Information: Bordetella pertussis is the highly contagious etiological agent of pertussis or
whooping cough. Bordetella parapertussis causes a similar, but generally less severe illness. Despite
vaccination efforts, B pertussis remains common in the United States, underscoring the need for
effective diagnostic tests. In the United States, pertussis is most common in the late summer months.
Pertussis vaccination does not prevent B parapertussis infection, which generally occurs in a younger
age group than disease caused by B pertussis. Diagnosis of pertussis is based on having a high clinical
index of suspicion for the infection, along with confirmation by laboratory testing. Laboratory testing
methods include nucleic acid amplification tests (eg, PCR), serology, culture and direct fluorescent
antibody testing. Culture and direct fluorescent antibody testing are limited by low sensitivity, rendering
nucleic acid amplification tests and serology the tests of choice. The Centers for Disease Control and
Prevention recommends PCR testing for patients suspected of having acute pertussis. B pertussis PCR
detects roughly twice as many cases as culture. B pertussis DNA can be detected up to 4 weeks, or
longer (up to 8 weeks in our experience),(1) after symptom onset. However, over time, the amount of B
pertussis and B parapertussis DNA will diminish, rendering the assay less sensitive. A serologic
response to B pertussis is typically mounted by 2 weeks following infection and, therefore, detection of
IgG-class antibodies to pertussis toxin (PT), which is only produced by B pertussis, can be a useful
adjunct for diagnosis at later stages of illness at a time when the amount of B pertussis may be below
the limit of detection of the PCR assay.
Useful For: Preferred diagnostic test for the detection of Bordetella pertussis or Bordetella
parapertussis
Interpretation: A positive result indicates the presence of DNA from Bordetella pertussis or B
parapertussis. In some cases, a patient may test positive for both B pertussis and B parapertussis.
Cross-reactivity with B holmesii and B bronchiseptica may occur with the B pertussis assay (see
Cautions). A negative result indicates the absence of detectable B pertussis and B parapertussis DNA in
the specimen but does not negate the presence of organism or active or recent disease (known inhibition
rate of <1%) and may occur due to inhibition of PCR, sequence variability underlying primers and/or
probes, or the presence of B pertussis or B parapertussis in quantities less than the limit of detection of
the assay. Additionally, patients presenting late after symptom onset may test negative; in such cases,
testing for B pertussis antibody, IgG, in serum may be considered.
Reference Values:
Not applicable
Clinical References: 1. Theofiles AG, Cunningham SA, Chia N, et al: Pertussis outbreak,
southeastern Minnesota, 2012. Mayo Clin Proc 2014 Oct;89(10):1378-1388 2. Guthrie JL, Robertson AV,
Tang P, et al: Novel duplex real-time PCR assay detects Bordetella holmesii in specimens from patients
with pertussis-like symptoms in Ontario, Canada. J Clin Microbiol 2010;48:1435-1437 3. Sloan LM,
Hopkins MK, Mitchell PS, et al: Multiplex LightCycler PCR assay for detection and differentiation of
Bordetella pertussis and Bordetella parapertussis in nasopharyngeal specimens. J Clin Microbiol
2002;40:96-100
BORDG Bordetella pertussis Antibody, IgG, Serum

64780 Clinical Information: Bordetella pertussis, the causative agent of whooping cough, is highly
contagious and remains endemic in the United States despite the high rate of vaccination. Acute B
pertussis infections are typically diagnosed by culture or nucleic acid amplification testing (NAAT).
However, symptomatic adults and adolescents often seek medical attention later in the course of infection,
at which time the sensitivity of these 2 methods to detect the infectious agent decreases. A serologic
response to B pertussis is typically mounted 2 weeks following infection, and therefore, detection of
IgG-class antibodies to pertussis toxin (PT), which is only produced by B pertussis, can be a useful
adjunct for diagnosis at later stages of illness. Prior to testing, providers should review whether the patient
was recently vaccinated using the Tdap (Tetanus-Diphtheria-acellular Pertussis) or DTap vaccines. The
acellular pertussis vaccine contains 1 to 5 B pertussis antigens, including filamentous hemagglutinin,
pertactin, 2 fimbrial agglutinogens, and significant levels of PT. Therefore, recent vaccination for B
pertussis, specifically within the last 2 to 6 months, may lead to a positive result by the anti-PT IgG assay,
and knowledge of the patient's vaccination history is important for accurate result interpretation.
Useful For: Diagnosis of recent infection with Bordetella pertussis in patients with symptoms
consistent with whooping cough for 2 or more weeks This test should not be used in neonates, young
infants or in children between the ages of 4 to 7 years as the routine childhood vaccine schedule may
interfere with result interpretation. This test should not be used as a test of cure, to monitor response to
treatment, or to determine vaccine status.
Interpretation: Negative (<40 IU/mL): No IgG antibodies to pertussis toxin (PT) detected. Results
may be falsely negative in patients with less than 2 weeks of symptoms. Borderline (40-<100 IU/mL):
Recommend follow-up testing in 10 to 14 days if clinically indicated. Positive (> or =100 IU/mL): IgG
antibodies to pertussis toxin (PT) detected. Results suggest recent infection with or recent vaccination
against Bordetella pertussis.
Reference Values:
> or =100 IU/mL (positive)
> or = 40-<100 IU/mL (borderline)
<40 IU/mL (negative)
Clinical References: 1. Leber AL: Pertussis: relevant species and diagnostic update. Clin Lab Med.
2014;34:237-255 2. Guiso N, Berbers G, Fry NK, et al: What to do and what not to do in serological
diagnosis of pertussis: recommendation from EU reference laboratories. Eur J Clin Microbiolo Infect Dis.
2011;30(3):307-312 3. Andre P, Caro V, Njamkepo E, et al: Comparison of serological and real-time PCR
assays to diagnose Bordetella pertussis infection in 2007. J Clin Microbiol. 2008;46(5):1672-1677
BOAC Boron, Serum/Plasma

9723 Interpretation: Specimens for elemental testing should be collected in certified metal-free containers.
Elevated results for elemental testing may be caused by environmental contamination at the time of
specimen collection and should be interpreted accordingly. It is recommended that unexpected elevated
results be verified by testing another specimen.
Reference Values:
Normally: Less than 100 mcg/L
BMIYB Borrelia miyamotoi Detection PCR, Blood

64970 Clinical Information: Borrelia miyamotoi is a spirochetal bacterium that is closely related to the
Borrelia species that cause tick-borne relapsing fever (TBRF), and it is more distantly related to the
Borrelia species that cause Lyme disease. This organism causes a febrile illness like TBRF, with body
and join pain, fatigue, and rarely, rash, and has been detected in Ixodes scapularis and I pacificus ticks.
These ticks are also the vectors for Lyme disease, anaplasmosis, and babesiosis. The preferred method
for detecting B miyamotoi is real-time PCR. Less sensitive and specific methods for detecting B
miyamotoi and agents of TBRF include identification of spirochetes in peripheral blood films, spinal
fluid preparations, and serologic testing. This assay does not detect the Borrelia species that cause Lyme
disease.
Useful For: Aids in the diagnosis of Borrelia miyamotoi infection in conjunction with clinical
findings Preferred method for detection of B miyamotoi using blood specimens
Interpretation: A positive result indicates the presence of Borrelia miyamotoi DNA and is
they should be correlated with symptoms and clinical findings of tick-borne relapsing fever.
Reference Values:
Negative
Clinical References: 1. Gugliotta JL, Goethert HK, Berardi VP, Telford SR III:
Meningoencephalitis from Borrelia miyamotoi in an Immunocompromised Patient. N Engl J Med
2013;368:240-245 2. Fomenko NV, Borgoyakov VY, Panov VV: Genetic Features of DNA of Borrelia
miyamotoi Transmitted by Ixodes persulcatus. Mol Gen Microbiol Virol 2011;26:60-65 3. Platonov AE,
Karan LS, Kolyasnikova NM, et al: Humans Infected with Relapsing Fever Spirochete Borrelia
miyamotoi, Russia. Emerg Infect Dis 2011;17:1816-1823
BMIYC Borrelia miyamotoi Detection PCR, Spinal Fluid

64969 Clinical Information: Borrelia miyamotoi is a spirochetal bacterium that is closely related to the
Borrelia species that cause tick-borne relapsing fever (TBRF), and it is more distantly related to the
Borrelia species that cause Lyme disease. This organism causes a febrile illness like TBRF, with body
and join pain, fatigue, and rarely, rash, and has been detected in Ixodes scapularis and I pacificus ticks.
These ticks are also the vectors for Lyme disease, anaplasmosis, and babesiosis. The preferred method
for detecting B miyamotoi is real-time PCR. Less sensitive and specific methods for detecting B
miyamotoi and agents of TBRF include identification of spirochetes in peripheral blood films,
cerebrospinal fluid (CSF) preparations, and serologic testing. This assay does not detect the Borrelia
species that cause Lyme disease.
Useful For: Aids in the diagnosis of Borrelia miyamotoi infection in conjunction with clinical
findings
Interpretation: A positive result indicates the presence of Borrelia miyamotoi DNA and is
they should be correlated with symptoms and clinical findings of tick-borne relapsing fever.
Reference Values:
Negative
Clinical References: 1. Gugliotta JL, Goethert HK, Berardi VP, Telford SR III:
Meningoencephalitis from Borrelia miyamotoi in an Immunocompromised Patient. N Engl J Med
2013;368:240-245 2. Fomenko NV, Borgoyakov VY, Panov VV: Genetic Features of DNA of Borrelia
miyamotoi Transmitted by Ixodes persulcatus. Mol Gen Microbiol Virol 2011;26:60-65 3. Platonov AE,
Karan LS, Kolyasnikova NM, et al: Humans Infected with Relapsing Fever Spirochete Borrelia
miyamotoi, Russia. Emerg Infect Dis 2011;17:1816-1823
BOT Botrytis cinerea, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Botrytis cinerea Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
BOV Bovine Serum Albumin, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to bovine serum albumin Defining the allergen
responsible for eliciting signs and symptoms Identifying allergens: - Responsible for allergic disease
and/or anaphylactic episode - To confirm sensitization prior to beginning immunotherapy - To
Testing for IgE antibodies is not useful in patients previously treated with immunotherapy to determine
if residual clinical sensitivity exists, or in patients in whom the medical management does not depend
upon identification of allergen specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
BXMPL Box Elder/Maple, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to box elder/maple Defining the allergen

Reference Values:
0 Negative

apply to all ages.
BRACH Brachyury Immunostain, Technical Component Only

70366 Clinical Information: Brachyury expression is required for the specification of mesodermal identity,
representing one of the key genes regulating notochord formation. The brachyury gene, a T-box
transcription factor, is uniquely expressed in chordomas.
Useful For: Aiding in the identification of chordomas

Interpretation: This test does not include pathologist interpretation only technical performance of the
Clinical References: 1. Sangoi AR, Dulai MS, Beck AH, et al: Distinguishing chordoid
meningiomas from their histologic mimics: an immunohistochemical evaluation. Am J Surg Pathol. 2009
May;33(5):669-681. doi: 10.1097/PAS.0b013e318194c566 2. Sangoi AR, Karamchandani J, Lane B, et
al: Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ
cell tumors: a study of 305 cases. Mod Pathol. 2011 Mar;24(3):425-429. doi:
10.1038/modpathol.2010.196 3. Kikuchi Y, Yamaguchi T, Kishi H, et al: Pulmonary tumor with
notochordal differentiation: report of 2 cases suggestive of benign notochordal cell tumor of extraosseous
origin. Am J Surg Pathol. 2011 Aug;35(8):1158-1164. doi: 10.1097/PAS.0b013e318220e085
BBRAF BRAF Analysis (Bill Only)

BRAFV BRAF V600E Immunostain, Technical Component Only
70367 Clinical Information: BRAF is a serine/threonine protein kinase and a member of the Raf family.
The BRAF V600E alteration leads to constitutive activation of the mitogen activated protein kinase
pathway, which plays a role in cell proliferation and tumorigenesis. This genetic alteration has been
detected in a variety of tumors such as melanoma, colorectal cancer, papillary thyroid carcinoma, hairy
cell leukemia, Langerhans cell histiocytosis, and pleomorphic xanthoastrocytomas.
Useful For: Identification of BRAF V600E-mutated protein

Interpretation: This test does not include pathologist interpretation: only technical performance of
upon request. Contact 855-516-8404. Interpretation of this test should be performed in the context of the
Clinical References: 1. Ida C, Vrana JA, Rodriguez FJ, et al: Immunohistochemistry is highly
sensitive and specific for detection of BRAF V600E mutation in pleomorphic xanthoastrocytoma. Acta
Neuopath communications 2013;1:20 2. Capper D, Berghoff AS, Magerle M, et al:
Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with
brain metastases. Acta Neuropathol 2012;123(2):223-233 3. Andrulis M, Penzel R, Weichert W, et al:
Application of a BRAF V600E Mutation-specific Antibody for the Diagnosis of Hairy Cell Leukemia.
Am J Surg Pathol 2012;36(12):1796-1800 4. Koperek O, Kornauth C, Capper D, et al:
Immunohistochemical detection of the BRAF V600E-mutated protein in papillary thyroid carcinoma.
Am J Surg Pathol 2012;36(6):844-850 5. Skorokhod A, Capper D, von Deimling A, et al: Detection of
BRAF V600E mutations in skin metastases of malignant melanoma by monoclonal antibody VE1. J Am
Acad skin metastases of malignant melanoma by monoclonal antibody VE1. J Am Acad Dermatol
2012;67(3):488-491
BRAFD BRAF V600E/V600K Somatic Mutation Analysis, Tumor

608305 Clinical Information: This test assesses for somatic (tumor-specific) BRAF V600E and V600K
alterations. The BRAF gene is a member of the mitogen-activated protein/extracellular signal-regulated
(MAP/ERK) kinase pathway, which plays a role in cell proliferation and differentiation. Dysregulation
of this pathway is a key factor in tumor progression and BRAF alterations occur frequently in many
different tumor types. BRAF variant analysis aids in the diagnosis of cancer types including anaplastic
and papillary thyroid carcinoma, hairy cell leukemia, and papillary craniopharyngioma. BRAF V600E
and V600K alterations are associated with response or resistance to specific targeted therapies in
cancers such as melanoma, colorectal cancer, and lung cancer. Targeted cancer therapies are defined as
antibody or small molecule drugs that block the growth and spread of cancer by interfering with specific
cell molecules involved in tumor growth and progression. Multiple targeted therapies have been
approved by the US Food and Drug Administration (FDA) for treatment of specific cancers. Molecular
genetic profiling is often needed to identify targets amenable to targeted therapies and to minimize
treatment costs and therapy-associated risks. BRAF variant analysis can provide helpful diagnostic
information in the context of evaluation for Lynch syndrome. See Lynch Syndrome Testing Algorithm
in Special Instructions.
Useful For: Therapy selection for patients with cancer (eg, melanomas that may respond to BRAF
inhibitors, colon cancers than may not respond to EGFR inhibitors) Aiding in the diagnosis/prognosis of
certain cancers (eg, hairy cell leukemia, papillary thyroid cancers, and association with aggressiveness)
Aid in determining risk for Lynch syndrome (eg, an adjunct to negative MLH1 germline testing in cases
where colon tumor demonstrates MSI-H and loss of MLH1 protein expression)

Reference Values:
Clinical References: 1. Chapman PB, Hauschild A, Robert C, et al: BRIM-3 Study Group.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011
Jun;364(26):2507-2516 2. Di Nicolantonio F, Martini M, Molinari F, et al: Wild-type BRAF is required
for response to Panitumumab or Cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;
26(35):5705-5712 3. Hyman DM, Puzanov I, Subbiah V, et al: Vemurafenib in Multiple Nonmelanoma
Cancers with BRAF V600 Mutations. N Engl J Med. 2015 Aug 20;373(8):726-736 4. Domingo E, Laiho
P, Ollikainen M, et al: BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic
testing. J Med Genet. 2004;41(9):664-668
FBNC1 Brazil Nut Component rBer e 1

75583 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10 - 0.34 Equivocal/Borderline 1
0.35 - 0.69 Low Positive 2 0.70 - 3.49 Moderate Positive 3 3.50 - 17.49 High Positive 4 17.50 - 49.99
Very High Positive 5 50.00 - 99.99 Very High Positive 6 >99.99 Very High Positive
Reference Values:
<0.10 kU/L
BRAZ Brazil Nut, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Brazil nut Defining the allergen responsible for

Reference Values:
0 Negative
apply to all ages.
HBOCZ BRCA1/BRCA2 Genes, Full Gene Analysis, Varies

614570 Clinical Information: Hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal
dominant hereditary cancer syndrome associated with germline variants in the BRCA1 or BRCA2
genes. Variants within BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian
cancer families.(1,2) However, there are additional genes that are known to be associated with
hereditary breast and ovarian cancer syndromes. See BRGYP / Hereditary Breast/Gynecologic Cancer
Panel, Varies. HBOC syndrome is predominantly characterized by early-onset breast cancer and ovarian
cancer. Individuals with breast and ovarian cancer are also at increased risks for prostate, pancreatic,
and male breast cancers. Some individuals develop multiple primary or bilateral cancers.(1,2)
Individuals with biallelic pathogenic variants in BRCA1 and BRCA2 are at risk for Fanconi anemia, an
autosomal recessive bone marrow failure syndrome. Of note, there are several other genes known to
cause Fanconi anemia.(1) The National Comprehensive Cancer Network and the American Cancer
Society provide recommendations regarding the medical management of individuals with HBOC
syndrome.(2-4)
Useful For: Evaluation for patients with a personal or family history suggestive of hereditary breast
and ovarian cancer (HBOC) syndrome Establishing a diagnosis of HBOC syndrome allowing for
targeted cancer surveillance based on associated risks Identifying variants within genes known to be
associated with increased risk for HBOC syndrome allowing for predictive testing of at-risk family
members Therapeutic eligibility including poly adenosine diphosphate-ribose polymerase (PARP)
inhibitors in select cancer types
known significance.
Reference Values:
Clinical References: 1. Petrucelli N, Daley MB, Pal T: BRCA1- and BRCA2-associated

hereditary breast and ovarian cancer. In: Adams MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews
[Internet]. University of Washington, Seattle; 1998. Updated December 15, 2016. Accessed May 4,
2021. Available at www.ncbi.nlm.nih.gov/books/NBK1247/ 2. Daly MB, Pal T, Berry M, et al: NCCN
Guidelines Insights: Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version
2.2021. J Natl Compr Canc Netw. 2021 Jan 6;19(1):77-102 3. Saslow D, Boetes C, Burke W, et al:
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA
Cancer J Clin. 2007 Mar-Apr;57(2):75-89 4. Smith RA, Andrews KS, Brooks D, et al. Cancer screening
in the United States, 2019: A review of current American Cancer Society guidelines and current issues
in cancer screening. CA Cancer J Clin. 2019 May;69(3):184-210 5. Richards S, Aziz N, Bale S, et al:
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation
of the American College of Medical Genetics and Genomics and the Association for Molecular
Pathology. Genet Med. 2015 May;17(5):405-424
C2729 Breast Carcinoma-Associated Antigen, Serum

606583 Clinical Information: Carcinoma of the breast is the most prevalent form of cancer in women.
These tumors often produce mucinous antigens, which are large-molecular-weight glycoproteins with
O-linked oligosaccharide chains. Monoclonal antibodies directed against these antigens have been
developed, and several immunoassays are available to quantitate the levels of tumor-associated
mucinous antigens in serum. The antibodies recognize epitopes of a breast cancer-associated antigen
encoded by the human mucin 1 (MUC-1) gene, which is known by several names including MAM6,
milk mucin antigen, cancer antigen (CA) 27.29, and CA 15-3. While CA 27.29 is expressed at the apical
surface of normal epithelial cells, it is present throughout malignant epithelial cells of the breast, lung,
ovary, pancreas, and other sites. The cancer-associated form of the antigen is less extensively
glycosylated than the normal form and more specific for tumor cells.
Useful For: Serial testing in women with prior stage II or III breast cancer who are clinically free of
disease Predicting early recurrence of disease in women with treated carcinoma of the breast Indicating
that additional tests or procedures should be performed to confirm recurrence of breast cancer This test is
not useful for screening women for carcinoma of the breast.
Interpretation: Increased levels of cancer-associated antigen (CA 27.29) (>38 U/mL) may indicate
recurrent disease in a woman with treated breast carcinoma.
Reference Values:
Males
> or =18 years: < or =38.0 U/mL (use not defined)
Females
> or =18 years: < or =38.0 U/mL
Clinical References: 1. Bon GG, von Mensdorff-Pouilly S, Kenemans P, van Kamp GJ, Verstraeten
RA, Hilgers J: Clinical and technical evaluation of ACS BR serum assay of MUC1 gene-derived
glycoprotein in breast cancer, and comparison with CA 15-3 assays. Clin Chem. 1997 Apr;43(4):585-593
2. Chan DW, Beveridge RA, Muss H: Use of Truquant BR radioimmunoassay for early detection of
breast cancer recurrence in patients with stage II and stage III disease. J Clin Oncol. 1997
Jun;15(6):2322-2328 3. Lin DC, Genzen JR: Concordance analysis of paired cancer antigen (CA) 15-3
and 27.29 testing. Breast Cancer Res Treat. 2018 Jan;167(1):269-276
BRG1 BRG1 (SMARCA4) Immunostain, Technical Component Only

71537 Clinical Information: BRG1 (SMARCA4) is a member of the switch/sucrose non-fermentable
(SWI/SNF) chromatin remodeling complex. Biallelic mutations in BRG1 (SMARCA4) have been
reported in ovarian small cell carcinoma of hypercalcemic type (SCCOHT), amongst other tumors.
Tumors with these mutations demonstrate a loss of BRG1 protein expression in the nucleus. SCCOHT is
difficult to diagnose and loss of BRG1 expression can help in differentiating SSCOHT from its mimics
including other primary or metastatic tumors of the ovaries.
Useful For: Diagnosing ovarian small cell carcinoma of hypercalcemic type (SCCOHT)
stain is performed. If an interpretation is required, order PATHC / Pathology Consultation for a full
Clinical References: 1. Clarke BA, Witkowski L, Ton Nu TN, et al: Loss of SMARCA4 (BRG1)
Protein Expression by Immunohistochemistry in Small Cell Carcinoma of the Ovary, Hypercalcemic
Type Distinguishes these Tumors from their Mimics. Histopathology 2016 Apr 21 2. Conlon N, Silva A,
Guerra E, et al: Loss of SMARCA4 Expression Is Both Sensitive and Specific for the Diagnosis of Small
Cell Carcinoma of Ovary, Hypercalcemic Type. Am J Pathol 2016;40:395-403 3. Karanian-Philippe M,
Velasco V, Longy M, et al: SMARCA4 (BRG1) Loss of Expression Is a Useful Marker for the Diagnosis
of Ovarian Small Cell Carcinoma of the Hypercalcemic Type (Ovarian Rhabdoid Tumor). Am J Surg
Pathol 2015;39:1197-1205 4. Ramos P, Karnezls A, Craig D, et al: Small Cell Carcinoma of the Ovary,
Hypercalcemic Type, Displays Frequent Inactivating Germline and Somatic Mutations in SMARCA4.
Nat Genet 2014;46(5):427-430
FBRIV Brivaracetam, Plasma

75682 Clinical Information: The recommended steady-state brivaracetam plasma concentration for
seizure control is 0.2 to 2.0 mcg/mL.
Reference Values:
Units: mcg/mL
BRBPS Broad Range Bacterial PCR and Sequencing, Varies

65058 Clinical Information: Cultures from patients with suspected bacterial infection involving normally
sterile sites may fail to provide bacterial (including mycobacterial) growth for identification due to the
presence of fastidious or slow-growing bacteria or as a result of antecedent antimicrobial chemotherapy.
Polymerase chain reaction amplification of a portion of the 16S ribosomal RNA (rRNA) gene followed
by sequencing of the amplified product can be used to detect bacterial (including mycobacterial) nucleic
acids in such situations, enabling a diagnosis. Sterile sources accepted for testing may have more than
one bacterial species present or the presence of copy variants of the 16S rRNA gene within a single
bacterial species, confounding Sanger sequencing analysis. Next-generation sequencing can be useful in
such cases. Ideal specimens are those in which bacteria (includes mycobacteria) are visualized by
microscopy. Heart valves from patients with endocarditis with positive Gram stains are, for example,
especially suitable.
Useful For: Detecting and identifying bacteria (including mycobacteria) from normally sterile
sources, including synovial fluid; body fluids such as pleural, peritoneal, and pericardial fluids,
cerebrospinal fluid; and both fresh and formalin-fixed paraffin-embeddedÂ tissues This test is not
recommended as a test of cure because nucleic acids may persist for long periods of time after
successful treatment.
Interpretation: A positive broad-range polymerase chain reaction (PCR)/sequencing result indicates

that bacterial nucleic acid of the specified organism was detected, which may be due to bacterial
infection or environmental or contaminating nucleic acids in the specimen. A negative broad-range
PCR/sequencing result indicates the absence of detectable bacterial (including mycobacterial) nucleic
acids in the specimen but does not rule-out false-negative results that may occur due to sampling error,
sequence variability underlying the primers, the presence of bacterial nucleic acids in quantities less
than the limit of detection of the assay, or inhibition of PCR. If PCR testing appears to be negative but
there is evidence of PCR inhibition, testing will be repeated. If inhibition is again detected, the result
will be reported as "PCR inhibition present."
Reference Values:
No bacterial DNA detected
Clinical References: 1. Oyvind K, Simmon K, Karaca D, Langeland N, Wiker HG: Dual priming
oligonucleotides for broad-range amplification of the bacterial 16S rRNA gene directly from human
clinical specimens. J Clin Microbiol. 2012;50(4):1289-1294. doi: 10.1128/JCM.06269-11 2. Gomez E,
Cazanave C, Cunningham SA, et al: Prosthetic joint infection diagnosis using broad-range PCR of
biofilms dislodged from knee and hip arthroplasty surfaces using sonication. J Clin Microbiol.
2012;50:3501-3508 3. Virk A, Pritt B, Patel R, et al: Mycobacterium lepromatosis Lepromatous leprosy
in US citizen who traveled to disease-endemic areas. Emerg Infect Dis. 2017 Nov; 23(11):1864-1866.
doi: 10.3201/eid2311.171104 4. Liesman RM, Pritt BS, Maleszewski JJ, Patel R: Laboratory diagnosis
of infective endocarditis. J Clin Microbiol. 2017 Sep;55(9):2599-2608. doi: 10.1128/JCM.00635-17 5.
Ramakrishna JM, Libertin CR, Yang JN, Diaz MA, Nengue AL, Patel R: 16S rRNA Gene
PCR/sequencing of cerebrospinal fluid in the diagnosis of post-operative meningitis. Access
Microbiology. 2020 Feb 3;2. doi: 10.1099/acmi.0.000100
FBRCG Broccoli IgG

Reference Values:
BROC Broccoli, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to broccoli Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
BROM Brome Grass, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to brome grass Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
FBROM Bromine - Total, Blood

Units: mg/L
The population reference interval derived from NMS Labs data (n=136) is usually between 1.4 and 8.8
mg/L (2.5th - 97.5th percentiles). Background concentrations are diet dependent. Workers exposed to
methyl bromide with blood bromide concentrations greater than 12 mg/L have shown 3.5 times higher
risk of electroencephalogram disturbances than compared to those with normal levels.
BRCMG Brucella Antibody Screen, IgM and IgG, ELISA, Serum

607346 Clinical Information: Brucellosis, major disease in humans and domesticated animals, is a systemic
bacterial infection caused by Gram negative coccobacilli of the genus Brucella. Brucellosis is a zoonotic
disease and a variety of domestic animals serve as reservoir species: Brucella infects goats (Brucella
melitensis), cattle (Brucella abortus), swine (Brucella suis), and dogs (Brucella canis). Transmission to
humans results from direct contact with infected animals, exposure to infectious aerosols, or ingestion of
unpasteurized dairy products; human-to-human transmission does not occur. While few cases are reported
in the US, the majority of cases occur in the Mediterranean region, Western Asia, and parts of Latin
America and Africa. Three species of Brucella commonly cause disease in humans: B melitensis, B suis,
and B abortus. Clinical manifestations of brucellosis consist of fever, sweats, malaise, weight loss,
headache, and weakness. The onset may be insidious or acute, generally beginning within 2 to 4 weeks
after exposure. Any organ or system of the body may be involved, although death is uncommon.
Presumptive diagnosis of brucellosis can be made by detection of high or rising titers of specific
antibodies, typically to smooth lipopolysaccharide (S-LPS), a major antigenic virulence determinant.
Serologic tests using S-LPS can detect antibody to the three major Brucella species due to this shared
epitope. IgM antibodies appear during the first week of infection followed by a switch to IgG synthesis
during the second week. A variety of serologic tests have been used for diagnosis of Brucella infection.
Detection of anti-Brucella antibodies using ELISA has been demonstrated to be a sensitive diagnostic
approach. However, all specimens testing positive by an ELISA should be confirmed by an agglutination
method as a means to increase assay specificity.
Useful For: Evaluating patients with suspected brucellosis

Interpretation: In the acute stage of the disease, there is an initial production of IgM antibodies
followed closely by production of IgG antibodies. IgG-class antibodies may decline after treatment;
however, high levels of circulating IgG-class antibodies may be found without any active disease. Rising
levels of specific antibody in paired sera can be regarded as serological evidence of recent infection. The
presence of specific IgM in a single specimen may also indicate a recent infection, although IgM-class
antibodies may persist for months following acute disease. The CDC recommends that specimens testing
positive for IgG or IgM by ELISA be confirmed by a Brucella-specific agglutination method.(1) The
CDC/Council of State and Territorial Epidemiologists case definition for human brucellosis states that the
laboratory criteria for diagnosis includes 1) isolation of Brucella species from a clinical specimen, 2)
four-fold or greater rise in Brucella agglutination titer between acute- and convalescent-phase serum
specimens obtained more than 2 weeks apart and studied at the same laboratory, and/or 3) demonstration
by immunofluorescence of Brucella species in a clinical specimen. Positive results by ELISA that are not
confirmed by Brucella-specific agglutination may represent false-positive screening results. If clinically
indicated, a new specimen should be tested after 14 to 21 days. If results of ELISA are negative and a
recent infection is suspected, a new specimen should be tested after 14 to 21 days.
Reference Values:
IgG SCREEN
Negative
IgM SCREEN
Negative
Clinical References: 1. Public health consequences of a false-positive laboratory test result for
Brucella-Florida, Georgia, and Michigan, 2005, MMWR Morb Mortal Wkly Rep 2008 Jun
6;57(22);603-605 2. Gunes H, Dogan M: False-positivity in diagnosis of brucellosis associated with
Rev-1 vaccine. Libyan J Med 2013;8:20417 3. Corbel MJ: Brucellosis: an overview. Emerg Infect Dis
1997;3:213-221 4. Araj GF, Lulu AR, Saadah MA, et al: Rapid diagnosis of central nervous system
brucellosis by ELISA. J Neuroimmunol 1986;12:173-182
BRUCB Brucella Culture, Blood
87345 Clinical Information: Brucella species are facultative intracellular Gram-negative-staining bacilli
capable of producing the disease "brucellosis" in humans. Human disease likely is acquired by contact
with animals infected with the organism (Brucella abortus, Brucella suis, Brucella melitensis, and
occasionally Brucella canis) either by direct contact or by ingestion of meat or milk. The signs and
symptoms associated with brucellosis may include fever, night sweats, chills, weakness, malaise,
headache, and anorexia. The physical examination may reveal lymphadenopathy and
hepatosplenomegaly. A definitive diagnosis of brucellosis is made by recovering the organism from
blood, fluid (including urine), or tissue specimens.
Useful For: Diagnosis of brucellosis in blood specimens

Interpretation: Isolation of a Brucella species indicates infection Cultures of blood and/or bone
marrow are positive in 70% to 90% of acute Brucella infections, but much less so in subacute or chronic
infections. In these latter instances, culture yield is highest from the specific tissue involved, or serology
may be necessary to establish diagnosis.
Reference Values:
No growth after 14 days
Clinical References: 1. Mandell GL, Bennett JE, Dolin R: Mandell, Douglas, and Bennett's
Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone; 1995:2053-2060 2. Procop
GW, Church DL, Hall GS, et al, eds: Miscellaneous Fastidious Gram-Negative Bacilli. In: Koneman's
Color Atlas and Textbook of Diagnostic Microbiology. 7th ed. Wolters Kluwer; 2017:472-595
BRUC Brucella Culture, Varies

8077 Clinical Information: Brucella species are facultative intracellular Gram-negative staining bacilli
with animals infected with the organism (Brucella abortus, B suis, B melitensis, and occasionally B
canis) either by direct contact or by ingestion of meat or milk. The signs and symptoms associated with
brucellosis may include fever, night sweats, chills, weakness, malaise, headache, and anorexia. The
physical examination may reveal lymphadenopathy and hepatosplenomegaly. A definitive diagnosis of
brucellosis is made by recovering the organism from blood, fluid (including urine), or tissue specimens.
Useful For: Diagnosis of brucellosis

Interpretation: Isolation of a Brucella species indicates infection. Cultures of blood and/or bone
marrow are positive in 70% to 90% of acute Brucella infections, but much less so in subacute or chronic
infections. In these latter instances, culture yield is highest from the specific tissue involved, or serology
may be necessary to establish diagnosis.
Reference Values:
No growth after 14 days
Clinical References: 1. Cem Gul H, Erdem H: Chapter 228: Brucellosis (Brucella Species). In
Douglas and Bennett's Principles and Practice of Infectious Diseases. Eighth edition. Edited by JE
Bennett, R Dolin, MJ Blaser. Philadelphia, PA, Elsevier Saunders, 2015. pp 2584-2589 2. Procop GW,
Church DL, Hall GS, et al: Chapter 9: Miscellaneous Fastidious Gram-Negative Bacilli. In Koneman's
Color Atlas and Textbook of Diagnostic Microbiology. Seventh edition. Philadelphia, Wolters Kluwer,
2017, pp 472-595
BRUTA Brucella Total Antibody Confirmation, Agglutination, Serum

8112 Clinical Information: Brucella species are facultative intracellular, gram-negative staining bacilli
with animals infected with the organism (Brucella abortus, Brucella suis, Brucella melitensis, and
occasionally Brucella canis) either by direct contact or by ingestion of meat or milk. The signs and
symptoms associated with brucellosis may include fever, night sweats, chills, weakness, malaise,
headache, and anorexia. The physical examination may reveal lymphadenopathy and
hepatosplenomegaly. A definitive diagnosis of brucellosis is made by recovering the organism from
bone marrow, blood, fluid (including urine), or tissue specimens. In cases of suspected brucellosis,
serology may assist in the diagnosis and play a supplementary role to routine culture. Antibodies to
Brucella species may not become detectable until 1 to 2 weeks following the onset of symptoms, so
serum specimens drawn during acute disease may be negative by serology in patients with brucellosis.
If serology is performed, the Centers for Disease Control and Prevention currently recommends that
specimens testing positive or equivocal for IgG or IgM by a screening enzyme immunoassay (EIA) be
confirmed by a Brucella-specific agglutination method.(1)
Useful For: Evaluating patients with suspected brucellosis

Interpretation: The Centers for Disease Control and Prevention (CDC) recommends that specimens
testing positive or equivocal for IgG or IgM by a screening enzyme immunoassay (EIA) be confirmed by
a Brucella-specific agglutination method.(1) Negative to a titer of 1:40 or higher can be seen in the
normal, healthy population. A titer of 1:80 or greater is often considered clinically significant(2);
however, a 4-fold or greater increase in titer between acute and convalescent phase sera is required to
diagnose acute infection. The CDC/Council of State and Territorial Epidemiologists case definition for
human brucellosis states that the laboratory criteria for diagnosis includes 1) isolation of Brucella species
from a clinical specimen, 2) four-fold or greater rise in Brucella agglutination titer between acute- and
convalescent-phase serum specimens drawn more than 2 weeks apart and studied at the same laboratory,
or 3) demonstration by immunofluorescence of Brucella species in a clinical specimen. Positive results by
a screening EIA that are not confirmed by Brucella-specific agglutination may represent false-positive
screening results. If clinically indicated, a new specimen should be tested after 7 to 14 days.
Reference Values:
<1:80
Clinical References: 1. Centers for Disease Control and Prevention (CDC): Public health
consequences of a false-positive laboratory test result for Brucella-Florida, Georgia, and Michigan, 2005.
MMWR Morb Mortal Wkly Rep. 2008 June 6;57(22):603-605 2. Welch RJ, Litwin CM: A comparison of
Brucella IgG and IgM ELISA assays with agglutination methodology. J Clin Lab Anal. 2010;24:160-162
3. Gunes H, Dogan M: False-positivity in diagnosis of brucellosis associated with Rev-1 vaccine. Libyan
J Med. 2013:8:20417
BRGGP Brugada Syndrome Multi-Gene Panel, Blood

63163 Clinical Information: Brugada syndrome (BrS) is a genetic cardiac disorder characterized by ST
segment elevation in leads V1-V3 on electrocardiography (EKG) with a high risk for ventricular
arrhythmias, which can lead to sudden cardiac death. BrS is inherited in an autosomal dominant manner
and is caused by pathogenic variants in genes that encode cardiac ion channels. The diagnosis of BrS is
established based on the characteristic EKG abnormality along with personal and family health history,
and requires exclusion of other causes including cardiac structural abnormalities, medications, and
electrolyte imbalances. BrS has also been called sudden unexplained nocturnal death syndrome (SUNDS)
due to the tendency for syncope and sudden cardiac death to occur at rest or during sleep. The most
common presentation of BrS is a male in his 40s with a history of syncopal episodes and malignant
arrhythmias. However, presentation may occur at any age including infancy, where BrS may present as
sudden infant death syndrome. Published studies indicate that BrS is responsible for 4% to 12% of
unexpected sudden deaths and for up to 20% of all sudden death in individuals with a structurally normal
heart. The prevalence of BrS in the general population is difficult to determine due to the challenges of
diagnosing the condition. In Southeast Asia where SUNDS is endemic, the prevalence of BrS is estimated
to be 1 in 2000. Of note, men are 8 to 10 times more likely to express symptoms of BrS, but the disease
affects females as well and both sexes are at risk for ventricular arrhythmia and sudden death.
Approximately 25% to 30% of BrS is accounted for by pathogenic variants in the genes known to cause
the disorder, with the majority of cases attributed to the SCN5A gene. Although the majority of
pathogenic variants identified to date have been detected by sequence analysis, large deletions in the
SCN5A, SCN3B, CACNA1C, and KCNE3 genes have been reported in BrS. Genetic testing for BrS is
supported by multiple consensus statements to confirm the diagnosis and identify at-risk family members.
This is particularly important because the majority of patients with BrS are asymptomatic, but
asymptomatic individuals may still be at increased risk for cardiac events. Pre- and post-test genetic
counseling is an important factor in the diagnosis and management of BrS and is supported by expert
consensus statements.
Useful For: Providing a genetic evaluation for patients with a personal or family history suggestive
of Brugada syndrome (BrS) Establishing a diagnosis of a BrS, in some cases, allowing for appropriate
management and surveillance for disease features based on the gene involved Identifying variants
within genes known to be associated with increased risk for disease features and allowing for predictive
testing of at-risk family members
Reference Values:
May;17(5):405-424 2. Brugada R, Campuzano O, Sarquella-Brugada G, Brugada P, Brugada J, Hong
K: Brugada syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al eds. GeneReviews [Internet]. eds.
University of Washington, Seattle; 2005. Updated November 17, 2016. Accessed June 2018. Available
at www.ncbi.nlm.nih.gov/books/NBK1517/ 3. Priori SG, Wilde AA, Horie M, et al:
HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with
inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10:12:1932-1963 4. Ackerman MJ, Priori
SG, Willems S, et al: HRS/EHRA expert consensus statement on the state of genetic testing for the
channelopathies and cardiomyopathies. Heart Rhythm.2011;8:1308-1339 5. Neilsen MW, Holst AG,
Olesen SP, Olesen MS: The genetic component of Brugada syndrome. Front Physiol. 2013;4:179:1-11
BSPR Brussels Sprouts, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to Brussels sprouts Defining the allergen
and/or anaphylactic episode - To confirm sensitization prior to beginning immunotherapy - To
Testing for IgE antibodies is not useful in patients previously treated with immunotherapy to determine
if residual clinical sensitivity exists, or in patients in whom the medical management does not depend
upon identification of allergen specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
BTKFP Bruton Tyrosine Kinase (BTK) Genotype and Protein Analysis,

89742 Full Gene Sequence and Flow Cytometry, Blood
Clinical Information: X-linked agammaglobulinemia (XLA) is a humoral primary
immunodeficiency affecting male patients in approximately 1 in 200,000 live births. XLA is caused by
variants in the Bruton tyrosine kinase gene (BTK),(1) which results in a profound block in B-cell
development within the bone marrow and a significant reduction, or complete absence, of mature B cells
in peripheral blood.(2) Approximately 85% of male patients with defects in early B-cell development
have XLA.(3) Due to the lack of mature B cells, XLA patients have markedly reduced levels of all major
classes of immunoglobulins in the serum and are, therefore, susceptible to severe and recurrent bacterial
infections. Pneumonia, otitis media, enteritis, and recurrent sinopulmonary infections are among the key
clinical diagnostic characteristics of the disease. The spectrum of infectious complications also includes
enteroviral meningitis, septic arthritis, cellulitis, and empyema, among others. The disease typically
manifests in boys younger than 1 year of age. BTK, the only gene associated with XLA, maps to the
X-chromosome at Xq21.3-Xq22 and consists of 19 exons spanning 37.5 kb genomic DNA.(4) BTK
encodes a nonreceptor tyrosine kinase of the BTK/Tec family. The BTK protein consists of 5 structural
domains (PH, TH, SH3, SH2, and TK). Variants causing XLA have been found in all domains of the BTK
gene, as well as noncoding regions of the gene. Missense variants account for 40% of all variants, while
nonsense variants account for 17%, deletions 20%, insertions 7%, and splice-site variants 16%. Over 900
unique variants in the BTK gene have been detected by full gene sequencing and are listed in BTKbase, a
database for BTK variants (https://databases.lovd.nl/shared/genes/BTK).(5) Genotype-phenotype
correlations have not been completely defined for BTK, but it is clear that nonsense variants are
overrepresented 4-fold compared to substitutions, which indicates that the latter may be tolerated without
causing a phenotype. The type and location of the variant in the gene clearly affect the severity of the
clinical phenotype. Some variants manifest within the first year or 2 of life, enabling an early diagnosis.
Others present with milder phenotypes, resulting in diagnosis later in childhood or in adulthood.(5)
Delayed diagnoses can be partly explained by the variable severity of XLA, even within families in which
the same variant is present. While the disease is considered fully penetrant, the clinical phenotype can
vary considerably depending on the nature of the specific BTK variant.(5) Lyonization of this gene is not
typical and only 1 case of XLA in a female patient has been reported so far due to skewed lyonization in a
carrier female patient. Therefore, female patients with clinical features that are identical to XLA should be
evaluated for autosomal recessive agammaglobulinemia when deemed clinically appropriate,(6) and for
XLA, if a male parent is affected with the disease. A flow cytometry test for intracellular BTK in
monocytes using an anti-BTK monoclonal antibody was developed, which was used to evaluate both
XLA patients and carriers.(7) In this study, 41 unrelated XLA families were studied and deficient BTK
protein expression was seen in 40 of these 41 patients, with complete BTK deficiency in 35 patients and
partial BTK deficiency in 5 patients. One patient had a normal level of BTK protein expression. The 6
patients with partial or normal BTK expression had missense BTK variants. Additionally, the flow
cytometry assay detected carrier status in the mothers of 35 of the 41 patients (approximately 85%). In the
6 patients where the BTK expression was normal in the mothers of XLA patients, it was noted that all
these patients were sporadic cases without previous family history of the disease.(7) It appears, therefore,
that most BTK variants result in deficient expression of BTK protein, which can be detected by flow
cytometry in monocytes.(7,8) Also, the mosaic expression of BTK protein in the monocytes by flow
cytometry is potentially useful in the diagnosis of female carriers.(8) The flow cytometry test therefore
provides a convenient screening tool for the diagnosis of XLA with confirmation of the diagnosis by BTK
genotyping.(7,8) In the rare patient with the clinical features of XLA but normal BTK protein expression,
BTK genotyping must be performed to determine the presence of a variant. A diagnosis of XLA should be
suspected in male patients with early-onset bacterial infections, marked reduction in all classes of serum
immunoglobulins, and absent B cells (CD19+ cells). The decrease in numbers of peripheral B cells is a
key feature, though this also can be seen in a small subset of patients with common variable
immunodeficiency. As well, some BTK variants can preserve small numbers of circulating B cells and,
therefore, all the 3 criteria mentioned above need to be evaluated. Patients should be assessed for the
presence of BTK protein by flow cytometry, although normal results by flow cytometry do not rule out
the presence of a BTK variant with aberrant protein function (despite normal protein expression). The
diagnosis is established or confirmed only in those individuals who have a variant identified in the BTK
gene by gene sequencing or who have male family members with hypogammaglobulinemia with absent or
low B cells. Appropriate clinical history is required with or without abnormal BTK protein results by flow
cytometry. It was shown that there are patients with XLA whose mothers have normal BTK protein
expression by flow cytometry and normal BTK genotyping, and that the variant in the patient is a result of
de novo variants in the maternal germline. In the same study, it was shown that there can be female
carriers who have normal BTK protein expression but are genetically heterozygous, and they do not show
abnormal protein expression due to extremely skewed inactivation of the altered X-chromosome.(6) Also,
the presence of one copy of the normal BTK gene and associated normal BTK protein can stabilize altered
protein abrogating the typical bimodal pattern of protein expression seen in female carriers. Therefore,
female carrier status can only conclusively be determined by genetic testing, especially if the BTK protein
flow test is normal. It is important to keep in mind that the mere presence of BTK gene variants does not
necessarily correlate with a diagnosis of XLA unless the appropriate clinical and immunological features
are present.(9,10)
Useful For: Preferred test for confirming a diagnosis of X-linked agammaglobulinemia (XLA) in
male patients with a history of recurrent sinopulmonary infections, profound hypogammaglobulinemia,
and below 1% peripheral B cells Identifying female carriers of XLA. Providing a comprehensive
assessment and enabling appropriate genotype-phenotype correlations due to the inclusion of both
protein and gene analyses
Interpretation: A patient-specific interpretive report is provided.

Reference Values:
BTKSP: An interpretive report will be provided.
BTK: Bruton tyrosine kinase expression will be reported as present, absent, partial deficiency, or
mosaic (carrier).
Clinical References: 1. Tsukada S, Saffran DC, Rawlings DJ, et al: Deficient expression of a B
cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993
Jan;72(2):279-290. doi: 10.1016/0092-8674(93)90667-f 2. Noordzij JG, de Bruin-Versteeg S,
Comans-Bitter WM, et al: Composition of precursor B-cell compartment in bone marrow from patients
with X-linked agammaglobulinemia compared with health children. Pediatr Res. 2002 Feb;2:159-168.
doi: 10.1203/00006450-200202000-00007 3. Conley ME, Broides A, Hernandez-Trujillo V, et al:
Genetic analysis of patients with defects in early B-cell development. Immunol Rev. 2005
Feb;203:216-234. doi: 10.1111/j.0105-2896.2005.00233.x 4. Lindvall JM, Blomberg KEM, Vargas L,
et al: Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA
modifications, and expression profiling. Immunol Rev. 2005 Feb;203:200-215. doi:
10.1111/j.0105-2896.2005.00225.x 5. Valiaho J, Smith CI, Vihinen M: BTKbase: the mutation database
for X-linked agammaglobulinemia. Hum Mutat. 2006 Dec;27(12):1209-1217. doi: 10.1002/humu.20410
6. Takada H, Kanegane H, Nomura A, et al: Female agammaglobulinemia due to the Bruton's tyrosine
kinase deficiency caused by extremely skewed X-chromosome inactivation. Blood. 2004
Jan;103(1):185-187. doi: 10.1182/blood-2003-06-1964 7. Futatani T, Miyawaki T, Tsukada S, et al:
Deficient expression of Bruton's tyrosine kinase in monocytes from X-linked agammaglobulinemia as
evaluated by a flow cytometric analysis and its clinical application to carrier detection. Blood. 1998
Jan;91(2):595-602. doi: 10.1067/mai.2001.120133 8. Kanegane H, Futatani T, Wang Y, et al: Clinical
and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow
cytometric assessment combined with genetic analysis. J Allergy Clin Immunol. 2001
Dec;108(6):1012-1020 9. Graziani S, Di Matteo G, Benini L, et al: Identification of a BTK mutation in
a dysgammaglobulinemia patient with reduced B cells: XLA or not? Clin Immunol. 2008
Sept;128(3):322-328. doi: 10.1016/j.clim.2008.05.012 10. Fleisher TA, Notarangelo LD: What does it
take to call it a pathogenic mutation? Clin Immunol 2008 Sep;128(3):285-286 11. Kraft MT, Pyle R,
Dong X, et al: Identification of 22 novel BTK gene variants in B cell deficiency with
hypogammaglobulinemia. Clin Immunol. 2021 Aug;229:108788. doi: 10.1016/j.clim.2021.108788
BTKS Bruton Tyrosine Kinase (BTK) Genotype, Full Gene Sequence,

89307 Blood
Clinical Information: X-linked agammaglobulinemia (XLA) is a humoral primary
immunodeficiency affecting males in approximately 1 in 200,000 live births. XLA is caused by variants
in the Bruton tyrosine kinase gene (BTK),(1) which results in a profound block in B-cell development
within the bone marrow and a significant reduction, or complete absence, of mature B cells in peripheral
blood.(2) Approximately 85% of male patients with defects in early B-cell development have XLA.(3)
Due to the lack of mature B cells, XLA patients have markedly reduced levels of all major classes of
immunoglobulins in the serum and are, therefore, susceptible to severe and recurrent bacterial infections.
Pneumonia, otitis media, enteritis, and recurrent sinopulmonary infections are among the key diagnostic
clinical characteristics of the disease. The spectrum of infectious complications also includes enteroviral
meningitis, septic arthritis, cellulitis, and empyema, among others. The disease typically manifests in male
children younger than 1 year. BTK, the only gene associated with XLA, maps to the X chromosome at
Xq21.3-Xq22 and consists of 19 exons spanning 37.5 kb genomic DNA.(4) BTK encodes a nonreceptor
tyrosine kinase of the Btk/Tec family. The Btk protein consists of 5 structural domains (PH, TH, SH3,
SH2, and TK). Variants causing XLA have been found in all domains of the BTK gene, as well as
noncoding regions of the gene. Over 800 unique variants in BTK have been detected by full gene
sequencing and are listed in BTKbase, a database for BTK variants
(http://structure.bmc.lu.se/idbase/BTKbase/).(5)Â Missense variants account for approximately 33% of
unique variants, nonsense variants 13%, frameshift 25%, in-frame deletions and insertions 4%, large
deletions 3% to 5%, and intronic and complex variants make up the remainder. Patients with a large
deletion spanning the BTK gene may also impact the adjacent TIMM8A gene (also known as DDP)
resulting in both XLA and deafness-dystonia-optic neuropathy syndrome (DDS or Mohr-Tranebjaerg
syndrome). Genotype-phenotype correlations have not been completely defined for BTK, but it is clear
that nonsense and frameshift variants are overrepresented 4-fold compared with substitutions, which
indicates that the latter may be tolerated without causing a phenotype or with a milder phenotype or later
age at presentation. Some individuals present within the first 2 years of life, enabling an early diagnosis.
Others present with milder phenotypes, resulting in diagnosis later in childhood or in adulthood.(5)
Delayed diagnoses can be partly explained by the variable severity of XLA, even within families in which
the same variant is present. While the disease is considered fully penetrant, the clinical phenotype can
vary considerably depending on the nature of the specific BTK variant.(5) Lyonization of this gene is not
typical and only 1 case of XLA in a female has been reported so far due to skewed lyonization in a carrier
female. Therefore, females with clinical features that are identical to XLA should be evaluated for
autosomal recessive agammaglobulinemia when deemed clinically appropriate(6) and for XLA, if a male
parent is affected with the disease. A diagnosis of XLA should be suspected in males with 1) early-onset
bacterial infections, 2) marked reduction in all classes of serum immunoglobulins, and 3) absent B cells
(CD19+ cells). The decrease in numbers of peripheral B cells is a key feature, though this also can be seen
in a small subset of patients with common variable immunodeficiency (CVID). Conversely, some BTK
variants can preserve small numbers of circulating B cells and, therefore, all 3 of the criteria mentioned
above need to be evaluated. The preferred approach for confirming a diagnosis of XLA in males and
identifying carrier females requires testing for the Btk protein expression on B cells by flow cytometry
and genetic testing for a BTK variant. Patients can be screened for the presence of Btk protein by flow
cytometry (BTK / Bruton Tyrosine Kinase [Btk], Protein Expression, Flow Cytometry, Blood); however,
normal results by flow cytometry do not rule out the presence of a BTK variant with normal protein
expression but aberrant protein function. The diagnosis is confirmed only in those individuals with
appropriate clinical history who have a varaint identified within BTK by gene sequencing or who have
male family members with hypogammaglobulinemia with absent or low B cells.
Useful For: Confirming a diagnosis of X-linked agammaglobulinemia (XLA) in male patients with a
history of recurrent sinopulmonary infections, profound hypogammaglobulinemia, and less than 1%
peripheral B cells, with or without abnormal Bruton tyrosine kinase (Btk) protein expression by flow
cytometry Evaluating for the presence of BTK variants in female relatives (of male XLA patients) who
do not demonstrate carrier phenotype by Btk flow cytometry
Interpretation: A patient-specific interpretive report is provided.

Reference Values:
Clinical References: 1. Tsukada S, Saffran DC, Rawlings DJ, et al: Deficient expression of a B
cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993 Jan
29;72(2):279-290 2. Noordzij JG, de Bruin-Versteeg S, Comans-Bitter WM, et al: Composition of
precursor B-cell compartment in bone marrow from patients with X-linked agammaglobulinemia
compared with healthy children. Pediatr Res. 2002 Feb;51(2):159-168 3. Conley ME, Broides A,
Hernandez-Trujillo V, et al: Genetic analysis of patients with defects in early B-cell development.
Immunol Rev. 2005 Feb;203:216-234 4. Lindvall JM, Blomberg KE, Valiaho J, et al: Bruton's tyrosine
kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression
profiling. Immunol Rev. 2005 Feb;203:200-215 5. Valiaho J, Smith CI, Vihinen M: BTKbase: the
mutation database for X-linked agammaglobulinemia. Hum Mutat. 2006 Dec;27(12):1209-1217 6.
Takada H, Kanegane H, Nomura A, et al: Female agammaglobulinemia due to the Bruton tyrosine
kinase deficiency caused by extremely skewed X-chromosome inactivation. Blood 2004 Jan
1;103(1):185-187
BTK Bruton Tyrosine Kinase, Protein Expression, Flow Cytometry,

89011 Blood
Clinical Information: The differential diagnosis for patients with primary
hypogammaglobulinemia of unclear etiology (after other secondary causes of hypogammaglobulinemia
have been ruled out) includes common variable immunodeficiency (CVID) and X-linked
agammaglobulinemia (XLA). CVID is the most common diagnosis of humoral immunodeficiency,
particularly in adults but also in children over 4 years of age. However, men with XLA may be
misdiagnosed with CVID. XLA is an independent humoral immunodeficiency and should not be
regarded as a subset of CVID. The BTK gene is present on the long arm of the X-chromosome and
encodes for a cytoplasmic tyrosine kinase with 5 distinct structural domains. While BTK gene
sequencing is the gold standard for definitively identifying variants and confirming a diagnosis of XLA,
it is labor intensive and expensive, and it may result in a variant of uncertain significance (VUS). Flow
cytometry is a screening test for XLA and should be included in the evaluation of patients with possible
CVID, particularly in male patients with less than 1% B cells. Bruton tyrosine kinase (BTK) is an
intracellular protein, and absence of the BTK protein by flow cytometry provides a strong rationale for
performing a BTK gene-sequencing test. However, 20% to 30% of patients with XLA may have intact
or truncated BTK protein with abnormal function; therefore, genetic analysis remains the more
definitive test for diagnosing XLA (besides other clinical and immunological parameters). XLA is a
prototypical humoral immunodeficiency caused by variants in the BTK gene, which encodes BTK, a
hematopoietic-specific tyrosine kinase. XLA is characterized by normal, reduced, or absent BTK
expression in monocytes and platelets, a significant reduction or absence of circulating B cells in blood,
and profound hypogammaglobulinemia of all isotypes (IgG, IgA, IgM, and IgE). The clinical
presentation includes early onset of recurrent bacterial infections and absent lymph nodes and tonsils.
BTK plays a critical role in B-cell differentiation. The defect in BTK may be "leaky" in some patients
(ie, a consequence of variants in the gene that result in a milder clinical and laboratory phenotype), such
that these patients may have some levels of IgG and/or IgM and a small number of B cells in blood.(1)
The vast majority of patients with XLA are diagnosed in childhood (median age of diagnosis in patients
with sporadic XLA is 26 months), although some patients are recognized in early adulthood or later in
life. The diagnosis of XLA in both children and adults indicates that the disorder demonstrates
considerable clinical phenotypic heterogeneity, depending on the position of the variants within the
gene. Female patients are typically carriers and asymptomatic. Testing in women should be limited to
those in their child-bearing years (<45 years). Carrier testing ideally should be confirmed by genetic
testing since it is possible to have a normal flow cytometry test for protein expression in the presence of
heterozygous (carrier) BTK gene variants. Flow cytometry is a preliminary screening test for XLA. It is
important to keep in mind that this flow cytometry test is only a screening tool and approximately 20%
to 30% of patients who have a variant within the BTK gene have normal protein expression (again
related to the position of the variant in the gene and the antibody used for flow cytometric analysis).
Therefore, in addition to clinical correlation, genetic testing is recommended to confirm a diagnosis of
XLA. Furthermore, it is helpful to correlate gene and protein data with clinical history
(genotype-phenotype correlation) in making a final diagnosis of XLA. Consequently, the preferred test
for XLA is BTKFP / Bruton Tyrosine Kinase (BTK) Genotype and Protein Analysis, Full Gene
Sequence and Flow Cytometry, Blood, which includes both flow cytometry and gene sequencing to
confirm the presence of a BTK variant. If a familial variant has already been identified, then FMTT /
Familial Mutation, Targeted Testing, Varies should be ordered.
Useful For: Preliminary screening for X-linked agammaglobulinemia, primarily in male patients (<65
years of age) or female carriers (child-bearing age: <45 years)
Interpretation: Results are reported as Bruton tyrosine kinase (BTK) protein expression present
(normal) or absent (abnormal) in monocytes and B cells if present. Additionally, mosaic BTK expression
(indicative of a carrier) and reduced BTK expression (consistent with partial BTK protein deficiency) are
reported when present and correlated with a healthy experimental control. BTK genotyping (BTKS /
Bruton Tyrosine Kinase [BTK] Genotype, Full Gene Sequence, Blood or FMTT / Familial Mutation,
Targeted Testing, Varies) should be performed in the following situations: -To confirm any abnormal
flow cytometry result -In the rare patient with the clinical features of X-linked agammaglobulinemia, but
normal BTK protein expression -In mothers of patients who do not show the classic carrier pattern of
bimodal protein expression (to determine if there is maternal germinal mosaicism or skewed altered
X-chromosome inactivation), or there is dominant expression of the normal protein in the presence of one
copy of a genetic variant.
Reference Values:
Present
Bruton tyrosine kinase expression will be reported as present, absent, partial deficiency, or mosaic
(carrier).
Clinical References: 1. Kanegane H, Futatani T, Wang Y, et al: Clinical and mutational

characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment
combined with genetic analysis. J Allergy Clin Immunol. 2001 Dec;108(6):1012-1020. doi:
10.1067/mai.2001.120133 2. Kanegane H, Tsukada S, Iwata T, et al: Detection of Bruton's tyrosine kinase
mutations in hypogammaglobulinemic males registered as common variable immunodeficiency (CVID)
in the Japanese Immunodeficiency Registry. Clin Exp Immunol. 2000 Jun;120(3):512-517. doi:
10.1046/j.1365-2249.2000.01244.x 3. Stewart DM, Tian L, Nelson DL: A case of X-linked
agammaglobulinemia diagnosed in adulthood. Clin Immunol. 2001 Apr;99(1):94-99. doi:
10.1006/clim.2001.5024 4. Futatani T, Miyawaki T, Tsukada S, et al: Deficient expression of Bruton's
tyrosine kinase in monocytes from X-linked agammaglobulinemia as evaluated by a flow cytometric
analysis and its clinical application to carrier detection. Blood. 1998 Jan 15;91(2):595-602 5. Kraft MT,
Pyle R, Dong X, et al: Identification of 22 novel BTK gene variants in B cell deficiency with
hypogammaglobulinemia. Clin Immunol. 2021 Aug;229:108788. doi: 10.1016/j.clim.2021.108788 6.
Chear CT, Ripen AM, Mohamed SAS, Dhaliwal JS: A novel BTK gene mutation creates a de-novo splice
site in an X-linked agammaglobulinemia patient. Gene. 2015 Apr 15;560(2):245-248. doi:
10.1016/j.gene.2015.02.019
BUCW Buckwheat, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to buckwheat Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
BDRP Budgerigar Droppings, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Budgerigar droppings Defining the allergen

Reference Values:
0 Negative

apply to all ages.
BFTH Budgerigar Feathers, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Budgerigar feathers Defining the allergen
the specificity of allergic reactions to insect venom allergens, drugs, or chemical allerge

Reference Values:
0 Negative

apply to all ages.
BPAB Bullous Pemphigoid, BP180 and BP230, IgG Antibodies,

606816 Serum
Clinical Information: Bullous pemphigoid (BP) is a chronic pruritic blistering disorder found
mainly in aged persons, characterized by the development of tense blisters over an erythematous or
urticarial base. IgG anti-basement membrane zone antibodies are found in the serum of patients, and
linear IgG and C3 sediment is found on the basement membrane zone of the lesion. Several well
characterized variants exist including localized, mucous membrane predominant and pemphigoid
gestationis, also referred to as herpes gestationis. Target antigens of the autoantibodies in BP patient
serum are BP230 and BP180, also called BPAG1 and BPAG2. Molecular weight of these antigens is
230 kDa and 180 kDa, respectively. BP180 is thought to be the direct target of the autoantibody because
of its location along the basement membranes, and the autoantibody against BP230 is thought to be
secondarily produced.
Useful For: Initial screening test in the diagnosis of bullous pemphigoid and its variants
Complementing the standard serum test of indirect immunofluorescence utilizing primate esophagus
substrate and primate salt-split skin substrate (CIFS / Cutaneous Immunofluorescence Antibodies [IgG],
Serum)
Interpretation: Antibodies to bullous pemphigoid (BP) BP180 and BP230 have been shown to be
present in most patients with pemphigoid. Adequate sensitivities and specificity for disease are
documented and Mayo Clinic's experience demonstrates a very good correlation between BP180 and
BP230 results and the presence of pemphigoid (see Supportive Data). However, in those patients
strongly suspected to have pemphigoid, either by clinical findings or by routine biopsy and/or direct
immunofluorescence, and in whom the BP180/BP230 assay is negative, follow-up testing by CIFS /
Cutaneous Immunofluorescence Antibodies [IgG], Serum is recommended. Antibody titer may correlate
with disease activity in some patients. Patients with severe disease may be expected to have high titers
of antibodies to BP. Titers may decrease with clinical improvement.
Reference Values:
BULLOUS PEMPHIGOID 180:
<20 RU/mL (negative)
> or =20 RU/mL (positive)
BULLOUS PEMPHIGOID 230:
Clinical References: 1. Liu Z, Diaz LA, Troy JL, et al: A passive transfer model of the
organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the
hemidesmosomal antigen, BP180. J Clin Invest. 1993 Nov;92(5):2480-2488 2. Matsumura K, Amagai M,
Nishikawa T, Hashimoto T: The majority of bullous pemphigoid and herpes gestationes serum samples
react with the NC16a domain of the e180-kD bullous pemphigoid antigen. Arch Dermatol Res. 1996
Aug;288(9):507-509 3. Stanley JR, Hawley-Nelson P, Yuspa SH, Shevach EM, Katz SI: Characterization
of bullous pemphigoid antigen: a unique basement membrane protein of stratified aqueous epithelia. Cell.
1981 Jun;24(3):897-903 4. Hamada T, Nagata Y, Tomita M, Salmhofer W, Hashimoto T: Bullous
pemphigoid sera react specially with various domains of BP230, most frequently with C-terminal domain,
by immunblot analyses using bacterial recombinant proteins covering the entire molecule. Exp Dermatol.
2001 Aug;10(4):256-263 5. Rico MJ, Korman NJ, Stanley JR, Tanaka T, Hall RP: IgG antibodies from
patients with bullous pemphigoid bind to localized epitopes on synthetic peptides encoded by bullous
pemphigoid antigen cDNA. J Immunol. 1990 Dec 1;145(11):3728-3733 6. Wieland CN, Comfere NI,
Gibson LE, Weaver AL, Krause PK, Murray JA: Anti-bullous pemphigoid 180 and 230 antibodies in a
sample of unaffected subjects. Arch Dermatol. 2010 Jan;146(1):21-25 7. Montagnon CM, Tolkachjov SN,
Murrell DF, Camilleri MJ, Lehman JS: Subepithelial autoimmune blistering dermatoses: Clinical features
and diagnosis. J Am Acad Dermatol. 2021 Jul;85(1):1-14 8. Montagnon CM, Lehman JS, Murrell DF,
Camilleri MJ, Tolkachjov SN: Subepithelial autoimmune bullous dermatoses: disease activity assessment
and therapy. J Am Acad Dermatol. 2021 Jul;85(1):18-27
FMARC Bupivacaine (Marcaine)

Reference Range: 0.1 - 4.0 ug/mL
BUPMX Buprenorphine and Norbuprenorphine, Chain of Custody,

65215 Random, Urine
Clinical Information: Clinically, buprenorphine is utilized as a substitution therapy for opioid
dependence and as an analgesic. Buprenorphine is a partial agonist of the mu-opioid receptor. These mu
binding sites are discretely distributed in the human brain, spinal cord, and other tissue. The clinical
effects of mu receptor agonists are sedation, euphoria, respiratory depression, and analgesia. As a partial
mu receptor agonist, buprenorphine's clinical effects are decreased, giving buprenorphine a wider safety
margin.(1) Buprenorphine has a prolonged duration of activity. The combination of decreased clinical
effects and prolonged activity gives buprenorphine the added advantage of a delayed and decreased
withdrawal syndrome, compared to other opioids.(1) Compared to morphine, buprenorphine is 25 to 40
times more potent.(1) As with any opioid, abuse is always a concern. To reduce illicit use of
buprenorphine, it is available mixed with naloxone in a ratio of 4:1. When the combination is taken as
prescribed, only small amounts of naloxone will be absorbed. However, if the combination is transformed
into the injectable form, naloxone then acts as an opioid receptor antagonist. Buprenorphine is
metabolized through N-dealkylation to norbuprenorphine through cytochrome P450 3A4. Both parent and
metabolite then undergo glucuronidation. Norbuprenorphine is an active metabolite possessing one-fifth
of the potency of its parent. The glucuronide metabolites are inactive.(1) The primary clinical utility of
quantification of buprenorphine in urine is to identify patients that have strayed from opioid dependence
therapy. Chain of custody is a record of the disposition of a specimen to document each individual who
collected, handled, and performed the analysis. When a specimen is submitted in this manner, analysis
will be performed in such a way that it will withstand regular court scrutiny.
Useful For: Monitoring of compliance of buprenorphine therapy Detection and confirmation of the
illicit use of buprenorphine Chain of custody is required whenever the results of testing could be used in a
court of law. Its purpose is to protect the rights of the individual contributing the specimen by
this control implies that the opportunity for specimen tampering would be limited.
Interpretation: The presence of buprenorphine above 5.0 ng/mL or norbuprenorphine above 2.5
ng/mL is a strong indicator that the patient has used buprenorphine.
Reference Values:
Negative
Buprenorphine: 5.0 ng/mL
Norbuprenorphine: 2.5 ng/mL
Clinical References: 1. Elkader A, Spuroule B: Buprenorphine: clinical pharmacokinetics in the

treatment of opioid dependence. Clin Pharmacokinet. 2005;44(7):661-680 2. Grimm D, Pauly E, Poschl
J, Linderkamp O, Skopp G: Buprenorphine and norbuprenorphine concentrations in human breast milk
samples determined by liquid chromatography-tandem mass spectrometry. Ther Drug Monit. 2005
Aug;27(4):526-530 3. Kacinko SL, Shakleya DM, Huestis MA: Validation and application of a method
for the determination of buprenorphine, norbuprenorphine, and their glucuronide conjugates in human
meconium. Anal Chem. 2008 Jan 1;80(1):246-252 4. Concheiro M, Shakleya DM, Huestis MA:
Simultaneous quantification buprenorphine, norbuprenorphine, buprenorphine-glucuronide and
norbuprenorphine-glucuronide in human umbilical cord by liquid chromatography tandem mass
spectrometry. Forensic Sci Int. 2009 Jul 1;188(1-3):144-151 5. Langman LJ, Bechtel LK, Meier BM,
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 6. Baselt RC: Disposition of
Toxic Drugs and Chemicals in Man. 10th ed. Biomedical Publications; 2014:2211
BUPM Buprenorphine and Norbuprenorphine, Random, Urine

66200 Clinical Information: Clinically, buprenorphine is utilized as a substitution therapy for opioid
prescribed, only small amounts of naloxone will be absorbed. However, if the combination is
transformed into the injectable form, naloxone then acts as an opioid receptor antagonist.
Buprenorphine is metabolized through N-dealkylation to norbuprenorphine through cytochrome P450
3A4. Both parent and metabolite then undergo glucuronidation. Norbuprenorphine is an active
metabolite possessing one-fifth of the potency of its parent. The glucuronide metabolites are inactive.(1)
The primary clinical utility of quantification of buprenorphine in urine is to identify patients that have
strayed from opioid dependence therapy.
Useful For: Monitoring of compliance utilizing buprenorphine Detection and confirmation of the
illicit use of buprenorphine
Interpretation: The presence of buprenorphine above 5.0 ng/mL or norbuprenorphine above 2.5
ng/mL is a strong indicator that the patient has used buprenorphine.
Reference Values:
Negative
Buprenorphine: 5.0 ng/mL
Norbuprenorphine: 2.5 ng/mL
Clinical References: 1. Elkader A, Spuroule B: Buprenorphine: clinical pharmacokinetics in the

treatment of opioid dependence. Clin Pharmacokinet. 2005;44(7):661-680 2. Grimm D, Pauly E, Poschl J,
Linderkamp O, Skopp G: Buprenorphine and norbuprenorphine concentrations in human breast milk
samples determined by liquid chromatography-tandem mass spectrometry. Ther Drug Monit. 2005
Aug;27(4):526-530 3. Kacinko SL, Shakleya DM, Huestis MA: Validation and application of a method
for the determination of buprenorphine, norbuprenorphine, and their glucuronide conjugates in human
meconium. Anal Chem. 2008 Jan 1;80(1):246-252 4. Concheiro M, Shakleya DM, Huestis MA:
Simultaneous quantification buprenorphine, norbuprenorphine, buprenorphine-glucuronide and
norbuprenorphine-glucuronide in human umbilical cord by liquid chromatography tandem mass
spectrometry. Forensic Sci Int. 2009 Jul 1;188(1-3):144-151 5. Langman LJ, Bechtel LK, Meier BM,
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 6. Baselt RC: Disposition of Toxic
Drugs and Chemicals in Man. 10th ed. Biomedical Publications; 2014:2211
BUPR Buprenorphine Screen with Reflex, Random, Urine

prescribed, only small amounts of naloxone will be absorbed. However, if the combination is transformed
into the injectable form, naloxone then acts as an opioid receptor antagonist. Buprenorphine is
metabolized through N-dealkylation to norbuprenorphine through cytochrome P450 3A4 (CYP 3A4).
Both parent and metabolite then undergo glucuronidation. Norbuprenorphine is an active metabolite
possessing one fifth of the potency of its parent. The glucuronide metabolites are inactive.(1) This
procedure uses immunoassay reagents that are designed to produce a negative result when no drugs are
present in a natural (ie, unadulterated) specimen of urine; the assay is designed to have a high
true-negative rate. Like all immunoassays, it can produce a false-positive result due to cross-reactivity
with natural chemicals and drugs other than those they were designed to detect. The immunoassay also
can produce a false-negative result due to the antibody's ability to cross-react with different drugs in the
target class.
Useful For: Screening and confirmation for drug abuse or use of buprenorphine
Interpretation: If the screen result is negative, buprenorphine concentrations were not detected. If the
screen result is positive, then confirmation by liquid chromatography tandem mass spectrometry will be
performed. A positive interpretation will be given if either the buprenorphine result is greater than or
equal to 5.0 ng/mL and/or the norbuprenorphine result is greater than or equal to 2.5 ng/mL. The presence
of buprenorphine above 5.0 ng/mL or norbuprenorphine above 2.5 ng/mL is a strong indicator that the
patient has used buprenorphine.
Reference Values:
Negative
Screening cutoff concentration:
Clinical References: 1. Elkader A, Spuroule B: Buprenorphine clinical pharmacokinetics in the

treatment of opioid dependence. Clin Pharmacokinet. 2005;44(7):661-680 2. Jannetto PJ, Bratanow NC,
Clark WA, et al: Executive Summary: American Association of Clinical Chemistry Laboratory Medicine
Practice Guideline-Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management
Patients. J Appl Lab Med. 2018;2:489-526 3. Langman LJ, Bechtel LK, Meier BM, Holstege CP: Clinical
Toxicology. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887
BUPS Buprenorphine Screen, Random, Urine

prescribed, only small amounts of naloxone will be absorbed. However, if the combination is
transformed into the injectable form, naloxone then acts as an opioid receptor antagonist.
Buprenorphine is metabolized through N-dealkylation to norbuprenorphine through cytochrome P450
3A4 (CYP 3A4). Both parent and metabolite then undergo glucuronidation. Norbuprenorphine is an
active metabolite possessing one fifth of the potency of its parent. The glucuronide metabolites are
inactive.(1) This procedure uses immunoassay reagents that are designed to produce a negative result
when no drugs are present in a natural (ie, unadulterated) specimen of urine; the assay is designed to
have a high true-negative rate. Like all immunoassays, it can produce a false-positive result due to
cross-reactivity with natural chemicals and drugs other than those they were designed to detect. The
immunoassay also can produce a false-negative result due to the antibody's ability to cross-react with
different drugs in the target class.
Useful For: Screening for drug abuse or use of buprenorphine

Interpretation: This assay only provides a preliminary analytical test result. A more specific
alternative method (ie, liquid chromatography-tandem mass spectrometry: LC-MS/MS) must be used to
obtain a confirmed analytical result.
Reference Values:
Negative
Screening cutoff concentration:
Clinical References: 1. Elkader A, Spuroule B: Buprenorphine clinical pharmacokinetics in the

treatment of opioid dependence. Clin Pharmacokinet 2005;44(7):661-680 2. Jannetto PJ, Bratanow NC,
Clark WA, et al: Executive summary: American association of clinical chemistry laboratory medicine
practice guideline-using clinical laboratory tests to monitor drug therapy in pain management patients. J
Appl Lab Med. 2018 Jan;2(4):489-526. doi: 10.1373/jalm.2017.023341 3. Langman LJ, Bechtel LK,
Meier BM, Holstege CP: Clinical Toxicology. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz
Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887
FBUMT Bupropion and Metabolite, Serum

75387 Interpretation: Bupropion: Maximum antidepressant response was observed at trough plasma
concentrations of 50 â€“ 100 ng/mL bupropion with virtually no response below 25 ng/mL. Reported
average bupropion peak plasma concentrations: Adults: Single 100 mg IR â€“ 120 +/- 10 ng/mL
(Males): 150 +/- 10 ng/mL (Females) Adults: Single 200 mg IR -220 +/- 20 ng/mL (Males): 270 +/- 20
ng/mL (Females) Adults: Single 150 mg SR - 140 +/- 20 ng/mL Juveniles: 100 mg/day SR for 2 weeks
â€“ 25 +/- 8 ng/mL Juveniles: 200 mg/day SR for 2 weeks â€“ 53 +/- 22 ng/mL Specimens must be kept
frozen. If specimens are not kept frozen, this may cause lower or negative values. Hydroxybupropion: 8
adults (Age 22 â€“ 42) taking thrice daily 100 mg normal release bupropion for 2 weeks had an average
peak plasma concentration of 1000 +/- 70 ng/mL hydroxybupropion. Juvenile patients taking once
daily, extended release bupropion for two weeks had the following peak plasma concentrations: 100
mg/day (n = 11), 450 +/- 210 ng/mL hydroxybupropion 200 mg/day (n = 8), 710 +/- 350 ng/mL
hydroxybupropion
Reference Values:
Reporting Limit determined each analysis.
Units: ng/mL
FBUS Buspirone (Buspar)

Units: ng/mL
Therapeutic and toxic ranges have not been established.
Expected serum buspirone concentrations in patients taking recommended daily dosages: up to 10.00
ng/mL.
BUAUC Busulfan, Intravenous Dose, Area Under the Curve, Plasma

83188 Clinical Information: Busulfan is an alkylating agent used to ablate bone marrow cells prior to
hematopoietic stem cell transplantation for chronic myelogenous leukemia.(1) Busulfan is typically
administered intravenously (IV) at the recommended dosage of 0.8 mg/kg of actual or ideal body weight
(whichever is lower) and given once every 6 hours over 4 days for a total of 16 doses. Dose-limiting
toxicity of busulfan includes veno-occlusive liver disease, seizures, and coma. To avoid toxicity while
ensuring busulfan dose adequacy to completely ablate the bone marrow, IV dosing should be guided by a
pharmacokinetic (PK) evaluation of the area under the curve (AUC) and clearance after the first dose.(2)
The PK evaluation should be carried out at the end of the first dose, with results of PK testing available to
facilitate dose adjustment before beginning the fifth dose.
Useful For: Guiding dosage adjustments to achieve complete bone marrow ablation while minimizing
dose-dependent toxicity
Interpretation: Results of the timed collections will be used to calculate a 6-hour area under the curve
(AUC). If a different dosing or specimen collection protocol is used, or if different calculations are
required, contact the Laboratory Director. The optimal result for AUC (6 hour) derived from this
pharmacokinetic (PK) evaluation of IV busulfan is 1100 (mcmol/L)(min). AUC results greater than 1500
(mcmol/L)(min) are associated with hepatic veno-occlusive disease. A dose reduction should be
considered before the next busulfan infusion. AUC results below 900 (mcmol/L)(min) are consistent with
incomplete bone marrow ablation. A dose increase should be considered before the next busulfan
infusion. Clearance of busulfan in patients with normal renal function is usually in the range of 2.1 to 3.5
(mL/min)/kg. Elevated AUC is typically associated with clearance below 2.5 (mL/min)/kg, most
frequently due to diminished activity of glutathione S-transferase A1-1 activity.(3)
Reference Values:
AREA UNDER THE CURVE
900-1500 (mcmol/L)(min)
CLEARANCE
2.1-3.5 (mL/minute)/kg
Clinical References: 1. Santos GW, Tutschka PJ, Brookmeyer R, et al: Marrow transplantation for
acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983
December 1;309(22):1347-1353 2. Slattery JT, Sanders JE, Buckner CD, et al: Graft-rejection and toxicity
following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transpl,
1995 July;16(1):31-42 3. Slattery JT, Risler LJ: Therapeutic monitoring of busulfan in hematopoietic stem
cell transplantation. Ther Drug Monit. 1998 October;20(5):543-549 4. Czerwinski M, Gibbs M, Slattery
JT: Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996
September;24(9):1015-1019 5. Vassal G, Re M, Gouyette A: Gas chromatographic-mass spectrometric
assay for busulfan in biological fluids using a deuterated internal standard. J Chromatogr.
1988;428:357-361 6. Baselt RC, ed: Disposition of Toxic Drugs and Chemicals in Man. 6th ed. Chemical
Toxicology Institute; 2002:720-721 7. Busulfex: Package insert. Otsuka Pharmaceutical Co, Ltd; Updated
January 2015. Accessed February 3, 2021. Available at
www.accessdata.fda.gov/drugsatfda_docs/label/2015/020954s014lbl.pdf
BUTAS Butalbital, Serum

8427 Clinical Information: Butalbital, short-acting barbiturate with hypnotic properties, is used in
combination with other drugs such as acetaminophen, salicylate, caffeine, and codeine.(1) Butalbital is
administered orally. The duration of its hypnotic effect is about 3 to 4 hours. The drug distributes
throughout the body, with a volume of distribution of 0.8 L/kg, and about 26% of a dose is bound to
plasma proteins. The half-life of butalbital is about 35 to 88 hours. Excretion occurs mainly in the
urine.(1,2)
Useful For: Monitoring butalbital therapy

Interpretation: Butalbital concentrations of 10 mcg/mL or greater have been associated with
toxicity.
Reference Values:
<10 mcg/mL
Biomedical Publications; 2014:2211 2. Milone MC, Shaw LM: Therapeutic drugs and their
management. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:800-831 3. Langman LJ, Bechtel LK, Meier BM,
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 4. Mihic SJ, Mayfield J, Harris
RA: Hypnotics and sedatives. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman and
Gilman's The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill Education; 2017
CPR C-Peptide, Serum

8804 Clinical Information: C-peptide (connecting peptide), a 31-amino-acid polypeptide, represents the
midportion of the proinsulin molecule. Proinsulin resembles a hairpin structure, with an N-terminal and
C-terminal, which correspond to the A and B chains of the mature insulin molecule, oriented parallel to
each other and linked by disulfide bonds. The looped portion of the hairpin between the A and B chains
is called C-peptide. During insulin secretion, C-peptide is enzymatically cleaved off and cosecreted in
equimolar proportion with mature insulin molecules. Following secretion, insulin and C-peptide enter
the portal circulation and are routed through the liver where at least 50% of the insulin binds to
receptors, initiates specific hepatic actions (stimulation of hepatic glucose uptake and suppression of
glycogenolysis, gluconeogenesis, and ketogenesis), and is subsequently degraded. Most of the insulin
molecules that pass through the liver into the main circulation bind to peripheral insulin receptors,
promoting glucose uptake, while the remaining molecules undergo renal elimination. Unlike insulin,
C-peptide is subject to neither hepatic nor significant peripheral degradation but is mainly removed by
the kidneys. As a result, C-peptide has a longer half-life than insulin (30-35 minutes versus 5-10
minutes), and the molar ratio of circulating insulin to circulating C-peptide is generally below 1, despite
equimolar secretion. Until recently, C-peptide was thought to have no physiological function, but it now
appears that there may be specific C-peptide cell-surface receptors (most likely belonging to the
super-family of G-protein coupled receptors), which influence endothelial responsiveness and skeletal
and renal blood flow. In most disease conditions associated with abnormal serum insulin levels, the
changes in serum C-peptide levels parallel insulin-related alterations (insulin to C-peptide molar ratio <
or =1). Both serum C-peptide and serum insulin levels are elevated in renal failure and in disease states
that lead to augmented primary endogenous insulin secretion (eg, insulinoma, sulfonylurea
intoxication). Both also may be raised in any disease states that cause secondary increases in
endogenous insulin secretion mediated through insulin resistance, primarily obesity, glucose
intolerance, and early type 2 diabetes mellitus (DM), as well as endocrine disorders associated with
hypersecretion of insulin-antagonistic hormones (eg, Cushing syndrome, acromegaly). Failing insulin
secretion in type 1 DM and longstanding type 2 DM is associated with corresponding reductions in
serum C-peptide levels. Discordant serum insulin and serum C-peptide abnormalities are mainly
observed in 2 situations: exogenous insulin administration and the presence of anti-insulin
autoantibodies. Factitious hypoglycemia due to surreptitious insulin administration results in
appropriate suppression of endogenous insulin and C-peptide secretion. At the same time, the
peripherally administered insulin bypasses the hepatic first-pass metabolism. In these situations, insulin
levels are elevated and C-peptide levels are decreased. In patients with insulin antibodies, insulin levels
are increased because of the prolonged half-life of autoantibody-bound insulin. Some patients with
anti-idiotypic anti-insulin autoantibodies experience episodic hypoglycemia caused by displacement of
autoantibody-bound insulin.
Useful For: Diagnostic workup of hypoglycemia: -Diagnosis of factitious hypoglycemia due to

surreptitious administration of insulin -Evaluation of possible insulinoma -Surrogate measure for the
absence or presence of physiological suppressibility of endogenous insulin secretion during diagnostic
insulin-induced hypoglycemia (C-peptide suppression test) Assessing insulin secretory reserve in selected
diabetic patients (as listed below) who either have insulin autoantibodies or who are receiving insulin
therapy: -Assessing residual endogenous insulin secretory reserve -Monitoring pancreatic and islet cell
transplant function -Monitoring immunomodulatory therapy aimed at slowing progression of preclinical,
or very early stage type 1 diabetes mellitus
Interpretation: To compare insulin and C-peptide concentrations (ie, insulin to C-peptide ratio):
-Convert insulin to pmol/L: insulin concentration in mcIU/mL x 6.945 = insulin concentration in pmol/L
-Convert C-peptide to pmol/L: C-peptide concentration in ng/mL x 331 = C-peptide concentration in
pmol/L Factitious hypoglycemia due to surreptitious insulin administration results in elevated serum
insulin levels and low or undetectable C-peptide levels, with a clear reversal of the physiological molar
insulin to C-peptide ratio (< or =1) to an insulin to C-peptide ratio of greater than 1. By contrast, insulin
and C-peptide levels are both elevated in insulinoma and the insulin to C-peptide molar ratio is 1 or less.
Sulfonylurea ingestion also is associated with preservation of the insulin to C-peptide molar ratio of 1 or
less. In patients with insulin autoantibodies, the insulin to C-peptide ratio may be reversed to greater than
1, because of the prolonged half-life of autoantibody-bound insulin. Dynamic testing may be necessary in
the workup of hypoglycemia; the C-peptide suppression test is most commonly employed. C-peptide
levels are measured following induction of hypoglycemia through exogenous insulin administration. The
test relies on the demonstration of the lack of suppression of serum C-peptide levels within 2 hours
following insulin-induced hypoglycemia in patients with insulinoma. Reference intervals have not been
formally verified in-house for pediatric patients. The published literature indicates that reference intervals
for adult and pediatric patients are comparable.
Reference Values:
1.1-4.4 ng/mL
Reference intervals have not been formally verified in-house for pediatric patients. The published
literature indicates that reference intervals for adult and pediatric patients are comparable.
Clinical References: 1. Service FJ, O'Brien PC, Kao PC, Young WF Jr: C-peptide suppression test:
effects of gender, age, and body mass index; implications for the diagnosis of insulinoma. J Clin
Endocrinol Metab. 1992;74:204-210 2. Lebowitz MR, Blumenthal SA: The molar ratio of insulin to
C-peptide. An aid to the diagnosis of hypoglycemia due to surreptitious (or inadvertent) insulin
administration. Arch Int Med. 1993 Mar 8;153(5):650-655 3. Leighton E, Sainsbury CA, Jones GC: A
practical review of C-peptide testing in diabetes. Diabetes Ther. 2017 Jun;8(3):475-487 4. Jones AG,
Hattersley AT: The clinical utility of C-peptide measurement in the care of patients with diabetes.
Diabet.Med. 2013 Jul;30(7):803-817. doi: 10.1111/dme.12159 5. Ahn CH, Kim LK, Lee JE, et al:
Clinical implications of various criteria for the biochemical diagnosis of insulinoma. Endocrinol Metab
(Seoul). 2014 Dec 29;29(4):498-504. doi: 10.3803/EnM.2014.29.4.498 6. Young DS, Huth EJ: SI Units
for Clinical Measurement. American College of Physicians; 1998
CRPRO C-Reactive Protein (CRP) Immunostain, Technical Component
70409 Only
Clinical Information: C-reactive protein (CRP) is an acute-phase reactant associated with host
defense that promotes agglutination and complement fixation. CRP can be used with a panel of
immunohistochemical markers (beta-catenin, liver fatty acid-binding protein, glutamine synthetase, and
amyloid A) to distinguish hepatic adenoma from focal nodular hyperplasia and non-neoplastic liver.
CRP, along with amyloid A, is overexpressed in inflammatory (type 3) hepatic adenoma. CRP may
stain hepatocytes in nonneoplastic liver tissue in areas of nonspecific inflammation.
Useful For: Classification of hepatic adenomas

the stain is performed. If an interpretation is required, order PATHC / Pathology Consultation for a full
Clinical References: 1. Ma Y, Lu M, Deng Y, et al: The Preparation of C-Reactive Protein

Immunosensor Based on Nano-Mimetic Enzyme Co3O4. J Biomed Nanotechnol 2018;14(6):1169-1177
2. Wang M, Meng S, Gu M, et al: An Enzyme-Linked Immunosorbent Assay for C-Reactive Protein
Based on Gold Nanoparticlesat Metal Porphyrin Porous Compound. J Biomed Nanotechnol
2019;15(10):2100-2107 3. Yeh Y, Lei H, Chen M, et al: C-Reactive Protein (CRP) is a Promising
Diagnostic Immunohistochemical Marker for Intrahepatic Cholangiocarcinoma and is Associated with
Better Prognosis. Am J Surg Pathol 2017;41(12):1630-1641
CRP C-Reactive Protein (CRP), Serum

9731 Clinical Information: C-reactive protein (CRP) is one of the most sensitive acute-phase reactants
for inflammation. CRP is synthesized by the liver and consists of 5 identical polypeptide chains that
form a 5-membered ring with a molecular weight of 105,000 daltons. Complexed CRP activates the
classical complement pathway. The CRP response frequently precedes clinical symptoms, including
fever. CRP elevations are nonspecific and may be useful for the detection of systemic inflammatory
processes; to assess treatment of bacterial infections with antibiotics; to detect intrauterine infections
with concomitant premature amniorrhexis; to differentiate between active and inactive forms of disease
with concurrent infection, eg, in patients suffering from systemic lupus erythematosus or colitis
ulcerosa; to therapeutically monitor rheumatic disease and assess anti-inflammatory therapy; to
determine the presence of postoperative complications at an early stage, such as infected wounds,
thrombosis, and pneumonia; and to distinguish between infection and bone marrow rejection.
Postoperative monitoring of CRP levels of patients can aid in the recognition of unexpected
complications (persisting high or increasing levels). Measuring changes in the concentration of CRP
provides useful diagnostic information about the level of acuity and severity of a disease. It also allows
judgments about the disease genesis. Persistence of a high serum CRP concentration is usually a grave
prognostic sign that generally indicates the presence of an uncontrolled infection.
Useful For: Detecting systemic inflammatory processes Detecting infection and assessing response
to antibiotic treatment of bacterial infections Differentiating between active and inactive disease forms
with concurrent infection
Interpretation: In normal healthy individuals, C-reactive protein (CRP) is a trace protein (<8 mg/L).
Elevated values are consistent with an acute inflammatory process. After onset of an acute phase
response, the serum CRP concentration rises rapidly (within 6-12 hours and peaks at 24-48 hours) and
extensively. Concentrations above 100 mg/L are associated with severe stimuli such as major trauma
and severe infection (sepsis).
Reference Values:
< or =8.0 mg/L
Clinical References: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Sixth
edition. Edited by N Rafai, AR Horvath, CT Wittwer. Elsevier, 2018
HSCRP C-Reactive Protein, High Sensitivity, Serum

606909 Clinical Information: C-reactive protein (CRP) is a biomarker of inflammation. Serum CRP
concentrations increase rapidly and dramatically (100-fold or more) in response to tissue injury or
inflammation. High-sensitivity CRP (hs-CRP) is more precise than standard CRP when measuring
baseline (ie, normal) concentrations and enables a measure of chronic inflammation. Atherosclerosis is an
inflammatory disease and hs-CRP has been endorsed by multiple guidelines as a biomarker of
atherosclerotic cardiovascular disease risk.(1-3) A large prospective clinical trial demonstrated
significantly less cardiovascular risk for patients with hs-CRP less than 2.0 mg/L.(1) More aggressive
treatment strategies may be warranted in patients with hs-CRP of 2.0 mg/L or higher.
Useful For: Assessment of risk of developing myocardial infarction in patients presenting with acute
coronary syndromes Assessment of risk of developing cardiovascular disease or ischemic events in
individuals who do not manifest disease at present
Interpretation: Values greater than 2.0 mg/L suggest an increased likelihood of developing
cardiovascular disease or ischemic events.
Reference Values:
> or =18 years: <2.0 mg/L
Reference values have not been established for patients who are less than18 years of age.
Clinical References: 1. European Association for Cardiovascular Prevention and Rehabilitation,

Reiner Z, Catapano AL, et al: ESC/EAS Guidelines for the management of dyslipidaemias: the Task
Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-1818 2. Goff DC, Lloyd-Jones DM,
Bennett G, et al: 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. Circulation.
2014;129:S49-S73 3. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association
recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin
Lipidol. 2014;8:473-488 4. Cardiac C-Reactive Protein (Latex) High Sensitive. V 12.0. Package insert:
Roche Diagnostics; 03/2019. 5. Ridker PM, Danielson E, Fonseca FA, et al: Reduction in C-reactive
protein and LDL-cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective
study of the JUPITER trial. Lancet. 2009;373:1175-1182 6. Arnett DK, Blumenthal RS, Albert MA, et al:
2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American
College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation.
2019; 140: 563-595 7. Pearson TA, Mensah GA, Alexander RW, et al: Markers of inflammation and
cardiovascular disease. Application to clinical and public health practice. A statement for healthcare
professionals from the Centers for Disease Control and Prevention and the American Heart Association.
Circulation. 2003; Jan 28;107(3):499-511. doi: 10.1161/01.cir.0000052939.59093.45
C1ES C1 Esterase Inhibitor Antigen, Serum

8198 Clinical Information: C1 esterase inhibitor blocks the activation of C1 (first component of the
complement cascade) to its active form. The deficiency of C1 esterase inhibitor results in the
inappropriate activation of C1 and the subsequent release of an activation peptide from C2 with kinin-like
activity. This kinin-like peptide enhances vascular permeability. C1 esterase inhibitor deficiency results in
hereditary or acquired angioedema. This disease is an autosomal dominant inherited condition, in which
exhaustion of the abnormally low levels of C1 esterase inhibitor results in C1 activation, breakdown of C2
and C4, and subsequent acute edema of subcutaneous tissue, the gastrointestinal tract, or the upper
respiratory tract. The disease responds to attenuated androgens. Because 15% of C1 inhibitor deficiencies
have nonfunctional protein, some patients will have abnormal functional results (FC1EQ / C1 Esterase
Inhibitor, Functional Assay, Serum) in the presence of normal (or elevated) antigen levels.
Useful For: Diagnosis of hereditary angioedema Monitoring levels of C1 esterase inhibitor in

response to therapy
Interpretation: Abnormally low results are consistent with a heterozygous C1 esterase inhibitor
deficiency and hereditary angioedema. Fifteen percent of hereditary angioedema patients have a normal
or elevated level but nonfunctional C1 esterase inhibitor protein. Detection of these patients requires a
functional measurement of C1 esterase inhibitor; FC1EQ / C1 Esterase Inhibitor, Functional Assay,
Serum. Measurement of C1q antigen levels; C1Q / Complement C1q, Serum, is key to the differential
diagnoses of acquired or hereditary angioedema. Those patients with the hereditary form of the disease
will have normal levels of C1q, while those with the acquired form of the disease will have low levels.
Studies in children show that adult levels of C1 inhibitor are reached by 6 months of age.
Reference Values:
19-37 mg/dL
Clinical References: 1. Frank MM: Complement deficiencies. Pediatr Clin North Am.
2000;47(6):1339-1354 2. Gelfand JA, Boss GR, Conley CL, et al: Acquired C1 esterase inhibitor
deficiency and angioedema: a review. Medicine. 1979;58(4):321-328 3. Rosen FS, Alper CA, Pensky J,
et al: Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary
angioneurotic edema. J Clin Invest. 1971;50(10):2143-2149 4. Frigas E: Angioedema with acquired
deficiency of the C1 inhibitor: a constellation of syndromes. Mayo Clin Proc. 1989;64:1269-1275 5.
Soldin SJ, Hicks JM, Bailey J, et al: Pediatric reference ranges for estradiol and C1 esterase inhibitor.
Clin Chem. 1998;44(6s):A17
FC1EQ C1 Esterase Inhibitor, Functional Assay, Serum

81493 Clinical Information: C1 inhibitor (C1-INH) is a multispecific protease inhibitor that is present in
normal human plasma and serum, and which regulates enzymes of the complement, coagulation,
fibrinolytic, and kinin-forming systems. The enzymes (proteases) regulated by this protein include the
C1r and C1s subunits of the activated first component of complement, activated Hageman factor (factor
XIa), kallikrein (Fletcher factor), and plasmin. A deficiency of functionally active C1-INH may lead to
life-threatening angioedema. Two major forms of C1-INH deficiency have been reported: the congenital
form, termed hereditary angioedema (HAE), and the acquired form that is associated with a variety of
diseases, including lymphoid malignancies. HAE is characterized by transient but recurrent attacks of
nonpruritic swelling of various tissues throughout the body. The symptomatology depends upon the
organs involved. Intestinal attacks lead to a diversity of symptoms including pain, cramps, vomiting,
and diarrhea. The most frequent cause of death in this disease is airway obstruction secondary to
laryngeal edema occurring during an attack. There are 2 types of HAE that can be distinguished
biochemically. Patients with the more common type (85% of HAE patients) have low levels of
functional C1-INH and C1-INH antigen. Patients with the second form (15% of HAE patients) have low
levels of functional C1-INH but normal or increased levels of C1-INH antigen that is dysfunctional. The
variable nature of the symptoms at different time periods during the course of the disease makes it
difficult to make a definitive diagnosis based solely on clinical observation.
Useful For: Diagnosing hereditary angioedema and for monitoring response to therapy
Interpretation: Hereditary angioedema (HAE) can be definitely diagnosed by laboratory tests
demonstrating a marked reduction in C1 inhibitor (C1-INH) antigen or abnormally low functional
C1-INH levels in a patient's plasma or serum that has normal or elevated antigen. Nonfunctional results
are consistent with HAE. Patients with current attacks will also have low C2 and C4 levels due to C1
activation and complement consumption. Patients with acquired C1-INH deficiency have a low C1q in
addition to low C1-INH.
Reference Values:
>67% normal (normal)
41-67% normal (equivocal)
<41% normal (abnormal)
Clinical References: 1. Stoppa-Lyonnet D, Tosi M, Laurent J, Sobel A, Lagrue G, Meo T: Altered
C1 inhibitor genes in type I hereditary angioedema. N Engl J Med. 1987;317:1-6. doi:
10.1056/NEJM198707023170101 2. Frigas E: Angioedema with acquired deficiency of the C1 inhibitor:
a constellation of syndromes. Mayo Clin Proc. 1989;64:1269-1275. doi: 10.1016/s0025-6196(12)61290-7
3. Frazer-Abel A, Sepiashvili L, Mbughuni MM, Willrich MA: Overview of laboratory testing and
clinical presentations of complement deficiencies and dysregulation. Adv Clin Chem. 2016;77:1-75. doi:
10.1016/bs.acc.2016.06.001
C1QFX C1q Complement, Functional, Serum

83374 Clinical Information: Complement proteins are components of the innate immune system. There are
3 pathways to complement activation: 1) the classical pathway, 2) the alternative (or properdin) pathway,
and 3) the lectin (or mannan binding lectin) pathway. The classical pathway of the complement system is
composed of a series of proteins that are activated in response to the presence of immune complexes. A
single IgM molecule or 2 IgG molecules are sufficient to trigger activation of the recognition complex
initiated by C1q. The activation process triggers a cascade that includes an amplification loop. The
amplification loop is mediated by C3, with cleavage of a series of proteins, and results in 3 main end
products: 1) anaphylatoxins that promote inflammation (C3a, C5a), 2) opsonization peptides that are
chemotactic for neutrophils (C3b) and facilitate phagocytosis, and 3) the membrane attack complex,
which promotes cell lysis. C1 is composed of 3 subunits designated as C1q, C1r, and C1s. C1q recognizes
and binds to immunoglobulin complexed to antigen and initiates the complement cascade. Congenital
deficiencies of any of the early complement components (C1-C4) result in an inability to generate the
peptides that are necessary to clear immune complexes and to attract neutrophils or generate lytic activity.
These patients have increased susceptibility to infections with encapsulated microorganisms. They may
also have symptoms that suggest autoimmune disease in which complement deficiency may be an
etiologic factor. Inherited deficiency of C1 is rare. Just over 40 cases have been reported for C1q
deficiency, and another 20 cases have been described for C1s and C1r deficiency. C1 deficiency is
associated with increased incidence of immune complex disease (systemic lupus erythematosus [SLE],
polymyositis, glomerulonephritis, and Henoch-Schonlein purpura), with SLE the most common
manifestation of C1 deficiency. The SLE associated with C1 deficiency is similar to SLE without
complement deficiency, but the age of onset is often prior to puberty. Low C1 levels have also been
reported in patients with abnormal immunoglobulin levels (Bruton and common variable
hypogammaglobulinemia and severe combined immunodeficiency), and this is most likely due to
increased catabolism. Complement levels can be detected by antigen assays that quantitate the amount of
the protein. For most of the complement proteins a small number of cases have been described in which
the protein is present but is nonfunctional. These rare cases require a functional assay to detect the
deficiency.
Useful For: Diagnosis of C1 deficiency Investigation of a patient with an absent total complement
level
Interpretation: Low levels of complement may be due to inherited deficiencies, acquired deficiencies,
or due to complement consumption (eg, as a consequence of infectious or autoimmune processes). The
measurement of C1q activity is an indicator of the amount of C1 present. Absent C1q levels in the
presence of normal C3 and C4 values are consistent with a C1 deficiency. Low C1q levels in the presence
of low C4 but normal C3 may indicate the presence of an acquired inhibitor (autoantibody) to C1 esterase
inhibitor.
Reference Values:
34-63 U/mL
Clinical References: 1. Sonntag J, Brandenburg U, Polzehl D, et al: Complement systems in healthy

term newborns: reference values in umbilical cord blood. Pediatr Dev Pathol. 1998 Mar-Apr;1(2):131-135
2. Prellner K, Sjoholm AG, Truedsson L: Concentrations of C1q, factor B, factor D and properdin in
healthy children, and the age-related presence of circulating C1r-C1s complexes. Acta Paediatr Scand.
1987 Nov;76(6):939-943 3. Davis ML, Austin C, Messmer BL, et al: IFCC-standardization pediatric
reference intervals for 10 serum proteins using the Beckman Array 360 system. Clin Biochem.
1996;29(5):489-492 4. Gaither TA, Frank MM: Complement. In: Henry JB, ed. Clinical Diagnosis and
Management by Laboratory Methods. 17th ed. WB Saunders Company: 1984:879-892 5. O'Neil KM:
Complement deficiency. Clin Rev Allergy Immunol. 2000;19:83-108 6. Frank MM: Complement
deficiencies. Pediatr Clin North Am. 2000;47(6):1339-1354 7. Brodszki N, Frazer-Abel A, Grumach AS,
et al: European Society for Immunodeficiencies (ESID) and European Reference Network on Rare
Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement
Guideline: Deficiencies, diagnosis, and management. J Clin Immunol. 2020;40(4):576-591 8. Willrich
MAV, Braun KMP, Moyer AM, Jeffrey DH, Frazer-Abel A. Complement testing in the clinical
laboratory. Crit Rev Clin Lab Sci. 2021 Nov;58(7):447-478. doi: 10.1080/10408363.2021.1907297
C2FXN C2 Complement, Functional, Serum

32137 Clinical Information: The classical pathway of the complement system is composed of a series of
proteins that are activated in response to the presence of immune complexes. A single IgM molecule or
2 IgG molecules are sufficient to trigger activation of the recognition complex initiated by C1q. This
activation process triggers a cascade that includes an amplification loop. The amplification loop is
mediated by C3, with cleavage of a series of proteins, and results in 3 main end products: 1)
anaphylatoxins that promote inflammation (C3a, C5a), 2) opsonizationÂ peptides that are chemotactic
for neutrophils (C3b) and facilitate phagocytosis, and 3) the membrane attack complex (MAC), which
promotes cell lysis. The absence of early components (C1, C2, C3, C4) of the complement cascade
results in the inability of immune complexes to activate the cascade. Patients with deficiencies of the
early complement proteins are unable to generate lytic activity or to clear immune complexes. They
may also have symptoms that suggest autoimmune disease in which complement deficiency may be an
etiologic factor. Although rare, C2 deficiency is the most common inherited complement deficiency.
Homozygous C2 deficiency has an estimated prevalence ranging from 1 in 10,000 to 1 in 40,000 (the
prevalence of heterozygotes is 1 in 100 to 1 in 50). Half of the homozygous patients are clinically
normal. However, discoid lupus erythematosus or systemic lupus erythematosus (SLE) occurs in
approximately one-third of patients with homozygous C2 deficiency. Patients with SLE and a C2
deficiency frequently have a normal anti-double-stranded DNA titer. Clinically, many have lupus-like
skin lesions and photosensitivity, but immunofluorescence studies may fail to demonstrate
immunoglobulin or complement along the epidermal-dermal junction. Other diseases reported to be
associated with C2 deficiency include dermatomyositis, glomerulonephritis, vasculitis, atrophodema,
cold urticaria, inflammatory bowel disease, and recurrent infections. The laboratory findings that
suggest C2 deficiency include a hemolytic complement of nearly zero, with normal values for C3 and
C4.
Useful For: Investigation of a patient with a low (absent) hemolytic complement

Interpretation: Low levels of complement may be due to inherited deficiencies, acquired
deficiencies, or due to complement consumption (eg, as a consequence of infectious or autoimmune
processes). Absent (or low) C2 levels in the presence of normal C3 and C4 values are consistent with a
C2 deficiency. Low C2 levels in the presence of low C3 and C4 values are consistent with a
complement-consumptive process. Low C2 and C4 values, in the presence of normal values for C3 is
suggestive of C1 esterase inhibitor deficiency.
Reference Values:
25-47 U/mL
Clinical References: 1. Gaither TA, Frank MM: Complement. In: Henry JB, ed. Clinical
Diagnosis and Management by Laboratory Methods. 17th ed. WB Saunders Company; 1984:879-892 2.
Agnello V: Complement deficiency states. Medicine. 1978;57:1-23 3. Buckley D, Barnes L: Childhood
subacute cutaneous lupus erythematosus associated with homozygous complement 2 deficiency. Pediatr
Dermatol. 1995;12:327-330 4. Willrich MAV, Braun KMP, Moyer AM, Jeffrey DH, Frazer-Abel A.
Complement testing in the clinical laboratory. Crit Rev Clin Lab Sci. 2021 Nov;58(7):447-478. doi:
10.1080/10408363.2021.1907297
C2 C2 Complement, Functional, with Reflex, Serum
81835 Clinical Information: The classical pathway of the complement system is composed of a series of
proteins that are activated in response to the presence of immune complexes. A single IgM molecule or 2
IgG molecules are sufficient to trigger activation of the recognition complex initiated by C1q. This
activation process triggers a cascade that includes an amplification loop. The amplification loop in
mediated by C3, with cleavage of a series of proteins, and results in 3 main end products: 1)
anaphylatoxins that promote inflammation (C3a, C5a), 2) opsonization peptides that are chemotactic for
neutrophils (C3b) and facilitate phagocytosis, and 3) the membrane attack complex, which promotes cell
lysis. The absence of early components (C1, C2, C3, C4) of the complement cascade results in the
inability of immune complexes to activate the cascade. Patients with deficiencies of the early complement
proteins are unable to generate lytic activity or to clear immune complexes. These patients have increased
susceptibility to infections with encapsulated microorganisms. They may also have symptoms that suggest
autoimmune disease, of which complement deficiency may be an etiologic factor. Although rare, C2
deficiency is the most common inherited complement deficiency. Homozygous C2 deficiency has an
estimated prevalence ranging from 1 in 10,000 to 1 in 40,000 (the prevalence of heterozygotes is 1 in 100
to 1 in 50). Half of the homozygous patients are clinically normal. However, discoid lupus erythematosus
or systemic lupus erythematosus (SLE) occurs in approximately one-third of patients with homozygous
C2 deficiency. Patients with SLE and a C2 deficiency frequently have a normal anti-double stranded
DNA titer. Clinically, many have lupus-like skin lesions and photosensitivity, but immunofluorescence
studies may fail to demonstrate immunoglobulin or complement along the epidermal-dermal junction.
Other diseases reported to be associated with C2 deficiency include dermatomyositis, glomerulonephritis,
vasculitis, atrophoderma, cold urticaria, inflammatory bowel disease, and recurrent infections. The
laboratory findings that suggest C2 deficiency include a hemolytic complement of nearly zero, with
normal values for C3 and C4.
Useful For: Investigation of a patient with a low (absent) hemolytic complement, with reflex testing to
C3 and C4, if appropriate
or due to complement consumption (eg, as a consequence of infectious or autoimmune processes). Absent
(or low) C2 levels in the presence of normal C3 and C4 values are consistent with a C2 deficiency. Low
C2 levels in the presence of low C3 and C4 values are consistent with a complement-consumptive
process. Low C2 and C4 values, in the presence of normal values for C3 is suggestive of C1 esterase
inhibitor deficiency.
Reference Values:
25-47 U/mL
Clinical References: 1. Gaither TA, Frank MM: Complement. In: Henry JB, ed. Clinical Diagnosis
and Management by Laboratory Methods. 17th ed. WB Saunders Company; 1984:879-892 2. O'Neil KM:
deficiencies. Pediatr Clin North Am. 2000;47(6):1339-1354 4. Agnello V: Complement deficiency states.
Medicine. 1978 Jan;57(1):1-23 5. Buckley D, Barnes L: Childhood subacute cutaneous lupus
erythematosus associated with homozygous complement 2 deficiency. Pediatr Dermatol. 1995
Dec;12(4):327-330 6. Willrich MAV, Braun KMP, Moyer AM, Jeffrey DH, Frazer-Abel A. Complement
testing in the clinical laboratory. Crit Rev Clin Lab Sci. 2021 Nov;58(7):447-478. doi:
10.1080/10408363.2021.1907297
C3FX C3 Complement, Functional, Serum

and 3) the lectin (or mannan-binding lectin) pathway. The classical pathway of the complement system is
chemotactic for neutrophils (C3b) and facilitate phagocytosis, and 3) the membrane attack complex
(MAC), which promotes cell lysis. The absence of early components (C1-C4) of the complement cascade
results in the inability of immune complexes to activate the cascade. Patients with deficiencies of the early
complement proteins are unable to clear immune complexes or to generate lytic activity. These patients
have increased susceptibility to infections with encapsulated microorganisms. They may also have
symptoms that suggest autoimmune disease in which complement deficiency may be an etiologic factor.
C3 is at the entry point for all 3 activation pathways to activate the MAC. C3 deficiency may result in
severe and recurrent pneumococcal and neisserial infections. Deficiency is very rare, with less than 30
cases described. Complement levels can be detected by antigen assays that quantitate the amount of the
protein (C3 / Complement C3, Serum). For most of the complement proteins, a small number of cases
have been described in which the protein is present but is nonfunctional. These rare cases require a
functional assay to detect the deficiency.
Useful For: Diagnosis of C3 deficiency Investigation of a patient with undetectable total complement
level

processes). Absent C3 levels in the presence of other normal complement values are consistent with a
C3 deficiency.
Reference Values:
21-50 U/mL
Clinical References: 1. Davis ML, Austin C, Messmer BL, et al: IFCC-standardization pediatric
Management by Laboratory Methods. 17th ed. WB Saunders Company; 1984:879-892 3. O'Neil KM:
deficiencies. Pediatr Clin North Am. 2000;47(6):1339-1354 5. Brodszki N, Frazer-Abel A, Grumach
AS, et al: European Society for Immunodeficiencies (ESID) and European Reference Network on Rare
Guideline: Deficiencies, diagnosis, and management. J Clin Immunol. 2020;40(4):576-591 6. Willrich
FC3AR C3a Level By RIA

0-780 ng/mL
C4U C4 Acylcarnitine, Quantitative, Random, Urine

88829 Clinical Information: An isolated elevation of iso-/butyrylcarnitine (C4) in plasma or newborn
screening blood spots is related to a diagnosis of either short chain acyl-CoA dehydrogenase (SCAD)
deficiency or isobutyryl-CoA dehydrogenase (IBD) deficiency. Diagnostic testing by acylcarnitine
analysis, including the evaluation of C4 excretion in urine, is necessary to differentiate the 2 clinical
entities.(1) Patients with IBD deficiency excrete an abnormal amount of C4 acylcarnitine in urine,
whereas patients with SCAD deficiency can have a normal excretion of this metabolite. See Newborn
Screening Follow-up for Isolated C4 Acylcarnitine Elevations (also applies to any plasma or serum C4
acylcarnitine elevation) for additional Information.
Useful For: Evaluation of patients with abnormal newborn screens showing elevations of
iso-/butyrylcarnitine to aid in the differential diagnosis of short-chain acyl-CoA dehydrogenase and
isobutyryl-CoA dehydrogenase deficiencies
Interpretation: Almost all patients with isobutyryl-CoA dehydrogenase deficiency excrete an
abnormal amount of iso-/butyrylcarnitine (C4) in their urine. Some, but not all, affected individuals also
excrete elevated levels of isobutyrylglycine. Conversely, patients with short-chain acyl-CoA
dehydrogenase deficiency can have a normal excretion of C4.
Reference Values:
<3.00 millimoles/mole creatinine
Clinical References: Clinical Reference 1. Miller MJ, Cusmano-Ozog K, Oglesbee D, Young S;

ACMG Laboratory Quality Assurance Committee: Laboratory analysis of acylcarnitines, 2020 update: a
technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med.
2021 Feb;23(2):249-258 2. Oglesbee D, Vockley J, Ensenauer RE, et al: Ten cases of isobutyryl-CoA
dehydrogenase (IBDH) deficiency detected by newborn screening. J Inherit Metab Dis. 2005;28(Suppl
1):13. doi: 10.1007/s10545-004-0001-x 3. Oglesbee D, He M, Majumder N, et al: Development of a
newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency.
Genet Med. 2007 Feb;9(2):108-116

chemotactic for neutrophils (C3b) and facilitate phagocytosis, and 3) the membrane attack complex,
which promotes cell lysis. The absence of early components (C1-C4) of the complement cascade results
in the inability of immune complexes to activate the cascade. Patients with deficiencies of the early
complement proteins are unable to generate the peptides that are necessary clear immune complexes and
to attract neutrophils or to generate to lytic activity. These patients have increased susceptibility to
infections with encapsulated microorganisms. They may also have symptoms that suggest autoimmune
disease, of which complement deficiency may be an etiologic factor. Approximately 30 cases of
homozygous C4 deficiency have been reported. Most of these patients have systemic lupus erythematosus
(SLE) or glomerulonephritis, IgA nephropathy. Patients with C4 deficiency may also have frequent
bacterial infections and may present with autoimmune diseases such as SLE and SLE-like syndromes or
rheumatoid arthritis. C4 is coded by two different genes in the major histocompatibility complex on
human chromosome 6. Seventy-five percent of the population has two C4A and two C4B genes.
However, the total sum of C4A and C4B genes in an individual can range from zero to 8 or more copies,
giving this protein a wide range of concentrations and an even wider range of function in the general
population. Most of the partial C4 deficiencies are without consequence, although deficiency of C4A is
associated with a 15% incidence of SLE. Complement levels can be detected by antigen assays that
quantitate the amount of the protein (C4 / Complement C4, Serum). For most of the complement proteins,
a small number of cases have been described in which the protein is present but is nonfunctional. These
rare cases require a functional assay to detect the deficiency.
Useful For: Diagnosis of C4 deficiency Investigation of a patient with an undetectable total

complement level
C4 levels in the presence of normal C3 and C2 values are consistent with a C4 deficiency. Normal results
indicate both normal C4 protein levels and normal functional activity. In hereditary angioedema, a
disorder caused by C1 esterase inhibitor deficiency, absent or low C4 and C2 values are seen in the
presence of normal C3 (due to activation and consumption of C4 and C2).
Reference Values:
22-45 U/mL
Clinical References: 1. Davis ML, Austin C, Messmer BL, et al: IFCC-standardization pediatric
Complement deficiency. Clin Rev in Allergy Immunol. 2000;19:83-108 4. Frank MM: Complement
deficiencies. Pediatr Clin North Am. 2000;47:1339-1354 5. Brodszki N, Frazer-Abel A, Grumach AS,
et al: European Society for Immunodeficiencies (ESID) and European Reference Network on Rare
Guideline: Deficiencies, Diagnosis, and Management. J Clin Immunol. 2020 May;40(4):576-591 6.
Willrich MAV, Braun KMP, Moyer AM, Jeffrey DH, Frazer-Abel A. Complement testing in the
clinical laboratory. Crit Rev Clin Lab Sci. 2021 Nov;58(7):447-478. doi:
10.1080/10408363.2021.1907297
FC4AL C4 Level by RIA

0 - 2830 ng/mL
C5AG C5 Complement, Antigen, Serum

are 3 pathways to complement activation: 1) the classic pathway, 2) the alternative (or properdin)
pathway, and 3) the lectin activation (mannan-binding protein: MBP) pathway. The classic pathway of
the complement system is composed of a series of proteins that are activated in response to the presence
of immune complexes. The activation process results in the generation of peptides that are chemotactic
for neutrophils and that bind to immune complexes and complement receptors. The end result of the
complement activation cascade is the formation of the lytic membrane attack complex (MAC). Â The
absence of early components (C1-C4) of the complement cascade results in the inability of immune
complexes to activate the cascade. Patients with deficiencies of the early complement proteins are
unable to clear immune complexes or to generate lytic activity. These patients have increased
susceptibility to infections with encapsulated microorganisms. They may also have symptoms that
suggest autoimmune disease and complement deficiency may be an etiologic factor in the development
of autoimmune disease.Â More than 30 cases of C5 deficiency have been reported. Most of these
patients have neisserial infections.
Useful For: Diagnosis of C5 deficiency Investigation of a patient with an absent total complement
(CH50) level

processes).Â Absent C5 levels in the presence of normal C3 and C4 values are consistent with a C5
deficiency. Absent C5 levels in the presence of low C3 and C4 values suggests complement
consumption. A small number of cases have been described in which the complement protein is present
but is nonfunctional. These rare cases require a functional assay to detect the deficiency C5FX / C5
Complement, Functional, Serum).
Reference Values:
10.6-26.3 mg/dL
Clinical References: 1. Sonntag J, Brandenburg U, Polzehl D, et al: Complement systems in

healthy term newborns: reference values in umbilical cord blood. Pediatr Dev Pathol 1998;1:131-135 2.
Prellner K, Sjoholm AG, Truedsson L: Concentrations of C1q, factor B, factor D and properdin in
healthy children, and the age-related presence of circulating C1r-C1s complexes. Acta Peidiatr Scand
1987;76:939-943 3. Davis ML, Austin C, Messmer BL, et al: IFCC-standardization pediatric reference
intervals for 10 serum proteins using the Beckman Array 360 system. Clin Biochem 1996;29,5:489-492
4. Gaither TA, Frank MM: Complement. In Clinical Diagnosis and Management by Laboratory
Methods. 17th edition. Edited by JB Henry. Philadelphia, WB Saunders Company, 1984, pp 879-892 5.
O'Neil KM: Complement deficiency. Clin Rev Allergy Immunol 2000;19:83-108 6. Frank MM:
Complement deficiencies. Pediatr Clin North Am 2000;47(6):1339-1354

(MAC), which promotes cell lysis. Patients with deficiencies of the late complement proteins (C5, C6, C7,
C8, and C9) are unable to form the MAC and may have increased susceptibility to neisserial infections.
Approximately 40 cases of C5 deficiency have been reported.Â Complement levels can be detected by
antigen assays that quantitate the amount of the protein (C5AG / C5 Complement, Antigen, Serum). For
most of the complement proteins, a small number of cases have been described in which the protein is
present but is nonfunctional. These rare cases require a functional assay to detect the deficiency.

complement level
C5 levels in the presence of normal C3 and C4 values are consistent with a C5 deficiency. Absent C5
levels in the presence of low C3 and C4 values suggest complement consumption. Normal results indicate
both normal C5 protein levels and normal functional activity.
Reference Values:
29-53 U/mL

reference intervals for 10 serum proteins using the Beckman Array 360 system. Clin Biochem. 1996
Oct;29,5:489-492 4. Gaither TA, Frank MM: Complement. In: Henry JB, ed. Clinical Diagnosis and
Complement deficiency. Clin Rev Allergy Immunol. 2000 Oct;19:83-108 6. Frank MM: Complement
deficiencies. Pediatr Clin North Am. 2000 Dec;47(6):1339-1354 7. Willrich MAV, Braun KMP, Moyer
AM, Jeffrey DH, Frazer-Abel A. Complement testing in the clinical laboratory. Crit Rev Clin Lab Sci.
2021 Nov;58(7):447-478. doi: 10.1080/10408363.2021.1907297
C5DCU C5-DC Acylcarnitine, Quantitative, Random, Urine

88831 Clinical Information: An isolated elevation of glutarylcarnitine (C5-DC) in plasma or newborn
screening blood spots is related to a diagnosis of glutaric aciduria type 1 (GA-1), also known as glutaric
acidemia type 1. GA-1 is caused by a deficiency of glutaryl-CoA dehydrogenase. Diagnostic testing by
acylcarnitine analysis, including the evaluation of C5DC in urine, is helpful to determine if a patient has
GA1.(1) Urinary excretion of C5-DC is a specific biochemical marker of GA-1 that appears to be elevated
even in low excretors, those patients who are affected but have normal levels of glutaric acid in urine.
GA-1 is characterized by bilateral striatal brain injury leading to dystonia, often a result of acute
neurologic crises triggered by illness. Many affected individuals also have macrocephaly. Dietary
treatment and aggressive interventions during time of illness are recommended to try to prevent or
minimize neurologic injury, which is most likely to occur in infancy and early childhood. Prevalence is
approximately 1 in 100,000 individuals. The American College of Medical Genetics and Genomics
newborn screening work group published diagnostic algorithms for the follow-up of infants who had a
positive newborn screening result. For more information, see the Practice Resources: ACT Sheets and
Algorithms at www.acmg.net.
Useful For: Evaluation of patients with an abnormal newborn screen showing elevations of
glutarylcarnitine Diagnosis of glutaric aciduria type 1 deficiency
Interpretation: Elevated excretion of glutarylcarnitine is a specific biochemical marker of glutaric

aciduria type 1 that is elevated in affected patients, apparently even in low excretors, ie, those affected
individuals with normal levels of glutaric acid in urine.
Reference Values:

Quality Assurance Committee: Laboratory analysis of acylcarnitines, 2020 update: a technical standard
Feb;23(2):249-258 2. Kolker S, Christensen E, Leonar JV, et al: Diagnosis and management of glutaric
aciduria type I-revised recommendations. J Inherit Metab Dis. 2011 Jun:34(3):677-694 3. Guenzel AJ,
Hall P, Scott AI, et al: The low excretor phenotype of glutaric acidemia type I is a source of false
negative newborn screening results and challenging diagnoses. JIMD Rep.2021 Apr 5;60(1)67â€“74
C5OHU C5-OH Acylcarnitine, Quantitative, Random, Urine

88830 Clinical Information: The differential diagnosis of an isolated elevation of
3-hydroxyisovaleryl-/2-methyl-3-hydroxy acylcarnitine (C5-OH) in plasma or (newborn screening)
blood spots includes the following disorders: -3-Methylcrotonyl-CoA carboxylase deficiency (common
name: 3-methylcrotonylglycinuria), either infantile or maternal -3-Hydroxy 3-methylglutaryl-CoA lyase
deficiency -Beta-ketothiolase deficiency -2-Methyl 3-hydroxybutyryl-CoA dehydrogenase deficiency
-3-Methylglutaconic aciduria type I -Biotinidase deficiency -Holocarboxylase deficiency Confirmatory
and diagnostic testing are necessary to differentiate these clinical entities. This test can be used to
differentiate patients with 3-methylcrotonylglycinuria and with 3-methylglutaconic aciduria as they
typically excrete larger amounts of C5-OH in urine compared to patients with the other diagnoses. The
American College of Medical Genetics and Genomics Newborn Screening Work Group published
diagnostic algorithms for the follow-up of infants who had positive newborn screening results. For more
information, see the Practice Resources: ACT Sheets and Algorithms at www.acmg.net.
Useful For: Evaluation of patients with an abnormal newborn screen showing elevations of
3-hydroxyisovaleryl-/2-methyl-3-hydroxybutyryl-carnitine
Interpretation: Preliminary data showed that an elevated excretion in urine and concentration in
plasma of 3-hydroxyisovaleryl-/2-methyl-3-hydroxy acylcarnitine can be the only biochemical
abnormalities in patients with 3-methylcrotonylglycinuria.
Reference Values:
Clinical References: 1. Wolfe LA, Finegold DN, Vockley J, et al: Potential misdiagnosis of
3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary
3-methylcrotonylglycine. Pediatrics. 2007 Nov;120(5):e1335-1340 2. Miller MJ, Cusmano-Ozog K,
Oglesbee D, Young S; ACMG Laboratory Quality Assurance Committee: Laboratory analysis of
acylcarnitines, 2020 update: a technical standard of the American College of Medical Genetics and
Genomics (ACMG). Genet Med. 2021 Feb;23(2):249-258
and 3) the lectin (mannan-binding lectin) pathway. The classical pathway of the complement system is
C8, and C9) are unable to form the MAC, and may have increased susceptibility to neisserial infections.
C6 deficiency is relatively rare, over 50 cases have been described. Most of these patients have systemic
meningococcal infection and some have had invasive gonococcal infections. Normal levels of C6 antigen
have been reported in patients with dysfunctional C6 lytic activity, hence the recommendation of
functional testing.

complement level
levels in the presence of low C3 and C4 values suggests complement consumption. Normal results
indicate both normal C6 protein levels and normal functional activity.
Reference Values:
32-57 U/mL

term newborns: reference values in umbilical cord blood. Pediatr Dev Pathol. 1998 Mar-Apr;
1(2):131-135 2. Prellner K, Sjoholm AG, Truedsson L: Concentrations of C1q, factor B, factor D and
properdin in healthy children, and the age-related presence of circulating C1r-C1s complexes. Acta
Paediatr Scand. 1987 Nov;76(6):939-943 3. Davis ML, Austin C, Messmer BL, et al:
IFCC-standardization pediatric reference intervals for 10 serum proteins using the Beckman Array 360
system. Clin Biochem. 1996 Oct;29(5):489-492 4.Â Gaither TA, Frank MM: Complement. In: Henry JB,
ed. Clinical Diagnosis and Management by Laboratory Methods. 17th ed. WB Saunders Company;
1984:879-892 5. O'Neil KM: Complement deficiency. Clin Rev Allergy Immunol. 2000 Oct;19:83-108 6.
Frank MM: Complement deficiencies. Pediatr Clin North Am. 2000 Dec;47(6):1339-1354 7. Willrich

C7 deficiency is relatively rare, over 50 cases have been described. The majority of C7 deficiency cases
have neisserial infections, but cases with systemic lupus erythematosus, rheumatoid arthritis, scleroderma,
and pyoderma gangrenosum have also been reported. The pathogenesis of the rheumatic disease is not
clear. Complement levels can be detected by antigen assays that quantitate the amount of the protein. For
most of the complement proteins, a small number of cases have been described in which the protein is
present but is nonfunctional. These rare cases require a functional assay to detect the deficiency.

complement level

processes). Absent C7 levels in the presence of normal C3 and C4 values are consistent with a C7
deficiency. Absent C7 levels in the presence of low C3 and C4 values suggest complement
consumption.
Reference Values:
36-60 U/mL
Clinical References: 1. Sonntag J, Brandenburg U, Polzehl D, et al: Complement systems in

healthy term newborns: reference values in umbilical cord blood. Pediatr Dev Pathol. 1998
Mar-Apr;1(2):131-135 2. Prellner K, Sjoholm AG, Truedsson L: Concentrations of C1q, factor B, factor
D and properdin in healthy children, and the age-related presence of circulating C1r-C1s complexes.
Acta Paediatr Scand. 1987 Nov;76(6):939-943 3. Davis ML, Austin C, Messmer BL, et al:
IFCC-standardization pediatric reference intervals for 10 serum proteins using the Beckman Array 360
system. Clin Biochem. 1996 Oct;29(5):489-492 4. Gaither TA, Frank MM: Complement. In: Henry JB,
ed. Clinical Diagnosis and Management by Laboratory Methods.Â 17th ed. WB Saunders Company;
1984:879-892 5. O'Neil KM: Complement Deficiency. Clin Rev Allergy Immunol. 2000 Oct;19:83-108
6. Frank MM: Complement deficiencies. Pediatr Clin North Am. 2000 Dec;47(6):1339-1354 7. Willrich

are 3 pathways to complement activation: 1) the classical pathway, 2) the alternative (or properdin)
pathway, and 3) the lectin (mannan-binding lectin) pathway. The classical pathway of the complement
system is composed of a series of proteins that are activated in response to the presence of immune
complexes. A single IgM molecule or 2 IgG molecules are sufficient to trigger activation of the
recognition complex initiated by C1q. The activation process triggers a cascade that includes an
amplification loop. The amplification loop is mediated by C3, with cleavage of a series of proteins, and
results in 3 main end products: 1) anaphylatoxins that promote inflammation (C3a, C5a), 2)
opsonization peptides that are chemotactic for neutrophils (C3b) and facilitate phagocytosis, and 3) the
membrane attack complex (MAC), which promotes cell lysis. Patients with deficiencies of the late
complement proteins (C5, C6, C7, C8, and C9) are unable to form the MAC, and may have increased
susceptibility to neisserial infections. C8 deficiency is relatively rare, over 50 cases have been
described. The C8 protein is comprised of 3 subunits: alpha, beta, and gamma. However, variants
leading to deficiency have not been reported in C8 gamma, and the majority are in the C8 beta subunit.
C8 deficiency is characterized by recurrent neisserial infections, particularly meningitis. Autoimmune
disease (systemic lupus erythematosus-like) has also been reported. Given the 3 subunits, it is possible
to have a low-normal C8 concentration but a nonfunctional protein, therefore the recommendation for
testing is the functional assay. For most of the complement proteins, a small number of cases have been
described in which the protein is present but is nonfunctional. These rare cases require a functional
assay to detect the deficiency.

hemolytic complement level

processes). Absent C8 levels in the presence of normal C3 and C4 values are consistent with a C8
deficiency. Absent C8 levels in the presence of low C3 and C4 values suggests complement
consumption. Normal results indicate both normal C8 protein levels and normal functional activity.
Reference Values:
33-58 U/mL

Oct;29(5):489-492 4.Â Gaither TA, Frank MM: Complement. In: Henry JB, ed. Clinical Diagnosis and
Management by Laboratory Methods.Â 17th ed. WB Saunders Company; 1984:879-892 5. O'Neil KM:
2021 Nov;58(7):447-478. doi: 10.1080/10408363.2021.1907297

C9 deficiency is common in the Japanese population, (1:1000), but is otherwise rare. The lytic activity of
C9-deficient serum is decreased. However, the assembly of C5b-C8 complexes will result in a
transmembrane channel with minimal lytic activity. Many C9-deficient patients are asymptomatic.
C9-deficient patients may, however, present with invasive neisserial infections. Complement levels can be
detected by antigen assays that quantitate the amount of the protein. For most of the complement proteins,
a small number of cases have been described in which the protein is present but is nonfunctional. These
rare cases require a functional assay to detect the deficiency.
Useful For: Diagnosis of C9 deficiency Investigation of a patient with a low total (hemolytic)
complement level
levels in the presence of low C3 and C4 values suggests complement consumption. Normal results
indicate both normal C9 protein levels and normal functional activity.
Reference Values:
37-61 U/mL

Oct;29(5):489-492 4. Gaither TA, Frank MM: Complement. In: Henry JB, ed. Clinical Diagnosis and
Management by Laboratory Methods.Â 17th ed. WB Saunders Company; 1984:879-892 5. O'Neil KM:
2021 Nov;58(7):447-478. doi: 10.1080/10408363.2021.1907297
C9ORF C9orf72 Hexanucleotide Repeat, Molecular Analysis, Varies

35377 Clinical Information: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative
disease affecting the upper and lower motor neurons. The disease is characterized by progressive
spasticity, muscle wasting and paralysis, typically leading to death from respiratory failure.
Frontotemporal dementia (FTD) is a dementia syndrome that predominantly involves the frontal and
temporal lobes of the brain. Clinical presentation is variable and includes progressive changes in
behavior and personality and language disturbances. Affected individuals may also exhibit
extrapyramidal signs. ALS and FTD are now thought to represent an overlapping spectrum of disease.
Recent literature has found that approximately 40% of familial ALS, 25% of familial FTD, and 90% of
familial ALS/FTD cases have a large hexanucleotide repeat (GGGGCC) expansion in a noncoding
region of C9orf72. At lower frequency, C9orf72 hexanucleotide repeat expansions have also been
observed in individuals with sporadic ALS, FTD, and ALS/FTD. The vast majority of individuals
affected with a C9orf72-related disorder (c9ALS, c9FTD, or c9ALS/FTD) have hexanucleotide repeat
expansions in the hundreds to thousands, while unaffected individuals have repeat sizes less than 20.
The significance of repeat sizes between 20 and 100 repeats is currently unclear as both healthy controls
and individuals with ALS and/or FTD phenotypes have been reported with repeat sizes in this range.
Useful For: Molecular confirmation of clinically suspected cases of c9FTD/ALS, frontotemporal

dementia (FTD), or amyotrophic lateral sclerosis (ALS) Presymptomatic testing for individuals with a
family history of c9FTD/ALS and a documented expansion in the C9orf72 gene

Reference Values:
Normal alleles (reference):<20 GGGGCC repeats
Indeterminate alleles: 20-100 GGGGCC repeats
Pathogenic alleles: >100* GGGGCC repeats
*The exact cutoff for pathogenicity is currently undefined. Although additional studies are needed to
confirm if 100 repeats is the cutoff for pathogenicity, most individuals affected with a C9orf72-related
disorder have C9orf72 hexanucleotide repeat expansions with hundreds to thousands of repeats.
Clinical References: 1. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al: Expanded

GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD
and ALS. Neuron 2011;72(2):245-256 2. Renton AE, Majounie E, Waite A, et al: A hexanucleotide
repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011,
72:257-268 3. Gijselinck I, Van Langenhove T, van der Zee J, et al: A C9orf72 promoter repeat
expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar
degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neuron
2012;11(1):54-65 4. Majounie E, Renton AE, Mok K, et al: Frequency of the C9orf72 hexanucleotide
repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a
cross-sectional study. Lancet Neurol 2012 Apr;11(4):323-330 5. Boeve BF, Boylan KB, Graff-Radford
NR, et al: Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated
with the GGGGCC repeat expansion in C9ORF72. Brain 2012;135(Pt 3):765-783 6. van Blitterswijk M,
DeJesus-Hernandez M, Niemantsverdriet E, et al: Association between repeat sizes and clinical and
pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional
cohort study. Lancet Neurol 2013 Oct;12(10):978-988 7. Nordin A, Akimoto C, Wuolikainen A, et al:
Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal
tissues in 18 patients with ALS or FTD. Hum Mol Genet 2015 Jun 1;24(11):3133-3142 8. Xi Z, van
Blitterswijk M, Zhang M, et al: Jump from pre-mutation to pathologic expansion in C9orf72. Am J
Hum Genet 2015 Jun 4;96(6):962-970 9. Gami P, Murray C, Schottlaender L, et al: A 30-unit
hexanucleotide repeat expansion in C9orf72 induces pathological lesions with dipeptide-repeat proteins
and RNA foci, but not TDP-43 inclusions and clinical disease. Acta Neuropathol 2015
Oct;130(4):599-601 10. Ng ASL, Tan EK: Intermediate C9orf72 alleles in neurological disorders: does
size really matter? J Med Genet 2017 Sep;54(9):591-597 11. Nordin A, Akimoto C, Wuolikainen A, et
al: Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on
repeat-primed PCR interpretation: a large multinational screening study. Amyotrophic Lateral Sclerosis
and Frontotemporal Degeneration. Amyotroph Lateral Scler Frontotemporal Degener 2017
May;18(3-4):256-264 12. Van Mossevelde S, van der Zee J, Cruts M, et al: Relationship between
C9orf72 repeat size and clinical phenotype. Curr Opin Genet Dev 2017;44:117-124
FCABB Cabbage IgG

Reference Values:
CABB Cabbage, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cabbage Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
COCOA Cacao/Cocoa, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cacao/cocoa Defining the allergen responsible

likelihood of allergic disease as opposed to other etiologies and defines the allergens responsible for
eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the
Reference Values:

0 Negative

apply to all ages.
CDOMB Cadmium for Occupational Monitoring, Blood
89539 Clinical Information: The toxicity of cadmium resembles the other heavy metals (arsenic, mercury,
and lead) in that it attacks the kidney; renal dysfunction with proteinuria with slow onset (over a period of
years) is the typical presentation. Breathing the fumes of cadmium vapors leads to nasal epithelial
deterioration and pulmonary congestion resembling chronic emphysema. The most common source of
chronic exposure comes from spray painting of organic-based paints without use of a protective breathing
apparatus; auto repair mechanics represent a susceptible group for cadmium toxicity. Tobacco smoke is
another common source of cadmium exposure.
Useful For: Detecting exposure to cadmium, a toxic heavy metal

Interpretation: Normal blood cadmium is <5.0 mcg/L, with most results in the range of 0.5 to 2.0
mcg/L. Acute toxicity will be observed when the blood level exceeds 50 mcg/L.
Reference Values:
0.0-4.9 mcg/L
Clinical References: 1. Moreau T, Lellouch J, Juguet B, et al: Blood cadmium levels in a general
male population with special reference to smoking. Arch Environ Health 1983;38:163-167 2.
Occupational Safety and Health Administration, US Department of Labor: Cadmium Exposure
Evaluation. Updated 9/2/2008. Available from URL:osha.gov/SLTC/cadmium/evaluation.html
CDOU Cadmium Occupational Exposure, Random, Urine

years) is the typical presentation. Measurable changes in proximal tubule function, such as decreased
clearance of para-aminohippuric acid, also occur over a period of years and precede overt renal failure.
Breathing the fumes of cadmium vapors leads to nasal epithelial deterioration and pulmonary congestion
resembling chronic emphysema. The most common source of cadmium exposure is tobacco smoke, which
has been implicated as the primary sources of the metal leading to reproductive toxicity in both males and
females. Chronic exposure to cadmium causes accumulated renal damage. The excretion of cadmium is
proportional to creatinine except when renal damage has occurred. Renal damage due to cadmium
exposure can be detected by increased cadmium excretion relative to creatinine. The Occupational Safety
and Health Administration (OSHA) mandated (Fed Reg 57:42,102-142,463, September 1992) that all
monitoring of employees exposed to cadmium in the workplace should be done using the measurement of
urine cadmium and creatinine, expressing the results of mcg of cadmium per gram of creatinine.
Useful For: Detecting occupational exposure to cadmium in random urine specimens

Interpretation: Cadmium excretion above 3.0 mcg/g creatinine indicates significant exposure to
cadmium. Results above 15 mcg/g creatinine are considered indicative of severe exposure
Reference Values:
-CDUOE / Cadmium Occupational Exposure, Random, Urine
-HMUOE / Heavy Metal Occupational Exposure, with Reflex, Random, Urine
Clinical References: 1. deBurbure C, Buchet JP, Leroyer A, et al: Renal and neurologic effects of
cadmium, lead, mercury, and arsenic in children: Evidence of early effects and multiple interactions at
environmental exposure levels. Environ Health Perspect. 2006;114:584-590 2. Schulz C, Angerer J,
Ewers U, et al: Revised and new reference values for environmental pollutants in urine or blood of
children in Germany derived from the German Environmental Survey on Children 2003-2006(GerESIV)
Int J Hyg Environ Health. 2009;212:637-647 3. Occupational Safety and Health Administration:
Cadmium exposure and control. Updated 9/2/2008. Accessed July 17, 2020. US Department of Labor
Available at osha.gov/SLTC/cadmium/evaluation.html 4. Agency for Toxic Substances and Disease
Registry: Toxicological profile for cadmium. US Department of Health and Human Services. September
2012. Available at www.atsdr.cdc.gov/ToxProfiles/tp5.pdf 5. Strathmann FG, Blum LM: Toxic elements.
In: Rafai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics. 6th ed. Elsevier; 2018:chap 42
CDUOE Cadmium Occupational Exposure, Random, Urine

608896 Clinical Information: The toxicity of cadmium resembles the other heavy metals (arsenic,
mercury, and lead) in that it attacks the kidney; renal dysfunction with proteinuria with slow onset (over
a period of years) is the typical presentation. Measurable changes in proximal tubule function, such as
decreased clearance of para-aminohippuric acid, also occur over a period of years and precede overt
renal failure. Breathing the fumes of cadmium vapors leads to nasal epithelial deterioration and
pulmonary congestion resembling chronic emphysema. For nonsmokers, the primary source of
cadmium exposure is from the food supply. In general, leafy vegetables such as lettuce and spinach,
potatoes and grains, peanuts, soybeans, and sunflower seeds contain high levels of cadmium. For
smokers, the most common source of cadmium exposure is tobacco smoke, which has been implicated
as the primary sources of the metal leading to reproductive toxicity in both males and females. Chronic
exposure to cadmium causes accumulated renal damage. The excretion of cadmium is proportional to
creatinine except when renal damage has occurred. Renal damage due to cadmium exposure can be
detected by increased cadmium excretion relative to creatinine. The Occupational Safety and Health
Administration (OSHA) mandated (Fed Reg 57:42,102-142,463, September 1992) that all monitoring of
employees exposed to cadmium in the workplace should be done using the measurement of urine
cadmium and creatinine, expressing the results of mcg of cadmium per gram of creatinine.
Useful For: Detecting occupational exposure to cadmium, a toxic heavy metal in random urine
specimens
Interpretation: Urine cadmium levels primarily reflect total body burden of cadmium. Cadmium
excretion above 3.0 mcg/g creatinine indicates significant exposure to cadmium. For occupational
testing, the Occupational Safety and Health Administration (OSHA) cadmium standard is below 3.0
mcg/g creatine and the biological exposure index is 5 mcg/g creatinine.
Reference Values:
Biological Exposure Indices (BEI): <5.0 mcg/g creatinine
Clinical References: 1. deBurbure C, Buchet J-P, Leroyer A, et al: Renal and neurologic effects of
children in Germany derived from the German Environmental Survey on Children
2003-2006(GerESIV) Int J Hyg Environ Health. 2009;212:637-647 3. Occupational Safety and Health
Administration:: Cadmium exposure and control. Updated 9/2/2008. Accessed July 17, 2020. US
Department of Labor Available at osha.gov/SLTC/cadmium/evaluation.html 4. Agency for Toxic
Substances and Disease Registry: Toxicological profile for cadmium. US Department of Health and
Human Services. September 2012. Available at www.atsdr.cdc.gov/ToxProfiles/tp5.pdf 5. Strathmann
FG, Blum LM: Toxic elements. In: Rafai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical
CDU Cadmium, 24 Hour, Urine

8678 Clinical Information: The toxicity of cadmium resembles the other heavy metals (arsenic,
mercury, and lead) in that it attacks the kidney; renal dysfunction with proteinuria with slow onset (over
a period of years) is the typical presentation. Measurable changes in proximal tubule function, such as
decreased clearance of para-aminohippuric acid also occur over a period of years, and precede overt
renal failure. Breathing the fumes of cadmium vapors leads to nasal epithelial deterioration and
pulmonary congestion resembling chronic emphysema. For nonsmokers, the primary source of
cadmium exposure is from the food supply. In general, leafy vegetables such as lettuce and spinach,
potatoes and grains, peanuts, soybeans, and sunflower seeds contain high levels of cadmium. For
smokers, the most common source of cadmium exposure is tobacco smoke, which has been implicated
as the primary sources of the metal leading to reproductive toxicity in both males and females. The
concentration of cadmium in the kidneys and in the urine is elevated in some patients exposed to
cadmium. See also CDUOE / Cadmium, Occupational Exposure, Random, Urine. If employees are
being monitored in the workplace, the Occupational Safety and Health Administration (OSHA) requires
that laboratory reports express the cadmium excretion rate per gram of creatinine rather than per 24
hours. This alternative test is available to accommodate that requirement. Mayo Clinic Laboratories is
certified to provide this test.
Useful For: Detecting exposure to cadmium, a toxic heavy metal in 24-hour urine specimens
excretion above 3.0 mcg/g creatinine indicates significant exposure to cadmium. For occupational testing,
the Occupational Safety and Health Administration (OSHA) cadmium standard is less than 3.0 mcg/g
creatine and the biological exposure index is 5 mcg/g creatinine.
Reference Values:
> or =18 years: <0.7 mcg/24 hour
Int J Hyg Environ Health. 2009;212:637-647 3. Occupational Safety and Health Administration::
Cadmium exposure and controls. US Department of Labor Updated 9/2/2008. Accessed July 17, 2020.
2012. Avaliable at www.atsdr.cdc.gov/ToxProfiles/tp5.pdf 5. Strathmann FG, Blum LM: Toxic elements.
In: Rafai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular
CDB Cadmium, Blood

years) is the typical presentation. Breathing the fumes of cadmium vapors leads to nasal epithelial
deterioration and pulmonary congestion resembling chronic emphysema. The most common source of
chronic exposure comes from spray painting of organic-based paints without use of a protective breathing
apparatus; auto repair mechanics represent a susceptible group for cadmium toxicity. In addition, another
common source of cadmium exposure is tobacco smoke.
Useful For: Detecting exposure to cadmium, a toxic heavy metal

Interpretation: Normal blood cadmium is <5.0 ng/mL, with most results in the range of 0.5 to 2.0
ng/mL. Acute toxicity will be observed when the blood level exceeds 50 ng/mL.
Reference Values:
<5.0 ng/mL
Clinical References: 1. Moreau T, Lellouch J, Juguet B, et al: Blood cadmium levels in a general
population with special reference to smoking. Arch Environ Health. 1983;38:163-167 2. Strathmann FG,
Blum LM: Toxic Elements. In: Rafai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics 6th ed. Elsevier, 2018;chap 42
CDUCR Cadmium/Creatinine Ratio, Random, Urine
608906 Clinical Information: The toxicity of cadmium resembles the other heavy metals (arsenic, mercury
and lead) in that it attacks the kidney; renal dysfunction with proteinuria with slow onset (over a period
of years) is the typical presentation. Measurable changes in proximal tubule function, such as decreased
Breathing the fumes of cadmium vapors leads to nasal epithelial deterioration and pulmonary
congestion resembling chronic emphysema. For nonsmokers, the primary source of cadmium exposure
is from the food supply. In general, leafy vegetables such as lettuce and spinach, potatoes and grains,
peanuts, soybeans, and sunflower seeds contain high levels of cadmium. For smokers, the most common
source of cadmium exposure is tobacco smoke, which has been implicated as the primary sources of the
metal leading to reproductive toxicity in both males and females. Chronic exposure to cadmium causes
accumulated renal damage. The excretion of cadmium is proportional to creatinine except when renal
damage has occurred. Renal damage due to cadmium exposure can be detected by increased cadmium
excretion relative to creatinine. The Occupational Safety and Health Administration (OSHA) mandated
(Fed Reg 57:42,102-142,463, September 1992) that all monitoring of employees exposed to cadmium in
the workplace should be done using the measurement of urine cadmium and creatinine, expressing the
results of mcg of cadmium per gram of creatinine.
Useful For: Detecting exposure to cadmium, a toxic heavy metal, using random urine specimens
excretion above 3.0 mcg/g creatinine indicates significant exposure to cadmium. For occupational
testing, the Occupational Safety and Health Administration (OSHA) cadmium standard is less than 3.0
mcg/g creatine and the biological exposure index is 5 mcg/g creatinine.
Reference Values:
> or =18 years: <0.6 mcg/g creatinine
children in Germany derived from the German Environmental Survey on Children
2003-2006(GerESIV) Int J Hyg Environ Health. 2009;212:637-647 3. Occupational Safety and Health
Administration:: Cadmium exposure and control. Updated 9/2/2008. Accessed July 17, 2020. US
Department of Labor Available at osha.gov/SLTC/cadmium/evaluation.html 4. Agency for Toxic
Substances and Disease Registry: Toxicological profile for cadmium. US Department of Health and
Human Services. September 2012. Available at www.atsdr.cdc.gov/ToxProfiles/tp5.pdf 5. Strathmann
FG, Blum LM: Toxic elements. In: Rifai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical
CDCU Cadmium/Creatinine Ratio, Urine

608902 Clinical Information: The toxicity of cadmium resembles the other heavy metals (arsenic, mercury
and lead) in that it attacks the kidney; renal dysfunction with proteinuria with slow onset (over a period
of years) is the typical presentation. Measurable changes in proximal tubule function, such as decreased
Breathing the fumes of cadmium vapors leads to nasal epithelial deterioration and pulmonary
congestion resembling chronic emphysema. The most common source of cadmium exposure is tobacco
smoke, which has been implicated as the primary sources of the metal leading to reproductive toxicity
in both males and females. Chronic exposure to cadmium causes accumulated renal damage. The
excretion of cadmium is proportional to creatinine except when renal damage has occurred. Renal
damage due to cadmium exposure can be detected by increased cadmium excretion relative to
creatinine. The Occupational Safety and Health Administration (OSHA) mandated (Fed Reg
57:42,102-142,463, September 1992) that all monitoring of employees exposed to cadmium in the
workplace should be done using the measurement of urine cadmium and creatinine, expressing the
results of mcg of cadmium per gram of creatinine.
Useful For: Detecting exposure to cadmium using random urine specimens

Interpretation: Cadmium excretion above 3.0 mcg/g creatinine indicates significant exposure to
cadmium. Results above15 mcg/g creatinine are considered indicative of severe exposure.
Reference Values:
Only orderable as part of profile. For more information, see:
CDUCR / Cadmium/Creatinine Ratio, Random, Urine
HMUCR / Heavy Metal/Creatinine Ratio, with Reflex, Random, Urine
Int J Hyg Environ Health. 2009;212:637-647 3. Occupational Safety and Health Administration:
Cadmium exposure and control. Updated 9/2/2008. Accessed July 17, 2020. US Department of Labor
2012. Available at www.atsdr.cdc.gov/ToxProfiles/tp5.pdf 5. Strathmann FG, Blum LM: Toxic elements.
In: Rifai N, Horwath AR., Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular
CAFF Caffeine, Serum

8754 Clinical Information: Caffeine is used to treat apnea of prematurity that occurs in newborn infants,
the most frequent complication seen in the neonatal nursery. In neonates, caffeine has a half-life that
ranges from approximately 3 to 4 days, which is much longer than in adults (typically 4-6 hours) due to
the immaturity of the neonatal liver. This requires that small doses be administered at much longer
intervals than would be predicted based on adult pharmacokinetics. The volume of distribution of caffeine
is 0.8-0.9 L/kg (infants) or 0.6 L/kg (adults) and the drug is approximately 36% protein bound. Toxicity
observed in neonates is characterized by central nervous system and skeletal muscle stimulation and
bradycardia. These symptoms are seen in adults at lower levels than in neonates, suggesting that neonates
have much greater tolerance to the drug.
Useful For: Monitoring caffeine therapy in neonates Assessing caffeine toxicity in neonates
Interpretation: Optimal pharmacologic response occurs when the serum level is in the range of 8.0 to
20.0 mcg/mL. Toxicity in neonates and adults may be seen when the serum level is above 20.0 mcg/mL.
Reference Values:
Therapeutic: 8.0-20.0 mcg/mL
Critical value: > or =30.0 mcg/mL
Clinical References: 1. Milone MC, Shaw LM: Therapeutic drugs and their management. In: Rifai
N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics,
Elsevier; 2018:800-831 2. Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman and Gilman's:
The Pharmacological Basis of Therapeutics. McGraw-Hill; 2018 3. Ou CN, Frawley VL: Concurrent
measurement of theophylline and caffeine in neonates by an interference-free liquid-chromatographic
method. Clin Chem. 1983;29:1934-1936
CALCI Calcitonin (CALCI) Immunostain, Technical Component Only

70368 Clinical Information: Calcitonin is a hormone involved in calcium metabolism. Staining for
calcitonin produces fine granular, cytoplasmic staining of C cells of thyroid, medullary thyroid
carcinomas, many atypical laryngeal carcinoids, and other neuroendocrine tumors. Amyloid deposits
within medullary thyroid carcinoma may also exhibit varying degrees of calcitonin immunoreactivity.
Useful For: Aids in the identification of C cells of thyroid, medullary thyroid carcinomas, many
atypical laryngeal carcinoids, and other neuroendocrine tumors
Clinical References: 1. Costante G, Meringolo D: Calcitonin as a biomarker of C cell disease:

recent achievements and current challenges. Endocrine. 2020;(67):273-280. doi:
10.1007/s12020-019-02183-6 2. Gambardella C, Offi C, Patrone R, et al: Calcitonin negative medullary
thyroid carcinoma: a challenging diagnosis or a medical dilemma?. BMC Endocr Disord. 2019;(19):45.
doi: 10.1186/s12902-019-0367-2 3. Gambardella C, Offi C, Clarizia G, et al: Medullary thyroid
carcinoma with double negative calcitonin and CEA: a case report and update of literature review. BMC
Endocr Disord. 2019;(19):103. doi: 10.1186/s12902-019-0435-7
CATLN Calcitonin, Fine-Needle Aspiration Biopsy Needle Wash,

61527 Lymph Node
Clinical Information: Calcitonin is a polypeptide hormone secreted by the parafollicular cells (also
referred to as calcitonin cells or C-cells) of the thyroid gland. Malignant tumors arising from thyroid
C-cells (medullary thyroid carcinoma: MTC) usually produce elevated levels of calcitonin. MTC is an
uncommon malignant thyroid tumor, comprising less than 5% of all thyroid malignancies. Measurement
of serum calcitonin is used in the follow-up of patients who underwent surgical removal of the thyroid
gland. Studies have reported that the measurement of calcitonin in fine-needle aspiration biopsy
(FNAB)-needle washes improves the evaluation of suspicious lymph nodes in patients with a history of
MTC when used in combination with cytology. Comparing the results of calcitonin in the needle rinse
with serum calcitonin is highly recommended. An elevated calcitonin in the serum could falsely elevate
calcitonin in the washings, if the rinse is contaminated with blood. In these cases, only calcitonin values
significantly higher than the serum should be considered as true-positives. Cytologic examination and
measurement of calcitonin can be performed on the same specimen. To measure calcitonin, the FNA
needle is rinsed with a small volume of normal saline solution immediately after a specimen for
cytological examination (for a smear or CytoTrap preparation) has been expelled from the needle.
Calcitonin levels are measured in the needle wash.
Useful For: As an adjunct to cytologic examination of fine-needle aspiration specimens in athyrotic

individuals treated for medullary thyroid carcinoma to confirm or exclude metastases in enlarged or
ultrasonographically suspicious lymph nodes
Interpretation: In athyrotic patients with a history of medullary thyroid carcinoma (MTC), a

fine-needle aspiration calcitonin value of 5.0 pg/mL and greater is suggestive of the presence of
metastatic MTC in the biopsied lymph node. Calcitonin values less than 5.0 pg/mL suggest the lymph
node does not contain medullary thyroid carcinoma. This result is dependent on accurate sampling and a
total needle wash volume between 0.5 to 1.5 mL. This test should be interpreted in the context of the
clinical presentation, imaging, and cytology findings. If the results are discordant with the clinical
presentation, a sampling error at the time of biopsy should be considered.
Reference Values:
Clinical References: 1. Trimboli P, Rossi F, Baldelli R, et al: Measuring calcitonin in washout of

the needle in patients undergoing fine needle aspiration with suspicious medullary thyroid cancer. Diagn
Cytopathol. 2012 May;40(5):394-398 2. Boi F, Maurelli I, Pinna G, et al: Calcitonin measurement in
wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic
medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007 Jun;92(6):2115-2118 3. Kudo T, Miyauchi
A, Ito Y, Takamura Y, Amino N, Hirokawa M: Diagnosis of medullary thyroid carcinoma by calcitonin
measurement in fine-needle aspiration biopsy specimens. Thyroid. 2007 Jul;17(7):635-638 4. Trimboli
P, Dâ€™Aurizio F, Tozzoli R, Giovanella L: Measurement of thyroglobulin, calcitonin, and PTH in
FNA washout fluids. Clin Chem Lab Med. 2017 Jun;55(7):914-925
CATN Calcitonin, Serum

9160 Clinical Information: Calcitonin is a polypeptide hormone secreted by the parafollicular cells (also
referred to as calcitonin cells or C cells) of the thyroid gland. The main action of calcitonin is the
inhibition of bone resorption by regulating the number and activity of osteoclasts. Calcitonin is secreted in
direct response to serum hypercalcemia and may prevent large oscillations in serum calcium levels and
excessive loss of body calcium. However, in comparison to parathyroid hormone and
1,25-dihydroxyvitamin D, the role of calcitonin in the regulation of serum calcium in humans is minor.
Measurements of serum calcitonin levels are, therefore, not useful in the diagnosis of disorders of calcium
homeostasis. Malignant tumors arising from thyroid C cells (medullary thyroid carcinoma: MTC) usually
produce elevated levels of calcitonin. MTC is an uncommon malignant thyroid tumor, comprising less
than 5% of all thyroid malignancies. Approximately 25% of these are familial cases, usually appearing as
a component of multiple endocrine neoplasia type II (MENII, Sipple syndrome). MTC may also occur in
families without other associated endocrine dysfunction, with similar autosomal dominant transmission as
MENII, which is then called familial medullary thyroid carcinoma (FMTC). Variants in the RET
proto-oncogene are associated with MENII and FMTC. Serum calcitonin concentrations are high in
infants, decline rapidly, and are relatively stable from childhood through adult life. In general, calcitonin
serum concentrations are higher in men than in women due to the larger C-cell mass in men. Serum
calcitonin concentrations may be increased in patients with chronic renal failure, and other conditions
such as hyperparathyroidism, leukemic and myeloproliferative disorders, Zollinger-Ellison syndrome,
autoimmune thyroiditis, small cell and large cell lung cancers, breast and prostate cancer, mastocytosis,
and various neuroendocrine tumors, in particular, islet cell tumors.
Useful For: Aids in the diagnosis and follow-up of medullary thyroid carcinoma Aids in the evaluation
of multiple endocrine neoplasia type II and familial medullary thyroid carcinoma This test is not useful
for evaluating calcium metabolic diseases.
Interpretation: Although most patients with sporadic medullary thyroid carcinoma (MTC) have high
basal serum calcitonin concentrations, 30% of those with familial MTC or multiple endocrine neoplasia
type II (MENII) have normal basal levels. In completely cured cases following surgical therapy for MTC,
serum calcitonin levels fall into the undetectable range over a variable period of several weeks.
Persistently elevated postoperative serum calcitonin levels usually indicate incomplete cure. The reasons
for this can be locoregional lymph node spread or distant metastases. In most of these cases, imaging
procedures are required for further workup. Those individuals who are then found to suffer only
locoregional spread may benefit from additional surgical procedures. However, the survival benefits
derived from such approaches are still debated. A rise in previously undetectable or very low
postoperative serum calcitonin levels is highly suggestive of disease recurrence or spread, and should
trigger further diagnostic evaluations.
Reference Values:
Pediatric
1 month: < or =34 pg/mL
2 months: < or =31 pg/mL
8 months: < or =19.0 pg/mL
12-14 months: < or =14.0 pg/mL
2 years: < or =8.0 pg/mL
3-9 years: < or =7.0 pg/mL
10-15 years: < or =6.0 pg/mL
16 years: < or =5.0 pg/mL
Adults
17 years and older:
Males: < or =14.3 pg/mL
Females: < or =7.6 pg/mL
Clinical References: 1. Wells SA Jr, Asa SL, Dralle H, et al: Revised American Thyroid
Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015
Jun;25(6):567-610 2. Griebeler ML, Gharib H, Thompson GB: Medullary thyroid carcinoma. Endocr
Pract. 2013 Jul-Aug;19(4):703-711 3. Richards ML: Familial syndromes associated with thyroid cancer
in the era of personalized medicine. Thyroid. 2010 Jul;20(7):707-713
CALU Calcium, 24 Hour, Urine

610595 Clinical Information: Calcium is the fifth most common element in the body. It is a fundamental
element necessary to form electrical gradients across membranes, an essential cofactor for many
enzymes, and the main constituent in bone. Under normal physiologic conditions, the concentration of
calcium in serum and in cells is tightly controlled. Calcium is excreted in both urine and feces.
Ordinarily about 20% to 25% of dietary calcium is absorbed and 98% of filtered calcium is reabsorbed
in the kidney. Traffic of calcium between the gastrointestinal tract, bone, and kidney is tightly
controlled by a complex regulatory system that includes vitamin D and parathyroid hormone. Sufficient
bioavailable calcium is essential for bone health. Excessive excretion of calcium in the urine is a
common contributor to kidney stone risk.
Useful For: Evaluation of calcium oxalate and calcium phosphate kidney stone risk, and calculation
of urinary supersaturation Evaluation of bone diseases, including osteoporosis and osteomalacia
Interpretation: Increased urinary calcium excretion (hypercalciuria) is a known contributor to

kidney stone disease and osteoporosis. Many cases are genetic (often termed idiopathic). Previously
such patients were often divided into fasting versus absorptive hypercalciuria depending on the level of
urine calcium in a fasting versus fed state, but the clinical utility of this approach is now in question.
Overall, the risk of stone disease appears increased when 24-hour urine calcium is above 250 mg in men
and above 200 mg in women. Thiazide diuretics are often used to reduce urinary calcium excretion, and
repeat urine collections can be performed to monitor the effectiveness of therapy. Known secondary
causes of hypercalciuria include hyperparathyroidism, Paget disease, prolonged immobilization, vitamin
D intoxication, and diseases that destroy bone (such as metastatic cancer or multiple myeloma). Urine
calcium excretion can be used to gauge the adequacy of calcium and vitamin D supplementation, for
example in states of gastrointestinal fat malabsorption that are associated with decreased bone
mineralization (osteomalacia).
Reference Values:
Males: <250 mg/24 hours*
Females: <200 mg/24 hours*
*Values represent clinical cutoffs above which studies have demonstrated increased risk of kidney
stone formation. These values were not determined in a reference range study.
Reference values have not been established for patients who are less than <18 years of age.
Reference values apply to 24-hour collection.
Clinical References: 1. Fraser WD: Bone and mineral metabolism. In: Rifai N, Horvath AR,
Wittwer CT, eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier;
2018:1438 2.Curhan GC, Willett WC, Speizer FE, Stampfer MJ: Twenty-four-hour urine chemistries and
the risk of kidney stones among women and men. Kidney Int. 2001;59:2290-2298 3. Metz MP:
Determining urinary calcium/creatinine cut-offs for the pediatric population using published data. Ann
Clin Biochem. 2006;43:398-401 4. Pak CY, Britton F, Peterson R, et al: Ambulatory evaluation of
nephrolithiasis. Classification, clinical presentation and diagnostic criteria. Am J Med. 1980;69:19-30 5.
Pak CY, Kaplan R, Bone H, Townsend J, Waters O: A simple test for the diagnosis of absorptive,
resorptive and renal hypercalciurias. N Engl J Med. 1975;292:497-500
CAI Calcium, Ionized, Serum

8378 Clinical Information: Ionized calcium, which accounts for 50% to 55% of total calcium, is the
physiologically active form of calcium. Low ionized calcium values are often seen in kidney disease,
critically ill patients, or patients receiving rapid transfusion of citrated whole blood or blood products.
Increased serum ionized calcium concentrations may be seen with primary hyperparathyroidism, ectopic
parathyroid hormone-producing tumors, excess intake of vitamin D, or various malignancies. Nomograms
have been used to calculate ionized calcium from total calcium, albumin, and pH values. However,
calculated ionized calcium results have proven to be unsatisfactory. A Mayo study of 114 patients found
significant differences between ionized and total calcium in 26% of patients.
Useful For: Assessing calcium states during liver transplantation surgery, cardiopulmonary bypass, or
any procedure requiring rapid transfusion of whole blood in neonates and critically ill patients
Second-order test in the evaluation of patients with abnormal calcium values
Interpretation: Serum ionized calcium concentrations 50% below normal will result in severely
reduced cardiac stroke work. With moderate to severe hypocalcemia, left ventricular function may be
profoundly depressed. Ionized calcium values are higher in children and young adults. Ionized calcium
result has been adjusted to pH 7.40 to account for changes in specimen pH that may occur during
transport. Ionized calcium concentration increases approximately 0.2 mg/dL per 0.1 pH unit decrease.
Reference Values:
IONIZED CALCIUM
< or =13 days old: Not established
14 days-<1 year: 5.21-5.99 mg/dL
1-<2 years: 5.04-5.84 mg/dL
2-<3 years: 4.87-5.67 mg/dL
3-23 years: 4.83-5.52 mg/dL
24-97 years: 4.57-5.43 mg/dL
> or =98 years: Not established
pH
< or =13 days old: Not established
14 days-97 years old: 7.35-7.48
> or =98 years old: Not established
For SI unit Reference Values, see www.mayocliniclabs.com/order-tests/si-unit-conversion.html
Clinical References: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry
CACR2 Calcium, Random, Urine

element necessary to form electrical gradients across membranes, an essential cofactor for many enzymes,
and the main constituent in bone. Under normal physiologic conditions, the concentration of calcium in
serum and in cells is tightly controlled. Calcium is excreted in both urine and feces. Ordinarily about 20%
to 25% of dietary calcium is absorbed, and 98% of filtered calcium is reabsorbed in the kidney. Traffic of
calcium between the gastrointestinal tract, bone, and kidney is tightly controlled by a complex regulatory
system that includes vitamin D and parathyroid hormone. Sufficient bioavailable calcium is essential for
bone health. Excessive excretion of calcium in the urine is a common contributor to kidney stone risk.
Useful For: Evaluation of calcium oxalate and calcium phosphate kidney stone risk in a random
urine collection Calculation of urinary supersaturation Evaluation of bone diseases, including
osteoporosis and osteomalacia

kidney stone disease and osteoporosis. Many cases are genetic (often termed idiopathic). Previously
Overall, the risk of stone disease appears increased when 24-hour urine calcium is greater than 250 mg
in men and greater than 200 mg in women. Thiazide diuretics are often used to reduce urinary calcium
excretion, and repeat urine collections can be performed to monitor the effectiveness of therapy. Known
secondary causes of hypercalciuria include hyperparathyroidism, Paget disease, prolonged
immobilization, vitamin D intoxication, and diseases that destroy bone (such as metastatic cancer or
multiple myeloma). Urine calcium excretion can be used to gauge the adequacy of calcium and vitamin
D supplementation, for example in states of gastrointestinal fat malabsorption that are associated with
decreased bone mineralization (osteomalacia).
Reference Values:
Only orderable as part of a profile. For more information see SSATR / Supersaturation Profile,
Pediatric, Random, Urine.
1 month-<12 months: 0.03-0.81 mg/mg creat

12 months-<24 months: 0.03-0.56 mg/mg creat
24 months-<3 years: 0.02-0.50 mg/mg creat
3 years-<5 years: 0.02-0.41 mg/mg creat
18 years-83 years: 0.05-0.27 mg/mg creat
Reference values have not been established for patients who are less than 1 month of age.
Reference values have not been established for patients who are greater than 83 years of age.
Clinical References: 1. Fraser WD: Bone and mineral metabolism. In: Rifai N, Horwath AR,
2018:1438 2. Curhan GC, Willett WC, Speizer FE, Stampfer MJ: Twenty-four-hour urine chemistries
and the risk of kidney stones among women and men. Kidney Int. 2001;59:2290-2298 3. Metz MP:
nephrolithiasis. Classification, clinical presentation and diagnostic criteria. AM J Med. 1980;69:19-30 5.
Pak CY, Kaplan R, Bone H, et al: A simple test for the diagnosis of absorptive, resorptive and renal
hypercalciurias. N Engl J Med. 1975;292:497-500
CALC5 Calcium, Random, Urine

Ordinarily about 20% to 25% of dietary calcium is absorbed, and 98% of filtered calcium is reabsorbed
Useful For: Measurement of calcium for the evaluation of calcium oxalate and calcium phosphate
kidney stone risk, and calculation of urinary supersaturations Evaluation of bone diseases, including
osteoporosis and osteomalacia
Interpretation: Increased urinary calcium excretion (hypercalciuria) is a known contributor to kidney

stone disease and osteoporosis. Many cases are genetic (often termed "idiopathic"). Previously such
patients were often divided into fasting versus absorptive hypercalciuria depending on the level of urine
calcium in a fasting versus fed state, but the clinical utility of this approach is now in question. Overall,
the risk of stone disease appears increased when 24-hour urine calcium is greater than 250 mg in men and
greater than 200 mg in women. Thiazide diuretics are often used to reduce urinary calcium excretion, and
Reference Values:
Only orderable as part of a profile. For more information see CACR3 /
Calcium/Creatinine Ratio, Random, Urine

Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed.
Elsevier;2018:1438 2. Curhan GC, Willett WC, Speizer FE, Stampfer MJ: Twenty-four-hour urine
chemistries and the risk of kidney stones among women and men. Kidney Int. 2001;59:2290-2298 3. Metz
MP: Determining urinary calcium/creatinine cut-offs for the pediatric population using published data.
Ann Clin Biochem. 2006;43:398-401 4. Pak CY, Britton F, Peterson R, et al: Ambulatory evaluation of
CA Calcium, Total, Serum

601514 Clinical Information: The calcium content of an adult is somewhat over 1 kg (about 2% of the body
weight). Of this, 99% is present as calcium hydroxyapatite in bones and less than 1% is present in the
extra-osseous intracellular space or extracellular space (ECS). The calcium level in the ECS is in dynamic
equilibrium with the rapidly exchangeable fraction of bone calcium. In serum, calcium is bound to a
considerable extent to proteins (approximately 40%), 10% is in the form of inorganic complexes, and 50%
is present as free or ionized calcium. Calcium ions affect the contractility of the heart and the skeletal
musculature, and are essential for the function of the nervous system. In addition, calcium ions play an
important role in blood clotting and bone mineralization. Hypocalcemia is due to the absence or impaired
function of the parathyroid glands or impaired vitamin-D synthesis. Chronic renal failure is also
frequently associated with hypocalcemia due to decreased vitamin-D synthesis as well as
hyperphosphatemia and skeletal resistance to the action of parathyroid hormone (PTH). Characteristic
symptoms of hypocalcemia are latent or manifest tetany and osteomalacia. Hypercalcemia is brought
about by increased mobilization of calcium from the skeletal system or increased intestinal absorption. A
majority of cases are due to primary hyperparathyroidism (pHPT) or bone metastasis of carcinoma of the
breast, prostate, thyroid gland, or lung. Patients who have pHPT and bone disease, renal stones or
nephrocalcinosis, or other signs or symptoms are candidates for surgical removal of the parathyroid
glands. Severe hypercalcemia may result in cardiac arrhythmia. Calcium levels may also reflect abnormal
vitamin D or protein levels.
Useful For: Diagnosis and monitoring of a wide range of disorders including diseases of bone,
kidney, parathyroid gland, or gastrointestinal tract
Interpretation: Hypocalcemia: Long-term therapy must be tailored to the specific disease causing
the hypocalcemia. The therapeutic endpoint is to achieve a serum calcium level of 8.0 to 8.5 mg/dL to
prevent tetany. For symptomatic hypocalcemia, calcium may be administered intravenously.
Hypercalcemia: The level at which hypercalcemic symptoms occur varies from patient to patient.
Symptoms are common when serum calcium levels are above 11.5 mg/dL, although patients may be
asymptomatic at this level. Levels above 12.0 mg/dL are considered a critical value. Severe
hypercalcemia (>15.0 mg/dL) is a medical emergency.
Reference Values:
<1 year: 8.7-11.0 mg/dL
1-17 years: 9.3-10.6 mg/dL
18-59 years: 8.6-10.0 mg/dL
> or =60 years: 8.8-10.2 mg/dL
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018. 2. Baldwin TE, Chernow B:
Hypocalcemia in the ICU. J Crit Illness. 1987;2:9-16 3. Estey MP, Cohen AH, Colantonio DA, et al:
CLSI-based transference of the CALIPER database of pediatric reference intervals from Abbott to
Beckman, Ortho, Roche and Siemens Clinical Chemistry Assays: direct validation using reference
samples from the CALIPER cohort. Clin Biochem. 2013;46:1197-1219
CCTR Calcium/Creatinine Ratio, Random, Urine

Ordinarily about 20% to 25% of dietary calcium is absorbed, and 98% of filtered calcium is reabsorbed
Useful For: Calculation of calcium concentration per creatinine concentration

kidney stone disease and osteoporosis. Many cases are genetic (often termed "idiopathic"). Previously
Overall, the risk of stone disease appears increased when 24-hour urine calcium is greater than 250 mg
in men and greater than 200 mg in women. Thiazide diuretics are often used to reduce urinary calcium
excretion, and repeat urine collections can be performed to monitor the effectiveness of therapy. Known
secondary causes of hypercalciuria include hyperparathyroidism, Paget disease, prolonged
immobilization, vitamin D intoxication, and diseases that destroy bone (such as metastatic cancer or
multiple myeloma). Urine calcium excretion can be used to gauge the adequacy of calcium and vitamin
D supplementation, for example in states of gastrointestinal fat malabsorption that are associated with
decreased bone mineralization (osteomalacia).
Reference Values:
Only orderable as part of a profile. For more information see CACR3 / Calcium/Creatinine Ratio,
Random, Urine

Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed.
Elsevier;2018:1438 2. Curhan GC, Willett WC, Speizer FE, Stampfer MJ: Twenty-four-hour urine
chemistries and the risk of kidney stones among women and men. Kidney Int. 2001;59:2290-2298 3. Metz
MP: Determining urinary calcium/creatinine cut-offs for the pediatric population using published data.
Ann Clin Biochem. 2006;43:398-401 4. Pak CY, Britton F, Peterson R, et al: Ambulatory evaluation of
CACR3 Calcium/Creatinine Ratio, Random, Urine

element necessary to form electrical gradients across membranes, an essential cofactor for many enzymes,
and the main constituent in bone. Under normal physiologic conditions, the concentration of calcium in
serum and in cells is tightly controlled. Calcium is excreted in both urine and feces. Ordinarily about 20%
to 25% of dietary calcium is absorbed, and 98% of filtered calcium is reabsorbed in the kidney. Traffic of
calcium between the gastrointestinal tract, bone, and kidney is tightly controlled by a complex regulatory
system that includes vitamin D and parathyroid hormone. Sufficient bioavailable calcium is essential for
bone health. Excessive excretion of calcium in the urine is a common contributor to kidney stone risk.
Useful For: Evaluation of calcium oxalate and calcium phosphate kidney stone risk Calculation of
urinary supersaturation Evaluation of bone diseases, including osteoporosis and osteomalacia
Interpretation: Increased urinary calcium excretion (hypercalciuria) is a known contributor to kidney

stone disease and osteoporosis. Many cases are genetic (often termed "idiopathic"). Previously such
patients were often divided into fasting versus absorptive hypercalciuria depending on the level of urine
calcium in a fasting versus fed state, but the clinical utility of this approach is now in question. Overall,
the risk of stone disease appears increased when 24-hour urine calcium is greater than 250 mg in men and
greater than 200 mg in women. Thiazide diuretics are often used to reduce urinary calcium excretion, and
Reference Values:
2018:1438 2. Curhan GC, Willett WC, Speizer FE, Stampfer MJ: Twenty-four-hour urine chemistries
and the risk of kidney stones among women and men. Kidney Int. 2001;59:2290-2298 3. Metz MP:
CALD Caldesmon Immunostain, Technical Component Only

70369 Clinical Information: Caldesmon is a smooth muscle specific protein that regulates smooth muscle
contraction. This clone recognizes the high-molecular-weight variant (h-caldesmon) and does not react
with the nonmuscle variant. Neither variant of caldesmon is present in skeletal muscle.
Anti-h-caldesmon seems to be a reliable marker of smooth muscle differentiation, and may assist in the
diagnosis of smooth muscle tumors.
Useful For: A marker of smooth muscle differentiation

upon request. Contact 855-516-8404. Â Interpretation of this test should be performed in the context of
the patient's clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Wick MR, Hornick JL: Immunohistology of soft tissue and osseous
neoplasms. In: Dabbs DJ, ed. Diagnostic Immunohistochemistry: Theranostic and Genomic
Applications. 3rd ed. 2010:chap 4 2. Horita A, Kurata A, Maeda D,Fukayama M, Sakamoto A:
Immunohistochemical characteristics of atypical polypoid adenomyoma with special reference to
h-caldesmon. Int J Gynecol Pathol 2011 Jan;30(1)64-70 3. Ordonez NG: Value of PAX8, PAX2,
claudin-4, and h-caldesmon immunostaining in distinguishing peritoneal epithelioid mesotheliomas
from serous carcinomas. Modern Pathology. 2013;26:553-562
CAVPC California Virus (La Crosse) Encephalitis Antibody Panel, IgG

83900 and IgM, Spinal Fluid
Clinical Information: California (La Crosse) virus is a member of the Bunyaviridae family and it is
one of the arthropod-borne encephalitides. It is transmitted by various Aedes and Culex mosquitoes and
is found in such intermediate hosts as the rabbit, squirrel, chipmunk, and field mouse. California
meningoencephalitis is usually mild and occurs in late summer. Ninety percent of infections are seen in
children less than 15 years of age, usually from rural areas. The incubation period is estimated to be 7
days and acute illness lasts 10 days or less in most instances. Typically, the first symptoms are
nonspecific, lasting 1 to 3 days, and are followed by the appearance of central nervous system (CNS)
signs and symptoms such as stiff neck, lethargy, and seizures, which usually abate within 1 week.
Symptomatic infection is almost never recognized in those over 18 years old. The most important
sequela of California virus encephalitis is epilepsy, which occurs in about 10% of children and almost
always in patients who have had seizures during the acute illness. An estimated 2% of patients have
persistent paresis. Learning disabilities or other objective cognitive deficits have been reported in a
small proportion (<2%) of patients. Learning performance and behavior of most recovered patients are
not distinguishable from comparison groups in these same areas. Infections with arboviruses can occur
at any age. The age distribution depends on the degree of exposure to the particular transmitting
arthropod relating to age, sex, and occupational, vocational, and recreational habits of the individuals.
Once humans have been infected, the severity of the host response may be influenced by age. Serious
California (La Crosse) virus infections primarily involve children, especially boys. Adult males exposed
to California viruses have high prevalence rates of antibody but usually show no serious illness.
Infection among males is primarily due to working conditions and sports activities taking place where
the vector is present.
Useful For: Aiding in the diagnosis of California (La Crosse) encephalitis using spinal fluid specimens
Interpretation: A positive result indicates intrathecal synthesis of antibody and is indicative of
neurological infection.
Reference Values:
IgG: <1:1
IgM: <1:1
Clinical References: 1. Gonzalez-Scarano F, Nathanson N: Bunyaviruses. In: Fields BM, Knipe

DM, eds. Fields Virology. Vol. 1. 2nd ed. Raven Press, 1990; 1195-1228 2. Donat JF, Rhodes KH,
meningoencephalitis. Mayo Clin Proc. 1980:55:156-160 3. Tsai TF: Arboviruses. In: Murray PR, Baron
EF, Pfaller MA, et al, eds. Manual of Clinical Microbiology. 7th ed. ASM Press; 1999: 1107-1124 4.
Calisher CH: Medically important arboviruses of the United States and Canada. Clin Microbiol Rev.
1994;7:89-116 5. Beckham JD, Tyler KL: Arbovirus Infections. Continuum (Minneap Minn). 2015
Dec;21(6 Neuroinfectious Disease):1599-1611. doi: 10.1212/CON.0000000000000240 6. Dolin R:
California encephalitis, hantavirus pulmonary syndrome, hantavirus hemorrhagic fever with renal
syndrome, and bunyavirus hemorrhagic fevers. In Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas,
and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020:2169-2176
CAVP California Virus (La Crosse) IgG and IgM, Serum

83153 Clinical Information: California virus (La Crosse) is a member of the Bunyaviridae family and is
one of the arthropod-borne encephalitides. It is transmitted by various Aedes and Culex mosquitoes and is
found in such intermediate hosts as the rabbit, chipmunk, and field mouse. California meningoencephalitis
is usually mild and occurs in late summer. Ninety percent of infections are seen in children under 15 years
of age, usually from rural areas. The incubation period is estimated to be 7 days and acute illness lasts 10
days or less in most instances. Typically, the first symptoms are nonspecific, lasting 1 to 3 days, and are
followed by the appearance of central nervous system signs and symptoms such as stiff neck, lethargy,
and seizures, which usually abate within 1 week. Symptomatic infection is almost never recognized in
those over 18 years old. The most important sequelae of California virus encephalitis is epilepsy, which
occurs in about 10% of children; almost always in patients who have had seizures during the acute illness.
A few patients (estimated 2%) have persistent paresis. Learning disabilities or other objective cognitive
deficits have been reported in a small proportion (no more than 2%) of patients. Learning performance
and behavior of most recovered patients are not distinguishable from comparison groups in these same
areas. Infections with arboviruses can occur at any age. The age distribution depends on the degree of
exposure to the particular transmitting arthropod relating to age, sex, and occupational, vocational, and
recreational habits of the individuals. Once humans have been infected, the severity of the host response
may be influenced by age. Serious California (La Crosse) virus infections primarily involve children,
especially boys. Adult males exposed to California viruses have high prevalence rates of antibody but
usually show no serious illness. Infection among males is primarily due to working conditions and sports
activities taking place where the vector is present.
Useful For: Aiding the diagnosis of California virus (La Crosse)
Interpretation: In patients infected with these or related viruses, IgG antibody is generally
detectable within 1 to 3 weeks of onset, peaking within 1 to 2 months and declining slowly thereafter.
IgM class antibody is also reliably detected within 1 to 3 weeks of onset, peaking and rapidly declining
within 3 months. Single serum specimen IgG of 1:10 or greater indicates exposure to the virus. Results
from a single serum specimen can differentiate early (acute) infection from past infection with
immunity if IgM is positive (suggests acute infection). A 4-fold or greater rise in IgG antibody titer in
acute and convalescent sera indicates recent infection.
Reference Values:
IgG: <1:10
IgM: <1:10

DM eds. Fields of Virology. Vol. 1. 2nd ed. Raven Press; 1990:1195-1228 2. Donat JF, Hable-Rhodes
KH, Groover RV, Smith TF: Etiology and outcome of 42 children with acute nonbacterial
meningoencephalitis. Mayo Clin Proc. 1980;55:156-160 3. Tsai TF: Arboviruses. In: Murray PR, Baron
EJ, Pfaller MA, et al. eds. Manual of Clinical Microbiology. 7th ed. ASM Press; 1999:1107-1124 4.
Calisher CH: Medically important arboviruses of the United States and Canada. Clin Microbiol Rev.
1994;7:89-116 5. Dolin R: California encephalitis, hantavirus pulmonary syndrome, hantavirus
hemorrhagic fever with renal syndrome, and bunyavirus hemorrhagic fevers. In Bennett JE, Dolin R,
Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed.
Elsevier; 2020:2169-2176
CAMTA Calmodulin-Binding Transcription Activator 1 (CAMTA1),

603417 Immunostain, Technical Component Only
Clinical Information: Calmodulin-binding transcription activator 1 (CAMTA1) protein
overexpression in the nucleus is the result of the WWTR1-CAMTA1 gene fusion, which is found in
approximately 90% of epithelioid hemangioendotheliomas (EHE). CAMTA1 can be used to distinguish
EHE from other tumors with epithelioid morphology.
Useful For: Aids in the diagnosis of epithelioid hemangioendotheliomas

Clinical References: 1. Shibuya R, Matsuyama A, Shiba E, et al: CAMTA1 is a useful

immunohistochemical marker for diagnosing epithelioid haemangioendothelioma. Histopathology. 2015
Dec; 67:827-835. doi: 10.1111/his.12713 2. Flucke U, Vogels RJ, de Saint Aubain Somerhausen N, et
al: Epithelioid Hemangioendothelioma: clinicopathologic, immunhistochemical, and molecular genetic
analysis of 39 cases. Diagn Pathol. 2014 Jul 1;9:131 doi: 10.1186/1746-1596-9-131 3. Doyle LA,
Fletcher CD, Hornick JL: Nuclear expression of CAMTA1 distinguishes epithelioid
hemangioendothelioma from histologic mimics. Am J Surg Pathol .2016 Jan;40:94-102. doi:
10.1097/PAS.0000000000000511
CALPN Calponin Immunostain, Technical Component Only

70370 Clinical Information: Calponin is a cytoskeleton-associated protein that can bind to actin,
tropomyosin, troponin C, and calmodulin and is involved in modulation of smooth muscle contraction.
Calponin expression has been demonstrated in smooth muscle cells of blood vessels and myoepithelial
cells in the lobules, ducts, and galactophorous sinuses of normal human breast.
Useful For: Marker for myoepithelium when differentiating ductal carcinomas in situ from infiltrating
breast carcinoma Characterization of tumors of smooth muscle or myoepithelial lineage
Clinical References: 1. Russell T D, Jindal S, Agunbiade S, et al: Myoepithelial cell differentiation

markers in ductal carcinoma in situ progression. Am J Pathol. 2015;185(11):3076-3089. doi:
10.1016/j.ajpath.2015.07.004 2. Gray E, Mitchell, E, Jindal S, Schedin P, Chang YH: A method for
quantification of calponin expression in myoepithelial cells in immunohistochemical images of ductal
carcinoma in situ. Proc IEEE Int Symp Biomed Imaging. 2018 Apr;2018:796-799. doi:
10.1109/isbi.2018.8363692 3. Liu R, Jin JP: Calponin isoforms CNN 1, CNN 2 and CNN 3: Regulators
for actin cytoskeleton functions in smooth muscle and non-muscle cells. Gene. 2016;585(1):143-153. doi:
10.1016/j.gene.2016.02.040
CALPR Calprotectin, Feces

63016 Clinical Information: Calprotectin, formed as a heterodimer of S100A8 and S100A9, is a member of
the S100 calcium-binding protein family. It is expressed primarily by granulocytes and, to a lesser degree,
by monocytes/macrophages and epithelial cells. In neutrophils, calprotectin comprises almost 60% of the
total cytoplasmic protein content. Activation of the intestinal immune system leads to recruitment of cells
from the innate immune system, including neutrophils. The neutrophils are then activated, which leads to
release of cellular proteins, including calprotectin. Calprotectin is eventually translocated across the
epithelial barrier and enters the lumen of the gut. As the inflammatory process progresses, the released
calprotectin is absorbed by fecal material before it is excreted from the body. The amount of calprotectin
present in the feces is proportional to the number of neutrophils within the gastrointestinal mucosa and
can be used as an indirect marker of intestinal inflammation. Calprotectin is most frequently used as part
of the diagnostic evaluation of patients with suspected inflammatory bowel disease (IBD). Patients with
IBD may be diagnosed with Crohn disease or ulcerative colitis. Although distinct in their pathology and
clinical manifestations, both are associated with significant intestinal inflammation. Elevated
concentrations of fecal calprotectin may be useful in distinguishing IBD from functional gastrointestinal
disorders, such as irritable bowel syndrome. When used for this differential diagnosis, fecal calprotectin
has sensitivity and specificity both of approximately 85%. However, it must be remembered that increases
in fecal calprotectin are not diagnostic for IBD, as other disorders such as celiac disease, colorectal
cancer, and gastrointestinal infections, may also be associated with neutrophilic inflammation.
Useful For: Evaluation of patients suspected of having a gastrointestinal inflammatory process

Distinguishing inflammatory bowel disease from irritable bowel syndrome, when used in conjunction
with other diagnostic modalities, including endoscopy, histology, and imaging
Interpretation: Calprotectin concentrations below 50.0 mcg/g are not suggestive of an active
inflammatory process within the gastrointestinal system. For patients experiencing gastrointestinal
symptoms, consider further evaluation for functional gastrointestinal disorders. Calprotectin
concentrations between 50.0 and 120 mcg/g are borderline and may represent a mild inflammatory
process, such as in treated inflammatory bowel disease (IBD) or associated with nonsteroidal
anti-inflammatory drug or aspirin usage. For patients with clinical symptoms suggestive of IBD, retesting
in 4 to 6 weeks may be indicated. Calprotectin concentrations above 120 mcg/g are suggestive of an
active inflammatory process within the gastrointestinal system. Additional diagnostic testing to determine
the etiology of the inflammation is suggested.
Reference Values:
< 50.0 mcg/g (Normal)
50.0-120 mcg/g (Borderline)
> 120 mcg/g (Abnormal)
Clinical References: 1. Gisbert JP, McNicholl AG: Questions and answers on the role of faecal
calprotectin as a biological marker in inflammatory bowel disease. Digest Liver Dis. 2009
Jan;41(1):56-66 2. Campeotto F, Butel MJ, Kalach N, et al: High faecal calprotectin concentrations in
newborn infants. Arch Dis Child-Fetal. 2004 Jul;89(4):F353-F355 3. Dabritz J, Musci J, Foell D:
Diagnostic utility of faecal biomarkers in patients with irritable bowel syndrome. World J Gastroentero.
2014 Jan 14;20(2):363-375 4. Fagerberg, UL, Loof L, Merzoug RD, et al: Fecal calprotectin levels in
healthy children studied with an improved assay. J Pediatr Gastr Nutr. 2003 Oct;37(4):438-472 5.
Sherwood RA, Walsham NE, Bjarnason I: Gastric, pancreatic, and intestinal function. In: Rifai N,
Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th
ed. Elsevier; 2018:1398-1420
CALX CALR Mutation Analysis, Myeloproliferative Neoplasm (MPN),

36997 Reflex, Varies
Clinical Information: The Janus kinase 2 gene (JAK2) codes for a tyrosine kinase (JAK2) that is
associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor
receptors important for signal transduction in hematopoietic cells. Signaling via JAK2 activation causes
phosphorylation of downstream signal transducers and activators of transcription (STAT) proteins (eg,
STAT5) ultimately leading to cell growth and differentiation. BCR-ABL1-negative myeloproliferative
neoplasms (MPN) frequently harbor an acquired single nucleotide mutation in JAK2 characterized as
c.G1849T; p. Val617Phe (V617F). The JAK2 V617F is present in 95% to 98% of polycythemia vera
(PV), and 50% to 60% of primary myelofibrosis (PMF) and essential thrombocythemia (ET). It has also
been described infrequently in other myeloid neoplasms, including chronic myelomonocytic leukemia
and myelodysplastic syndrome. Detection of the JAK2 V617F is useful to help establish the diagnosis
of MPN. However, a negative JAK2 V617F result does not indicate the absence of MPN. Other
important molecular markers in BCR-ABL1-negative MPN include CALR exon 9 mutation (20%-30%
of PMF and ET) and MPL exon 10 mutation (5%-10% of PMF and 3%-5% of ET). Mutations in JAK2,
CALR, and MPL are essentially mutually exclusive. A CALR mutation is associated with decreased
risk of thrombosis in both ET and PMF, and confers a favorable clinical outcome in PMF patients. A
triple negative (JAK2 V617F, CALR, and MPL-negative) genotype is considered a high-risk molecular
signature in PMF.
Useful For: Aiding in the distinction between a reactive cytosis and a chronic myeloproliferative
disorder Evaluates for mutations in CALR in an algorithmic process for the MPNR / Myeloproliverative
Neoplasm (MPN), JAK2 V617F with Reflex to CALR and MPL
Interpretation: An interpretation will be provided under the MPNR / Myeloproliferative Neoplasm

(MPN), JAK2 V617F with Reflex to CALR and MPL.
Reference Values:
Only orderable as a reflex. For more information see MPNR / Myeloproliferative Neoplasm (MPN),
JAK2 V617F with Reflex to CALR and MPL.
CALR CALR Mutation Analysis, Myeloproliferative Neoplasm (MPN),

62912 Varies
Clinical Information: The most frequent genetic mutation in BCR-ABL1-negative
myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), and primary myelofibrosis
(PMF) is the JAK2V617F mutation, which is present in approximately 50% to 60% of patients. It serves
as a confirmatory molecular marker of these diseases. Mutations in the MPL gene are found in an
additional 5% to 10% of ET and PMF cases. It was recently discovered that somatic mutation
(insertions and deletions) in exon 9 of the CALR gene is the second most frequent somatic mutation
after JAK2 in ET and PMF patients, and it is mutually exclusive of JAK2 and MPL mutations.(1,2) It
has a frequency of approximately 49% to 88% in JAK2 and MPL-wild type (WT) ET and PMF, and is
not found in polycythemia vera (PV) patients.(1-4) Therefore, CALR mutation serves as an important
diagnostic molecular marker in ET and PMF. The CALR gene encodes for calreticulin, a
multifunctional protein with a C-terminus rich in acidic amino acids and a KDEL ER-retention motif.
All the pathologic CALR mutations reported to date are out-of-frame insertion and/or deletions (indel)
in exon 9, generating a 1 base-pair (bp) frame shift and a mutant protein with a novel C-terminus rich in
basic amino acids and loss of the KDEL ER-retention signal. The most common mutation types are
52-bp deletion (c.1092_1143del, L367fs*46) and 5-bp insertion (c.1154_1155insTTGCC, K385fs*47),
and they comprise approximately 85% of CALR mutations in MPN.(1,2) CALR mutations have been
found in hematopoietic stem and progenitor cells in MPN patients(2) and may activate the STAT5
signaling pathway.(1) They are associated with decreased risk of thrombosis in ET (1,3-5), and better
survival in PMF compared to JAK2 mutations.(5)
Useful For: Rapid and sensitive detection of insertion and deletion-type mutations in exon 9 of CALR
An aid in distinction between reactive thrombocytosis and leukocytosis versus a myeloproliferative
neoplasm (MPN), especially essential thrombocythemia (ET) and primary myelofibrosis (PMF), and is
highly informative in cases in which JAK2 and MPL testing are negative Especially helpful to the
pathologist in those bone marrow cases with ambiguous etiology of thrombocytosis, equivocal bone
marrow morphologic findings of MPN, and unexplained reticulin fibrosis An aid in prognostication of
PMF and thrombosis risk assessment in ET
Interpretation: An interpretive report will be issued. The results will be reported as 1 of the 3 states if
DNA amplification is successful (see Cautions): -Positive. A deletion/insertion-type mutation was
detected in CALR, exon 9. -Negative. No deletion or insertion was detected in CALR, exon 9. -Equivocal.
A small amplicon suspicious for a deletion/insertion type mutation was detected in CALR, exon 9.
Positive mutation status is highly suggestive of a myeloid neoplasm, but must be correlated with clinical
and other laboratory and morphologic features for definitive diagnosis. Negative mutation status does not
exclude the presence of a myeloproliferative neoplasm or other neoplastic disorders.
Reference Values:
Clinical References: 1. Klampfl T, Gisslinger H, Harutyunyan AS, et al: Somatic mutation of

calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379-90 2. Nangalia J, Massie CE,
Baxter EJ, et al: Somatic CALR mutation in myeloproliferative neoplasms with nonmutated JAK2. N
Engl J Med 2013;369:2391-2405 3. Rumi E, Pietra D, Ferretti V, et al: JAK2 or CALR mutation status
defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes.
Blood 2014 Mar 6;123(10):1544-1551 4. Rotunno G, Mannarelli C, Guglielmelli P, et al: Impact of
calreticulin mutations on clinical and hematological phenotype and outcome in essential
thrombocythemia. Blood 2014;123(10):1552-1555 5. Tefferi A, Lasho TL, Finke CM, et al: CALR vs
JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons.
Leukemia 2014 Jul;28(7):1472-1477
CALRC Calreticulin ex9mut Immunostain, Technical Component Only

71486 Clinical Information: The detection of calreticulin exon 9 frameshift alterations can assist in the
diagnosis and prognostication of myeloproliferative diseases. Although these alterations are
heterogeneous, they all result in a protein with a novel 36-amino acid C terminus the anticalreticulin
CAL2 clone specifically identifies. Most patients with essential thrombocythemia or primary
myelofibrosis not associated with Janus kinase 2 (JAK2) or MPL variants are associated with CALR exon
9 variants and primary myelofibrosis patients carrying CALR variants have a more indolent clinical
course.
Useful For: Identifying the presence of CALR exon 9 frameshift alterations in myeloproliferative
neoplasms
Interpretation: This test does not include pathologist interpretation; if an interpretation is required
order PATHC / Pathology Consultation for a full diagnostic evaluation or second opinion of the case.
The positive and negative controls are verified as showing appropriate immunoreactivity and
documentation is retained at Mayo Clinic Rochester. If a control tissue is not included on the slide, a
scanned image of the relevant quality control tissue is available upon request. Contact 855-516-8404.
Interpretation of this test should be performed in the context of the patient's clinical history and other
diagnostic tests by a qualified pathologist.
Clinical References: 1. Vannucchi AM, Rotunno G, Bartalucci N, et al: Calreticulin

mutation-specific immunostaining in myeloproliferative neoplasms: pathogenetic insight and diagnostic
value. Leukemia. 2014 Sep;28(9):1811-1818. doi: 10.1038/leu.2014.100 2. Stein H, Bob R, Durkop H,
et al: A new monoclonal antibody (CAL2) detects CALRETICULIN mutations in formalin-fixed and
paraffin-embedded bone marrow biopsies. Leukemia. 2016 Jan;30(1):131-135. doi:
10.1038/leu.2015.192 3. Klampfl T, Gisslinger H, Harutyunyan AS, et al: Somatic mutations of
calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013 Dec 19;369(25):2379-2390. doi:
10.1056/NEJMoa1311347
CALNN Calretinin Immunostain, Technical Component Only

70371 Clinical Information: Calretinin is expressed in benign and malignant mesothelial cells and
strongly expressed in Leydig cells of the testis.
Useful For: Separating mesotheliomas from carcinomas, which usually lack expression of calretinin
Clinical References: 1. Arora R, Agarwal S, Mahur SR, Verma K, Iyer VK, Aron M: Utility of a
limited panel of calretinin and Ber-EP4 immunocytochemistry on cytospin preparation of serous
effusions: A cost-effective measure in resource-limited settings. Cytojournal. 2011;8:14 2. Musa ZA,
Qasim BJ, Ghazi HF, et al: Diagnostic roles of calretinin in hirschsprung disease: A comparison to
neuron-specific enolase. Saudi J Gastroentrol. 2017;23:60-66 3. Sheir M, Samaka RM, Fakhry T,
Albatanony AA: Comparative study between use of calretinin and synaptophysin immunostaining in
diagnosis of Hirschsprung disease. Int Surg J. 2019;6(3):658-663
CAMPC Campylobacter Culture, Feces

determine the appropriate testing to be performed. Campylobacter enteritis is an important cause of
acute diarrhea worldwide. The organism inhabits the intestinal tracts of a wide range of animal hosts,
notably poultry; contamination from these sources can lead to foodborne disease that is typically caused
by Campylobacter jejuni or Campylobacter coli. Campylobacter infection can also be transmitted via
water-borne routes or direct contact with animals or animal products. Early symptoms (1-7 days after
exposure) include abrupt onset of abdominal pain, diarrhea, and occasionally vomiting. The acute
illness is characterized by cramping, abdominal pain, and diarrhea. Patients may report 10 or more
bowel movements per day. Bloody feces may be observed. Diarrhea is typically self-limited, lasting
around 7 days. Proper hydration is necessary. Antibiotics are not needed for most cases of
Campylobacter gastroenteritis, except if patients experience severe disease or if they are
immunocompromised.
Useful For: Determining whether Campylobacter species may be the cause of diarrhea Reflexive
testing for Campylobacter species from nucleic acid amplification test-positive feces This test is generally
not useful for patients hospitalized more than 3 days because the yield from specimens from these patients
is very low, as is the likelihood of identifying a pathogen that has not been detected previously.
Interpretation: The growth of Campylobacter species identifies a potential cause of diarrhea.

Reference Values:
Clinical References: 1. Pillai DR: Fecal culture for aerobic pathogens of gastroenteritis. In Clinical
Microbiology Procedures Handbook, Fourth edition. Washington, DC, ASM Press, 2016, Section 3.8.1 2.
DuPont HL: Persistent diarrhea: A clinical review. JAMA 2016;315(24):2712-2723
doi:10.1001/jama.2016.78334 3. Skirrow MB, Blaser MJ: Clinical aspects of Campylobacter infection. In
Campylobacter, Second edition. Edited by I Nachamkin, MJ Blaser. Washington DC, ASM Press, 2000,
pp69 4. Blaser MJ, Berkowitz ID, LaForce FM, et al: Campylobacter enteritis: clinical and epidemiologic
features. Ann Intern Med 1979;91:179
CFTH Canary Feathers, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to canary feathers Defining the allergen responsible

Reference Values:
0 Negative
apply to all ages.
CAGR Canary Grass, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to canary grass Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
CA25 Cancer Antigen 125 (CA 125), Serum

9289 Clinical Information: Cancer antigen 125 (CA 125) is a glycoprotein antigen normally expressed
in tissues derived from coelomic epithelia (ovary, fallopian tube, peritoneum, pleura, pericardium,
colon, kidney, stomach). Serum CA 125 is elevated in approximately 80% of women with advanced
epithelial ovarian cancer, but assay sensitivity is suboptimal in early disease stages. The average
reported sensitivities are 50% for stage I and 90% for stage II or greater. Elevated serum CA 125 levels
have been reported in individuals with a variety of nonovarian malignancies including cervical, liver,
pancreatic, lung, colon, stomach, biliary tract, uterine, fallopian tube, breast, and endometrial
carcinomas. Elevated serum CA 125 levels have been reported in individuals with a variety of benign
conditions including: cirrhosis, hepatitis, endometriosis, first trimester pregnancy, ovarian cysts, and
pelvic inflammatory disease. Elevated levels during the menstrual cycle also have been reported.
Useful For: Evaluating patients' response to ovarian cancer therapy Predicting recurrent ovarian cancer
This test is not useful for cancer detection screening in the normal population.
Interpretation: In monitoring studies, elevations of cancer antigen 125 (CA 125) above the reference
interval after debulking surgery and chemotherapy indicate that residual disease is likely (>95%
accuracy). However, normal levels do not rule out recurrence. A persistently rising CA 125 value suggests
progressive malignant disease and poor therapeutic response. Physiologic half-life of CA 125 is
approximately 5 days. In patients with advanced disease who have undergone cytoreductive surgery and
are on chemotherapy, a prolonged half-life (>20 days) may be associated with a shortened disease-free
survival.
Reference Values:
Males: Not applicable
Females: <46 U/mL
Clinical References: 1. Sturgeon CM, Duffy MJ, Stenman UH, et al: National Academy of Clinical
Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate
colorectal, breast, and ovarian cancers. Clin Chem. 2008 Dec;54(12):11-79 2. Salani R, Backles FJ, Fung
MFK, et al: Posttreatment surveillance and diagnosis of recurrence in women with gynecologic
malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol.2011
Jun;204(6):466-478 3. The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial
Ovarian Cancer. American College of Obstetricians and Gynecologists. 2011. Committee Opinion
Number 477
CA153 Cancer Antigen 15-3 (CA 15-3), Serum

81607 Clinical Information: Carcinoma of the breast is the most prevalent form of cancer in women. These
tumors often produce mucinous antigens, which are large molecular weight glycoproteins with O-linked
oligosaccharide chains. Tumor-associated antigens encoded by the human MUC-1 gene are known by
several names, including MAM6, milk mucin antigen, cancer antigen (CA) 27.29, and CA 15-3. CA 15-3
assay values are not elevated in most normal individuals and are frequently elevated in sera from breast
cancer patients. Nonmammary malignancies in which elevated CA 15-3 assay values have been reported
include: lung, colon, pancreas, primary liver, ovary, cervix, and endometrium.
Useful For: Managing breast cancer patients when used in conjunction with clinical information and
other diagnostic procedures Serial testing to assist in early detection of disease recurrence in previously
treated stage II and III breast cancer patients Monitoring response to therapy in metastatic breast cancer
patients This test is not useful as a cancer screening test.
Interpretation: Increasing and decreasing values show correlation with disease progression and
regression, respectively.(1) Increasing cancer antigen 15-3 (CA 15-3) assay values in patients at risk for
breast cancer recurrence after primary therapy may be indicative of recurrent disease before it can be
detected clinically (2,3) and may be used as an indication that additional tests or procedures should be
performed.
Reference Values:
Males: <30 U/mL (use not defined)
Females: <30 U/mL
Clinical References: 1. Molina R, Zanon G, Filella X, et al: Use of serial carcinoembryonic antigen
and CA 15-3 assays in detecting relapses in breast cancer patients. Breast Cancer Res Treat. 1995
Jan;36:41-48 2. Geraghty JG, Coveney EC, Sherry F, O'Higgins NJ, Duffy MJ: CA 15-3 in patients with
locoregional and metastatic breast carcinoma. Cancer. 1992 Dec 15;70(12):2831-2834 3. Kallioniemi OP,
Oksa H, Aaran RK, Hietanen T, Lehtinen M, Koivula T: Serum CA 15-3 assay in the diagnosis and
follow-up of breast cancer. Br J Cancer. 1988 Aug;58(2):213-215 4. Lin DC, Genzen JR: Concordance
analysis of paired cancer antigen (CA) 15-3 and 27.29 testing. Breast Cancer Research and Treatment.
2018;167:269-276
FCARP Cancer-Associated Retinopathy Panel (CARP) by Immunoblot

75447 and IHC
Reference Values:
CDAB Candida albicans (Monilia), IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Candida albicans (Monilia) Defining the
allergen responsible for eliciting signs and symptoms Identifying allergens: -Responsible for allergic
disease and/or anaphylactic episode -To confirm sensitization prior to beginning immunotherapy -To

Reference Values:
0 Negative

apply to all ages.
FCANG Candida albicans IgG

75605 Clinical Information: Although there have been many publications concerning the measurement of
allergen-specific IgG, the clinical utility of such tests has not been established except in special situations.
Thus, the quantitative IgG test should only be ordered by specialists who recognize the limitations of the
test. The normal reference ranges reported represent the expected results for individuals who have no
unusual exposure and have not been immunized with the indicated allergen. The ranges reported have no
disease-associated significance.
Reference Values:
<52.0 mcg/mL
CAURS Candida auris Surveillance, Molecular Detection, PCR, Varies

607883 Clinical Information: Candida auris is a yeast that was first identified as causing disease in an
individual in Japan in 2009. Since then, cases have been reported in more than 30 countries worldwide.
The first case of Candida auris in the US was reported in 2015, and cases have been reported in a number
of states. In addition to causing disease, Candida auris can colonize individuals without signs or
symptoms of disease. Candida auris can cause serious and sometimes fatal infections, is often resistant to
one or more classes of antifungal drugs, and inappropriate treatment may occur as it can be misidentified
in the laboratory. In addition, Candida auris appears to be more resistant to disinfection than other yeasts,
leading to prolonged survival in the environment and increasing the possibility of transmission in
hospitals and nursing homes. In December 2018, the Center for Disease Control and Prevention (CDC)
recommended that health care facilities implement routine surveillance screening of patients who have
had an overnight stay in a health care facility outside of the US over the past year, particularly if the
hospitalization was in a country with confirmed cases of Candida auris. The CDC also recommended
considering screening of patients who have been hospitalized outside of the US and have a documented
infection or colonization with a carbapenamase-producing Gram-negative bacteria. These patients have
frequently been found to have Candida auris colonization as well. A second group of people for whom
screening is recommended includes health care workers who have been in close contact with patients who
have previously unrecognized Candida auris infection or colonization. The Candida auris polymerase
chain reaction (PCR) assay detects and identifies Candida auris from blood or urine specimens and also
from swabs including combination groin/axilla surveillance swabs and nares surveillance swabs.
Useful For: Detection of Candida auris from surveillance swabs This test should not be used to
determine cure or to monitor response to therapy.
Interpretation: A positive result indicates the presence of Candida auris DNA. A negative result
indicates the absence of detectable Candida auris DNA. An inhibited result indicates that inhibitors are
present in the specimen that could prevent the detection of C auris DNA. A new specimen can be
resubmitted under a new order, if desired.
Reference Values:
Not applicable
Clinical References: 1. Spivak ES, Hanson KE: Candida auris: An Emerging Fungal Pathogen. J
Clin Microbiol. 2018;56:e01588-17 2. Centers for Disease Control and Prevention (CDC) National Center
for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne, and
Environmental Diseases (DFWED): Candida auris. CDC; Updated October 26, 2020. Accessed
November 2, 2020. Available at: www.cdc.gov/fungal/candida-auris/index.html 3. Navalkele BD,
Revankar S, Chandrasekar P: Candida Auris: A Worrisome, Globally Emerging Pathogen. Expert Rev
Anti Infect Ther. 2017 Sep;15(9):819-827
CAURB Candida auris, Molecular Detection, PCR, Blood
The first case of Candida auris in the US was reported in 2015, and cases have been reported in a
number of states. In addition to causing disease, Candida auris can colonize individuals without signs or
symptoms of disease. Candida auris can cause serious and sometimes fatal infections, is often resistant
to one or more classes of antifungal drugs, and inappropriate treatment may occur as it can be
misidentified in the laboratory. In addition, Candida auris appears to be more resistant to disinfection
than other yeasts, leading to prolonged survival in the environment and increasing the possibility of
transmission in hospitals and nursing homes. In December 2018, the Center for Disease Control and
Prevention (CDC) recommended that health care facilities implement routine surveillance screening of
patients who have had an overnight stay in a health care facility outside of the US over the past year,
particularly if the hospitalization was in a country with confirmed cases of Candida auris. The CDC also
recommended considering screening of patients who have been hospitalized outside of the US and have
a documented infection or colonization with a carbapenamase-producing Gram-negative bacteria. These
patients have frequently been found to have Candida auris colonization as well. A second group of
people for whom screening is recommended includes health care workers who have been in close
contact with patients who have previously unrecognized Candida auris infection or colonization. The
Candida auris polymerase chain reaction (PCR) assay detects and identifies Candida auris from blood or
urine specimens and also from swabs including combination groin/axilla surveillance swabs and nares
surveillance swabs.
Useful For: Detection of Candida auris in whole blood specimens This test should not be used to
determine cure or to monitor response to therapy.
present in the specimen that could prevent the detection of Candida auris DNA. A new specimen can be
Reference Values:
Not applicable
Clin Microbiol. 2018;56:e01588-17 2. Centers for Disease Control and Prevention (CDC) National
Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne,
and Environmental Diseases (DFWED): Candida auris. CDC; Updated October 26, 2020. Accessed
CAURP Candida auris, Molecular Detection, PCR, Random, Urine

The first case of Candida auris in the U S was reported in 2015, and cases have been reported in a
number of states. In addition to causing disease, Candida auris can colonize individuals without signs or
symptoms of disease. Candidia auris can cause serious and sometimes fatal infections, is often resistant
to one or more classes of antifungal drugs, and inappropriate treatment may occur as it can be
misidentified in the laboratory. In addition, Candida auris appears to be more resistant to disinfection
than other yeasts, leading to prolonged survival in the environment and increasing the possibility of
transmission in hospitals and nursing homes. In December 2018, the Center for Disease Control and
Prevention (CDC) recommended that health care facilities implement routine surveillance screening of
patients who have had an overnight stay in a health care facility outside of the US over the past year,
particularly if the hospitalization was in a country with confirmed cases of Candida auris. The CDC also
recommended considering screening of patients who have been hospitalized outside of the US and have
a documented infection or colonization with a carbapenamase-producing Gram-negative bacteria. These
patients have frequently been found to have Candida auris colonization as well. A second group of
people for whom screening is recommended includes health care workers who have been in close
contact with patients who have previously unrecognized Candida auris infection or colonization. The
Candida auris polymerase chain reaction (PCR) assay detects and identifies Candida auris from blood or
urine specimens and also from swabs including combination groin/axilla surveillance swabs and nares
surveillance swabs.
Useful For: Detection of Candida auris in urine specimens This test should not be used to determine
cure or to monitor response to therapy.
present in the specimen that could prevent the detection of Candida auris DNA. A new specimen can be
Reference Values:
Not applicable
Clin Microbiol. 2018;56:e01588-17 2. Centers for Disease Control and Prevention (CDC) National Center
for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne, and
Environmental Diseases (DFWED): Candida auris. CDC; Updated October 26, 2020. Accessed
FCBDS Cannabidiol, Serum

75527 Clinical Information: Mean peak CBD plasma concentrations at 3-4 hours post-dose with Sativex at
a low dose (5.4 mg of Delta-9 THC and 5.0 mg of Cannabidiol) were 1.6 +/- 0.4 ng/mL and at a high dose
(16 mg of Delta-9 THC and 15 mg of Cannabidiol) were 6.7 +/- 2.0 ng/mL. Following high dose 400 and
800 mg oral synthetic CBD in corn oil administration, mean peak CBD plasma concentrations occurred
within 1.5-3 hours post-dose and were 181.2 +/- 39.8 and 221.1 +/- 35.6 ng/mL, respectively. The ratio of
blood to serum or plasma concentration is unknown for this analyte.
Reference Values:
Units: ng/mL
FMARI Cannabinoid Analysis, Whole Blood

Cannabinoid Screen:
THC (MARIJUANA) Metabolite- Negative; Cutoff: 5 ng/mL
Cannabinoid Confirmation:
Tetrahydrocannabinol (THC)
Carboxy-THC
Hydroxy-THC
Cannabinol
Cannabidiol
Confirmation threshold: 1.0 ng/mL
FCDU7 Cannabinoids, Umbilical Cord Tissue

Units: ng/g
CWAY Caraway, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to caraway Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CARBR Carbamazepine Hypersensitivity Pharmacogenomics, Varies

610048 Clinical Information: Carbamazepine and oxcarbazepine are aromatic anticonvulsants, as are
eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. Carbamazepine is
FDA-approved for the treatment of epilepsy, trigeminal neuralgia, and bipolar disorder. Oxcarbazepine
is FDA-approved for the treatment of partial seizures. A minority of carbamazepine- or
oxcarbazepine-treated persons have cutaneous adverse reactions that vary in prevalence and severity,
with some forms associated with substantial morbidity and mortality. The most severe reactions, such as
the Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are characterized by a
blistering rash affecting a variable percentage of the body-surface area. TEN is the rarest of these
phenotypes and is associated with mortality of up to 30%. Drug reaction with eosinophilia and systemic
symptoms (DRESS) and maculopapular exanthema (MPE) may also be related to carbamazepine
exposure. According to the FDA-approved label for carbamazepine, the estimated incidence of
SJS-TEN is 1 to 6 cases in 10,000 persons of European ancestry who are exposed to the drug. The rate
of SJS-TEN as a result of carbamazepine exposure is about 10 times higher in some Asian countries.
According to the FDA label for oxcarbazepine, the rate of TEN and SJS among individuals exposed to
oxcarbazepine exceeds the background incidence by a factor of 3- to 10-fold, but this is expected to be
an underestimate due to underreporting. Clinical studies have demonstrated associations between some
human leukocyte antigen (HLA) genotypes and drug-associated cutaneous adverse reactions. The
presence of the HLA-B*15:02 allele varies throughout Asia: 10% to 15% frequency in Chinese; 2% to
4% frequency in Southeast Asians and Indians; and less than 1% frequency in Japanese and Koreans.
This allele is strongly associated with greater risk of SJS and TEN in patients treated with
carbamazepine or oxcarbazepine and has also been associated with SJS/TEN with phenytoin use. There
is very limited evidence associating SJS/TEN/DRESS or MPE and other aromatic anticonvulsants in
patients who are positive for HLA-B*15:02. The HLA-A*31:01 allele, which has a prevalence of 2% to
5% in Northern European populations, 6% among Hispanic/South American populations, and 8%
among Japanese populations, has been significantly associated with greater risk of MPE, DRESS, and
SJS/TEN among patients treated with carbamazepine. In the absence of HLA-A*31:01, the risk for
drug-associated cutaneous adverse reactions is 3.8%, but in the presence of this allele, the risk increases
to 26%. The evidence linking other aromatic anticonvulsants with SJS/TEN in the presence of the
HLA-A*31:01 allele is weaker; however, an alternative medication should be chosen with caution. The
FDA-approved label for carbamazepine states that the screening of patients in genetically at-risk
populations (ie, patients of Asian descent) for the presence of the HLA-B*15:02 allele should be carried
out prior to initiating treatment with carbamazepine. The FDA-approved label also notes the association
of HLA-A*31:01 allele with drug-associated cutaneous adverse reactions regardless of ethnicity, but it
does not specifically mandate screening of patients. The FDA-approved label for oxcarbazepine
indicates that testing for the presence of the HLA-B*15:02 allele should be considered in patients with
ancestry including genetically at-risk populations prior to initiation of therapy. According to the most
recent Clinical Pharmacogenetic Implementation Consortium (CPIC) guideline, patients who are
HLA-B*15:02 positive should not be prescribed carbamazepine or oxcarbamazepine if alternative
agents are available; however, caution should be used in selecting an alternative medication as there is
weaker evidence that also links other aromatic anticonvulsants with SJS/TEN in patients positive for
HLA-B*15:02. Furthermore, phenytoin is the subject of a separate CPIC guideline with
recommendations to avoid phenytoin in HLA-B*15:02 positive individuals, along with additional
recommendations based on CYP2C9 genotype. Patients who are HLA-A*31:01 positive should not be
prescribed carbamazepine if alternative agents are available. However, although very limited evidence
links SJS/TEN/DRESS/MPE with other aromatic anticonvulsants, among HLA-A*31:01-positive
patients, caution should be used in selecting an alternative medication.
Useful For: Identifying individuals with increased risk of risk of carbamazepine- or

oxcarbazepine-associated cutaneous adverse reactions
Interpretation: The presence of the HLA-B*15:02 and/or HLA-A*31:01 allele confers increased risk
for hypersensitivity to carbamazepine. The presence of the HLA-B*15:02 allele also confers increased
risk for hypersensitivity to oxcarbazepine and phenytoin. For additional information regarding
pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables. This
resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate
drug choices.
Reference Values:
Clinical References: 1. Phillips EJ, Sukasem C, Whirl-Carrillo M, et al: Clinical Pharmacogenetics

Implementation Consortium guideline for HLA genotype and use of carbamazepine and oxcarbazepine:
2017 Update. Clin Pharmacol Ther. 2018;103(4):574-581 2. Caudle KE, Rettie AE, Whirl-Carrillo M, et
al: Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes
and phenytoin dosing. Clin Pharacol Ther. 2014;96(5):542-548 3. McCormack M, Alfirevic A, Bourgeois
S, et al: HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J
Med. 2011;364:1134-1143 4. Amstutz U, Shear NH, Rieder MJ, et al: Recommendations for
HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced
hypersensitivity reactions. Epilepsia. 2014;55:496-506 5. Caudle KE, Rettie AE, Whirl-Carrillo M, et al:
Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA-B genotypes
and phenytoin dosing. Clin Pharmacol Ther. 2014;96(5):542-548
CARTF Carbamazepine Profile, Serum

37037 Clinical Information: Carbamazepine is a common antiepileptic drug. It is a first-line drug for
treatment of partial seizures and trigeminal neuralgia. Carbamazepine is metabolized by the liver to
carbamazepine-10,11-epoxide (CBZ10-11), which is pharmacologically active and potentially toxic.
CBZ10-11 is, in turn, inactivated by hepatic conversion to a transdiol derivative. CBZ10-11 may be
responsible for the congenital abnormalities that are sometimes associated with the use of
carbamazepine during early pregnancy. There have been cases of severe seizures exacerbation when
serum epoxide levels were increased. Toxic levels of CBZ10-11 can occur during: -Concomitant
administration of other drugs that induce hepatic oxidizing enzymes (eg, most antiepileptic drugs [with
the exception of valproic acid and the benzodiazepines], propoxyphene) -Concomitant administration of
drugs that inhibit its breakdown such as valproic acid, felbamate, and lamotrigine -High-dose
carbamazepine therapy, especially in combination with the above conditions
Useful For: Monitoring patients exhibiting symptoms of carbamazepine toxicity whose total serum
carbamazepine concentration is within the therapeutic range, but who may be producing significant
levels of the active metabolite epoxide Free carbamazepine concentration may also be useful to monitor
in patients with altered or unpredictable protein binding capacity
Interpretation: The clinically acceptable serum concentration of carbamazepine-10,11-epoxide

(CBZ10-11) is not well established, but 4.0 mcg/mL has often been used as an upper limit for its
therapeutic range. The ratio of CBZ10-11 to carbamazepine is usually less than or equal to 0.2 mcg/mL
in symptomatic adults and less than or equal to 0.3 mcg/mL in children. Clinical correlation is aided by
comparing values obtained when the patient is symptomatic with those obtained when the patient has
improved.
Reference Values:
CARBAMAZEPINE, TOTAL
CARBAMAZEPINE-10,11-EPOXIDE
Toxic concentration: > or =8.0 mcg/mL
CARBAMAZEPINE, FREE
Clinical References: 1. Theodore WH, Narang PK, Holmes MD, et al: Carbamazepine and its
epoxide: relation of plasma levels to toxicity and seizure control. Ann Neurol 1989;25:194-196 2.
Tomson T, Almkvist O, Nilsson BY, et al: Carbamazepine-10, 11-epoxide in epilepsy. A pilot study.
Arch Neurol 1990;47:888-892 3. McKauge L, Tyrer JH, Eadie MI: Factors influencing simultaneous
concentrations of carbamazepine and its epoxide in plasma. Ther Drug Monit 1981;3:63-70 4. Brodie
MJ, Forrest G, Rapeport WG: Carbamazepine-10,11-epoxide concentrations in epileptics of
carbamazepine alone and in combination with other anticonvulsants. Br J Clin Pharmacol
1983;16:747-749 5. Shoeman JF, Elyas AA, Brett EM, Lascelles PT: Correlation between plasma
carbamazepine-10,11-epoxide concentration and drug side-effects in children with epilepsy. Dev Med
Child Neurol 1984;26:756-764
CARFT Carbamazepine, Free and Total, Serum

37039 Clinical Information: Carbamazepine (Tegretol) is an effective treatment for complex partial
seizures, with or without generalization to tonic-clonic seizures. It is frequently administered in
conjunction with other antiepileptic agents, such as phenytoin and valproic acid. Under normal
circumstances, the carbamazepine that circulates in blood is 75% protein bound. In severe uremia,
carbamazepine may be displaced from protein, resulting in a higher free (unbound) fraction of the drug
circulating in blood. Since neurologic activity and toxicity are directly related to the circulating free
fraction of drug, adjustment of dosage based on knowledge of the free carbamazepine level may be useful
in patients with severe uremia.
Useful For: Monitoring carbamazepine (free and total) therapy in uremic patients
Interpretation: In patients with normal renal function, optimal response is often associated with free
(unbound) carbamazepine levels greater than 1.0 mcg/mL, and toxicity may occur when the free
carbamazepine is greater than or equal to 4.0 mcg/mL. In uremic patients, the free carbamazepine level
may be a more useful guide for dosage adjustments than the total level. In patients with severe uremia,
subtherapeutic total carbamazepine levels in the range of 1.0 to 2.0 mcg/mL may be associated with
therapeutic free levels. Toxicity may occur in these patients when the free carbamazepine level is greater
than or equal to 4.0 mcg/mL (even though the total carbamazepine concentration is <15.0 mcg/mL). As
with the serum levels of other anticonvulsant drugs, total and free carbamazepine levels should be
correlated with the patient's clinical condition. They are best used as a guide in dose adjustment.
Reference Values:
CARBAMAZEPINE, FREE
Clinical References: 1. Svinarov DA, Pippenger CE: Relationships between carbamazepine-diol,

carbamazepine-epoxide, and carbamazepine total and free steady-state concentrations in epileptic patients:
the influence of age, sex, and comedication. Ther Drug Monit 1996;18:660-665 2. Bernus I, Dickinson
RG, Hooper WD, Eadie MJ: The mechanism of the carbamazepine-valproate interactions in humans. Br J
Clin Phamacol 1997;44:21-27 3. Dasgupta A, Volk A: Displacement of valproic acid and carbamazepine
from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of
inhibitor in uremic serum that blocks valproic acid-naproxen interactions. Ther Drug Monit
1996;18:284-287 4. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry.
Edited by CA Burtis, ER Ashwood. Fourth edition. Philadelphia, PA. WB Saunders Company 2005 pp
1237-1285 5. Patsalos PN, Berry DJ, Bourgeois BF, et al: Antiepileptic drugs-best practice guidelines for
therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring,
ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49(7):1239-1276
CARF Carbamazepine, Free, Serum

37038 Clinical Information: Carbamazepine (Tegretol) is an effective treatment for complex partial
seizures, with or without generalization to tonic-clonic seizures.(1) It is frequently administered in
conjunction with other antiepileptic agents, such as phenytoin and valproic acid.(2) Under normal
circumstances, the carbamazepine that circulates in blood is 70% to 80% protein-bound.(3) Only the free
drug is able to enter the interstitial space in the brain where the pharmacological effects occur.(4) Patient
management is best guided by monitoring free serum concentrations when protein binding is altered.
Altered protein binding occurs in patients with hypoalbuminemia observed during pregnancy, in the
malnourished, and liver disease. In patients with renal disease, uremia may develop whose byproducts can
displace bound carbamazepine increasing the unbound fraction. Administration of drugs that are able to
compete for serum protein binding sites may also increase the unbound fraction of carbamazepine. Since
neurologic activity and toxicity of carbamazepine are directly related to the circulating free fraction of
drug, adjustment of dosage based on knowledge of the free carbamazepine concentration may be more
useful in these patient populations.
Useful For: Monitoring unbound or free carbamazepine levels in patients where the total
carbamazepine result is within the therapeutic range but the patient is experiencing side effects
Monitoring carbamazepine (free) therapy in uremic patients
Interpretation: In patients with normal renal function, optimal response is often associated with free
(unbound) carbamazepine levels above 1.0 mcg/mL, and toxicity may occur when the free
carbamazepine is greater than or equal to 4.0 mcg/mL. Under normal circumstances, the carbamazepine
that circulates in blood is 75% protein-bound. Therapies or conditions such as uremia that displace
carbamazepine from protein cause a higher free (unbound) fraction of the drug circulating in blood. In
uremia, the free carbamazepine level may be a more useful guide for dosage adjustments than the total
level. In patients with severe uremia, subtherapeutic total carbamazepine levels in the range of 1.0 to 2.0
mcg/mL may be associated with therapeutic free carbamazepine levels. Toxicity may occur when the
free carbamazepine level is greater than or equal to 4.0 mcg/mL (even though the total carbamazepine
concentration is <15.0 mcg/mL). As with the serum levels of other anticonvulsant drugs, total and free
carbamazepine levels should be correlated with the patient's clinical condition. Serum levels are best
used as a guide in dose adjustment.
Reference Values:
Clinical References: 1. Svinarov DA, Pippenger CE: Relationships between carbamazepine-diol,

carbamazepine-epoxide, and carbamazepine total and free steady-state concentrations in epileptic
patients: the influence of age, sex, and comedication. Ther Drug Monit 1996;18:660-665 2. Bernus I,
Dickinson RG, Hooper WD, Eadie MJ: The mechanism of the carbamazepine-valproate interactions in
humans. Br J Clin Phamacol 1997;44:21-27 3. Dasgupta A, Volk A: Displacement of valproic acid and
carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen:
presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions. Ther Drug Monit
1996;18:284-287 4 Patsalos PN, Berry DJ, Bourgeois BF, et al: Antiepileptic drugs-best practice
guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug
monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49(7):1239-1276
CARTA Carbamazepine, Total, Serum

37035 Clinical Information: Carbamazepine (Tegretol) is used in the control of partial seizures with both
temporal lobe and psychomotor symptoms as well as for generalized tonic-clonic seizures. It is also
used for analgesia in trigeminal neuralgia. Carbamazepine exhibits a volume of distribution of 1.4 L/kg
with an elimination half-life of 15 hours. Protein binding averages 70%. Carbamazepine-10,11-epoxide
(CBZ10-11) is an active metabolite that represents the predominant form of the drug in children. The
volume of distribution of CBZ10-11 is 1.1 L/kg, and the half-life is 5 to 8 hours. Aplastic anemia and
agranulocytosis are rare side effects of treatment with carbamazepine; baseline hematologic data should
be documented before treatment is initiated. Toxicity associated with carbamazepine overdose occurs
when the blood level is 15.0 mcg/mL or higher and is typified by irregular breathing, muscle irritability,
and hyperreflexia; followed by hyporeflexia, tachycardia, hypotension, and impaired consciousness
with coma in severe toxicity. The higher the blood level, the more severe the symptoms.
Useful For: Monitoring therapy Determining compliance Assessing toxicity

Interpretation: Dosage adjustments are usually guided by monitoring blood levels. Most patients
respond well when the serum concentration is in the range of 4.0 to 12.0 mcg/mL. Toxicity often occurs
when levels are greater than or equal to 15.0 mcg/mL.
Reference Values:
Clinical References: 1. Cereghino JJ, Meter JC, Brock JT, Penry JK, Smith LD, White BG:
Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology. 1973
Apr;23(4):357-366. doi: 10.1212/wnl.23.4.357 2. Patsalos PN, Berry DJ, Bourgeois BF, et al:
Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the
subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia.
2008 Jul;49(7):1239-1276. doi: 10.1111/j.1528-1167.2008.01561.x 3. Scheuer ML, Pedley TA: The
evaluation and treatment of seizures. N Engl J Med. 1990 Nov 22;323(21):1468-1474.
10.1056/NEJM199011223232107 4. Milone MC, Shaw LM: Therapeutic Drug Monitoring. In: Rifai N,
Horvath AR, Wittwer CT, eds. Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics. 8th
ed. Saunders; 2019:549 5. Patsalos PN, Zugman M, Lake C, James A, Ratnaraj N, Sander JW. Serum
protein binding of 25 antiepileptic drugs in a routine clinical setting: a comparison of free
non-protein-bound concentrations. Epilepsia. 2017 Jul;58(7):1234-1243. doi: 10.1111/epi.13802
CARBG Carbamazepine-10,11-Epoxide, Serum

37036 Clinical Information: Carbamazepine is a common antiepileptic drug. It is a first-line drug for
treatment of partial seizures and trigeminal neuralgia. Carbamazepine is metabolized by the liver to
carbamazepine-10,11-epoxide (CBZ10-11) which is pharmacologically active and potentially toxic.
CBZ10-11 is, in turn, inactivated by hepatic conversion to a transdiol derivative. CBZ10-11 may be
responsible for the congenital abnormalities that are sometimes associated with the use of carbamazepine
during early pregnancy. There have been cases of severe seizures exacerbation when serum epoxide levels
were increased. Toxic levels of CBZ10-11 can occur during: -Concomitant administration of other drugs
that induce hepatic oxidizing enzymes (eg, most antiepileptic drugs [with the exception of valproic acid
and the benzodiazepines], propoxyphene) -Concomitant administration of drugs that inhibit its breakdown
such as valproic acid, felbamate, and lamotrigine -High-dose carbamazepine therapy, especially in
combination with the above conditions
Useful For: Monitoring patients exhibiting symptoms of carbamazepine toxicity whose total serum
carbamazepine concentration is within the therapeutic range, but who may be producing significant levels
of the active metabolite epoxide, which can accumulate to concentrations equivalent to carbamazepine
Interpretation: The clinically acceptable serum concentration of carbamazepine-10,11-epoxide

(CBZ10-11) is not well established, but 4.0 mcg/mL has often been used as an upper limit for its
therapeutic range. The ratio of CBZ10-11 to carbamazepine is usually < or =0.2 mcg/mL in symptomatic
adults and < or =0.3 mcg/mL in children. Clinical correlation is aided by comparing values obtained when
the patient is symptomatic with those obtained when the patient has improved.
Reference Values:
CARBAMAZEPINE-10,11-EPOXIDE
Toxic concentration: > or =8.0 mcg/mL
Clinical References: 1. Theodore WH, Narang PK, Holmes MD, et al: Carbamazepine and its
epoxide: relation of plasma levels to toxicity and seizure control. Ann Neurol 1989;25:194-196 2. Tomson
T, Almkvist O, Nilsson BY, et al: Carbamazepine-10, 11-epoxide in epilepsy. A pilot study. Arch Neurol
1990;47:888-892 3. McKauge L, Tyrer JH, Eadie MI: Factors influencing simultaneous concentrations of
carbamazepine and its epoxide in plasma. Ther Drug Monit 1981;3:63-70 4. Brodie MJ, Forrest G,
Rapeport WG: Carbamazepine-10,11-epoxide concentrations in epileptics of carbamazepine alone and in
combination with other anticonvulsants. Br J Clin Pharmacol 1983;16:747-749 5. Shoeman JF, Elyas AA,
Brett EM, Lascelles PT: Correlation between plasma carbamazepine-10,11-epoxide concentration and
drug side-effects in children with epilepsy. Dev Med Child Neurol 1984;26:756-764
CARNB Carbapenemase Detection-Carba NP Test (Bill Only)

CARNP Carbapenemase Detection-Carba NP Test, Varies

62606 Clinical Information: Gram-negative bacilli (GNB) with acquired carbapenemases have
disseminated worldwide, rendering them a global threat. The therapeutic armamentarium for infections
caused by carbapenem-resistant Enterobacteriaceae (CRE) is limited, and CRE infections have been
associated with significant mortality. Enterobacteriaceae harboring Klebsiella pneumoniae
carbapenemase are endemic in some regions of the United States, and although still sporadic, GNB
harboring New Delhi metallo-beta-lactamase have been reported from several states. Timely detection
of these carbapenemases (along with emerging carbapenemases such as OXA-48 and VIM) is
important. Detection is challenging since isolates may have only borderline reductions in susceptibility
to carbapenems, and carbapenem resistance may be mediated by mechanisms other than
carbapenemases (eg, AmpC or extended-spectrum beta-lactamase with decreased membrane
permeability). While molecular methods are confirmatory, testing may not be immediately available and
may be limited by the number of targets assayed. The modified Hodge test suffers from lack of
specificity, a long turnaround time, and poor sensitivity for metallo-beta-lactamase detection. The Carba
NP test is preferred over the modified Hodge test due to improved specificity and faster turnaround
time. The Carba NP test is more specific than and as sensitive as the carbapenemase-modified Hodge
test. If an isolate is suspected to possess KPC or NDM carbapenemase (eg, due to local epidemiology),
KPC and NDM PCR (KPNRP / KPC (blaKPC) and NDM (blaNDM) in Gram-Negative Bacilli,
Molecular Detection, PCR) may be preferred over the Carba NP test.
Useful For: Confirmation of carbapenemase production from pure isolates of Enterobacteriaceae or

Pseudomonas aeruginosa
Interpretation: A positive result indicates production of a carbapenemase by the isolate submitted

for testing. A negative result indicates lack of production of a carbapenemase by the isolate submitted
for testing.
Reference Values:
Negative
Clinical References: 1. Vasoo S, Cunningham SA, Kohner P, et al: Comparison of a novel, rapid
chromogenic biochemical assay, the Carba NP test, with the modified Hodge test for detection of
carbapenemase-producing Gram-negative bacilli. J Clin Microbiol 2013;51(9):3097-3101 2. Nordmann
P, Poirel L, Dortet L: Rapid detection of carbapenemase-producing Enterobacteriaceae. Emerg Infect
Dis 2012;18:1503-1507
199PC Carbohydrate Antigen 19-9 (CA 19-9), Pancreatic Cyst Fluid

89508 Clinical Information: Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group
antigen, which has been used as a tumor marker. Serum CA 19-9 concentrations may be elevated in
patients with gastrointestinal malignancies such as cholangiocarcinoma, colon cancer, or pancreatic
cancer. While serum CA 19-9 is neither sensitive nor specific for pancreatic cancer, concentrations of
CA 19-9 in pancreatic cyst fluid may help determine whether a pancreatic cyst is benign. Cystic lesions
of the pancreas are of various types: -Benign cysts: Â -Inflammatory cysts (pseudocysts) Â -Serous
cysts (serous cystadenoma) -Mucinous cysts: Â -Premalignant (mucinous cystadenoma) Â -Malignant
(cystadenocarcinoma, intrapapillary mucinous neoplasia) Pancreatic cyst fluid CA 19-9 results should
be used in conjunction with imaging studies, cytology, and other cyst-fluid tumor markers, such as
carcinoembryonic antigen and amylase.
Useful For: As an adjunct in the assessment of pancreatic cysts, when used in conjunction with
carcinoembryonic antigen, amylase, imaging studies and cytology
Interpretation: Cyst fluid carbohydrate antigen 19-9 (CA19-9) concentrations less than or equal to 37
U/mL indicate a low risk for a mucinous cyst and are more consistent with serous cystadenoma or
pseudocyst. The sensitivity and specificity are approximately 19% and 98%, respectively, at this
concentration. Correlation of these test results with cytology and imaging is recommended.
Reference Values:
Clinical References: 1. Snozek CL, Jenkins SM, Bryant SC, et al: Analysis of CEA, CA19-9 and
amylase in pancreatic cyst fluid for diagnosis of pancreatic lesions. Clin Chem. 2008;54(6 Suppl
S):A126-127 2. van der Waaij LA, van Dullemen HM, Porte RJ: Cyst fluid analysis in the differential
diagnosis of pancreatic cystic lesions: a polled analysis. Gastrointest Endosc. 2005;62:383-389 3. Khalid
A, Brugge W: ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts.
Am J Gastroenterol. 2007 Oct;102(10):2339-2349
199PT Carbohydrate Antigen 19-9 (CA 19-9), Peritoneal Fluid

Malignant disease can cause ascites by various mechanisms including: peritoneal carcinomatosis (53%),
massive liver metastasis causing portal hypertension (13%), peritoneal carcinomatosis plus massive liver
metastasis (13%), hepatocellular carcinoma plus cirrhosis (7%), and chylous ascites due to lymphoma
(7%). The evaluation and diagnosis of malignancy-related ascites is based on the patient clinical history,
ascites fluid analysis, and imaging tests. The overall sensitivity of cytology for the detection of
malignancy-related ascites ranges from 58% to 75%. Cytology examination is most successful in patients
with ascites related to peritoneal carcinomatosis as viable malignant cells are exfoliated into the ascitic
fluid. However, only approximately 53% of patients with malignancy-related ascites have peritoneal
carcinomatosis. Patients with other causes of malignancy-related ascites almost always have a negative
cytology. Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group antigen. CA 19-9 may
be elevated in the serum patients with gastrointestinal malignancies such as cholangiocarcinoma,
pancreatic cancer, or colon cancer. Measurement of CA 19-9 in ascitic fluid is sometimes used in
combination with cytology for detecting malignancy-related ascites.
Useful For: An adjunct to cytology to differentiate between malignancy-related ascites and benign
causes of ascites formation
Interpretation: A peritoneal fluid carbohydrate antigen 19-9 (CA 19-9) concentration >32 U/mL is
suspicious, but not diagnostic, of a malignancy-related ascites. This clinical decision limit cutoff yielded
44% sensitivity and 93% specificity in a study of 137 patients presenting with ascites. However, ascites
caused by malignancies not associated with increase serum CA 19-9 concentrations, including lymphoma,
mesothelioma, leukemia, and melanoma, routinely had CA 19-9 concentrations <32 U/mL. Therefore,
negative results should be interpreted with caution, especially in patients who have or are suspected of
having a malignancy not associated with elevated CA 19-9 levels in serum.
Reference Values:
Clinical References: 1. Trape J, Molina R, Sant F: Clinical evaluation of the simultaneous

determination of tumor markers in fluid and serum and their ratio in the differential diagnosis of serous
effusions. Tumour Biol 2004 Sep-Dec;25(5-6):276-281 2. Sari R, Yildirim B, Sevinc A, et al: The
importance of serum and ascites fluid alpha-fetoprotein, carcinoembryonic antigen, CA 19-9, and CA
15-3 levels in differential diagnosis of ascites etiology. Hepatogastroenterology 2001
Nov-Dec;48(42):1616-1621
PF199 Carbohydrate Antigen 19-9 (CA 19-9), Pleural Fluid
60230 Clinical Information: Pleural effusions occur as a consequence of either nonmalignant conditions
(including congestive heart failure, pneumonia, pulmonary embolism, and liver cirrhosis) or malignant
conditions (including lung, breast, and lymphoma cancers). Diagnosing the cause of an effusion can be
difficult, requiring cytological examination of the fluid. Analysis of various tumor markers in pleural
fluid has shown that these markers can differentiate between effusions caused by nonmalignant and
malignant conditions and can enhance cytology findings. Carbohydrate antigen 19-9 (CA 19-9) is a
modified Lewis(a) blood group antigen. Healthy adults typically produce low to undetectable levels of
CA 19-9. Serum concentrations of CA 19-9 may be elevated in patients with certain malignancies that
secrete CA 19-9 into circulation, including cholangiocarcinoma, colorectal, stomach, bile duct, lung,
ovarian, and pancreatic cancers. Pleural fluid concentrations of CA 19-9 have been reported to be
elevated in patients with certain malignancies. Malignancies that can secrete CA 19-9 and elevate serum
CA 19-9 concentrations, including cholangiocarcinoma, colorectal, stomach, bile duct, lung, ovarian,
and pancreatic cancers, typically also elevate CA 19-9 in pleural fluid. In contrast, malignancies that do
not secrete CA 19-9, including mesothelioma, lymphoma, leukemia, and melanoma, have low
concentrations of CA 19-9 in pleural fluid comparable to concentrations observed in nonmalignant
effusions. CA 19-9 results should be used in conjunction with cytological analysis of pleural fluid,
imaging studies, and other clinical findings.
Useful For: An adjuvant to cytology and imaging studies to differentiate between nonmalignant and
malignant causes of pleural effusions
Interpretation: A pleural fluid carbohydrate antigen 19-9 (CA 19-9) concentration of 20.0 U/mL or
higher is suspicious, but not diagnostic, of a malignant source of the effusion. This cutoff yielded a
sensitivity of 35%, specificity of 95%, and positive predictive value of 88% in a study of 200 patients
presenting with effusion. CA 19-9 concentrations were significantly higher in effusions caused by CA
19-9-secreting malignancies, including cholangiocarcinoma, colorectal, stomach, bile duct, lung,
ovarian, and pancreatic cancers. However, effusions caused by non-CA 19-9-secreting malignancies,
including lymphoma, mesothelioma, leukemia, and melanoma, routinely had CA 19-9 concentrations
below 20.0 U/mL. Therefore, negative results should be interpreted with caution, especially in patients
who have or are suspected of having a non-CA 19-9-secreting malignancy. Correlation of all tumor
marker results with cytology and imaging is highly recommended.
Reference Values:
Clinical References: 1. Shitrit D, Zingerman B, Shitrit AB, et al: Diagnostic value of CYFRA
21-1, CEA, CA 19-9, CA 15-3, and CA 125 assays in pleural effusions: analysis of 116 cases and
review of the literature. Oncologist 2005;10:501-507 2. Hackbarth JS, Murata K, Reilly W,
Algeciras-Schimnich A: Performance of CEA and CA19-9 in identifying pleural effusions caused by
specific malignancies. Clin Biochem 2010 Sep;43(13-14):1051-1055
CA19 Carbohydrate Antigen 19-9 (CA 19-9), Serum

9288 Clinical Information: Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group
antigen. CA 19-9 may be elevated in patients with gastrointestinal malignancies such as
cholangiocarcinoma, pancreatic cancer, or colon cancer. Benign conditions such as cirrhosis,
cholestasis, and pancreatitis also result in elevated serum CA 19-9 concentrations but in these cases
values usually are below 1000 U/mL. Individuals that are Lewis negative (5%-7% of the population) do
not express CA 19-9 due to the lack of the enzyme fucosyltransferase needed for CA 19-9 production.
In these individuals, a low or undetectable serum CA 19-9 concentration is not informative regarding
cancer recurrence.
Useful For: As a potential adjunct for diagnosis and monitoring of pancreatic cancer Potentially
differentiating patients with cholangiocarcinoma and primary sclerosing cholangitis (PSC) from those
with PSC alone
Interpretation: Serial monitoring of carbohydrate antigen 19-9 (CA 19-9) should begin prior to
therapy to verify post-therapy decreases in CA 19-9 and to establish a baseline for evaluating possible
recurrence. Single values of CA 19-9 are less informative. Elevated values may be caused by a variety
of malignant and nonmalignant conditions including cholangiocarcinoma, pancreatic cancer, and colon
cancer.
Reference Values:
<35 U/mL
Clinical References: 1. Torok N, Gores GJ: Cholangiocarcinoma. Semin Gastrointest Dis. 2001
Apr;12(2):125-132 2. Scara S, Bottoni P, Scatena R: CA 19-9: Biochemical and clinical aspects. Adv Exp
Med Biol. 2015;867:247-60. doi: 10.1007/978-94-017-7215-0_15
CDG Carbohydrate Deficient Transferrin for Congenital Disorders of

89891 Glycosylation, Serum
Clinical Information: Glycosylation is the post-translational modification of proteins and lipids by
the addition of glycans (sugars and sugar chains) in a complex stepwise fashion in the endoplasmic
reticulum, Golgi apparatus, cytosol and sarcolemmal membrane. Congenital disorders of glycosylation
(CDG) are a group of over 150 inherited metabolic disorders characterized by abnormal protein and lipid
glycosylation. There are 2 main groups of CDG: type I, characterized by defects in the assembly or
transfer of the dolichol-linked glycan in either the cytosol or endoplasmic reticulum (ER) and type II,
involving processing defects of the glycan in the ER and Golgi apparatus. In addition, there are 2
categories of glycosylation: N-glycosylation where N-linked glycans are attached to a protein backbone
via an asparagine residue on the protein, and O-glycosylation where O-glycans are attached to the
hydroxyl group of threonine or serine. Apolipoprotein CIII (Apo-CIII) isoforms, with a single core 1
mucin type O-glycosylate protein, is a complementary evaluation for the CDG type II profile. This
analysis will evaluate mucin type O-glycosylation, a defect involving the Golgi apparatus, which is
detected biochemically by the change in ratios of the 3 isoforms. CDG typically present as multi-systemic
disorders with a broad clinical spectrum including, but not limited to, developmental delay, hypotonia,
with or without neurological abnormalities, abnormal magnetic resonance imaging findings, skin
manifestations, and coagulopathy. There is considerable variation in the severity of this group of diseases
ranging from a mild presentation in adults and children to severe multi-organ dysfunctions causing
infantile lethality. In some subtypes, phosphomannose isomerase-CDG (MPI-CDG or CDG-Ib) in
particular, intelligence is not compromised. CDG should be suspected in all patients with neurological
abnormalities including developmental delay and seizures, brain abnormalities such as cerebellar atrophy
or hypoplasia as well as unexplained liver dysfunction. Abnormal subcutaneous fat distribution and
chronic diarrhea each may or may not be present. The differential diagnosis of abnormal transferrin
patterns also includes liver disease not related to CDG including galactosemia, hereditary fructose
intolerance in acute crisis, and liver disease of unexplained etiology. Transferrin and apolipoprotein CIII
isoform analysis are the initial screening tests for CDG. The results of the transferrin and apolipoprotein
CIII isoform analysis should be correlated with the clinical presentation to determine the most appropriate
follow-up testing strategy including enzyme, molecular, and research-based testing. Enzymatic analysis
for phosphomannomutase and phosphomannose isomerase in leukocytes (PMMIL /
Phosphomannomutase and Phosphomannose Isomerase, Leukocytes) should be performed if either
PMM2-CDG (CDG-Ia) or MPI-CDG (CDG-Ib) is suspected. Other glycosylation pathways, in addition to
N- and O-glycosylation, have been elucidated, in particular, glycophosphatidylinositol (GPI)-anchored
protein glycosylation disorders in which there is absent or decreased expression of all the GPI-linked
antigens, and alpha-dystroglycanopathies caused by impaired synthesis of O-mannose glycans. Neither
class of disorders are routinely picked up by CDG analysis in serum but are typically diagnosed using
molecular methods (CDGGP / Congenital Disorders of Glycosylation Gene Panel, Varies).
Useful For: Screening for congenital disorders of glycosylation This test is not useful for screening
patients for chronic alcohol abuse.
Interpretation: Positive test results could be due to a genetic or nongenetic condition; additional
confirmatory testing is required. In serum, the bi-antennary transferrin (di-oligo) fraction is the most
abundant transferrin isoform. Congenital disorders of glycosylation (CDG)-I generally show increases in
mono-oligo- and/or a-oligo transferrin isoforms whereas CDG-II shows elevated increased transferrin
with truncated glycans of varying degree depending on the type of defect.(1) Results are reported as the
mono-oligosaccharide/di-oligosaccharide transferrin ratio, the a-oligosaccharide/di-oligosaccharide
transferrin ratio, the tri-sialo/di-oligosaccharide transferrin ratio, and the apolipoprotein
CIII-1/apolipoprotein CIII-2 ratio, and the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio. The report
will include the quantitative results and an interpretation. The congenital disorders of glycosylation
(CDG) profiles are categorized into 5 types: 1. CDG type I profile.
Mono-oligosaccharide/di-oligosaccharide transferrin ratio and/or the a-oligosaccharide/di-oligosaccharide
transferrin ratio are abnormal. This group should have the apolipoprotein C-III profile within the normal
ranges, because the Golgi system is not affected in CDG type I. 2. CDG type II profile. The
tri-sialo/di-oligosaccharide transferrin ratio is abnormal. In this category, the apolipoprotein C-III profile
will have 2 scenarios: A. The apolipoprotein CIII-1/apolipoprotein CIII-2 ratio and/or the apolipoprotein
CIII-0/apolipoprotein CIII-2 ratio will be abnormal. In this case, the defect is most likely glycan
processing in the Golgi apparatus; therefore, a CDG (conserved oligomeric Golgi [COG]) defect or defect
that alters the Golgi apparatus is likely. B. The apolipoprotein CIII-1/apolipoprotein CIII-2 ratio and/or
the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio are normal. In this case, the defects most likely do
not involve the Golgi system, thus the molecular defect is different. 3. CDG mixed type profile (type I and
II together). In this type of profile one can have abnormal tri-sialo/di-oligosaccharide transferrin ratio with
the mono-oligosaccharide/di-oligosaccharide transferrin ratio and/or the
a-oligosaccharide/di-oligosaccharide transferrin ratio abnormal and may have the apolipoprotein
CIII-1/apolipoprotein CIII-2 ratio and the apolipoprotein CIII-0/apolipoprotein CIII-2 ratio normal or
abnormal, depending on if the defects involve Golgi apparatus. 4. CDG with normal transferrin and
apolipoprotein profile. Some CDG (eg, PGM3, some ALG13, MOGS, NGLY1, SLC35C1, Fut8) pose a
problem for their detection. Thus, a careful medical history, physical exam, and analysis of other protein
status may be informative for general protein glycosylation defects. If suspicious for either NGLY1- or
MOGS-CDG, specific oligosaccharides in urine can be detected (OLIGU / Oligosaccharide Screen,
Random, Urine). 5. When the profile cannot be categorized following the above classification, the
abnormalities will be reported descriptively according to the molecular mass of the glycan isoform
structures. Reports of abnormal results will include recommendations for additional biochemical and
molecular genetic studies to identify the correct form of CDG more precisely. If applicable, treatment
options, the name and telephone number of contacts who may provide studies, and a telephone number for
one of the laboratory directors (if the referring physician has additional questions) will be provided. For
more information, see Transferrin and Lipoprotein-CIII Isoform Analysis.
Reference Values:
Ratio Normal Indeterminate Abnormal
Transferrin mono-oligo/di-oligo ratio < or =0.06 0.07-0.09 > or =0.10
Transferrin A-oligo/di-oligo ratio < or =0.011 0.012-0.021 > or =0.022
Transferrin tri-sialo/di-oligo ratio < or =0.05 0.06-0.12 > or =0.13
Apo CIII-1/Apo CIII-2 ratio < or =2.91 2.92-3.68 > or =3.69
Apo CIII-0/Apo CIII-2 ratio < or =0.48 0.49-0.68 > or =0.69
Clinical References: 1. Lefeber DJ, Morava E, Jaeken J: How to find and diagnose a CDG due to
defective N-glycosylation. J Inherit Metab Dis. 2011 Aug;34(4):849-852 2. Peanne R, de Lonlay P,
Foulquier F, et al: Congenital disorders of glycosylation (CDG): Quo vadis? Eur J Med Genet. 2018
Nov;61(11):643-663 3. Freeze HH, Eklund EA, Ng BG, Patterson MC: Neurology of inherited
glycosylation disorders. Lancet Neurol. 2012 May;11(5):453-466 4. Hennet T, Cabalzar J: Congenital
disorders of glycosylation: a concise chart of glycocalyx dysfunction. Trends Biochem Sci. 2015
Jul;40(7):377-384 5. Freeze HH, Chong JX, Bamshad MJ, Ng BG: Solving glycosylation disorders:
fundamental approaches reveal complicated pathways. Am J Hum Genet. 2014 Feb 6;94(2):161-175 6.
Sparks SE, Krasnewich DM: Congenital disorders of N-linked glycosylation and multiple pathway
overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of
Washington, Seattle; 2005. Updated January 12, 2017. Accessed April 25, 2022. Available at
www.ncbi.nlm.nih.gov/books/NBK1332/ 7. Ng BG, Freeze HH: Human genetic disorders involving
glycosylphosphatidylinositol (GPI) anchors and glycosphingolipids (GSL). J Inherit Metab Dis. 2015
Jan;38(1):171-178. doi:10.1007/s10545-014-9752-1 8. Bouchet-Seraphin C, Vuillaumier-Barrot S, Seta
N. Dystroglycanopathies: About numerous genes involved in glycosylation of one single glycoprotein. J
Neuromuscul Dis. 2015;2(1):27-38
CDTA Carbohydrate Deficient Transferrin, Adult, Serum

82425 Clinical Information: Chronic alcoholism causes a transient change in the glycosylation pattern of
transferrin where the relative amounts of disialo- and asialotransferrin (carbohydrate deficient transferrin:
CDT) are increased over the amount of normally glycosylated tetrasialotransferrin. This recognition led to
the use of CDT in serum as a marker for chronic alcohol abuse. CDT typically normalizes within several
weeks of abstinence of alcohol use. However, it is important to recognize that there are other causes of
abnormal CDT levels, which include congenital disorders of glycosylation and other genetic and
nongenetic causes of acute or chronic liver disease. CDT testing alone is not recommended for general
screening for alcoholism; however, when combined with other methods (ie, gamma-glutamyltransferase,
mean corpuscular volume, patient self-reporting, ethylglucuronide analysis), clinicians can expect to
identify the majority of patients who consume a large amount of alcohol.
Useful For: Indicating chronic alcohol abuse This test is not appropriate for screening patients for
congenital disorders of glycosylation.
Interpretation: Patients with chronic alcoholism may develop abnormally glycosylated transferrin
isoforms (ie, carbohydrate deficient transferrin: CDT >0.12). CDT results from 0.11 to 0.12 are
considered indeterminate. Patients with liver disease due to genetic or nongenetic causes may also have
abnormal results.
Reference Values:
< or =0.10
0.11-0.12 (indeterminate)
Clinical References: 1. De Giovanni N, Cittadini F, Martello S: The usefulness of biomarkers of

alcohol abuse in hair and serum carbohydrate-deficient transferrin: a case report. Drug Test Anal. 2015
Aug;7(8):703-707 2. Fleming MF, Anton RF, Spies CD: A review of genetic, biological,
pharmacological, and clinical factors that affect carbohydrate-deficient transferrin levels. Alcohol Clin
Exp Res. 2004;28(9):1347-1355 3. Gough G, Heathers L, Puckett D, et al: The Utility of Commonly Used
Laboratory Tests to Screen for Excessive Alcohol Use in Clinical Practice. Alcohol Clin Exp Res. 2015
Aug;39(8):1493-1500 4. Shibamoto A, Namisaki T, Suzuki J, et al: Clinical significance of
gamma-glutamyltranspeptidase combined with carbohydrate-deficient transferrin for the assessment of
excessive alcohol consumption in patients with alcoholic cirrhosis. Medicines (Basel). 2021 Jul
19;8(7):39 5. Torrente MP, Freeman WM, Vrana KE: Protein biomarkers of alcohol abuse. Expert Rev
Proteomics. 2012 Aug;9(4):425-436
CHOU Carbohydrate, Urine

9255 Clinical Information: Carbohydrates are a group of mono-, di-, and oligosaccharides of endogenous
and exogenous sources. Their presence frequently reflects dietary consumption but can indicate specific
pathology if either a particular saccharide or a particular excretory pattern is present. Most saccharides
(except glucose) have low renal thresholds and are readily excreted in the urine. In addition to several
other saccharide species, chromatography of urinary saccharides identifies galactose and fructose and is,
therefore, useful to screen for inborn errors of galactose and fructose metabolism. Xylose may also be
detected in individuals with hereditary pentosuria, a benign trait with high frequency among individuals
with Ashkenazi Jewish descent.
Useful For: Screening for conditions associated with increased excretion of fructose, galactose, and
xylose This test is not recommended as a follow up test for abnormal newborn screening for galactosemia.
Interpretation: An interpretive comment is provided.
Reference Values:
Negative
If positive, carbohydrate is identified.
Clinical References: 1. Steinmann B, Gitzelmann R, Van den Berghe G: Disorders of fructose

metabolism. In: Valle D, Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online
Metabolic and Molecular Bases of Inherited Disease McGraw-Hill; 2019. Accessed January 09, 2020.
Available at http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225080452 2.
OMIM. #260800 Pentosuria; PNTSU. Johns Hopkins University; 1986. Updated July 9, 2016. Accessed
April 23, 2021. Available at https://omim.org/entry/260800 3. Gaughan S, Ayres L, Baker P II:
Hereditary fructose intolerance. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews
[Internet]. University of Washington, Seattle;2015. Updated February 18, 2021. Accessed April 23,
2021. Available at www.ncbi.nlm.nih.gov/books/NBK333439
COHBB Carbon Monoxide, Blood

8649 Clinical Information: Carbon monoxide (CO) is a colorless, odorless, tasteless gas that is a product
of incomplete combustion of carbonaceous material. CO poisoning causes hypoxia because CO binds to
hemoglobin with an affinity 250 times greater than that of oxygen, thus preventing delivery of oxygen
to the tissues, but concentrations greater than 20% are associated with symptoms of toxicity (eg,
headache, fatigue, dizziness, confusion, nausea, vomiting, increased pulse and respiratory rate). CO
levels greater than 50% are potentially fatal. Common exogenous sources of carbon monoxide include
cigarette smoke, gasoline engines, and improperly ventilated home heating units. Small amounts of
carbon monoxide are produced endogenously in the metabolic conversion of heme to biliverdin. This
endogenous production of carbon monoxide is accelerated in hemolytic anemias.
Useful For: Verifying carbon monoxide toxicity in cases of suspected exposure

Interpretation: The toxic effects of carbon monoxide can be seen in levels above 20%
carboxyhemoglobin. It must be emphasized that the carboxyhemoglobin concentration, although helpful
in diagnosis, does not always correlate with the clinical findings or prognosis. Factors other than
carboxyhemoglobin concentration that contribute to toxicity include length of exposure, metabolic
activity, and underlying disease, especially cardiac or cerebrovascular disease. Moreover, low
carboxyhemoglobin concentrations relative to the severity of poisoning may be observed if the patient
was removed from the carbon monoxide-contaminated environment a significant amount of time before
blood sampling. An insidious effect of carbon monoxide poisoning is the delayed development of
neuropsychiatric sequelae, which may include personality changes, motor disturbances, and memory
impairment. These manifestations do not correlate with the length of exposure or with the maximum
blood carboxyhemoglobin concentration.
Reference Values:
Normal Concentration
Non-Smokers: 0-2%
Smokers: < or =9%
Toxic concentration: > or =20%
Clinical References: 1. Langman LJ, Bechtel LK, Meier BM, Holstege C: In Tietz Textbook of
Clinical Chemistry and Molecular Diagnostics. Sixth edition. Chapter 41: Clinical toxicology. Edited by
N Rifai, AR Horvath, CT Wittwer. Elsevier; 2018. pp 832-887 2. Disposition of Toxic Drugs and
Chemicals in Man. 10th edition. Edited by RC Baselt. Biomedical Publications, 2014
CAIX Carbonic Anhydrase IX (CA-IX) Immunostain, Technical

Clinical Information: Carbonic anhydrase IX (CA-IX) is a hypoxia-induced protein expressed in
the gastrointestinal tract, mainly in the stomach. Expression of CA-IX is useful in the diagnosis of clear
cell renal cell carcinoma and clear cell papillary renal cell carcinoma. It can assist in distinguishing
clear cell carcinoma from chromophobe carcinoma, oncocytoma, and several other renal cell
carcinomas.
Useful For: Diagnosis of clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma
Clinical References: 1. Alshenawy H: Immunohistochemical panel for differentiating renal cell

carcinoma with clear and papillary features. J Microsc Ultrastruct. 2015;3(2):68-74 2. Genega E,
Ghebremichael M, Najarian R, et al: Carbonic anhydrase IX expression in renal neoplasms: correlation
with tumor type and grade. Am J Clin Pathol. 2010;134(6):873-879. doi: 10.1309/AJCPPPR57HNJMSLZ
3. Stillebroer A, Mulders P, Boerman O, Oyen WJG, Oosterwijk Eet al: Carbonic anhydrase IX in renal
cell carcinoma: Implications for prognosis, diagnosis, and therapy. Euro Urol. 2010;58(3):75-83. doi:
10.1016/j.eururo.2010.03.015 4. Zhanyong B, Lal P, Lu S, Ziober A, Tomaszewski JEet al: Role of
carbonic anhydrase IX, alpha-methylacyl coenzyme a racemase, cytokeratin 7, and galectin-3 in the
evaluation of renal neoplasms: a tissue microarray immunohistochemical study. Annals of Diag Pathol.
2013;17(8) 58-62. doi: 10.1016/j.anndiagpath.2012.07.002
THCX Carboxy-Tetrahydrocannabinol (THC) Confirmation, Chain of

62743 Custody, Random, Urine
Clinical Information: Delta-9-tetrahydrocannabinol is the active agent of the popularly abused street
drug, marijuana. After consumption, either by inhalation or ingestion, the drug is metabolized to a variety
of inactive chemicals, one of them being delta-9-tetrahydrocannabinol carboxylic acid. The immunoassay
used to screen for tetrahydrocannabinol (THC) is designed to cross-react with THC carboxylic acid. In
almost all medico-legal cases and in screening of employees, or when the patient adamantly denies THC
use and the immunoassay test is positive, confirmation of the result by gas chromatography-mass
spectrometry is required. Chain of custody is required whenever the results of testing could be used in a
court of law. Its purpose is to protect the rights of the individual contributing the specimen by
this control implies that the opportunity for specimen tampering would be limited. This includes a record
of the disposition of a specimen to document the personnel who collected it, who handled it, and who
performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such
a way that it will withstand regular court scrutiny.
Useful For: Detection and confirmation of drug abuse involving delta-9-tetrahydrocannabinol

(marijuana) in urine specimens handled through the chain-of-custody process
Interpretation: The presence of tetrahydrocannabinol carboxylic acid (THC-COOH), a major

metabolite of delta-9-tetrahydrocannabinol (THC), in urine at concentrations greater than 15 ng/mL is a
strong indicator that the patient has used marijuana. THC-COOH has a long half-life and can be detected
in urine for more than 7 days after a single use. The presence of THC-COOH in urine greater than 100
ng/mL indicates relatively recent use, probably within the past 7 days. Levels greater than 500 ng/mL
suggest chronic and recent use. Chronic use causes accumulation of THC and THC-COOH in adipose
tissue such that it is excreted into the urine for as long as 30 to 60 days from the time chronic use is
halted.
Reference Values:
Negative
Positives are reported with a quantitative GC-MS result.
IMMUNOASSAY SCREEN
<50 ng/mL
THC CARBOXYLIC ACID BY GC-MS

<3 ng/mL
Clinical References: 1. Moyer TP, Palmen MA, Johnson P, et al: Marijuana testing-how good is
it? Mayo Clin Proc 1987;62:413-417 2. Disposition of Toxic Drugs and Chemicals in Man. 10th edition.
Edited by RC Baselt. Biomedical Publications, 2014 3. Langman LJ, Bechtel LK, Meier BM, Holstege
C: Chapter 41: Clinical Toxicology. In Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics. Edited by N Rifai, AR Horvath, CT Wittwer. Sixth edition. Elsevier, 2018, pp 832-887
THCU Carboxy-Tetrahydrocannabinol (THC) Confirmation, Random,

8898 Urine
Clinical Information: Delta-9-tetrahydrocannabinol (THC) is the active agent of the popularly
abused street drug, marijuana. Following consumption of the drug, either by inhalation or ingestion, it is
metabolized to a variety of inactive chemicals, one of them being delta-9-tetrahydrocannabinol
carboxylic acid. In almost all medico-legal cases and in screening of employees, or when the patient
adamantly denies THC use and the immunoassay test is positive, confirmation of the result by gas
chromatography-mass spectrometry (GC-MS) is required.
Useful For: Confirmation of drug abuse involving delta-9-tetrahydrocannabinol (marijuana)

Interpretation: The presence of tetrahydrocannabinol carboxylic acid (THC-COOH), a major
metabolite of delta-9-tetrahydrocannabinol, in urine at concentrations greater than 15.0 ng/mL is a
strong indicator that the patient has used marijuana. The metabolite of marijuana (THC-COOH) has a
long half-life and can be detected in urine for more than 7 days after a single use. The presence of
THC-COOH in urine greater than 100.0 ng/mL indicates relatively recent use, probably within the past
7 days. Levels greater than 500.0 ng/mL suggest chronic and recent use. Chronic use causes
accumulation of THC and THC-COOH in adipose tissue such that it is excreted into the urine for as
long as 30 to 60 days from the time chronic use is halted.
Reference Values:
Negative
Cutoff concentration:
Carboxy-THC- by GC/MS <3.0 ng/mL
Clinical References: 1. Disposition of Toxic Drugs and Chemicals in Man. Tenth edition. Edited
by RC Baselt. Biomedical Publications, 2014 2. Langman LJ Bechtel LK, Meier BM, Holstege C:
Chapter 41:Â Clinical Toxicology. In Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics. Edited by N Rifai, AR Horvath, CT Wittwer. Sixth edition. Elsevier, 2018, pp 832-887
THCCR Carboxy-Tetrahydrocannabinol (THC-COOH) Confirmation and

616333 Creatinine Ratio, Random, Urine
abused/used drug, marijuana. Following consumption of the drug, either by inhalation or ingestion, it is
metabolized to a variety of inactive chemicals, one of them being delta-9-tetrahydrocannabinol
carboxylic acid (carboxy-THC). For confirmation of abstinence, urine analysis is a useful tool. The
presence of carboxy-THC is a strong indicator that a patient has used marijuana. However, increases in
urine carboxy-THC concentrations resulting from changes in urinary output may be mistakenly
interpreted as new drug use rather than carryover from previous drug exposure. Individuals continue to
excrete carboxy-THC for days after abstinence, and although concentrations generally decrease with
time, the concentrations can fluctuate with levels of hydration. As a result, the division of urinary
carboxy-THC concentrations by creatinine produces a metabolite/creatinine ratio that should decrease
until a new episode of drug use occurs. Carboxy-THC /creatinine ratios of specimens collected over
time can be compared to determine if new marijuana use has occurred.
Useful For: Measuring the carboxy-tetrahydrocannabinol to creatinine ratio to detect use of

tetrahydrocannabinol
Interpretation: Carboxy-tetrahydrocannabinol (carboxy-THC) and creatinine concentrations must be

obtained for at least 2 urine specimens with a known time interval (1-7 days) between collections. Using
these creatinine-normalized carboxy-THC concentrations, a ratio is calculated between the concentration
of any urine specimen (U2) divided by the concentration in a previously collected urine specimen (U1).
The most conservative method for reporting new cannabis use between collections would apply a U2/U1
decision ratio equal to the maxima listed in Table 1. A more realistic decision ratio with reasonable
certainty would be to use the 95% below limits in the same table. U2/U1 ratios above these limits would
indicate new usage between those collection time points. Table 1. Adapted from Smith ML et al. for less
than daily users of marijuana.(1) Time interval between urine collections (hours) Maximum ratio (U2/U1)
95% Below (U2/U1) 0-23.9 6.29 1.42 24-47.9 2.27 1.01 48-71.9 1.47 0.853 72-95.9 1.63 0.595 96-119.9
0.555 0.347 120-143.9 0.197 0.146 144-167.9 0.080 0.073
Reference Values:
Carboxy-Tetrahydrocannabinol (THC):
Negative
Carboxy-THC by Gas Chromatography-Mass Spectrometry (GC-MS) <3.0 ng/mL
Creatinine:
> or =18 years old: 16-326 mg/dL
Clinical References: 1. Smith ML, Barnes AJ, Huestis MA: Identifying new cannabis use with urine
creatinine normalized THCCOOH concentrations and time intervals between specimen collections. J Anal
Toxicol. 2009 May;33(4):185-9. doi: 10.1093/jat/33.4.185 2. Huestis MA, Cone EJ: Differentiating new
marijuana use from residual drug excretion in occasional marijuana users. J Anal Toxicol. 1998
Oct;22(6):445-54. doi: 10.1093/jat/22.6.445 3. Langman LJ, Bechtel L, Meier BM, Holstege CP: Clinical
toxicology. In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 4. Delaney MP, Lamb EJ: Kidney disease. In:
Rifai N, Horvath AR, Wittwer CT, eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics.
6th ed. Elsevier; 2018:1256-1323 5. Meeusen J, Rule A, Voskoboev N, Baumann N, Lieske J:
Performance of cystatin C- and creatinine-based estimated glomerular filtration rate equations depends on
patient characteristics. Clin Chem. 2015 Oct;61(10):1265-1272. doi: 10.1373/clinchem.2015.243030 6.
Newman DJ, Price CP: Renal function and nitrogen metabolites. In: Burtis CA, Ashwood ER, eds. Tietz
Textbook of Clinical Chemistry. 3rd ed. WB Saunders Company; 1999:1204-1270 7. Kasiske BL, Keane
WF: Laboratory assessment of renal disease: clearance, urinalysis, and renal biopsy. In: Brenner BM, ed.
The Kidney. 6th ed. WB Saunders Company; 2000:1129-1170
THCCU Carboxy-Tetrahydrocannabinol Confirmation and Creatinine

616334 Ratio, Random, Urine
abused/used drug, marijuana. Following consumption of the drug, either by inhalation or ingestion, it is
metabolized to a variety of inactive chemicals, one of them being delta-9-tetrahydrocannabinol carboxylic
acid (carboxy-THC). For confirmation of abstinence, urine analysis is a useful tool. The presence of
carboxy-THC is a strong indicator that a patient has used marijuana. However, increases in urine
carboxy-THC concentrations resulting from changes in urinary output may be mistakenly interpreted as
new drug use rather than carryover from previous drug exposure. Individuals continue to excrete
carboxy-THC for days after abstinence and although concentrations generally decrease with time, the
concentrations can fluctuate with levels of hydration. As a result, the division of urinary carboxy-THC
concentrations by creatinine produces a metabolite/creatinine ratio that should decrease until a new
episode of drug use occurs. Carboxy-THC/creatinine ratios of specimens collected over time can be
compared to determine if new marijuana use has occurred.
Useful For: Measuring the carboxy-tetrahydrocannabinol to creatinine ratio as a part of a profile

Interpretation: Carboxy-tetrahydrocannabinol (carboxy-THC) and creatinine concentrations must
be obtained for at least 2Â urine specimens with a known time interval (1-7 days) between collections.
Using these creatinine-normalized carboxy-THC concentrations, a ratio is calculated between the
concentration of any urine specimen (U2) divided by the concentration in a previously collected urine
specimen (U1). The most conservative method for reporting new cannabis use between collections
would apply a U2/U1 decision ratio equal to the maxima listed in Table 1. A more realistic decision
ratio with reasonable certainty would be to use the 95% below limits in the same table. U2/U1 ratios
above these limits would indicate new usage between those collection time points. Table 1. Adapted
from Smith ML et al. for less than daily users of marijuana.(1) Time interval between urine collections
(hours) Maximum ratio (U2/U1) 95% Below (U2/U1) 0-23.9 6.29 1.42 24-47.9 2.27 1.01 48-71.9 1.47
0.853 72-95.9 1.63 0.595 96-119.9 0.555 0.347 120-143.9 0.197 0.146 144-167.9 0.080 0.073
Reference Values:
Only orderable as part of a profile. For more information see THCCR / Carboxy-Tetrahydrocannabinol
(THC-COOH) Confirmation and Creatinine Ratio, Random, Urine
Negative
Carboxy-tetrahydrocannabinol by Gas Chromatography-Mass Spectrometry (GC-MS) <3.0 ng/mL
Clinical References: 1. Smith ML, Barnes AJ, Huestis MA: Identifying new cannabis use with
urine creatinine normalized THCCOOH concentrations and time intervals between specimen
collections. J Anal Toxicol. 2009 May;33(4):185-9. doi: 10.1093/jat/33.4.185 2. Huestis MA, Cone EJ:
Differentiating new marijuana use from residual drug excretion in occasional marijuana users. J Anal
Toxicol. 1998 Oct;22(6):445-54. doi: 10.1093/jat/22.6.445 3. Langman LJ, Bechtel L, Meier BM,
Holstege CP: Clinical toxicology. In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of
Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 4. Delaney MP, Lamb
EJ: Kidney disease. In: Rifai N, Horvath AR, Wittwer CT, eds: Tietz Textbook of Clinical Chemistry
and Molecular Diagnostics. 6th ed. Elsevier; 2018:1256-1323 5. Meeusen J, Rule A, Voskoboev N,
Baumann N, Lieske J: Performance of cystatin C- and creatinine-based estimated glomerular filtration
rate equations depends on patient characteristics. Clin Chem. 2015 Oct;61(10):1265-1272. doi:
10.1373/clinchem.2015.243030 6. Newman DJ, Price CP: Renal function and nitrogen metabolites. In:
Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. 3rd ed. WB Saunders Company;
1999:1204-1270 7. Kasiske BL, Keane WF: Laboratory assessment of renal disease: clearance,
urinalysis, and renal biopsy. In: Brenner BM, ed. The Kidney. 6th ed. WB Saunders Company;
2000:1129-1170
CEAPC Carcinoembryonic Antigen (CEA), Pancreatic Cyst Fluid

89509 Clinical Information: Cystic lesions of the pancreas are of various types including: -Benign cysts:
Â -Inflammatory cysts (pseudocysts) Â -Serous cysts (serous cystadenoma) -Mucinous cysts:
Â -Premalignant (mucinous cystadenoma) Â -Malignant (cystadenocarcinoma, intrapapillary mucinous
neoplasia) The diagnosis of pancreatic cyst type is often difficult and may require correlating imaging
studies with results of cytological examination and tumor marker testing performed on cyst aspirates.
Various tumor markers have been evaluated to distinguish non-mucinous, nonmalignant pancreatic
cysts from mucinous cysts, which have a high likelihood of malignancy. Carcinoembryonic antigen
(CEA) has been found to be the most reliable tumor marker for identifying those pancreatic cysts that
are likely mucinous. In cyst aspirates, CEA concentrations of 200 ng/mL and above are highly
suspicious for mucinous cysts. The greater the CEA concentration, the greater the likelihood that the
mucinous cyst is malignant. However, CEA testing does not reliably distinguish between benign,
premalignant, or malignant mucinous cysts. CEA test results should be correlated with the results of
imaging studies, cytology, other cyst fluid tumor markers (ie, amylase and CA 19-9), and clinical
findings for diagnosis.
Useful For: When used in conjunction with imaging studies, cytology, and other pancreatic cyst fluid
tumor markers: -Distinguishing between mucinous and nonmucinous pancreatic cysts -Determining the
likely type of malignant pancreatic cyst
Interpretation: A pancreatic cyst fluid carcinoembryonic antigen (CEA) concentration of 200 ng/mL
and higher is very suggestive for a mucinous cyst but is not diagnostic. The sensitivity and specificity for
mucinous lesions are approximately 62% and 93%, respectively, at this concentration. Cyst fluid CEA
concentrations of 5 ng/mL and below indicate a low risk for a mucinous cyst, and are more consistent
with serous cystadenoma, fluid collections complicating pancreatitis, cystic neuroendocrine tumor, or
metastatic lesions. CEA values between these extremes have limited diagnostic value.
Reference Values:
Clinical References: 1. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al: Diagnosis of

pancreatic cystic neoplasms: a report of cooperative pancreatic cyst study. Gastroenterology. 2004
May;126:1330-1336 2. Snozek CL, Jenkins SM, Bryant SC, et al: Analysis of CEA, CA 19-9, and
amylase in pancreatic cyst fluid for diagnosis of pancreatic lesions. Clin Chem. 2008;54(Suppl
S):A126-127 3. Khalid A, Brugge W: ACG practice guidelines for the diagnosis and management of
neoplastic pancreatic cysts. Am J Gastroenterol. 2007 Oct;102(10):2339-2349 4. Elta GH, Enestvedt BK,
Sauer BG, Lennon AM: ACG clinical guideline: diagnosis and management of pancreatic cysts. Am J
Gastroenterol. 2018 Apr;113(4):464-479. doi: 10.1038/ajg.2018.14
CEAPT Carcinoembryonic Antigen (CEA), Peritoneal Fluid

Malignant disease can cause ascites by various mechanisms including peritoneal carcinomatosis (53%),
massive liver metastasis causing portal hypertension (13%), peritoneal carcinomatosis plus massive liver
metastasis (13%), hepatocellular carcinoma plus cirrhosis (7%), and chylous ascites due to lymphoma
(7%). The evaluation and diagnosis of malignancy-related ascites is based on the patient clinical history,
ascites fluid analysis, and imaging tests. The overall sensitivity of cytology for the detection of
malignancy-related ascites ranges from 58% to 75%. Cytology examination is most successful in patients
with ascites related to peritoneal carcinomatosis as viable malignant cells are exfoliated into the ascitic
fluid. However, only approximately 53% of patients with malignancy-related ascites have peritoneal
carcinomatosis. Patients with other causes of malignancy-related ascites almost always have a negative
cytology. Carcinoembryonic antigen (CEA) is a glycoprotein that is shed from the surface of malignant
cells. Measurement of CEA in ascitic fluid has been proposed as a helpful test in detecting
malignancy-related ascites given the limited sensitivity of cytology.
Useful For: An adjunct to cytology to differentiate between malignancy-related and benign causes of
ascites formation
Interpretation: A peritoneal fluid carcinoembryonic antigen (CEA) concentration greater than 6.0
ng/mL is suspicious but not diagnostic of malignancy-related ascites. This clinical decision limit cutoff
yielded 48% sensitivity and 99% specificity in a study of 137 patients presenting with ascites. CEA
concentrations were significantly higher in ascites caused by malignancies known to be associated with
elevated serum CEA levels including lung, breast, ovarian, gastrointestinal, and colorectal cancers.
However, ascites caused by other malignancies such as lymphoma, mesothelioma, leukemia, and
melanoma and hepatocellular carcinoma, routinely had CEA concentrations less than 6.0 ng/mL.
Therefore, negative results should be interpreted with caution, especially in patients who have or are
suspected of having a malignancy not associated with elevated CEA levels in serum.
Reference Values:
Clinical References: 1. Torresini RJ, Prolla JC, Diehl AR, Morais EK, Jobim LF: Combined
carcinoembryonic antigen and cytopathologic examination in ascites. Acta Cytol. 2000
Sep-Oct;44(5):778-782 2. Tuzun Y, Yilmaz S, Dursun M, et al: How to increase the diagnostic value of
malignancy-related ascites: discriminative ability of the ascitic tumour markers. J Int Med Res. 2009
Jan-Feb;37(1):87-95 3. Kaleta EJ, Tolan NV, Ness KA, O'Kane D, Algeciras-Schimnich A: CEA, AFP
and CA 19-9 analysis in peritoneal fluid to differentiate causes of ascites formation. Clin Biochem.
2013 Jun;46(9):814-8. doi: 10.1016/j.clinbiochem.2013.02.010 4. Trape J, Sant F, Montesinos J, et al:
Comparative assessment of two strategies for interpreting tumor markers in ascitic effusions. In Vivo.
2020 Mar-Apr;34(2):715-722. doi: 10.21873/invivo.11829
PFCEA Carcinoembryonic Antigen (CEA), Pleural Fluid

83742 Clinical Information: Pleural effusions occur as a consequence of either nonmalignant conditions
(including congestive heart failure, pneumonia, pulmonary embolism, and liver cirrhosis) or malignant
conditions (including lung, breast, and lymphoma cancers). Diagnosing the cause of an effusion can be
difficult, often requiring cytological examination of the pleural fluid and imaging studies of the pleural
tissue. Analysis of various tumor markers in pleural fluid has shown that these markers can differentiate
between effusions caused by nonmalignant and malignant conditions and can enhance cytology and
imaging findings. Carcinoembryonic antigen (CEA) is a glycoprotein produced during fetal
development. Nonsmoking, healthy adults typically produce low to undetectable levels of CEA. Serum
concentrations of CEA may be elevated in patients with certain malignancies that secrete CEA into
circulation, including medullary thyroid carcinoma and breast, gastrointestinal tract, colorectal, liver,
lung, ovarian, pancreatic, and prostate cancers. Pleural fluid concentrations of CEA have been reported
to be elevated in patients with certain malignancies. Malignancies that can secrete CEA and elevate
serum CEA concentrations, including lung, breast, ovarian, gastrointestinal, and colorectal cancers,
typically also elevate CEA in pleural fluid. In contrast, malignancies that do not secrete CEA, including
mesothelioma, lymphoma, leukemia, and melanoma, have low concentrations of CEA in pleural fluid
comparable to concentrations observed in non-malignant effusions. Elevated CEA concentrations in
pleural fluid have also been reported with certain nonmalignant conditions, including liver cirrhosis,
pancreatitis, complicated parapneumonic effusions and empyemas, and rarely with tuberculosis. CEA
results should be used in conjunction with cytological analysis of pleural fluid, imaging studies, and
other clinical findings.
Useful For: An adjuvant to cytology and imaging studies to differentiate between nonmalignant and
malignant causes of pleural effusions
Interpretation: A pleural fluid carcinoembryonic antigen (CEA) concentration of 3.5 ng/mL or

higher is suspicious but not diagnostic of a malignant source of the effusion. This cutoff yielded a
sensitivity of 52%, specificity of 95%, and part per volume of 93% in a study of 200 patients presenting
with effusion. CEA concentrations were significantly higher in effusions caused by CEA-secreting
malignancies, including lung, breast, ovarian, gastrointestinal, and colorectal cancers. However,
effusions caused by non-CEA-secreting malignancies, including lymphoma, mesothelioma, leukemia,
and melanoma, routinely had CEA concentrations below 3.5 ng/mL. Therefore, negative results should
be interpreted with caution, especially in patients who have or are suspected of having a
non-CEA-secreting malignancy. Correlation of all tumor marker results with cytology and imaging is
highly recommended.
Reference Values:
Clinical References: 1. Shitrit D, Zingerman B, Shitrit ABG, Shlomi D, Kramer MR: Diagnostic
value of CYFRA 21-1, CEA, CA 19-9, CA 15-3, and CA 125 assays in pleural effusions: analysis of
116 cases and review of the literature. Oncologist. 2005 Aug;10(7):501-507 2. Hackbarth JS, Murata K,
Reilly WM, Algeciras-Schimnich A: Performance of CEA and CA19-9 in identifying pleural effusions
caused by specific malignancies. Clin Biochem. 2010 Sep;43(13-14):1051-1055 3. Garcia-Pachon E,
Padilla-Navas I, Dosda MD, Miralles-Llopis A: Elevated level of carcinoembryonic antigen in
nonmalignant pleural effusions. Chest. 1997 Mar;111(3):643-647 4. Hackner K, Errhalt P, Handzhiev S:
Ratio of carcinoembryonic antigen in pleural fluid and serum for the diagnosis of malignant pleural
effusion. Ther Adv Med Oncol. 2019 May 22;11:1758835919850341. doi: 10.1177/1758835919850341
5. Tozzoli R, Basso SM, D'Aurizio F, Metus P, Lumachi F: Evaluation of predictive value of pleural
CEA in patients with pleural effusions and histological findings: A prospective study and literature
review. Clin Biochem. 2016 Nov;49(16-17):1227-1231. doi: 10.1016/j.clinbiochem.2016.08.006
CEA Carcinoembryonic Antigen (CEA), Serum

8521 Clinical Information: Carcinoembryonic antigen (CEA) is a glycoprotein normally found in
embryonic entodermal epithelium. Increased levels may be found in patients with primary colorectal
cancer or other malignancies including medullary thyroid carcinoma and breast, gastrointestinal tract,
liver, lung, ovarian, pancreatic, and prostatic cancers. Serial monitoring of CEA should begin prior to
therapy to verify post therapy decrease in concentration and to establish a baseline for evaluating possible
recurrence. Levels generally return to normal within 1 to 4 months after removal of cancerous tissue.
Useful For: Monitoring colorectal cancer and selected other cancers such as medullary thyroid
carcinoma May be useful in assessing the effectiveness of chemotherapy or radiation treatment This test is
not useful for screening the general population for undetected cancers.
Interpretation: Grossly elevated carcinoembryonic antigen (CEA) concentrations (>20 ng/mL) in a

patient with compatible symptoms are strongly suggestive of the presence of cancer and suggest
metastasis. Most healthy subjects (97%) have values less than or equal to 3.0 ng/mL. After removal of a
colorectal tumor, the serum CEA concentration should return to normal by 6 weeks, unless there is
residual tumor. Increases in test values over time in a patient with a history of cancer suggest tumor
recurrence.
Reference Values:
Nonsmokers: < or =3.0 ng/mL
Some smokers may have elevated CEA, usually <5.0 ng/mL.
Clinical References: 1. Sturgeon C: Tumor markers. In: Rifai N, Horvath AR, Wittwer CT, eds:
Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:436-478 2.
Locker, GY, Hamilton S, Harris J, et al: ASCO 2006 update of recommendations for the use of tumor
markers in gastrointestinal cancer. J Clin Oncol. 2006;24:5313-5327 3. Moertel CG, Fleming TR,
Macdonald JS, et al: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients
with resected colon cancer. JAMA. 1993;270:943-947
CEASF Carcinoembryonic Antigen (CEA), Spinal Fluid

90695 Clinical Information: Carcinoembryonic antigen (CEA) normally is present in cerebrospinal fluid
(CSF) in very low concentrations. Elevations in serum CEA can cause passive transfer to CSF. Tumors of
the brain, especially metastatic tumors, can elevate CSF CEA.
Useful For: Detecting meningeal carcinomatosis and intradural or extradural infiltration Differentiating
brain parenchymal metastasis from adenocarcinoma or squamous-cell carcinoma
Interpretation: Increased values are seen in approximately 60% of patients with meningeal
carcinomatosis.
Reference Values:
<0.6 ng/mL
Tumor markers are not specific for malignancy, and values may vary by method.
Clinical References: 1. Klee GG, Tallman RD, Goellner JR, Yanagihara T: Elevation of
carcinoembryonic antigen in cerebrospinal fluid among patients with meningeal carcinomatosis. Mayo
Clin Proc. 1986;61:9-13 2. Moertel CG, Fleming TR, Macdonald JS, et al: An evaluation of the
carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA.
1993;270:943-947 3. Duffy MJ: Carcinogenic antigen as a marker for colorectal cancer: is it clinically
useful? Clin Chem. 2001;47(4):624-30 4. Block DR, Algeciras-Schimnich A: Body fluid analysis: clinical
utility and applicability of published studies to guide interpretation of today's laboratory testing in serous
fluids. Crit Rev Clin Lab Sci. 2013;5(4-5):107-124
MCEA Carcinoembryonic Antigen, Monoclonal Immunostain,

70506 Technical Component Only
Clinical Information: In tissue sections of normal colon, carcinoembryonic antigen (CEA) is
mainly localized at the apical border of the epithelial cells. Monoclonal CEA antibodies label the
epithelium of colonic adenocarcinoma, normal adult colonic mucosa, and normal gastric foveolar
mucus-producing cells.
Useful For: Marker of epithelial cells

Clinical References: 1. Costa MJ, Kenny MB, Judd R: Adenocarcinoma and adenosquamous
carcinoma of the uterine cervix. Histologic and immunohistochemical features with clinical correlation.
Int J Surg Pathol. 1994;1:181-189 2. Sheahan K, O'Brien MJ, Burke B, et al: Differential reactivities of
carcinoembryonic antigen (CEA) and CEA-related monoclonal and polyclonal antibodies in common
epithelial malignancies. Am J Clin Pathol. 1990;94:157-164 3. Sumitoma S, Kumasa S, Mitani H, Mori
M: Comparison of CEA distribution in lesions and tumors of salivary glands as determined with
monoclonal and polyclonal antibodies. Circhows Arch B. 1987;53:133-139 4. Wong HH, Chu P:
Immunohistochemical features of the gastrointestinal tract tumors. J Gastrointest Oncol.
2012;3(3):262-284
PCEAI Carcinoembryonic Antigen, Polyclonal Immunostain,

Clinical Information: Polyclonal carcinoembryonic antigen labels normal and neoplastic
epithelium of the small and large intestine, stomach, and pancreatic ducts. The polyclonal antibody also
reacts with biliary canaliculi and granulocytes.
Useful For: Marker of epithelial cells

Clinical References: 1. Costa MJ, Kenny MB, Judd R: Adenocarcinoma and adenosquamous
carcinoma of the uterine cervix. Histologic and immunohistochemical features with clinical correlation.
Int J Surg Pathol. 1994;1:181-189 2. Sheahan K, O'Brien MJ, Burke B, et al: Differential reactivities of
carcinoembryonic antigen (CEA) and CEA-related monoclonal and polyclonal antibodies in common
epithelial malignancies. Am J Clin Pathol. 1990;94:157-164 3. Sumitoma S, Kumasa S, Mitani H, Mori
M: Comparison of CEA distribution in lesions and tumors of salivary glands as determined with
monoclonal and polyclonal antibodies. Circhows Arch B. 1987;53:133-139 4. Wong HH, Chu P:
Immunohistochemical features of the gastrointestinal tract tumors. J Gastrointest Oncol.
2012;3(3):262-284
CARD Cardamom, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to cardamom Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CRMP1 Cardiovascular Risk Marker Panel, Serum

616727 Clinical Information: Lipoprotein cholesterol measures are essential in managing risk for
atherosclerotic cardiovascular disease (ASCVD). Atherosclerosis is defined by a buildup of plaque within
arterial walls. ASCVD includes coronary heart disease, strokes, and peripheral artery disease. ASCVD
develops over decades and is often asymptomatic until the patient experiences a life-threatening event
such as a heart attack, stroke, or aneurysm. Cholesterol is a lipid that is synthesized in most tissues and
actively absorbed from the diet. There is a strong association between serum cholesterol concentrations
and cardiovascular disease. Cholesterol is carried in the blood by lipoproteins. Some lipoproteins carry a
stronger risk of cardiovascular disease while others are associated with reduced cardiovascular risk. Total
cholesterol concentration includes the sum of all "good" and "bad" cholesterol. Therefore, total
cholesterol is recommended to be interpreted in context of a lipid panel that includes high-density
lipoprotein cholesterol (HDL-C) and triglyceride measures. Low-density lipoprotein cholesterol (LDL-C)
is the primary lipoprotein responsible for atherogenic plaque. Very low-density lipoprotein cholesterol
(VLDL-C) is also atherogenic and the combination of LDL-C and VLDL-C is called non-HDL-C and
often referred to as "bad" cholesterol. Serum total cholesterol, LDL-C and non-HDL-C are all directly
associated with risk for ASCVD. HDL-C is associated with lower risk of cardiovascular disease. Excess
cholesterol is actively pumped into HDL to be carried in the blood circulation and cleared by the liver in a
process known as reverse cholesterol transport. For these reasons, HDL-C is often referred to as "good"
cholesterol. Triglycerides are oily lipids carried in the blood by lipoproteins. Triglycerides are primarily
carried by VLDL, chylomicrons and remnant lipoproteins. Recent evidence supports triglycerides as an
independent risk factor for ASCVD. Several conditions are associated with increased plasma
triglycerides, including obesity, pregnancy, physical inactivity, excess alcohol intake, kidney disease, and
diabetes. Elevated triglycerides are often associated with reduced HDL-C, insulin resistance,
hypertension, fatty liver disease, and increased waist circumference. In addition to cardiovascular risk,
elevated triglycerides confer a risk for acute pancreatitis. Apolipoprotein B (ApoB), high-sensitivity
C-reactive protein (hsCRP), and lipoprotein (a) (Lp[a]) are serological risk factors endorsed by multiple
international guidelines for use in cardiovascular disease risk assessment. Several recent guidelines have
suggested that clinicians utilize ApoB, hsCRP, and Lp(a) in selected persons to augment risk
classification, guide intensity of risk-reduction therapy, and modulate clinical judgment when making
therapeutic decision.(1-3)
Useful For: Assessment for risk of developing cardiovascular disease, major adverse cardiovascular
events, or ischemic cerebrovascular events
Interpretation: Maintaining desirable concentrations of lipids lowers atherosclerotic cardiovascular

disease risk. Establishing appropriate treatment strategies and lipid goals require that blood lipid values
be considered in context with other risk factors including, age, sex, smoking status, and medical history
of hypertension, diabetes, and cardiovascular disease. Triglycerides results of 500 mg/dL or above are
severely elevated increasing the risk of pancreatitis. Triglycerides can be lowered by increasing physical
activity, low-fat diet, weight loss and/or triglyceride lowering pharmaceuticals. Low high-density
lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. HDL-C can be increased by
the same lifestyle changes that reduce risk for cardiovascular disease; physical activity, smoking
cessation, and eating healthier. However, medications that specifically increase HDL levels have failed
to reduce cardiovascular disease. Extremely low HDL values (<20 mg/dL) may indicate liver disease or
inherited dyslipidemia. Low-density lipoprotein cholesterol results of 190 mg/dL or above in adults (>
or =160 mg/dL in children) are severely elevated and may indicate familial hypercholesterolemia. For
non-HDL cholesterol results of 220 mg/dL or above, consider possible inherited hyperlipidemia.
Reference Values:
Age 2-17 years > or =18 years
CALCULATED NON-HDL ** Acceptable: High: 120-144 High: * Desirable: Above Desirable:

CHOLESTEROL (mg/dL) > or =145 130-159 mg/dL Borderline High:
160-189 mg/dL High: 190-219
mg/dL Very high: > or =220 mg/dL
CALCULATED LDL CHOLESTEROL ** Acceptable: High: 110-129 High: *** Desirable: Desirable: 100-129
(mg/dL) > or =130 Borderline High: 130-159 High:
160-189 Very high: > or =190
HDL CHOLESTEROL (mg/dL) ** Low: Low: 40-45 Acceptable: > *** Males: > or =40 Females: > or
45 =50
TOTAL CHOLESTEROL (mg/dL) ** Acceptable: High: 170-199 High: * Desirable: < 200 Borderline High:
> or =200 200 - 239 High: > or = 240
LIPOPROTEIN (a) (nmol/L) Not established < 75 nmol/L Values >= 75 nmol/L
may suggest increased risk of
coronary heart disease.
C-REACTIVE PROTEIN, HIGH * Lower risk: Higher risk: >=2.0 * Lower risk: Higher risk: >=2.0
SENSITVITY mg/L Acute inflammation: >10.0 mg/L Acute inflammation: >10.0
mg/L mg/L
APOLIPOPROTEIN B(mg/dL) Acceptable: High: 90-109 High: > Desirable: Desirable: 90-99
or =110 Borderline High: 100-119 High:
120-139 Very High: > or =140
Age 2-9 years 10-17 years > or =18 years
TRIGLYCERIDES (mg/dL) ** Acceptable: High: ** Acceptable: High: * Normal: High: 150-199

75-99 High: > or =100 90-129 High: > or =130 High: 200-499 Very High: >
or =500 *National Lipid
Association 2014 **Expert
Panel on Integrated
Guidelines for
Cardiovascular Health and
Risk Reduction in Children
and Adolescents ***National
Cholesterol Education
Program (NCEP)
Clinical References: 1. Grundy SM, Stone NJ, Bailey AL, et al: 2018
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the
Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-e1143
2. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for
patient-centered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol. 2014
Sep-Oct;8(5):473-488. doi: 10.1016/j.jacl.2014.07.007 3. Expert Panel on Integrated Guidelines for
Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and
Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in
children and adolescents: Summary report. Pediatrics. 2011 Dec;128 Suppl 5(Suppl 5):S213-S256. doi:
10.1542/peds.2009-2107C 4. Sampson M, Ling C, Sun Q, et al: A new equation for calculation of
low-density lipoprotein cholesterol in patients with normolipidemia and/or hypertriglyceridemia. JAMA
Cardiol. 2020 May 1;5(5):540-548
FCRDE Carmine Dye/Red Dye Cochineal (Dactylopius coccus) IgE (Red

57524 # 4)
Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10-0.34 Equivocal 1 0.35-0.69
Low Positive 2 0.70-3.4 Moderate Positive 3 3.5-17.4 High Positive 4 17.5-49.9 Very High Positive 5
50.0-99.9 Very High Positive 6 > or = 100 Very High Positive
Reference Values:
<0.35 kU/L
CARN Carnitine, Plasma

8802 Clinical Information: Carnitine and its esters are required for normal energy metabolism and serve 4
primary functions: -Importing long-chain fatty acids into the mitochondria -Exporting naturally-occurring
short-chain acyl-CoA groups from the mitochondria -Maintaining the ratio of free CoA to esterified CoA
-Removing potentially toxic acyl-CoA groups from the cells and tissues Evaluation of carnitine in serum,
plasma, and urine is a biochemical screening test for suspected primary disorders of the carnitine cycle or
secondary disturbances in carnitine levels as a result of organic acidemias and fatty acid oxidation
disorders. In the latter, acyl-CoA groups accumulate and are excreted into the urine and bile as carnitine
derivatives, resulting in a secondary carnitine deficiency. More than 100 such primary and secondary
disorders have been described. Collectively, their incidence is approximately 1 in 1000 live births.
Primary carnitine deficiency has an incidence of approximately 1 in 21,000 live births based on
Minnesota newborn screening data. Other conditions that could cause an abnormal carnitine level include
neuromuscular diseases, gastrointestinal disorders, familial cardiomyopathy, renal tubulopathies and
chronic renal failure (dialysis), and prolonged treatment with steroids, antibiotics (pivalic acid),
anticonvulsants (valproic acid), and total parenteral nutrition. Follow-up testing is required to differentiate
primary and secondary carnitine deficiencies and to elucidate the exact cause.
Useful For: Evaluation of patients with a clinical suspicion of a wide range of conditions including
organic acidemias, fatty acid oxidation disorders, and primary carnitine deficiency using plasma
specimens
of differential diagnosis, recommendations for additional biochemical testing, and a phone number to
reach one of the laboratory directors in case the referring physician has additional questions.
Reference Values:
Total carnitine Free carnitine (FC) Acylcarnitine (AC) AC/FC Ratio

(TC)
Age Group Range* Range* Range* Range
< or =1 day 23-68 12-36 7-37 0.4-1.7
2-7 days 17-41 10-21 3-24 0.2-1.4
8-31 days 19-59 12-46 4-15 0.1-0.7
32 days-12 months 38-68 27-49 7-19 0.2-0.5
13 months-6 years 35-84 24-63 4-28 0.1-0.8
7-10 years 28-83 22-66 3-32 0.1-0.9
11-17 years 34-77 22-65 4-29 0.1-0.9
> or =18 years 34-78 25-54 5-30 0.1-0.8 *Values expressed as

nmol/mL Schmidt-Sommerfeld
E, Werner E, Penn D: Carnitine
plasma concentrations in 353
metabolically healthy children.
Eur J Pediatr.
1988;147:356-360 Used with
permission of European Journal
of Pediatrics.
Clinical References: 1. Magoulas PL, El-Hattab AW: Systemic primary carnitine deficiency: an
overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012 Sep
18;7:68 2. Longo N, Amat di San Filippo C, Pasquali M: Disorders of carnitine transport and the
carnitine cycle. Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):77-85 3. Zammit VA,
Ramsay RR, Bonomini M, Arduini A: Carnitine, mitochondrial function and therapy. Adv Drug Deliv
Rev. 2009 Nov 30;61(14):1353-1362 4. El-Hattab AW: Systemic primary carnitine deficiency. In:
Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington,
Seattle; 2012. Updated November 3, 2016. Accessed November 16, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK84551/ 5. Almannai M, Alfadhel M, El-Hattab AW: Carnitine
inborn errors of metabolism. Molecules. 2019 Sep 6;24(18):3251
CARNU Carnitine, Random, Urine

81123 as of July 20, 2022 12:05 pm CDT
Clinical Information: Carnitine and its esters are required for normal energy metabolism and serve 4
primary functions: -Importing long-chain fatty acids into the mitochondria -Exporting naturally occurring
for secondary disturbances in carnitine levels as a result of organic acidemias and fatty acid oxidation
disorders. In the latter, acyl-CoA groups accumulate and are excreted into the urine and bile as carnitine
derivatives, resulting in a secondary carnitine deficiency. More than 100 such primary and secondary
disorders have been described. Collectively, their incidence is approximately 1 in 1000 live births.
Primary carnitine deficiency has an incidence of approximately 1 in 21,000 live births based on
chronic kidney failure (dialysis), and prolonged treatment with steroids, antibiotics (pivalic acid),
organic acidemias and fatty acid oxidation disorders Monitoring carnitine treatment
of differential diagnosis, recommendations for additional biochemical testing and a phone number to
Reference Values:
FREE CARNITINE:
77-214 nmol/mg of creatinine
TOTAL CARNITINE:
180-412 nmol/mg of creatinine
RATIO:
Acylcarnitine to free carnitine: 0.7-3.4
overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012 Sep 18;7:68
2. Longo N, Amat di San Filippo C, Pasquali M: Disorders of carnitine transport and the carnitine cycle.
Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):77-85 3. Zammit VA, Ramsay RR,
Bonomini M, Arduini A: Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev. 2009 Nov
30;61(14):1353-1362 4. El-Hattab AW: Systemic primary carnitine deficiency. In: Adam MP, Ardinger
November 3, 2016. Accessed November 16, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK84551/ 5. Almannai M, Alfadhel M, El-Hattab AW: Carnitine inborn
errors of metabolism. Molecules. 2019 Sep 6;24(18):3251
CARNS Carnitine, Serum

60449 Clinical Information: Carnitine and its esters are required for normal energy metabolism and serve 4
primary functions: -Importing long-chain fatty acids into the mitochondria -Exporting naturally-occurring
secondary disturbances in carnitine levels as a result of organic acidemias and fatty acid oxidation
disorders. In the latter disorders, acyl-CoA groups accumulate and are excreted into the urine and bile as
carnitine derivatives, resulting in a secondary carnitine deficiency. More than 100 such primary and
secondary disorders have been described. Collectively, their incidence is approximately 1 in 1000 live
births. Primary carnitine deficiency has an incidence of approximately 1 in 21,000 live births based on
chronic renal failure (dialysis), and prolonged treatment with steroids, antibiotics (pivalic acid),
organic acidemias, fatty acid oxidation disorders, and primary carnitine deficiency using serum
specimens
of differential diagnosis, recommendations for additional biochemical testing, and a phone number to
Reference Values:
Total carnitine Free carnitine (FC) Acylcarnitine (AC) AC/FC Ratio

(TC)
Age Group Range* Range* Range* Range
< or =1 day 23-68 12-36 7-37 0.4-1.7
2-7 days 17-41 10-21 3-24 0.2-1.4
8-31 days 19-59 12-46 4-15 0.1-0.7
32 days-12 months 38-68 27-49 7-19 0.2-0.5
13 months-6 years 35-84 24-63 4-28 0.1-0.8
7-10 years 28-83 22-66 3-32 0.1-0.9
11-17 years 34-77 22-65 4-29 0.1-0.9
> or =18 years 34-78 25-54 5-30 0.1-0.8 *Values expressed as

nmol/mL Schmidt-Sommerfeld
E, Werner E, Penn D: Carnitine
plasma concentrations in 353
metabolically healthy children.
Eur J Pediatr.
1988;147:356-360 Used with
permission of European Journal
of Pediatrics.
overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012 Sep
18;7:68 2. Longo N, Amat di San Filippo C, Pasquali M: Disorders of carnitine transport and the
carnitine cycle. Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):77-85 3. Zammit VA,
Ramsay RR, Bonomini M, Arduini A: Carnitine, mitochondrial function and therapy. Adv Drug Deliv
Rev. 2009 Nov 30;61(14):1353-1362 4. El-Hattab AW: Systemic primary carnitine deficiency. In:
Seattle; 2012. Updated November 3, 2016. Accessed November 16, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK84551/ 5. Longo N., Frigeni M., Pasquali M. Carnitine transport and
fatty acid oxidation. Biochim. Biophys. Acta. 2016;1863:2422â€“2435 6. Almannai M, Alfadhel M,
El-Hattab AW: Carnitine inborn errors of metabolism. Molecules. 2019 Sep 6;24(18):3251
CAROB Carob, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to carob Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
FCARO Carotene, Beta

75178 Useful For: Confirm the diagnosis of carotenoderma; detect fat malabsorption; depressed carotene
levels may be found in cases of steatorrhea.
Interpretation: High levels are useful to rule out steatorrhea but lower values lack specificity. There is
poor sensitivity. High in the serum of those ingesting large amounts of vegetables.
Reference Values:
3 - 91 ug/dL
FCRTG Carrot IgG

Reference Values:
CROT Carrot, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to carrot Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
FCASG Casein IgG

Reference Values:
CASE Casein, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to casein Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
FCCA3 Cashew Component rAna o 3

75556 Clinical Information: This assay is used to detect allergen specific-IgE using the ImmunoCAPÂ®
FEIA method. In vitro allergy testing is the primary testing mode for allergy diagnosis.
Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10 - 0.34 Equivocal/Borderline
1 0.35 - 0.69 Low Positive 2 0.70 - 3.49 Moderate Positive 3 3.50 - 17.49 High Positive 4 17.50 - 49.99
Reference Values:
<0.10 kU/L
Clinical References: Borja J et al. Anaphylaxis from Brazil nut. Allergy 54, 1999 / 1004-1013.
Clark A et al. Cashew nut causes more severe reactions than peanut: case-matched comparison in 141
children. Allergy 2007; 62(8): 913-6. Davoren M et al. Cashew nut allergy is associated with a high risk
of anaphylaxis. Arch Dis Child 2005; 90(10): 1084-5. Egger m et al. The Role of Lipid Transfer
Proteins in Allergic Diseases. Curr Allergy Asthma Rep 2010; 10:326-335. Masthoff L et al. A
systematic review of the effect of thermal processing on the allergenicity of tree nuts. Allergy. 2013; 68:
983-993. Pastorello E et al. Lipid transfer protein and vicilin are important walnut allergens in patients
not allergic to pollen. J Allergy Clin Immunol 2004; 114940: 908-14. Robotham J et al. Ana o 3, an
important cashew nut (Anacardium occidentale L.) allergen of the 2S albumin family. J Allergy Clin
Immunol. 2005; 115(6): 1284-90. Rosenfeld L et al. Walnut Allergy in Peanut-Allergic Patients:
Significance of Sequential Epitopes of Walnut Homologous to Linear Epitopes of Ara h 1, 2 and 3 in
Relation to Clinical Reactivity. Int Arch Allergy Immunol. 2012; 157: 238-245. Roux K et al. Tree nut
allergens. Int Arch Allergy Immunology 2003; 131: 234-244. Wang F et al. Ana o 2, a major cashew
(Anacardium occidentale L.) nut allergen of the legumin family. Int Arch Allergy Immunol. 2003 Sep:
132(1): 27-39. www.phadia.com
FCASH Cashew IgG

Reference Values:
CASH Cashew, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cashew Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
CASRZ CASR Gene, Full Gene Analysis, Varies

37439 Clinical Information: The extracellular G-protein-coupled calcium-sensing receptor (CASR) is an
essential component of calcium homeostasis. CASR is expressed at particularly high levels in the
parathyroid glands and kidneys. It forms stable homodimeric cell-membrane complexes, which signal
upon binding of extracellular calcium ions (Ca[++]). In the parathyroid glands, this results in
downregulation of gene expression of the main short-term regulator of calcium homeostasis, parathyroid
hormone (PTH), as well as diminished secretion of already synthesized PTH. At the same time, renal
calcium excretion is upregulated and sodium chloride excretion is downregulated. Ca(++) binding to
CASR is highly cooperative within the physiological Ca(++) concentration range, leading to a steep
dose-response curve, which results in tight control of serum calcium levels. To date, over 100 different
alterations in the CASR gene have been described. Many of these cause diseases of abnormal serum
calcium regulation. Inactivating mutations result in undersensing of Ca(++) concentrations and
consequent PTH overproduction and secretion. This leads to either familial hypocalciuric hypercalcemia
(FHH) or neonatal severe primary hyperparathyroidism (NSPHT), depending on the severity of the
functional impairment. Except for a very small percentage of cases with no apparent CASR mutations,
FHH is due to heterozygous inactivating CASR mutations. Serum calcium levels are
mildly-to-moderately elevated. PTH is within the reference range or modestly elevated, phosphate is
normal or slightly low, and urinary calcium excretion is low for the degree of hypercalcemia. Unlike
patients with primary hyperparathyroidism (PHT), which can be difficult to distinguish from FHH, the
majority of FHH patients do not seem to suffer any adverse long-term effects from hypercalcemia and
elevated PTH levels. They should, therefore, generally not undergo parathyroidectomy. NSPHT is usually
due to homozygous or compound heterozygous inactivating CASR mutations, but can occasionally be
caused by dominant-negative heterozygous mutations. The condition presents at birth, or shortly
thereafter, with severe hypercalcemia requiring urgent parathyroidectomy. Activating mutations lead to
oversensing of Ca(++), resulting in suppression of PTH secretion and consequently hypoparathyroidism.
All activating mutations described are functionally dominant and disease inheritance is therefore
autosomal dominant. However, sporadic cases also occur. Autosomal dominant hypoparathyroidism
caused by CASR mutations may account for many cases of idiopathic hypoparathyroidism. Disease
severity depends on the degree of gain of function, spanning the spectrum from mild hypoparathyroidism,
which is diagnosed incidentally, to severe and early onset disease. In addition, while the majority of
patients suffer only from hypoparathyroidism, a small subgroup with extreme gain of function mutations
suffer from concomitant inhibition of renal sodium chloride transport. These individuals may present with
additional symptoms of hypokalemic metabolic alkalosis, hyperreninemia, hyperaldosteronism, and
hypomagnesemia, consistent with type V Bartter syndrome.
Useful For: Establishing a diagnosis of familial hypocalciuric hypercalcemia As part of the workup
of some patients with primary hyperparathyroidism Establishing a diagnosis of neonatal severe primary
hyperparathyroidism Establishing a diagnosis of autosomal dominant hypoparathyroidism As part of the
workup of idiopathic hypoparathyroidism As part of the workup of patients with Bartter syndrome
published American College of Medical Genetics recommendations as a guideline.(1) Variants are
classified based on known, predicted, or possible pathogenicity and reported with interpretive comments
detailing their potential or known significance. Multiple in silico evaluation tools may be used to assist
in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is
highly dependent upon the data available for a given gene, and predictions made by these tools may
change over time. Results from in silico evaluation tools should be interpreted with caution and
professional clinical judgment.
Reference Values:
Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med
2015;17:405-423 2. Hendy GN, D'Souza-Li L, Yang B, et al: Mutations of the calcium-sensing receptor
(CASR) in familial hypocalciuric hypercalcemia, neonatal severe hypocalciuric hyperparathyroidism,
and autosomal dominant hypocalcemia. Hum Mutat 2000 Oct;16(4):281-296. The authors maintain a
CASR polymorphism/mutation database available at www.casrdb.mcgill.ca/ 3. Lienhardt A, Bai M,
Lgarde JP, et al: Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J
Clin Endocrinol Metab 2001 Nov;86(1):5313-5323 4. Hu J, Spiegel AM: Naturally occurring mutations
of the extracellular Ca2+ -sensing receptor: implications for its structure and function. Trends
Endocrinol Metab 2003 Aug;14(6):282-288 5. Naesens M, Steels P, Verberckmoes R, et al: Bartter's
and Gitelman's syndromes: from gene to clinic. Nephron Physiol 2004;96(3):65-78 6. Egbuna OI,
Brown EM: Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations.
Best Pract Res Clin Rheumatol 2008;22:129-148
CAT Cat Epithelium, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cat epithelium Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
COMTQ Catechol-O-Methyltransferase (COMT) Genotype, Varies

610049 Clinical Information: Catechol-O-methyltransferase (COMT) is involved in phase II (conjugative)
metabolism of catecholamines and catechol drugs, such as dopamine, as well as the catechol-estrogens.
COMT transfers a donor methyl-group from S-adenosylmethionine to acceptor hydroxy groups on
catechol structures (aromatic ring structures with vicinal hydroxy-groups).(1) Bioactive catecholamine
metabolites are metabolized by COMT in conjunction with monoamine oxidase (MAO): -Norepinephrine
is methylated by COMT forming normetanephrine. -Epinephrine is methylated by COMT forming
metanephrine. -Dopamine is converted to homovanillic acid through the combined action of MAO and
COMT. Parkinsonism patients receiving levodopa (L-Dopa) therapy are frequently also prescribed a
COMT inhibitor to minimize metabolism of L-Dopa by COMT, thereby prolonging L-Dopa action.
COMT is also involved in the inactivation of estrogens. Estradiol can be hydroxylated forming the
catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol.(2) These hydroxylated estradiols are
methylated by COMT, forming the corresponding methoxyestradiols. The gene encoding COMT is
transcribed from alternative promoters to produce 2 forms of the enzyme, a soluble short form of the
enzyme and a membrane-bound long form. Variants in the COMT gene are therefore designated in the
literature by the position of the amino acid change in both the short and long form of the enzyme. A single
nucleotide variant (SNV) in exon 4 of the gene produces an amino acid change from valine to methionine
(Val108/158Met). The presence of methionine at this position reduces the maximum activity of the
variant enzyme by 25% and also results in significantly less immunoreactive COMT protein, resulting in a
3-fold to 4-fold decrease in activity compared to wild type (valine at this position). This variant has been
associated with prediction of response and risk of relapse when using nicotine replacement therapy for
smoking cessation.(3) The following information outlines the relationship between the polymorphism
detected in this assay and the effect on the activity of the enzyme produced by that allele: Amino acid
change cDNA nucleotide change (NM_000754.3) Effect on enzyme activity/metabolism None (wild-type)
None (wild type) Normal activity p.Val158Met (known as Val108Met) c.472G>A Reduced activity
Useful For: Prediction of response to nicotine replacement therapy for smoking cessation Investigation
of inhibitor dosing for decreasing levodopa metabolism Research use for assessing estrogen metabolism

Reference Values:
Clinical References: 1. Weinshilboum RM, Otterness DM, Szumlanski CL. Methylation

pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine
N-methyltransferase. Annu Rev Pharmacol Toxicol. 1999;39:19-52. doi:
10.1146/annurev.pharmtox.39.1.19 2. Sun H, Guo S, Chen D, et al: Association of functional COMT
Val108/Met polymorphism with smoking cessation in a nicotine replacement therapy. J Neural Transm
(Vienna). 2012;119(12):1491-1498. doi: 10.1007/s00702-012-0841-8 3. Herman AI, Jatlow PI, Gelernter
J, Listman JB, Sofuoglu M: COMT Val158Met modulates subjective responses to intravenous nicotine
and cognitive performance in abstinent smokers. Pharmacogenomics J. 2013;13(6):490-497. doi:
10.1038/tpj.2013.1 4. Worda C, Sator MO, Schneeberger C, Jantschev T, Ferlitsch K, Huber JC: Influence
of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women.
Hum Reprod. 2003;18(2):262-266. doi: 10.1093/humrep/deg059 5. Shield AJ, Thomae BA, Eckloff BW,
Wieben ED, Weinshilboum RM: Human catechol O-methyltransferase genetic variation: gene
resequencing and functional characterization of variant allozymes. Mol Psychiatry. 2004;9(2):151-160.
doi: 10.1038/sj.mp.4001386 6. Crews KR, Monte AA, Huddart R, et al: Clinical Pharmacogenetics
Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid
Therapy. Clin Pharmacol Ther. 2021 Jan 2. doi: 10.1002/cpt.2149. Epub ahead of print
CATU Catecholamine Fractionation, Free, 24 Hour, Urine

9276 Clinical Information: The catecholamines (dopamine, epinephrine, and norepinephrine) are
derived from tyrosine via a series of enzymatic conversions. All 3 catecholamines are important
neurotransmitters in the central nervous system and play crucial roles in the autonomic regulation of
many homeostatic functions, namely, vascular tone, intestinal and bronchial smooth muscle tone,
cardiac rate and contractility, and glucose metabolism. Their actions are mediated via alpha and beta
adrenergic receptors and dopamine receptors, all existing in several subforms. The 3 catecholamines
overlap but also differ in their receptor activation profile and consequent biological actions. The
systemically circulating fraction of the catecholamines is derived almost exclusively from the adrenal
medulla, with small contributions from sympathetic ganglia. They are normally present in the plasma in
minute amounts, but levels can increase dramatically and rapidly in response to change in posture,
environmental temperature, physical and emotional stress, hypovolemia, blood loss, hypotension,
hypoglycemia, and exercise. In patients with pheochromocytoma, a potentially curable tumor of
catecholamine producing cells of the adrenal medulla, or less commonly of sympathetic ganglia
(paraganglioma), urine catecholamine levels may be elevated. This results in episodic or sustained
hypertension and often in intermittent attacks of palpitations, cardiac arrhythmias, headache, sweating,
pallor, anxiety, tremor, and nausea ("spells"). Elevations of the urine levels of 1 or several of the
catecholamines also may be observed in patients with neuroblastoma and related tumors
(ganglioneuroblastomas and ganglioneuromas) and, very occasionally, in other neuroectodermal tumors.
At the other end of the spectrum, inherited and acquired syndromes of autonomic dysfunction/failure
and autonomic neuropathies are characterized by either inadequate production of 1 or several of the
catecholamines, or by insufficient release of catecholamines upon appropriate physiological stimuli (eg,
change in posture from supine to standing, cold exposure, exercise, stress).
Useful For: An auxiliary test to fractionated plasma and urine metanephrine measurements in the
diagnosis of pheochromocytoma and paraganglioma An auxiliary test to urine vanillylmandelic acid and
homovanillic acid determination in the diagnosis and follow-up of patients with neuroblastoma and
related tumors
Interpretation: Diagnosis of Pheochromocytoma: This test should not be used as the first-line test
for pheochromocytoma. PMET / Metanephrines, Fractionated, Free, Plasma (the most sensitive assay)
and/or METAF / Metanephrines, Fractionated, 24 Hour, Urine (almost as sensitive and highly specific)
are the recommended first-line laboratory tests for pheochromocytoma. However, urine catecholamine
measurements can still be useful in patients whose plasma metanephrines or urine metanephrines
measurements do not completely exclude the diagnosis. In such cases, urine catecholamine specimens
have an 86% diagnostic sensitivity when cut-offs of >80 mg/24 hour for norepinephrine and >20 mg/24
hour for epinephrine are employed. Unfortunately, the specificity of these cut-off levels for separating
tumor patients from other patients with similar symptoms is only 88%. When more specific (98%)
decision levels of >170 mg/24 hours for norepinephrine or >35 mg/24 hours for epinephrine are used,
the assayÃ¢â‚¬â„¢s sensitivity falls to about 77%. Diagnosis of Neuroblastoma: Vanillylmandelic acid,
homovanillic acid, and sometimes urine catecholamine measurements on spot urine or 24-hour urine are
the mainstay of biochemical diagnosis and follow-up of neuroblastoma; 1 or more of these tests may be
elevated.
Reference Values:
NOREPINEPHRINE
<1 year: <11 mcg/24 hours
1 year: 1-17 mcg/24 hours
2-3 years: 4-29 mcg/24 hours
> or =10 years: 15-80 mcg/24 hours
EPINEPHRINE
<1 year: <2.6 mcg/24 hours
1 year: <3.6 mcg/24 hours
2-3 years: <6.1 mcg/24 hours
4-9 years: 0.2-10.0 mcg/24 hours
10-15 years: 0.5-20.0 mcg/24 hours
> or =16 years: <21 mcg/24 hours
DOPAMINE
<1 year: <86 mcg/24 hours
1 year: 10-140 mcg/24 hours
Clinical References: 1. Young WF Jr: Pheochromocytoma and primary aldosteronism. In Endocrine

Neoplasms. Edited by A Arnold. Kluwer Academic Publishers, 1997, pp 239-261 2. Hernandez FC,
Sanchez M, Alvarez A, et al: A five-year report on experience in the detection of pheochromocytoma.
Ann Intern Med 2000;33:649-655 3. Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in
genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001;134:315-329
4. Alexander F: Neuroblastoma. Urol Clin North Am 2000;27:383-392 5. McDougall AJ, McLeod JG:
Autonomic neuropathy, I. Clinical features, investigation, pathophysiology, and treatment. J Neurol Sci
1996;137:79-88 6. Lenders JW, Pacak K, Walther MM, et al: Biochemical diagnosis of
pheochromocytoma: which test is best? JAMA 2002;287:1427-1434 7. Shen Y, Cheng L: Chapter 2:
Biochemical diagnosis of pheochromocytoma and paraganglioma. In Paraganglioma: A Multidisciplinary
Approach. Edited by R Mariani-Costantini. Codon Publications; 2019
doi:10.15586/paraganglioma.2019.ch2. Available at www.ncbi.nlm.nih.gov/books/NBK543224/ 8.
Pussard E, Neveux M, Guiqueno N: Reference intervals for urinary catecholamines and metabolites from
birth to adulthood. Clin Biochem 2009 Apr;42(6):536-539
CATP Catecholamine Fractionation, Free, Plasma

8532 Clinical Information: The catecholamines (dopamine, epinephrine, and norepinephrine) are derived
from tyrosine via a series of enzymatic conversions. All 3 catecholamines are important neurotransmitters
in the central nervous system and play a crucial role in the autonomic regulation of many homeostatic
functions, namely, vascular tone, intestinal and bronchial smooth muscle tone, cardiac rate and
contractility, and glucose metabolism. Their actions are mediated via alpha- and beta-adrenergic receptors
and dopamine receptors, all existing in several subforms. The 3 catecholamines overlap, but also differ in
their receptor activation profile and consequent biological actions. The systemically circulating fraction of
the catecholamines is derived almost exclusively from the adrenal medulla, with small contributions from
sympathetic ganglia. The catecholamines are normally present in the plasma in minute amounts, but levels
can increase dramatically and rapidly in response to change in posture, environmental temperature,
physical and emotional stress, hypovolemia, blood loss, hypotension, hypoglycemia, and exercise. In
patients with pheochromocytoma (a potentially curable tumor of catecholamine-producing cells of the
adrenal medulla), or less commonly of sympathetic ganglia (paraganglioma), plasma catecholamine levels
may be continuously or episodically elevated. This results in episodic or sustained hypertension and in
intermittent attacks of palpitations, cardiac arrhythmias, headache, sweating, pallor, anxiety, tremor, and
nausea. Intermittent or continuous elevations of the plasma levels of one or several of the catecholamines
may also be observed in patients with neuroblastoma and related tumors (ganglioneuroblastomas and
ganglioneuromas) and, very occasionally, in other neuroectodermal tumors. At the other end of the
spectrum, inherited and acquired syndromes of autonomic dysfunction or failure and autonomic
neuropathies are characterized by either inadequate production of one or several of the catecholamines or
by insufficient release of catecholamines upon appropriate physiological stimuli (eg, change in posture
from supine to standing, cold exposure, exercise, stress).
Useful For: Diagnosis of pheochromocytoma and paraganglioma, as an auxiliary test to fractionated

plasma and urine metanephrine measurements (plasma metanephrine is the preferred test for this
diagnosis) Diagnosis and follow-up of patients with neuroblastoma and related tumors, as an auxiliary
test to urine vanillylmandelic acid and homovanillic acid measurements Evaluation of patients with
autonomic dysfunction or failure or autonomic neuropathy
Interpretation: Diagnosis of Pheochromocytoma: This test should not be used as the first-line test
for pheochromocytoma, as plasma catecholamine levels may not be continuously elevated but only
secreted during a "spell." By contrast, production of metanephrines (catecholamine metabolites) appears
to be increased continuously. The recommended first-line laboratory tests for pheochromocytoma are:
-PMET / Metanephrines, Fractionated, Free, Plasma: the most sensitive assay -METAF /
Metanephrines, Fractionated, 24 Hour, Urine: highly specific and almost as sensitive as PMET
However, plasma catecholamine measurements can still be useful in patients whose plasma
metanephrine or urine metanephrine measurements do not completely exclude the diagnosis. In such
cases, plasma catecholamine specimens, if drawn during a "spell," have a 90% to 95% diagnostic
sensitivity when cutoffs of greater than 750 pg/mL for norepinephrine and greater than 110 pg/mL for
epinephrine are employed. A lower value during a "spell," particularly when plasma or urinary
metanephrine measurements were also normal, essentially rules out pheochromocytoma. Unfortunately,
the specificity of these high-sensitivity cutoff levels is not good for separating tumor patients from other
patients with similar symptoms. When more specific (95%) decision levels of 2000 pg/mL for
norepinephrine or 200 pg/mL for epinephrine are used, the assay's sensitivity falls to about 85%.
Diagnosis of Neuroblastoma: Vanillylmandelic acid, homovanillic acid, and sometimes urine
catecholamine measurements on spot urine or 24-hour urine are the mainstay of biochemical diagnosis
and follow-up of neuroblastoma. Plasma catecholamine levels can aid diagnosis in some cases, but
diagnostic decision levels are not well established. The most useful finding is disproportional elevations
in 1 of the 3 catecholamines, particularly dopamine, which may be observed in these tumors. Diagnosis
of Autonomic Dysfunction or Failure and Autonomic Neuropathy: Depending on the underlying cause
and pathology, autonomic dysfunction or failure and autonomic neuropathies are associated with
subnormal resting norepinephrine levels, or an absent rise of catecholamine levels in response to
physiological release stimuli (eg, change in posture from supine to standing, cold exposure, exercise,
stress), or both. In addition, there may be significant abnormalities in the ratios of the plasma values of
the catecholamines to each other (normal: norepinephrine>epinephrine>dopamine). This is observed
most strikingly in the inherited dysautonomic disorder dopamine-beta-hydroxylase deficiency, which
results in markedly elevated plasma dopamine levels and a virtually total absence of plasma epinephrine
and norepinephrine.
Reference Values:
NOREPINEPHRINE
Supine: 70-750 pg/mL
Standing: 200-1,700 pg/mL
EPINEPHRINE
Supine: < or =111 pg/mL
Standing: < or =141 pg/mL
DOPAMINE
<30 pg/mL (no postural change)
Clinical References: 1. Young WF Jr: Pheochromocytoma and primary aldosteronism. In: Arnold
A, ed. Endocrine Neoplasms. Kluwer Academic Publishers; 1997:239-261 2. Hernandez FC, Sanchez M,
Alvarez A, et al: A five-year report on experience in the detection of pheochromocytoma. Ann Intern
Med. 2000;33:649-655 3. Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in genetics,
diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134:315-329 4.
Alexander F: Neuroblastoma. Urol Clin North Am. 2000;27:383-392 5. McDougall AJ, McLeod JG:
Autonomic neuropathy, I. Clinical features, investigation, pathophysiology, and treatment. J Neurol Sci.
1996;137:79-88 6. Lenders JW, Pacak K, Walther MM, et al: Biochemical diagnosis of
pheochromocytoma: which test is best? JAMA. 2002;287:1427-1434
FCATE Catfish (Siluriformes spp) IgE

57554 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10-0.34 Equivocal 1 0.35-0.69
Low Positive 2 0.70-3.4 Moderate Positive 3 3.5-17.4 High Positive 4 17.5-49.9 Very High Positive 5
50.0-99.9 Very High Positive 6 >100 Very High Positive
Reference Values:
<0.35 kU/L
FCLPF Cathartic Laxatives Profile, Stool

75676 Interpretation: Magnesium: Magnesium concentrations in stool water above the normal levels of
0.7-1.2 mg/mL have been indicative of surreptitious abuse of magnesium containing laxatives. NMS Labs
Calculated Normal: approximately 0.5-10 mg/g (Based on the reported range of magnesium eliminated
per day in stool and the range of stool mass per day in adults). Phosphorus: Phosphorus concentration in
stool water averaged 1.8 +/- 0.3 mg/mL (ranged from 0.3-4.2 mg/mL) following administration of 105
mmol of sodium phosphate. NMS Labs calculated normal: approximately 1.4-22 mg/g (Based on the
reported range of phosphorus eliminated per day in stool and the range of stool mass per day in adults).
Reference Values:
Units: mg/g
CTSK Cathepsin K Immunostain, Technical Component Only

607887 Clinical Information: Â· Cathepsin K is a protease whose expression is driven by microphthalmia
transcription factor (MITF) in osteoclasts. Cathepsin K is also expressed in renal perivascular epithelioid
cell neoplasms (PEComas), alveolar soft part sarcoma, and most MiT family translocation -renal cell
carcinomas. This includes most transcription factor EB- (TFEB) rearranged renal cell carcinomas, those
with amplifications of TFEB, and renal cell carcinomas that harbor various TFE3 gene fusions.
Useful For: A marker of myeloid lineage

Clinical References: 1. Martignoni G, Bonetti F, Chilosi M, et al: Cathepsin K expression in the

spectrum of perivascular epithelioid cell (PEC) lesions of the kidney. Mod Pathol. 2012;25(1):100-111.
doi: 10.1038/modpathol.2011.136 2. Rao Q, Cheng L, Xia QY, et al: Cathepsin K expression in a wide
spectrum of pervascular epithelioid cell neoplasms (PEComas): a clinicopathological study emphasizing
external PEComas. Histol. 2013;62(4):642-650. doi: 10.1111/his.12059 3. Martignoni G, Gobbo S,
Camparo P, et al: Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions. Mod
Pathol. 2011;24(10):1313-1319. doi: 10.1038/modpathol.2011.93 4. Rao Q, Wang Y, Xia Q, et al:
Cathepsin K in the immunohistochemical diagnosis of melanocytic lesions. Int J Clin Exp Pathol.
2014;7(3):1132-1139
FCAFG Cauliflower IgG

Reference Values:
CALFL Cauliflower, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to cauliflower Defining the allergen responsible

Reference Values:
0 Negative
apply to all ages.
2017:1057-1070
IN16Q CBFB-MYH11 Inversion(16), Quantitative Detection and Minimal

610266 Disease Risk Monitoring, qRT-PCR, Varies
Clinical Information: CBFB-MYH11 minimal residual disease (MRD) monitoring in patients with
acute myeloid leukemia (AML) with inv(16) or t(16;16) is useful for evaluating disease response after
therapy and identifying individuals with increased risk of relapse. Quantitative real-time reverse
transcription polymerase chain reaction testing in neoplasms with known clonal genetic markers can
achieve highly sensitive detection of neoplastic cells in peripheral blood or bone marrow samples. It is
one of the most mature technologies available for this purpose. In this assay, inversion or translocation of
chromosome 16 resulting in fusion of two genes, CBFB and MYH11, will be evaluated. Quantitative
results will provide physicians with an accurate and precise measurement of disease burden to guide
patient intervention decisions. This assay can be used for post-therapy MRD monitoring as well as
detection of CBFB-MYH11 fusion in AML patients at the time of diagnosis.
Useful For: Detection of CBFB-MYH11 gene fusion in patients recently diagnosed with acute myeloid
leukemia (AML) Minimal residual disease monitoring during the clinical and therapeutic course of
patients with AML
Interpretation: The assay is reported in the form of a normalized ratio of CBFB-MYH11 fusion
transcript to the control gene ABL1 expressed as a percentage, which is an estimate of the level of
CBFB-MYH11 fusion RNA present in the specimen, expressed in relation to the level of RNA from an
internal control gene (ABL1). The normalized ratio has no units but is directly related to the level of
CBFB-MYH11 detected (ie, larger numbers indicate higher relative levels of CBFB-MYH11, and smaller
numbers indicate lower levels). A relative expression value minimizes variability in the RNA levels and
cell numbers measured in separate specimens tested at different times. The precision of the quantitative
assay is excellent, but interassay variability can occur such that result changes should not be considered
significant if 2 single measurements differ by less than 0.5 log. More critical results, such as a change in
the status of positivity or greater or equal to 1 log increase between 2 positive samples should be repeated
on a separate specimen with appropriate time interval to verify the result.
Reference Values:
Clinical References: 1. Krauter J1, Hoellge W, Wattjes MP, et al: Detection and quantification of
CBFB/MYH11 fusion transcripts in patients with inv(16)-positive acute myeloblastic leukemia by
real-time RT-PCR. Genes Chromosomes Cancer. 2001 Apr;30(4):342-348. doi: 10.1002/gcc.1100 2.
Dohner H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN
recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi:
10.1182/blood-2016-08-733196 3. O'Donnell MR, Tallman MS, Abboud CN, et al: Acute Myeloid
Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw.
2017 Jul;15(7):926-957. doi: 10.6004/jnccn.2017.0116 4. Schuurhuis GJ, Heuser M, Freeman S, et al:
Minimal/measurable residual disease in AML: a consensus document from the European Leukemia Net
MRD Working Party. Blood. 2018 Mar 22;131(12):1275-1291. doi: 10.1182/blood-2017-09-801498 5.
Jourdan E, Boissel N, Chevret S, et al: Prospective evaluation of gene mutations and minimal residual
disease in patients with core binding factor acute myeloid leukemia. Blood. 2013 Mar
21;121(12):2213-2223. doi: 10.1182/blood-2012-10-462879 6. Lane S, Saal R, Mollee P, et al: A > or =1
log rise in RQ-PCR transcript levels defines molecular relapse in core binding factor acute myeloid
leukemia and predicts subsequent morphologic relapse. Leuk Lymphoma. 2008 Mar;49(3):517-523. doi:
10.1080/10428190701817266 7. Yin JA, O'Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK:
Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk
stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood. 2012 Oct
4;120(14):2826-2835. doi: 10.1182/blood-2012-06-435669 8. Corbacioglu A, Scholl C, Schlenk RF, et al:
Prognostic impact of minimal residual disease in CBFB-MYH11-positive acute myeloid leukemia. J Clin
Oncol. 2010 Aug 10;28(23):3724-3729. doi: 10.1200/JCO.2010.28.6468
CD10 CD10 Immunostain, Technical Component Only

70373 Clinical Information: CD10 is a cell surface glycoprotein present on bone marrow B precursors
(hematogones) and myeloid cells (including neutrophils), follicle center B cells, and a subset of
follicular T helper cells. CD10 is also expressed in the brush border of the upper part of the intestinal
tract, bile canaliculi, kidney (glomerular and proximal tubular cells), pulmonary alveolar cells,
myoepithelial cells of breast, prostate glandular cells, placental trophoblastic cells, endometrial stromal
cells, some endothelial cells, and a minority of (myo-)fibroblasts (stromal cells). CD10 is most useful in
the diagnosis of B-precursor-acute lymphoblastic leukemia, Burkitt lymphoma, and lymphomas of
follicle cell center origin (follicular lymphoma, subset of large B-cell lymphomas).
Useful For: Phenotyping leukemias and lymphomas

Clinical References: 1. Al-Masri M, Darwazeh G, Sawalhi S et al: Phyllodes tumor of the breast:
role of CD10 in predicting metastasis. Ann Surg Oncol. 2012;19:1181-1184. doi:
10.1245/s10434-011-2076-6 2. Taghizadeh-Kermani Ali, Jafarian AH, Ashabymin R, et al: The stromal
overexpression of CD10 in invasive breast cancer and its association with clincophathologic factors.
Iran J Cancer Prev. Winter 2014;7(1):17-21 3. Lloyd J, Owens S: CD10 immunohistochemistry stains
enteric mucosa, but negative staining is unreliable in the setting of active enteritis. Mod Pathol.
2011;24:1627-1632. doi: 10.1038/modpathol.2011.122

70372 Clinical Information: CD103, also known as integrin alpha E, is an integrin subunit protein, which
is widely expressed on T cells. CD103 is a useful diagnostic tool in the diagnosis of hairy cell leukemia.
Useful For: Aids in the diagnosis of hairy cell leukemia and marginal zone lymphomas
Clinical References: 1. Morgan EA, Yu H, Pinkus JL, Pinkus GS: Immunohistochemical

detection of hairy cell leukemia in paraffin sections using a highly effective CD103 rabbit monoclonal
antibody. Am J Clin Pathol. 2013;139:220-230 2. Shao H, Calvo KR, Gronborg M, et al: Distinguishing
hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria.
Leuk Res. 2013;37:401-409 3. Abdel-Ghafar AA, El Din El Telbany MA, Mahmoud HM, El-Sakhawy
YN: Immunophenotyping of chronic B-cell neoplasms: flow cytometry versus immunohistochemistry.
Hematol Rep. 2012;4(1):e3
CD11C CD11c Immunostain, Technical Component Only
70412 Clinical Information: CD11c is a member of the leukocyte specific integrin family, involved in
adherence to activated endothelial cells and complement-mediated phagocytosis. CD11c is normally
expressed on histiocytes and monocytes, and weakly expressed on granulocytes. CD11c is also expressed
on certain B cell neoplasms, including hairy cell leukemia and splenic marginal zone lymphoma.
Useful For: Aiding in the diagnosis of hematological malignancies and identification of cells of the
macrophage/dendritic cell lineage within tissues
Clinical References: 1. Wu J, Wu H, An J, Ballantyne CM, Cyster JG: Critical role of integrin

CD11c in splenic dendritic cell capture of missing-self CD47 cells to induce adaptive immunity. Proc Natl
Acad Sci USA. 2018; 115(26), 6786-6791 2. Troussard X, Cornet E: Hairy cell leukemia 2018: Update on
diagnosis, risk-stratification, and treatment. Am J Hematol. 2017; 92(12), 1382-1390 3. Devin J,
Kassambara A, Bruyer A, Moreaux J, Bret C: Phenotypic characterization of diffuse large B-cell
lymphoma cells and prognostic impact. J Clin Med. 2019; 8(7), 1074

70413 Clinical Information: In normal lymphoid tissues, CD123 is expressed in plasmacytoid monocytes
and mast cells in interfollicular regions. In bone marrow, it is expressed in hematopoietic precursors, mast
cells, and megakaryocytes. CD123 is part of the IL3 receptor complex, involved in cellular growth and
differentiation. Certain reactive lymph nodes show increased numbers of plasmacytoid monocytes, eg,
Kikuchi lymphadenitis. CD123 is characteristically expressed in blastic plasmacytoid dendritic cell
neoplasm, aiding in its distinction from acute monocytic leukemia.
Useful For: Marker of plasmacytoid monocytes, mast cells, and megakaryocytes

stain. If an interpretation is required order PATHC / Pathology Consultation for a full diagnostic
appropriate immunoreactivity and documentation is retained at Mayo Clinic Rochester. If a control tissue
is not included on the slide, a scanned image of the relevant quality control tissue is available upon
request. Contact 855-516-8404. Interpretation of this test should be performed in the context of the
Clinical References: 1. Arai N, Homma M, Abe M, et al: Impact of CD123 expression, analyzed by
immunohistochemistry, on clinical outcomes in patients with acute myeloid leukemia. Int J Hematol.
2019; 109, 539-544 2. Testa U, Pelosi E, Frankel A: CD 123 is a membrane biomarker and a therapeutic
target in hematologic malignancies. Biomark Res. 2014;2(1):4 3. Rollins-Raval M, Pillai R,
Mitsuhashi-Warita T, et al: CD123 immunohistochemical expression in acute myeloid leukemia is
associated with underlying FLT3-ITD and NPM1 mutations. Appl Immunohistochem Mol Morphol.
2013; 21, 212-217

70374 Clinical Information: CD13 (cluster of differentiation 13) plays roles in peptide metabolism (brush
border membranes of small intestine, renal proximal tubules, and placenta), cell growth and
differentiation, and phagocytosis. CD13 is normally expressed on myeloid lineage cells, including
granulocytes and monocytes. It is also expressed on non-hematolymphoid cells including endothelial cells
and fibroblasts, and is present in a soluble form in plasma. This immunostain may be useful as a marker
of myeloid lineage in acute leukemias.
Useful For: A marker of myeloid lineage

Clinical References: 1. Yamanaka C, Wada H, Eguchi H, et al: Clinical significance of CD13 and
epithelial mesenchymal transition (EMT) markers in hepatocellular carcinoma. Jpn J Clin Oncol. 2018;
Jan 1;48(1):52-60 2. Kessler T, Baumeier A, Brand C, et al: Aminopeptidase N (CD13): expression,
prognostic impact, and use as therapeutic target for tissue factor induced tumor vascular infarction in
soft tissue sarcoma. Transl Oncol. 2018;11(6):1271-1282 3. Dominguez JM, Perez-Chacon G, Guillen
MJ, et al: CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate
MI130110. J Hematol Oncol. 2020; 13, 32
CD138 CD138 (Syndecan) Immunostain, Technical Component Only

70414 Clinical Information: CD138 is expressed on plasma cells and can be useful in the diagnosis of
plasma cell neoplasms. Epithelial cells and endothelial cells may also express CD138. In normal tonsil
tissue, CD138 strongly stains the membranes of mature plasma cells and squamous epithelial cells.
Useful For: Marker of plasma cells and squamous epithelial cells

Clinical References: 1. Chen Y, Fang R., Luo Y, Luo C: Analysis of the diagnostic value of
CD138 for chronic endometritis, the risk factors for the pathogenesis of chronic endometritis and the
effect of chronic endometritis on pregnancy: a cohort study. BMC Women's Health. 2016; 16,60 2.
Waisberg J, Theodoro TR, Matos LL, et al: Immunohistochemical expression of heparanase isoforms
and syndecan-1 proteins in colorectal adenomas. Eur J Histochem. 2016;60(1):2590 3. Kind S,
Merenkow C, Buscheck F, et al: Prevalence of syndecan-1 (CD138) expression in different kinds of
human tumors and normal tissues. Dis Markers. 2019;2019:4928315
CD14I CD14 Immunostain, Technical Component Only

70375 Clinical Information: CD14 is a glycosylphosphatidylinositol-linked glycoprotein that is
preferentially expressed by mature cells of monocytic lineage (monocytes, macrophages, Langerhans
cells) and follicular dendritic cells. Neutrophils exhibit lower levels of expression. This antibody may be
useful as a marker of histiocytic/monocytic lineage in acute leukemias.
Useful For: A marker of histiocytic and monocytic lineage and follicular dendritic cells
Clinical References: 1. Heiskala, M., Leidenius, M., Joensuu, K. et al: High expression of CCL2 in
tumor cells and abundant infiltration with CD14 positive macrophages predict early relapse in breast
cancer. Virchows Arch. 2019;474, 3â€“12. doi:10.1007/s00428-018-2461-7 2. Smeltzer JP, Jones JM,
Ziesmer SC, Heikkila P:: Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently
predicts time to transformation in follicular lymphoma. Clin Cancer Res. 2014 Jun;20(11):2862-2872.
doi:10.1158/1078-0432.CCR-13-2367 3. Li M, Zhang G, Zhang X, et al: Overexpression of B7-H3 in
CD14+ monocytes is associated with renal cell carcinoma progression. Med Oncol. 2014;31, 349
doi:10.1007/s12032-014-0349-1

70376 Clinical Information: CD15 is expressed in granulocytes and can be expressed in malignant
lymphomas and acute myeloid leukemias. The Reed-Sternberg cells of classical Hodgkin lymphoma are
characteristically positive for CD15 and CD30.

Clinical References: 1. Benharroch D, Pilosof S, Gopas J, Levi I: Primary refractory and relapsed
classical Hodgkin lymphoma - Significance of differential CD15 expression in Hodgkin-Reed-Sternberg
cells. J Cancer. 2012;3: 322-327 2. Roge R, Nielsen S, Vyberg M: Carb-3 is the superior antiCD15
monoclonal antibody for immunohistochemistry. Appl Immunohistochem Mol Morphol. 2014; 22(6):
449-458 3. Venkataraman G, Raffeld M, Pittaluga S, et al: CD15-expressing nodular
lymphocyte-predominant Hodgkin lymphoma. Histopathology. 2011;5:803-805

70415 Clinical Information: CD163 (cluster of differentiation 163) is a scavenger receptor for the
hemoglobin-haptoglobin complex. CD163 is a marker of monocytic/histiocytic lineage, expressed late in
maturation. It has superior specificity for monocytic/histiocytic lineage compared to CD68. In normal
lymphoid tissues, staining of histiocytes in the paracortex and follicle center (tingible body macrophages)
is seen. CD163 is usually negative in immature monocytic/histiocytic tumors (acute myeloid leukemia
with monocytic differentiation).
Useful For: Identification of cells of monocytic/histiocytic lineage, expressed late in maturation

available upon request; contact 855-516-8404. Â Interpretation of this test should be performed in the
Clinical References: 1. Ma C, Horlad H, Ohnishi K, et al. CD163-positive cancer cells are
potentially associated with high malignant potential in clear cell renal cell carcinoma. Med Mol
Morphol. 2018 Mar;51(1):13-20 2. Garton T, Keep RF, Hua Y, Xi G: CD163, a
hemoglobin/haptoglobin scavenger receptor, after intracerebral hemorrhage: functions in
microglia/macrophages versus neurons. Trans Stroke Res. 2017 Dec;8(6):612-616 3. Yuan X, Zhang J,
Li D, et al: Prognostic significance of tumor-associated macrophages in ovarian cancer: A
meta-analysis. Gynecol Oncol. 2017 Oct;147(1):181-187
C19BM CD19 Immunostain, Bone Marrow, Technical Component Only

603205 Clinical Information: CD19 is expressed by normal and neoplastic B cells but is not expressed by
T cells, monocytes, or granulocytes. CD19 protein appears early during B-cell maturation and is found
during all stages of B-cell maturation, including plasma cells. CD19 is useful as an additional marker of
B cell lineage in leukemias and lymphomas. Expression of CD19 may be seen in some acute myeloid
leukemias.
Useful For: Identification of normal and neoplastic B cells

quality control tissue is available upon request, call 855-516-8404. Â Interpretation of this test should
be performed in the context of the patient's clinical history and other diagnostic tests by a qualified
pathologist.
Clinical References: 1. Masir N, Marafioti T, Jones M, et al: Loss of CD19 expression in B-cell
neoplasms. Histopathology 2006;48:239-246 2. Kirk CM, Lewin D, Lazarchick J, et al: Primary hepatic
B-cell lymphoma of mucosa-associated lymphoid tissue. Arch Pathol Lab Med 1999;123:716-719

70377 Clinical Information: CD19 is expressed by normal and neoplastic B cells but is not expressed by
T cells, monocytes, or granulocytes. CD19 protein appears early during B-cell maturation and is found
during all stages of B-cell maturation, including plasma cells. CD19 is useful as an additional marker of
B cell lineage in leukemias and lymphomas. Expression of CD19 may be seen in some acute myeloid
leukemias.
Useful For: Identification of normal and neoplastic B cells

the stain.Â If an interpretation is required order PATHC / Pathology Consultation for a full diagnostic
upon request; call 855-516-8404. Â Interpretation of this test should be performed in the context of the
Clinical References: 1. Wang H, Zu Y: Diagnostic algorithm of common mature B-cell

lymphomas by immunohistochemistry. Arch Pathol Lab Med. 2017;141(9):1236-1246 2. O'Malley DP,
Auerbach A, Weiss LM: Practical applications in immunohistochemistry: evaluation of diffuse large
B-cell lymphoma and related large B-cell lymphomas. Arch Pathol Lab Med. 2015;139(9):1094-1107 3.
Wang K, Wei G, Liu D: CD19: a biomarker for B cell development, lymphoma diagnosis and therapy.
Exp Hematol Oncol. 2012;1:36
CD1A CD1a Immunostain, Technical Component Only

70378 Clinical Information: CD1a is a membrane surface glycoprotein that is expressed in Langerhans
cells and immature T cells. CD1a expression is useful in phenotyping acute lymphoblastic
leukemia/lymphoma of T-cell lineage and in the diagnosis of Langerhans cell histiocytosis.
Useful For: Marker of Langerhans cells and immature T cells

Interpretation: This test does not includes pathologist interpretation; only technical performance of
the stain. (no pathologist interpretation is performed). If diagnostic consultation by a pathologist
interpretation is required order PATHC / Pathology Consultation for a full diagnostic evaluation or second
opinion of the case. The positive and negative controls are verified as showing appropriate
Clinical References: 1. Nasiri S, Bidari Zerehpoosh F, Abdollahimajd F, Younespour S, Esmaili

Azad M: A comparative immunohistochemical study of epidermal and dermal/perifollicular Langerhans
cell concentration in discoid lupus erythematosus and lichen planopilaris: a cross-sectional study. Lupus.
2018;27(14):2200-2205. doi:10.1177/0961203318808587 2. Wang P, Peng X, Deng X, Gao L, Zhang X,
Feng Y: Diagnostic challenges in T-lymphoblastic lymphoma, early T-cell precursor acute lymphoblastic
leukemia or mixed phenotype acute leukemia: A case report. Medicine (Baltimore). 2018;97(41):e12743.
doi:10.1097/MD.0000000000012743 3. Kim HK, Park CJ, Jang S, et al: Bone marrow involvement of
Langerhans cell histiocytosis: immunohistochemical evaluation of bone marrow for CD1a, Langerin, and
S100 expression. Histopathology. 2014;65(6):742-748. doi:10.1111/his.12481
CD2B CD2 Immunostain, Bone Marrow, Technical Component Only

603203 Clinical Information: CD2 is a pan T-cell antigen, expressed on normal and neoplastic T cells and
natural killer cells. In normal tonsil, the T cells predominate in interfollicular regions. CD2
immunostaining is useful in determining T-cell lineage in cases of T-cell lymphoma.
Useful For: Determining T-cell lineage

available upon request, call 855-516-8404. Â Interpretation of this test should be performed in the
Clinical References: 1. Campbell AM, Peters SB, Zirwas MJ, et al: Immunophenotypic diagnosis of
primary cutaneous lymphomas. A review for the practicing dermatologist. J Clin Aesthet Dermatol
2010;3(10):21-25 2. Jordan JH, Walchshofer S, Jurecka W, et al: Immunohistochemical properties of
bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and
bcl-x(L). Hum Pathol 2001;32(5):545-552 3. Went P, Agostinelli C, Gallamini A, et al: Marker
expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol
2006;24(16):2472-2479
70384 Clinical Information: CD2 is a pan T-cell antigen that is expressed on normal and neoplastic T
cells and natural killer cells. CD2 immunostaining is useful in determining T-cell lineage in cases of
T-cell lymphoma.
Useful For: Determining T-cell lineage

the stain. (no pathologist interpretation is performed). If diagnostic consultation by a pathologist
interpretation is required order PATHC / Pathology Consultation for a full diagnostic evaluation or
second opinion of the case. The positive and negative controls are verified as showing appropriate
Clinical References: 1. Campbell AM, Peters SB, Zirwas MJ, et al: Immunophenotypic diagnosis
of primary cutaneous lymphomas. A review for the practicing dermatologist. J Clin Aesthet Dermatol.
2010;3(10):21-25 2. Rai MP, Bedi PS, Marinas EB, Khan NNS: Angioimmunoblastic T-cell lymphoma:
a rare subtype of peripheral T-cell lymphoma. Clin Case Rep. 2018;6(4):750-752.
doi:10.1002/ccr3.1388 3. Stenman L, Persson M, Enlund F, Clasen-Linde E, Stenman G, Heegaard S:
Primary orbital precursor T-cell lymphoblastic lymphoma: Report of a unique case. Mol Clin Oncol.
2016;5(5):593-595. doi:10.3892/mco.2016.1008
CEE20 CD20 Cell Expression Evaluation, Varies

65660 Clinical Information: Monoclonal antibodies are critical tools for detecting cellular antigens in
various hematologic diseases and are used to provide critical prognostic information (CD49d).
Monoclonal antibodies are also used as therapeutic agents in a variety of hematologic diseases. For
example: -Anti-CD20 (Rituxan): B-cell malignant lymphomas and multiple myeloma -Anti-CD52
(Campath-1H): B-cell chronic lymphocytic leukemia and T-cell disorders This list will undoubtedly
expand over time to include other antibodies. It may be necessary to document expression of these
markers by the malignant cells prior to initiating the respective monoclonal antibody therapy.
Expression of these markers may also be required for follow-up to monitor the impact of treatment on
residual normal counterparts (eg, CD20-positive lymphocytes in patients treated with anti-CD20). The
distribution of these cellular antigens is well established in normal, reactive, and in various malignant
disorders. The laboratory has several years of experience with therapeutic antibody monitoring of Mayo
Clinic patients as part of the routine B-cell, T-cell, or acute immunophenotyping panels.
Useful For: Detecting cell-surface antigens on malignant cells that are potential therapeutic antibody
targets, specifically CD20 Determining the eligibility of patients for monoclonal antibody therapies
Monitoring response to the therapeutic antibody
Interpretation: The immunophenotyping report will summarize the pattern of antigenic expression
on malignant cells and, if appropriate, the normal cellular counterparts that correspond to the therapeutic
monoclonal antibody target.
Reference Values:
Normal individuals have B lymphocytes, T lymphocytes, or myeloid cells that express the
corresponding cell-surface antigens in question.
Clinical References: 1. Davis AT: Monoclonal antibody-based therapy of lymphoid neoplasms:

what's on the horizon? Semin Hematol. 2000;37(4 Suppl 7):34-42 2. Czuczman MS, Grillo-Lopez AJ,
White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of
chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268-276 3.
Flynn JM, Byrd JC: Campath-1H monoclonal antibody therapy. Curr Opin Oncol. 2000;12:574-581 4.
Kreitman RJ, Wilson WH, Bergeron K, et al: Efficacy of the anti-CD22 recombinant immunotoxin
BL22 in chemotherapy-resistant hairy-cell leukemia. N Eng J Med. 2001;345:241-247 5. Shanafelt TD,
Geyer SM, Bone ND, et al: CD49D expression is an independent predictor of overall survival in
patients with CLL: a prognostic parameter with therapeutic potential. Br J Haematol. 2008;140:537-546

70379 Clinical Information: CD20 is a phosphorylated protein preferentially expressed by mature B
lymphocytes. CD20 is not expressed by most normal plasma cells. It is one of the most specific B-cell
lineage-associated antigens used in the diagnosis of B-cell lymphomas.

available upon request; call 855-516-8404. Interpretation of this test should be performed in the context of
Clinical References: 1. Choi CH, Park YH, Lim JH, et al: Prognostic implication of
semi-quantitative immunohistochemical assessment of CD20 expression in diffuse large B-cell
lymphoma. J Pathol Transl Med. 2016;50(2):96-103 doi:10.4132/jptm.2016.01.12 2. Duman BB, Sahin B,
Ergin M, Guvenc B: Loss of CD20 antigen expression after rituximab therapy of CD20 positive B cell
lymphoma (diffuse large B cell extranodal marginal zone lymphoma combination): A case report and
review of the literature. Med Oncol. 2012;29:1223-1226 doi:10.1007/s12032-011-9955-3 3. Cang S,
Mukhi N, Wang K, Liu D: Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol.
2012;5:64 doi:10.1186/1756-8722-5-64
CD20B CD20 on B Cells, Blood

89584 Clinical Information: CD20 (cluster of differentiate 20) is a protein that is expressed on the surface
of B cells, starting at the pre-B cell stage and on mature B cells in the bone marrow and in the periphery.
CD20 is not expressed on hematopoietic stem cells, pro-B cells, or normal plasma cells.(1) Plasmablasts
and stimulated plasma cells may express CD20.(2) CD20 is generally coexpressed on B cells with CD19,
another B-cell differentiation marker. CD20 appears to play a role in B-cell development, differentiation,
B-cell receptor (BCR) signaling, and cell-cycle initiation events.(3) CD20 is not shed from the surface of
B cells and does not internalize on binding with anti-CD20 antibody, nor is it typically present as a
soluble free antigen in circulation.(3) Certain primary humoral immunodeficiencies, such as X-linked
agammaglobulinemia and autosomal recessive agammaglobulinemia, are characterized by a complete
absence or profound reduction of peripheral B cells, expressing both CD20 and CD19 (another B-cell
differentiation marker). Variants in the CD19 gene have been shown to be associated with a primary
humoral immunodeficiency, sometimes classified as common variable immunodeficiency (CVID).(4)
This defect accounts for less than 1% to 2% of CVID patients and appears to be inherited as an autosomal
recessive defect.(4) Since these patients have normal numbers of B cells with absent CD19 expression on
the cell surface (4), CD20 can be used as a marker to help identify these patients. Genetic CD20
deficiency (autosomal recessive) is also associated with a primary humoral immunodeficiency. In this
disease, B cells can be identified by CD19 expression.(5) A contrasting situation exists for patients
receiving rituximab, ofatumumab, and other anti-CD20 monoclonal antibodies that are used to treat
certain cancers, autoimmune diseases, or for B-cell depletion to prevent humoral rejection in positive
crossmatch kidney transplantation. These agents block available CD20-binding sites and, therefore, the
antibody used for this flow cytometric assay cannot recognize the CD20 molecule on B cells. The
concomitant use of the CD19 marker provides information on the extent of B-cell depletion when using
this particular treatment strategy. The absolute counts of lymphocyte subsets are known to be influenced
by a variety of biological factors, including hormones, the environment, and temperature. The studies on
diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell
count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 a.m. and noon,
with no change between noon and afternoon. Natural killer cell counts, on the other hand, are constant
throughout the day.(6) Circadian variations in circulating T-cell counts have been shown to be negatively
correlated with plasma cortisol concentration.(7-9) In fact, cortisol and catecholamine concentrations
control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(7) It is
generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening(10),
and during summer compared to winter.(11) These data, therefore, indicate that timing and consistency in
timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.
Useful For: Evaluation of CD19 deficiency in patients with a suspected CD19 deficiency (humoral
immunodeficiency) Confirming complete absence of B cells in suspected primary humoral
immunodeficiencies using both CD19 and CD20 markers Assessing therapeutic B-cell depletion
quantitatively (absolute counts of cells/mcL) in any clinical context, including malignancies,
autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and membranous
glomerulonephritis among others, and treatment or prevention of acute humoral rejection in positive
crossmatch renal transplant recipients This test is not useful for assessing whether B cells express the
target molecule (CD20) in the context of initiating therapeutic monoclonal anti-CD20 antibody therapy
(rituximab, ofatumumab, and tositumomab) for any of the hematological malignancies, or in other
clinical contexts, such as autoimmunity.
Interpretation: The presence of CD20+ B cells with corresponding absence of CD19 staining in
individuals not receiving anti-CD20 monoclonal antibody treatment or with clinical features of variable
primary humoral immunodeficiency may suggest an underlying CD19 deficiency, which should be
further evaluated. Absence of both CD20 and CD19 markers on B cells in blood from individuals not on
anti-CD20 monoclonal antibody treatment is consistent with complete mature and immature peripheral
B-cell depletion, which may be due to an underlying primary immunodeficiency. Patients receiving
B-cell depleting therapy with anti-CD20 antibodies can show unusual populations of B cells on
reconstitution that express either CD19 or CD20 due to a phenomenon known as trogocytosis.
Reference Values:
%CD19 B CELLS
> or =19 years: 4.6-22.1%
CD19 ABSOLUTE
> or =19 years: 56.6-417.4 cells/mcL
%CD20 B CELLS
> or =19 years: 5.0-22.3%
CD20 ABSOLUTE
> or =19 years: 74.4-441.1 cells/mcL
CD45 ABSOLUTE
18-55 years: 0.99-3.15 thou/mcL
>55 years: 1.00-3.33 thou/mcL
Clinical References: 1. Nadler LM, Ritz J, Hardy R, et al: A unique cell-surface antigen
identifying lymphoid malignancies of B-cell origin. J Clin Invest. 1981;67:134 2. Robillard N,
Avet-Loiseau H, Garand R, et al: CD20 is associated with a small mature plasma cell morphology and
t(11;14) in multiple myeloma. Blood. 2003;102(3):1070-1071 3. Pescovitz MD: Rituximab, an
anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant. 2006;6:859-866 4.
van Zelm MC, Reisli I, van der Burg M, et al: An antibody-deficiency syndrome due to mutations in the
CD19 gene. N Engl J Med. 2006;354:1901-1912 5. Kuijpers TW, Bende RJ, Baars PA, et al. CD20
deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest. 2010
Jan;120(1):214-222. doi:10.1172/JCI40231 6.Carmichael KF, Abayomi A: Analysis of diurnal variation
of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th
International Conference on AIDS, Bangkok, Thailand, 2004, Abstract B11052 7. Dimitrov S, Benedict
C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets.
Blood. 2009 May 21;113(21):5134-5143 8. Dimitrov S, Lange T, Nohroudi K, Born J: Number and
function of circulating antigen presenting cells regulated by sleep. Sleep. 2007;30:401-411 9. Kronfol Z,
Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to
hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Psychosom Med.
1997;59:42-50 10. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper
lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle
are important. J AIDS. 1990;3:144-151 11. Paglieroni TG, Holland PV: Circannual variation in
lymphocyte subsets, revisited. Transfusion. 1994;34:512-516 12. Engel ER, Walter JE. Rituximab and
eculizumab when treating nonmalignant hematologic disorders: infection risk, immunization
recommendations, and antimicrobial prophylaxis needs. Hematology Am Soc Hematol Educ Program.
2020 Dec 4;2020(1):312-318. doi:10.1182/hematology.2020000171

70380 Clinical Information: CD21 strongly stains the cytoplasm and membranes of the follicular dendritic
cells and the membranes of a subset of the mantle zone lymphocytes. Follicular dendritic cells form a
basket-weave meshwork in the germinal centers of lymphoid follicles, where they present antigens to B
cells. Diagnostically, CD21 may be useful to support a diagnosis of follicular dendritic cell sarcoma, or to
confirm the presence of lymphoid follicles.
Useful For: Identification of follicular dendritic cells and a subset of mantle zone lymphocytes
included on the slide, a scanned image of the relevant quality control tissue is available upon request; call
855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history
and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Fujihara M: Study of CD21-positive FDC-like structures in MALT

lymphoma: Does it provide helpful information for histopathological diagnosis? Pathol Int.
2010;60(9):642-643 2. Kurshumliu F, Sadiku-Zehri F, Qerimi A, et al: Divergent immunohistochemical
expression of CD21 and CD23 by follicular dendritic cells with increasing grade of follicular lymphoma.
World J Surg Oncol. 2019;17:115 doi:10.1186/s12957-019-1659-8 3. Fujihara M: Study of CD21-positive
FDC-like structures in MALT lymphoma: does it provide helpful information for histopathological
diagnosis? Pathol Int. 2010;60(9):642-643

70381 Clinical Information: CD22 is expressed on B lymphocytes. It can be used as an alternative B-cell
marker to CD20 or CD79a. Diagnostically, CD22 is useful to confirm B-cell lineage in malignant
lymphomas.
Useful For: Determining B-cell lineage

included on the slide, a scanned image of the relevant quality control tissue is available upon request; call
Clinical References: 1. Kreitman RJ, Arons E: Update on hairy cell leukemia. Clin Adv Hematol
Oncol. 2018;16(3):205-215 2. Pop LM, Barman S, Shao C, et al: A reevaluation of CD22 expression in
human lung cancer. Cancer Res. 2014;74(1):263-271 doi:10.1158/0008-5472.CAN-13-1436 3. Remon J,
Abedallaa N, Taranchon-Clermont E, et al: CD52, CD22, CD26, EG5 and IGF-1R expression in thymic
malignancies. Lung Cancer. 2017;108:168-172 doi:10.1016/j.lungcan.2017.03.019
70382 Clinical Information: CD23 strongly stains the cytoplasm and membranes of follicular dendritic
cells and the membranes of a subset of follicular mantle zone B-lymphocytes. Typically, B-cell small
lymphocytic lymphoma/chronic lymphocytic leukemias are CD5 positive and CD23 positive, while
mantle cell lymphoma is CD5 positive and CD23 negative. Antibodies to CD23 are diagnostically
useful in the classification of low-grade B-cell lymphomas.
Useful For: Identification of follicular dendritic cells Classification of low-grade B-cell lymphomas
the stain.If an interpretation is required, refer to PATHC / Pathology Consultation for a full diagnostic
upon request; call 855-516-8404. Â Interpretation of this test should be performed in the context of the
Clinical References: 1. van den Brand M, van Krieken JH: Small cell B-cell lymphoma. Diagn
Histopathol. 2015;21(10):383-390 2. Zhang XM, Aguilera N: New immunohistochemistry for B-cell
lymphoma and Hodgkin lymphoma. Arch Pathol Lab Med. 2014;138(12):1666-1672 3. Gualco G,
Natkunam Y, Bacchi CE: The spectrum of B-cell lymphoma, unclassifiable, with features intermediate
between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: a description of 10 cases.
Mod Pathol. 2012;25(5):661-674

70383 Clinical Information: CD25 is the receptor for IL2 and is expressed on activated T cells, B cells,
and macrophages. It will stain only scattered cells in normal tonsil. CD25 is expressed in certain types
of B-cell lymphoma (hairy cell leukemia) and T-cell lymphoma (adult T-cell lymphoma/leukemia
[ATLL]). An anti-CD25 therapy can be used in patients who have lymphomas that express CD25.

Clinical References: 1. Kageyama Y, Miwa H, Arakawa R, et al: Expression of CD25 fluctuates

in the leukemia-initiating cell population of CD25-positive AML. PLoS One. 2018;13(12):e0209295.
doi:10.1371/journal.pone.0209295 2. deLeeuw RJ, Kroeger DR, Kost SE, Chang PP, Webb JR, Nelson
BH: CD25 identifies a subset of CD4+FoxP3- TIL that are exhausted yet prognostically favorable in
human ovarian cancer. Cancer Immunol Res. 2015 Mar;3(3):245-253.
doi:10.1158/2326-6066.CIR-14-0146 3. Zhang W, Pan Y, Gou P, et al: Effect of xanthohumol on
Th1/Th2 balance in a breast cancer mouse model. Oncol Rep. 2018 Jan;39(1):280-288.
doi:10.3892/or.2017.6094 4. Liu Y, Zhang H, Wang Z, Wu P, Gong W: 5-Hydroxytryptamine1a
receptors on tumour cells induce immune evasion in lung adenocarcinoma patients with depression via
autophagy/pSTAT3. Eur J Cancer. 2019 Jun;114:8-24. doi:10.1016/j.ejca.2019.03.017
CD273 CD273 (PD-L2) Immunostain, Technical Component Only

601986
Clinical Information: CD273 also known as programmed cell death 1-ligand 2 (PD-L2) regulates
T-cell activation in addition to immune responses and is a member of the B7 family of cell surface
ligands. CD273 (PD-L2) is useful in the distinction of primary mediastinal large B cell lymphoma
(PMBL) from diffuse large B cell lymphoma (DLBCL).
Useful For: Differentiation of primary mediastinal large B-cell lymphoma (PMLBL) from diffuse large
B cell-lymphoma (DLBCL)
of second opinion of the case. The positive and negative controls are verified as showing appropriate
immunoreactivity and documentation is retained at Mayo Clinic in Rochester. If a control tissue is not
Clinical References: 1. Chong LC, Twa DDW, Mottok A, et al: Comprehensive characterization of
programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. Blood. 2016 Sep
1;128(9):1206-1213 2. Shin S, Jeon YK, Kim P, et al: Clinicopathologic analysis of PD-L1 and PD-L2
expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol. 2016
Feb;23:694-702 3. Shi M, Roemer MGM, Chapuy B, et al: Expression of programmed cell death 1 ligand
2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and
associated with PDCD1LG2 copy gain. Am J Surg Pathol. 2014 Dec;38(12):1715-1723
CD279 CD279 (PD-1) Immunostain, Technical Component Only

70417 Clinical Information: CD279 (cluster of differentiation 279 or programmed cell death 1: PD-1) is an
immunoregulatory receptor highly expressed by follicular T helper cells, and its expression has also been
shown in the neoplastic counterpart of this T-cell subset, angioimmunoblastic T-cell lymphoma. This
molecule interacts with PD-L1 (B7H1) expressed on follicular dendritic cells and other cell types, which
serves to attenuate T-cell activation. In the appropriate histologic context, a background rich in
CD279-positive T cells can support a diagnosis of nodular lymphocyte-predominant Hodgkin lymphoma.
Useful For: Identification of follicular T helper cells Phenotyping of angioimmunoblastic T-cell

lymphoma
included on the slide, a scanned image of the relevant quality control tissue is available upon request;
contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's
Clinical References: 1. Wada DA, Wilcox RA, Harrington SM, Kwon ED, Ansell SM, Comfere NI:
Programmed death 1 is expressed in cutaneous infiltrates of mycosis fungoides and Sezary syndrome. Am
J Hematol. 2011;86:325-327 doi: 10.1002/ajh.21960 2. Steele KE, Brown C: Multiplex
immunohistochemistry for image analysis of tertiary lymphoid structures in cancer. Methods Mol Biol.
2018;1845:87-98 doi: 10.1007/978-1-4939-8709-2_6 3. Cogbill CH, Swerdlow SH, Gibson SE: Utility of
CD279/PD-1 immunohistochemistry in the evaluation of benign and neoplastic T-cell-rich bone marrow
infiltrates. Am J Clin Pathol. 2014;142(1):88-98 doi: 10.1309/AJCPWF77VOGNOVZU 4. Cetinozman F,
Jansen PM, Willemze R: Expression of programmed death-1 in primary cutaneous CD4-positive
small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo-T-cell lymphoma, and other types
of cutaneous T-cell lymphoma. Am J Surg Pathol. 2012;36(1):109-116
doi:10.1097/PAS.0b013e318230df87

Current 70391
Clinical Information: CD3 (cluster of differentiation 3) is part of the T-cell antigen receptor
complex found on the surface of T lymphocytes. In paraffin sections, antibodies to CD3 will also react
with a subset of natural killer cells that express the cytoplasmic epsilon chain of CD3. In normal tonsil,
the T cells predominate in the interfollicular regions. Diagnostically, antibodies to CD3 are useful in
demonstrating T-cell lineage of malignant lymphomas.
Useful For: Demonstrating T-cell lineage

Clinical References: 1. Cooper R, Papworth NJ, Harris C, et al: Counting intraepithelial

lymphocytes: A comparison between routine staining and CD3 immunohistochemistry. Int J Surg
Pathol. 2020 Jun;28(4):367-370. doi: 10.1177/1066896919894644 2. Toki MI, Merritt CR, Wong PF, et
al: High-plex predictive marker discovery for melanoma immunotherapy-treated patients using digital
spatial profiling. Clin Cancer Res. 2019 Sep 15;25(18):5503-5512. doi:
10.1158/1078-0432.CCR-19-0104 3. Moradi-Kalbolandi S, Sharifi-K A, Darvishi B, et al: Evaluation
the potential of recombinant anti-CD3 nanobody on immunomodulatory function. Mol Immunol. 2020
Feb;118:174-181. doi: 10.1016/j.molimm.2019.12.017

70385 Clinical Information: CD30 is a member of the tumor necrosis factor receptor (TNF-R)
superfamily. Expression of CD30 can also be seen in embryonal carcinomas, malignant melanomas,
mesenchymal tumors, and activated T and B lymphocytes and plasma cells. Reed-Sternberg cells of
classic Hodgkin lymphoma, as well as the neoplastic cells of anaplastic large cell lymphoma, express
CD30.
Useful For: Identification of CD30 expression in a variety of neoplasms

the stain. If an interpretation is required order PATHC / Pathology Consultation for a full diagnostic
Clinical References: 1. Goyal A, Patel S, Goyal K, Morgan EA, Foreman RK: Variable loss of
CD30 expression by immunohistochemistry in recurrent cutaneous CD30+ lymphoid neoplasms treated
with brentuximab vedotin. J Cutan Pathol. 2019:Nov;46(11):823-829. doi: 10.1111/cup.13545 2.
Bossard C, Dobay MP, Parrens M, et al: Immunohistochemistry as a valuable tool to assess CD30
expression in peripheral T-cell lymphomas: high correlation with mRNA levels. Blood. 2014:Nov
6;124(19):2983-2986. doi: 10.1182/blood-2014-07-584953 3. Sabattini E, Pizzi M, Tabanelli V, et al:
CD30 expression in peripheral T-cell lymphomas. Haematologica. 2013;98(8):e81-e82
CD303 CD303 (BDCA-2) Immunostain, Technical Component Only

607891 Clinical Information: CD303 (BDCA-2) is a highly specific marker for normal and neoplastic
plasmacytoid dendritic cells (PDC) and may be useful as a specific marker for the diagnosis of blastic
plasmacytoid dendritic cell neoplasm (BPDCN). CD303 (BDCA-2) is expressed in the
cytoplasm/membrane of plasmacytoid dendritic cells.
Useful For: The diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN)
is performed). If diagnostic consultation by a pathologist is required order PATHC / Pathology
Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If
a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is
available upon request; call 855-516-8404. Interpretation of this test should be performed in the context of
Clinical References: 1. Boiocchi L, Lonardi S, Vermi W, et al: BDCA-2 (CD303): a highly specific
marker for normal and neoplastic plasmacytoid dendritic cells. Blood 2013;122:296-297 2. Julia F, Dalle
S, Duru G, et al: Blastic plasmacytoid dendritic cell neoplasms: Clinico-immunohistochemical
correlations in a series of 91 patients. Am J Surg Pathol 2014;38:673-680 3. Ohe R, Aung N, Shiono Y, et
al: Detection of Minimal Bone Marrow involvement of Blastic Plasmacytoid Dendritic Cell Neoplastic
Cells - CD303 immunostaining as a diagnostic tool. J Clin Exp Hematopathol 2018;58(1):1-9 4. Sangle N,
Schmidt R, Patel J, et al: Optimized immunohistochemical panel to differentiate myeloid sarcoma from
blastic plasmacytoid dendritic cell neoplasm. Mod Pathol 2014;27:1137-1143

70386 Clinical Information: CD31 (cluster of differentiation 31) is expressed on endothelial cells, showing
some membrane and occasional cytoplasmic staining. It is not expressed on discontinuous endothelium
(eg, splenic red pulp). It is also expressed on megakaryocytes, histiocytes, plasma cells, and T-cell
subsets. Tonsil sections will exhibit endothelial positivity in vessels primarily located in connective tissue
areas around follicles and near the epithelial borders. Diagnostically, CD31 expression can confirm a
diagnosis of angiosarcoma, a neoplasm of endothelial cells.
Useful For: Marker of endothelial cells

Interpretation: This test does not include pathologist interpretation: only technical performance of the
stain. If an interpretation is required order PATHC / Pathology Consultation for a full diagnostic
request. Contact 855-516-8404. Interpretation of this test should be performed in the context of the
Clinical References: 1. Patel SD, Peterson A, Bartczak A, et al: Primary cardiac angiosarcoma - a
review. Med Sci Monit. 2014;20:103-109. doi: 10.12659/MSM.889875 2. Sullivan HC, Edgar MA,
Cohen C, Kovach CK, Hookim K, Reid MD: The utility of ERG, CD31 and CD34 in the cytological
diagnosis of angiosarcoma: an analysis of 25 cases. J Clin Pathol. 2014;68(1):44-50. doi:
10.1136/jclinpath-2014-202629 3. Rao P, Lahat G, Arnold C, et al: Angiosarcoma: A tissue microarray
study with diagnostic implications. Am J Dermatopathol. 2013;35(4):432-437. doi:
10.1097/DAD.0b013e318271295a

70387 Clinical Information: CD33 is a transmembrane protein that is a member of the sialic acid-binding
immunoglobulin-like lactic (Siglec) family. The exact function of CD33 is not known, but it may be
involved in cell to cell adhesion. It is not expressed on hematopoietic stem cells but is expressed on
maturing myelomonocytic cells. As granulocytes mature, there is progressive down regulation of CD33.
Monocytes and macrophage/histiocytic cells maintain strong expression of CD33. In normal bone
marrow, weak to moderate CD33 staining is seen on granulocytic and monocytic precursors, with strong
staining in scattered mast cells. CD33 staining is useful for diagnosis of myeloid neoplasms and
classification of acute leukemias. A therapeutic antibody targeting CD33 (gemtuzumab/Myelotarg) is
available.
Useful For: Classification of myeloid neoplasms and acute leukemias
Clinical References: 1. Soeno T, Katoh H, Ishii S, et al: CD33+ immature myeloid cells critically
predict recurrence in advanced gastric cancer. J Surg Res. 2020;245:552-563 2. Wadai GM, Hussain
TA, Hussain MJ: Detect the level of expression of Cluster Differentiation (CD) marker (CD13 and
CD33) in acute myeloid leukamia Iraqi patients. Al-Kufa University Journal for Biology. Special
Second International Scientific Conference for the Life Sciences. 2016;113-116 3. Kenderian SS, Ruella
M, Shestova O, et al: CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity
against human acute myeloid leukemia. Leukemia. 2015;29(8):1637-1647

70388 Clinical Information: CD34 is 115 kDa membrane associated antigen found on human
hematopoietic progenitor cells and vascular endothelial cells. In normal tonsil sections, antibodies to
CD34 strongly stain vascular endothelial cells. CD34 is used as a marker of immaturity in the setting of
acute myeloid leukemia or B lymphoblastic leukemia. It is also useful in the diagnosis of
gastrointestinal stromal tumors, solitary fibrous tumors, and angiosarcomas.
Useful For: A marker of immaturity in the setting of acute myeloid leukemia or B lymphoblastic
leukemia The diagnosis of gastrointestinal stromal tumors, solitary fibrous tumors, and angiosarcomas
Clinical References: 1. Lopez-Nunez O, Surrey LF, Alaggio R, Fritchie KJ, John I: Novel
PPP1CB-ALK fusion in spindle cell tumor defined by S100 and CD34 coexpression and distinctive
stromal and perivascular hyalinization. Genes Chromosomes Cancer. 2020;59(8):495-499. doi:
10.1002/gcc.22844 2. Matoso A, Epstein JI: Epithelioid angiosarcoma of the bladder: A series of 9
cases. Am J Surg Pathol. 2015;39(10):1377-1382. doi: 10.1097/PAS.0000000000000444 3. Stanek J,
Abdaljaleel M: CD34 immunostain increases the sensitivity of placental diagnosis of fetal vascular
malperfusion in stillbirth. Placenta. 2019;77:30-38. doi: 10.1016/j.placenta.2019.02.001 4. Sardina LA,
Piliang M, Bergfeld WF: Diagnostic value of CD34 and calretinin immunostaining in the diagnosis of
proliferating tricholemmal tumor and trichoblastoma [published online ahead of print, 2019 Apr 23]. Int
J Dermatol. 2019;10.1111/ijd.14461. doi: 10.1111/ijd.14461

70389 Clinical Information: CD35 (cluster of differentiation 35) stains the membrane and cytoplasm of
follicular dendritic cells and granulocytes. Follicular dendritic cells form a basketweave meshwork in
the germinal centers of lymphoid follicles, where they present antigens to B cells. CD35 is useful in the
diagnosis of follicular dendritic-cell sarcoma.
Useful For: Identification of follicular dendritic cells and granulocytes

Clinical References: 1. Durham BH. Molecular characterization of the histiocytoses: Neoplasia of

dendritic cells and macrophages. Semin Cell Dev Biol. 2019 Feb;86:62-76. doi:
10.1016/j.semcdb.2018.03.002 2. Duan GJ, Wu YL, Sun H, Lang L, Chen ZW, Yan XC. Primary
follicular dendritic cell sarcoma of the urinary bladder: the first case report and potential diagnostic
pitfalls. Diagn Pathol. 2017 Apr 24;12(1):35. doi: 10.1186/s13000-017-0625-4 3. Liu H, Xiang C, Wu M,
Hu S. Follicular dendritic cell sarcoma with co-expression of CD4 and CD30 mimics anaplastic large cell
lymphoma. Front Oncol. 2020 May 29;10:876. doi: 10.3389/fonc.2020.00876

70390 Clinical Information: CD38 (cluster of differentiation 38) is expressed in a variety of cell types
including hematopoietic precursors, plasma cells, germinal center B cells (weakly), a subset of T and NK
cells, erythrocytes, platelets, prostatic epithelium, and smooth and striated muscle cells. Its expression
maybe useful in the diagnosis of lymphoproliferative and plasma cell proliferative disorders.
Useful For: Classification of lymphoproliferative and plasma cell proliferative disorders

diagnostic evaluation or second opinion of the case. Â The positive and negative controls are verified as
Clinical References: 1. Cole S, Walsh A, Yin X, et al: Integrative analysis reveals CD38 as a
therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus
erythematosus. Arthritis Res Ther. 2018;20:85. doi: 10.1186/s13075-018-1578-z 2. Sanchez L, Wang Y,
Siegel DS, et al: Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple
myeloma. J Hematol Oncol. 2016;9:51. doi: 10.1186/s13045-016-0283-0 3. Sahoo D, Wei W, Auman H,
et al. Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer. Oncotarget.
2018;9(5):6550-6561. doi: 10.18632/oncotarget.23973
TCD4 CD4 Count for Immune Monitoring, Blood

84348 Clinical Information: Lymphocytes in peripheral blood (circulation) are heterogeneous and can be
broadly classified into T cells, B cells, and natural killer cells. There are various subsets of each of these
individual populations with specific cell-surface markers and function. This assay provides absolute
(cells/mcL) and relative (%) quantitation for total T cells and CD4+ and CD8+ T-cell subsets, in addition
to a total lymphocyte count (CD45+). Each of these lymphocyte subpopulations have distinct effector and
regulatory functions and are maintained in homeostasis under normal physiological conditions. Each of
these lymphocyte subsets can be identified by a combination of 1 or more cell surface markers. The CD3
antigen is a pan-T-cell marker, and T cells can be further divided into 2 broad categories, based on the
expression of CD4 or CD8 coreceptors. The absolute counts of lymphocyte subsets are known to be
influenced by a variety of biological factors, including hormones, the environment, and temperature. The
studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in
CD4 T-cell count throughout the day, while CD8 T cells increase between 8:30 a.m. and noon with no
change between noon and afternoon.(1) Circadian variations in circulating T-cell counts have been shown
to be negatively correlated with plasma cortisol concentration.(2-4) In fact, cortisol and catecholamine
concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T
cells.(2) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared to the
evening(5) and during summer compared to winter.(6) These data, therefore, indicate that timing and
consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte
subsets. Abnormalities in the number and percent of CD3, CD4, and CD8 T cells have been described in a
number of different disease conditions. In patients who are infected with HIV, the CD4 count is measured
for AIDS diagnosis and for initiation of antiviral therapy. The progressive loss of CD4 T lymphocytes in
patients infected with HIV is associated with increased infections and complications. The Public Health
Service has recommended that all HIV-positive patients be tested every 3 to 6 months for the level of
CD4 T lymphocytes. Basic T-cell subset quantitation is also very useful in the evaluation of patients with
primary cellular immunodeficiencies of all ages, including follow-up for newborn screening for severe
combined immunodeficiency and immune monitoring following immunosuppressive therapy for
transplantation, autoimmunity, or any other relevant clinical condition where immunomodulatory
treatment is used, and the T-cell compartment is specifically affected. It is also helpful as a preliminary
screening assay for gross quantitative anomalies in T cells, whether related to malignancies or infection.
Useful For: Serial monitoring of CD4 T cell count in patients who are HIV-positive Follow-up and
diagnostic evaluation of primary cellular immunodeficiencies, including severe combined
immunodeficiency T-cell immune monitoring following immunosuppressive therapy for
transplantation, autoimmunity, and other immunological conditions where such treatment is utilized
Assessment of T-cell immune reconstitution post hematopoietic cell transplantation Early screening of
gross quantitative anomalies in T cells in infection or malignancies
Interpretation: HIV treatment guidelines from the US Department of Health and Human Services
and the International Antiviral Society USA Panel recommend antiviral treatment in all patients with
HIV infection, regardless of CD4 T-cell count.(7,8) Additionally, antibiotic prophylaxis for
Pneumocystis jiroveci infection is recommended for patients with CD4 counts below 200 cells/mcL. For
other opportunistic infections, see the recommendations from the Centers for Disease Control and
Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious
Diseases Society of America.(9)
Reference Values:
Clinical References: 1. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte

AIDS, Bangkok, Thailand, 2004, Abstract B11052 2. Dimitrov S, Benedict C, Heutling D, Westermann
J, Born J, Lange T: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets.
Blood. 2009 May 21;113(21):5134-5143 3. Dimitrov S, Lange T, Nohroudi K, Born J: Number and
function of circulating antigen presenting cells regulated by sleep. Sleep. 2007 Apr;30(4):401-411 4.
Kronfol Z, Nair M, Zhang Q, Hill EE, Brown MB: Circadian immune measures in healthy volunteers:
relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters.
Psychosom Med. 1997 Jan-Feb;59(1):42-50 5. Malone JL, Simms TE, Gray GC, Wagner KF, Burge JR,
Burke DS: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients:
total lymphocyte count fluctuations and diurnal cycle are important. J Acquir Immune Defic Syndr.
1990;3(2):144-151 6. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited.
Transfusion. 1994 Jun;34(6):512-516 7. Panel on Antiretroviral Guidelines for Adults and Adolescents:
Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of
Health and Human Services; Updated January 20, 2022. Accessed April 4, 2022. Available at
https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/guidelines-adult-adolescent-arv.pdf
8. Thompson MA, Horberg MA, Agwu AL, et al: Primary care guidance for persons with human
immunodeficiency virus: 2020 update by the HIV Medicine Association of the Infectious Diseases
Society of America. Clin Infect Dis. 2021 Dec 6;73(11):e3572-e3605. Erratum in: Clin Infect Dis. 2021
Dec 08 9. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the
prevention and treatment of opportunistic infections in adults and adolescents with HIV:
recommendations from the Centers for Disease Control and Prevention, the National Institutes of
Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Department
of Health and Human Services; Updated February 17, 2022. Accessed April 4, 2022. Available at
https://clinicalinfo.hiv.gov/en/guidelines
CD4NY CD4 Count for Monitoring, New York, Blood
28334 Clinical Information: Lymphocytes in peripheral blood (circulation) are heterogeneous and can be
broadly classified into T cells, B cells, and natural killer cells. There are various subsets of each of these
individual populations with specific cell-surface markers and function. This assay provides absolute
(cells/mcL) and relative (%) quantitation for total T cells and CD4+ and CD8+ T-cell subsets, in addition
to a total lymphocyte count (CD45+). Each of these lymphocyte subpopulations have distinct effector and
regulatory functions and are maintained in homeostasis under normal physiological conditions. Each of
these lymphocyte subsets can be identified by a combination of 1 or more cell surface markers. The CD3
antigen is a pan T-cell marker, and T cells can be further divided into 2 broad categories, based on the
expression of CD4 or CD8 coreceptors. The absolute counts of lymphocyte subsets are known to be
influenced by a variety of biological factors, including hormones, the environment, and temperature. The
studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in
CD4 T-cell count throughout the day, while CD8 T cells increase between 8:30 a.m. and noon with no
change between noon and afternoon.(1) Circadian variations in circulating T-cell counts have been shown
to be negatively correlated with plasma cortisol concentration.(2-4) In fact, cortisol and catecholamine
concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T
cells.(2) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared to the
evening(5) and during summer compared to winter.(6) These data therefore indicate that timing and
consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte
subsets. Abnormalities in the number and percent of CD3, CD4, and CD8 T cells have been described in a
number of different disease conditions. In patients who are infected with HIV, the CD4 count is measured
for AIDS diagnosis and for initiation of antiviral therapy. The progressive loss of CD4 T lymphocytes in
patients infected with HIV is associated with increased infections and complications. The Public Health
Service has recommended that all patients who are HIV-positive be tested every 3 to 6 months for the
level of CD4 T lymphocytes. Basic T-cell subset quantitation is also very useful in the evaluation of
patients with primary cellular immunodeficiencies of all ages, including follow-up for newborn screening
for severe combined immunodeficiency and immune monitoring following immunosuppressive therapy
for transplantation, autoimmunity, or any other relevant clinical condition where immunomodulatory
treatment is used, and the T-cell compartment is specifically affected. It is also helpful as a preliminary
screening assay for gross quantitative anomalies in T cells, whether related to malignancies or infection.
Useful For: Only orderable by New York clients Serial monitoring of CD4 T-cell count in patients
who are HIV-positive Follow-up and diagnostic evaluation of primary cellular immunodeficiencies,
including severe combined immunodeficiency T-cell immune monitoring following immunosuppressive
therapy for transplantation, autoimmunity, and other immunological conditions where such treatment is
utilized Assessment of T-cell immune reconstitution post hematopoietic cell transplantation Early
screening of gross quantitative anomalies in T cells in infection or malignancies
Interpretation: HIV treatment guidelines from the US Department of Health and Human Services and
the International Antiviral Society-USA Panel recommend antiviral treatment in all patients with HIV
infection, regardless of CD4 T-cell count.(7,8) Additionally, antibiotic prophylaxis for Pneumocystis
jiroveci infection is recommended for patients with a CD4 count below 200 cells/mcL. For other
opportunistic infections, see the recommendations from the Centers for Disease Control and Prevention,
the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of
America.(9)
Reference Values:
Clinical References: 1. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte

AIDS, Bangkok, Thailand, 2004, Abstract # B11052. Afr J Med Med Sci. 2006 Mar;35(1):53-57 2.
Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in
T-cell subsets. Blood. 2009 May 21;113(21):5134-5143 3. Dimitrov S, Lange T, Nohroudi K, Born J:
Number and function of circulating antigen presenting cells regulated by sleep. Sleep. 2007
Apr;30(4):401-411 4. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy
volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic
neurotransmitters. Psychosom Med. Jan-Feb 1997;59(1):42-50 5. Malone JL, Simms TE, Gray GC, et al:
Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total
lymphocyte count fluctuations and diurnal cycle are important. J AIDS. 1990;(3):144-151 6. Paglieroni
TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion. 1994
Jun;34(6):512-516 7. Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the
use of antiretroviral agents in adults and adolescents living with HIV. Department of Health and Human
Services; Updated January 20, 2022. Accessed April 4, 2022. Available at
https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/guidelines-adult-adolescent-arv.pdf 8.
Thompson MA, Horberg MA, Agwu AL, et al: Primary care guidance for persons with human
immunodeficiency virus: 2020 update by the HIV Medicine Association of the Infectious Diseases
Society of America. Clin Infect Dis. 2021 Dec 06;73(11):e3572-e3605. Erratum in: Clin Infect Dis. 2021
Dec 08 9. Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the
prevention and treatment of opportunistic infections in adults and adolescents with HIV:
recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health,
and the HIV Medicine Association of the Infectious Diseases Society of America. Department of Health
and Human Services; Updated February 17, 2022. Accessed April 4, 2022. Available at
https://clinicalinfo.hiv.gov/en/guidelines

70393 Clinical Information: CD4 (cluster of differentiation 4) is expressed on a subset of T cells (T
helper cells), histiocytes, and monocytes. In normal tonsil, the T cells predominate in interfollicular
regions. This immunostain is also used to support T cell or histiocytic lineage in hematolymphoid
neoplasms.
Useful For: Identification of T helper cells, histiocytes, and monocytes

Clinical References: 1. Kristensen LK, Frohlich C, Christensen C, et al: CD4(+) and CD8a (+)
PET imaging predicts response to novel PD-1 checkpoint inhibitor: studies of Sym021 in syngeneic
mouse cancer models. Theranostics. 2019 Oct 18;9(26):8221-8238. doi: 10.7150/thno.37513 2. Prat A,
Navarro A, Pare L, et al: Immune-related gene expression profiling after PD-1 blockade in non-small
cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma. Cancer Res. 2017 Jul
1;77(13):3540-3550. doi: 10.1158/0008-5472.CAN-16-3556 3. Sharma A, Subudhi SK, Blando J, et al:
Anti-CTLA-4 immunotherapy does not deplete FOXP3(+) regulatory T cells (Tregs) in human cancers.
Clin Cancer Res. 2019 Feb 15;25(4):1233-1238. doi: 10.1158/1078-0432.CCR-18-0762
CD4RT CD4 T-Cell Recent Thymic Emigrants, Blood

89504 Clinical Information: Naive T cells are generated in the thymus and exported to peripheral blood
to form the peripheral T-cell repertoire. There is a decrease in naive T cells derived from the thymus
with age due to age-related decline in thymic output. Recent thymic emigrants (RTE) typically refers to
those populations of naive T cells that have not diluted their TREC (T-cell receptor excision circles)
copies by homeostatic or antigen-driven cell division. Naive T cells can be long-lived in the periphery
and postpuberty, and in adults, peripheral T-cell homeostasis is maintained by a balance of thymic
output and peripheral T-cell expansion and this proportion changes with age. In infants and prepubertal
children, the T-cell repertoire is largely maintained by thymic-derived naive T cells. RTE express TREC
indicative of naive T cells derived from the thymus.(1) In the CD4 T-cell compartment, it has been
shown that naive CD45RA+ T cells coexpressing CD31 had a higher frequency of TREC compared to
T cells lacking CD31.(2) The higher proportion of TREC+ naive T cells indicate a more recent thymic
ontogeny since TREC can be diluted by cell division (since they are extrachromosomal). It has been
shown that CD31+CD4+ T cells continue to possess a relatively higher proportion of TREC despite an
age-related 10-fold reduction after the neonatal period.(3) CD4 RTE (CD31+CD4+CD45RA+) have
longer telomeres and higher telomerase activity, which, along with the increased frequency of TREC
positivity, suggests a population of T cells with low replicative history.(3) The same study has also
shown that CD31+ CD4+ T cells are an appropriate cell population to evaluate thymic reconstitution in
lymphopenic children post-hematopoietic cell transplant.(3) A Mayo study (unpublished) shows that the
CD31 marker correlates with TREC-enriched T cells across the spectrum of age and correlates with
thymic recovery in adults after autologous hematopoietic cell transplantation.(4) CD31+ CD4 RTE have
also been used to evaluate T-cell homeostatic anomalies in patients with relapsing-remitting multiple
sclerosis.(5) For patients with DiGeorge syndrome (DGS)-a cellular immunodeficiency associated with
other congenital problems including cardiac defects, facial dysmorphism, hypoparathyroidism, and
secondary hypocalcemia, and chromosome 22q11.2 deletion (in a significant proportion of
patients)-measurement of thymic function provides valuable information on the functional phenotype,
ie, complete DGS (associated with thymic aplasia in a minority of patients) or partial DGS (generally
well-preserved thymic function seen the in the majority of patients). Thymus transplants have been
performed in patients with complete DGS but are typically not required in partial DGS. There can be
change in peripheral T-cell counts in DGS patients with age.(6)
Useful For: Evaluating thymic reconstitution in patients following hematopoietic cell transplantation,
chemotherapy, immunomodulatory therapy, and immunosuppression Evaluating thymic recovery in
patients who are HIV-positive and on highly active antiretroviral therapy Evaluating thymic output in
patients with DiGeorge syndrome or other cellular immunodeficiencies Assessing the naive T-cell
compartment in a variety of immunological contexts (autoimmunity, cancer, immunodeficiency, and
transplantation) Identification of thymic remnants post-thymectomy for malignant thymoma or as an
indicator of relapse of disease (malignant thymoma) or other contexts of thymectomy
Interpretation: The absence or reduction of CD31+CD4 recent thymic emigrants (RTE) generally
correlates with loss or reduced thymic output and changes in the naive CD4 T-cell compartment,
especially in infancy and prepubertal children. The CD4RTE result must be interpreted more cautiously in
adults due to age-related decline in thymic function and correlated with total CD4 T cell count and other
relevant immunological data. CD4 RTE measured along with TREC (TREC / T-Cell Receptor Excision
Circles (TREC) Analysis, Blood) provides a comprehensive assessment of thymopoiesis but should not be
used in adults over the sixth decade of life as clinically meaningful information on thymic function is
limited in the older population due to a physiological decline in thymic activity. To evaluate immune
reconstitution or recovery of thymopoiesis post-T-cell depletion due to post-hematopoietic cell transplant,
immunotherapy, or other clinical conditions, it is helpful to systematically (serially) measure CD4RTE
and TREC copies in the appropriate age groups.
Reference Values:
CD4 ABSOLUTE
Males
1 month-17 years: 153-1745 cells/mcL
18-70 years: 290-1,175 cells/mcL
Reference values have not been established for patients that are younger than 30 days of age.
Reference values have not been established for patients that are older than 70 years of age.
Females
1 month-17 years: 582-1630 cells/mcL
18-70 years: 457-1,766 cells/mcL
CD4 RTE %
Males
1 month-17 years: 19.4-60.9%
18-25 years: 6.4-51.0%
26-55 years: 6.4-41.7%
> or =56 years: 6.4-27.7%
Females
1 month-17 years: 25.8-68.0%
18-25 years: 6.4-51.0%
26-55 years: 6.4-41.7%
> or =56 years: 6.4-27.7%
CD4 RTE ABSOLUTE

Males
1 month-17 years: 50.0-926.0 cells/mcL
18-70 years: 42.0-399.0 cells/mcL
Females
1 month-17 years: 170.0-1007.0 cells/mcL
18-70 years: 42.0-832.0 cells/mcL
Clinical References: 1. Hassan J, Reen DJ: Human recent thymic emigrants-identification,

expansion, and survival characteristics. J Immunol. 2001 Aug 15;167(4):1970-1976 2. Kimmig S,
Przybylski GK, Schmidt CA, et al: Two subsets of naive T-helper cells with distinct T-cell receptor
excision circle content in human adult peripheral blood. J Exp Med. 2002 Mar 18;195(6):789-794 3.
Junge S, Kloeckener-Gruissem B, Zufferey R, et al: Correlation between recent thymic emigrants and
CD31+ (PECAM-1) CD4 T-cells in normal individuals during aging and in lymphopenic children. Eur J
Immunol. 2007 Nov;37(11):3270-3280 4. Dong X, Hoeltzle MV, Abraham RS: Evaluation of CD4 and
CD8 recent thymic emigrants in healthy adults and children. Unpublished data 2008 5. Duszczyszyn
DA, Beck JD, Antel J, et al: Altered naiveCD4 and CD8 T-cell homeostasis in patients with
relapsing-remitting multiple sclerosis: thymic versus peripheral (non-thymic) mechanisms. Clin Exp
Immunol. 2006 Feb;143(2):305-313 6. Nain E, Kiykim A, Ogulur I, et al. Immune system defects in
DiGeorge syndrome and association with clinical course. Scand J Immunol. 2019 Nov;90(5):e12809.
doi:10.1111/sji.12809

70392 Clinical Information: CD43 (cluster of differentiation 43) is expressed by T lymphocytes and
myeloid cells including granulocytes and precursors, monocytes, macrophages, histiocytes, plasma cells
and megakaryocytes. In normal tonsil, CD43 will mainly show staining in T lymphocytes, histiocytes
and plasma cells.
Useful For: Identification of T lymphocytes, monocytes, macrophages, granulocytes, plasma cells,

and a subset of B lymphocytes
the stain. If an interpretation is required order PATHC / Pathology Consultation for a full diagnostic
Clinical References: 1. Zargaran M, Baghaei F, Moghimbeigi A, Baghai F: Explanation for

different behavior of peripheral and central giant cell granuloma by CD44 and CD34 immunostaining. J
Investig Clin Dent. 2019 Nov;10(4):e12451. doi: 10.1111/jicd.12451 2. Xiong B, Nie Y, Tang Z, Xue
M, Zuo X: Prognostic evaluation of ALIP and CD34 immunostaining in IPSS-R subgroups of
myelodysplastic syndromes. Pathology. 2017 Aug;49(5):526-533. doi: 10.1016/j.pathol.2017.05.001 3.
Sardina LA, Piliang M, Bergfeld WF: Diagnostic value of CD34 and calretinin immunostaining in the
diagnosis of proliferating tricholemmal tumor and trichoblastoma. Int J Dermatol. 2019 Apr 23. doi:
10.1111/ijd.14461
CD45I CD45 Leukocyte Common Antigen (LCA) Immunostain,

Clinical Information: CD45 is also called leukocyte common antigen given its shared expression in
the vast majority of cells of hematolymphoid lineage. The CD45 antibody used is a cocktail of 2 clones,
PD7/26 (detects the CD45RB isoform), and 2B11 (detects a common CD45 protein). CD45 expression is
very specific and quite sensitive for cells of hematolymphoid lineage, thus, distinguishing
lymphoma/leukemia from other neoplasms. The main exception is classical Hodgkin lymphoma, in which
CD45 expression is absent.
Useful For: Aiding in distinguishing lymphoma/leukemia from other neoplasms

Clinical References: 1. D'Cruze L, Dutta R, Rao S, et al: The role of immunohistochemistry in the
analysis of the spectrum of small round cell tumours at a tertiary care centre. J Clin Diagn Res. 2013;
7(7): 1377-1382. doi: 10.7860/JCDR/2013/5127.3132 2. O'Malley DP, Auerbach A, Weiss LM: Practical
applications in immunohistochemistry: Evaluation of diffuse large B-cell lymphoma and related large
B-cell lymphomas. Arch Path Lab Med. 2015;139(9):1094-1107. doi: 10.5858/arpa.2014-0451-CP 3.
Wang H-Y, Zu Y: Diagnostic algorithm of common mature B-cell lymphomas by immunohistochemistry.
Arch Pathol Lab Med. 2017;141(9):1236-1246. doi: 10.5858/arpa.2016-0521-RA
CEE49 CD49d Cell Expression Evaluation, Varies

markers by the malignant cells prior to initiating the respective monoclonal antibody therapy. Expression
of these markers may also be required for follow-up to monitor the impact of treatment on residual normal
counterparts (eg, CD20-positive lymphocytes in patients treated with anti-CD20). The distribution of
these cellular antigens is well established in normal, reactive, and in various malignant disorders. The
laboratory has several years of experience with therapeutic antibody monitoring of Mayo Clinic patients
as part of the routine B-cell, T-cell, or acute immunophenotyping panels.
targets, specifically CD49d Determining the eligibility of patients for monoclonal antibody therapies
Interpretation: The immunophenotyping report will summarize the pattern of antigenic expression on
malignant cells and, if appropriate, the normal cellular counterparts that correspond to the therapeutic
Reference Values:
Normal individuals have B lymphocytes, T lymphocytes, or myeloid cells that express the
corresponding cell-surface antigens in question.

White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of
chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268-276 3.
Flynn JM, Byrd JC: Campath-1H monoclonal antibody therapy. Curr Opin Oncol. 2000;12:574-581 4.
Kreitman RJ, Wilson WH, Bergeron K, et al: Efficacy of the anti-CD22 recombinant immunotoxin
BL22 in chemotherapy-resistant hairy-cell leukemia. N Eng J Med. 2001;345:241-247 5. Shanafelt TD,
Geyer SM, Bone ND, et al: CD49D expression is an independent predictor of overall survival in
patients with CLL: a prognostic parameter with therapeutic potential. Br J Haematol. 2008;140:537-546

70396 Clinical Information: CD5 (cluster of differentiation 5) is expressed normally on all T cells (one of
the pan T-cell antigens). It can be aberrantly expressed by B-cell lymphomas (most commonly mantle
cell lymphoma, B-cell small lymphocytic lymphoma). Expression of CD5 is useful to support T-cell
lineage in T-cell lymphomas or to help subclassify B-cell lymphomas.
Useful For: Marker of T-cell lineage Phenotyping B-cell lymphomas

Clinical References: 1. Selves J, Long-Mira E, Mathieu MC, Rochaix P, Ilie M:

Immunohistochemistry for diagnosis of metastatic carcinomas of unknown primary site. Cancers.
2018:Apr;10(4):108. doi: 10.3390/cancers10040108 2. Haninger D, Slone S: The utility of
immunohistochemical staining for CD5 in urothelial carcinoma. American Journal of Clinical
Pathology. 2012;138(2):A036. doi.org/10.1093/ajcp/138.suppl2.267 3. Li Y, Hu S, Zuo Z, et al:
CD5-positive follicular lymphoma: clinicopathologic correlations and outcome in 88 cases. Mod Pathol.
2015 Jun; 28(6):787-798. doi: 10.1038/modpathol.2015.42
CEE52 CD52 Cell Expression Evaluation, Varies

markers by the malignant cells prior to initiating the respective monoclonal antibody therapy.
Expression of these markers may also be required for follow-up to monitor the impact of treatment on
residual normal counterparts (eg, CD20-positive lymphocytes in patients treated with anti-CD20). The
distribution of these cellular antigens is well established in normal, reactive, and in various malignant
disorders. The laboratory has several years of experience with therapeutic antibody monitoring of Mayo
Clinic patients as part of the routine B-cell, T-cell, or acute immunophenotyping panels.
targets, specifically CD52 Determining the eligibility of patients for monoclonal antibody therapies
Interpretation: The immunophenotyping report will summarize the pattern of antigenic expression on
malignant cells and, if appropriate, the normal cellular counterparts that correspond to the therapeutic
Reference Values:
Normal individuals have B lymphocytes, T lymphocytes, or myeloid cells that express the corresponding
cell-surface antigens in question.

White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric
anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268-276 3. Flynn JM,
Byrd JC: Campath-1H monoclonal antibody therapy. Curr Opin Oncol. 2000;12:574-581 4. Kreitman RJ,
Wilson WH, Bergeron K, et al: Efficacy of the anti-CD22 recombinant immunotoxin BL22 in
chemotherapy-resistant hairy-cell leukemia. N Eng J Med. 2001;345:241-247 5. Shanafelt TD, Geyer SM,
Bone ND, et al: CD49D expression is an independent predictor of overall survival in patients with CLL: a
prognostic parameter with therapeutic potential. Br J Haematol. 2008;140:537-546

70394 Clinical Information: CD56 is an adhesion molecule mediating homophilic and heterophilic
adhesion in neurons, natural killer cells, and a small subset of CD4- and CD8-positive T cells. It is
expressed in tumors with neuroendocrine differentiation (small cell lung carcinoma and neural-derived
tumors) or natural killer cell lineage (subset of lymphomas). In normal small intestine, the ganglion cells
in the muscle wall and nerves will show strong staining. Scattered lymphocytes may also be positive.
Useful For: Aiding in the identification of tumors with neuroendocrine differentiation Aiding in the
identification of natural killer cell lineage in a subset of lymphomas
Clinical References: 1. Kerekes D, Visscher DW, Hoskin TL, et al: CD56+ immune cell infiltration
and MICA are decreased in breast lobules with fibrocystic changes. Breast Cancer Res Treat.
2018;167(3):649-658. doi: 10.1007/s10549-017-4558-0 2. Skaria PE, Ahmed AA, Yin H, Nicol K, Reid
KJ, Singh V: Expression of HBME-1 and CD56 in follicular variant of papillary carcinoma in children:
An immunohistochemical study and their diagnostic utility. Pathol Res Pract. 2019;215(5):880-884. doi:
10.1016/j.prp.2019.01.031 3. Moritz AW, Schlumbrecht MP, Nadji M, Pinto A: Expression of
neuroendocrine markers in non-neuroendocrine endometrial carcinomas. Pathology. 2019;51(4):369-374.
doi:10.1016/j.pathol.2019.02.003 4. Alshenawy HA: Utility of immunohistochemical markers in
diagnosis of follicular cell derived thyroid lesions. Pathol Oncol Res. 2014;20(4):819-828. doi:
10.1007/s12253-014-9760-3

70395 Clinical Information: CD57 (cluster of differentiation 57) is present in tumors of neuroectodermal
origins; small cell lung carcinoma, carcinoid tumors, adenocarcinomas of the prostate. It is also expressed
in normal and hyperplastic prostatic epitheliums as well as in natural killer (NK) cells and a subset of T
cells.
Useful For: Marker of natural killer cells and a subset of follicular T helper cells Aiding in the
identification of tumors of neuroectodermal origin
Clinical References: 1. Fang J, Li X, Ma D, et al: Prognostic significance of tumor infiltrating

immune cells in oral squamous cell carcinoma. BMC Cancer. 2017;375(17) 2. Greenberg SA, Pinkus
JL, Amato AA, Kristensen T, Dorfman DM: Association of inclusion body myositis with T cell large
granular lymphocytic leukaemia. Brain. 2016 May;139(5):1348-1360 3. David JA, Huang JZ:
Diagnostic utility of flow cytometry analysis of reactive T cells in nodular lymphocyte-predominant
Hodgkin lymphoma. Am J Clin Pathol. 2016 Jan;145(1):107-115

70397 Clinical Information: Cluster of differentiation 61 (CD61) shows cytoplasmic staining of normal
and abnormal megakaryocytes and occasional endothelial cells. Antibodies to CD61 are most useful in
recognizing micromegakaryocytes, cytologically abnormal megakaryocytes, and megakaryoblasts in
cases of acute megakaryoblastic leukemia, myeloproliferative disorders, and myelodysplastic
syndromes.
Useful For: Identification of micromegakaryocytes, cytologically abnormal megkaryocytes, and

megakaryoblasts
Clinical References: 1. Klairmont MM, Hoskoppal D, Yadak N, Choi JK: The comparative
sensitivity of immunohistochemical markers of megakaryocytic differentiation in acute
megakaryoblastic leukemia. Am J Clin Pathol. 2018 Oct 1;150(5):461-467 2. Cicchini M, Chakrabarti
R, Kongara S, et al: Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1
activation and following parity. Autophagy. 2014;10(11):2036-2052. doi: 10.4161/auto.34398 3.
Gonzalo E, Toldos O, Martinez-Vidal MP, et al: Clinicopathologic correlations of renal
microthrombosis and inflammatory markers in proliferative lupus nephritis. Arthritis Res Ther. 2012
May 28;14(3):R126
CDKPB CD68 (KP1) Immunostain, Bone Marrow, Technical Component

603209 Only
Clinical Information: In normal tissues, CD68 KP-1 stains the cytoplasm of the granulocytes and
myeloid progenitors in the bone marrow, monocytes, and macrophages, and osteoclasts. KP-1 reacts
against a carbohydrate moiety of CD68. Although CD68 KP-1 is primarily used as a histiocytic marker,
it is not specific for histiocytes. It can also be expressed in malignant melanoma, granular cell tumors,
peripheral nerve sheath tumors, malignant fibrous histiocytoma, and other mesenchymal neoplasms and
rare carcinomas.
Useful For: Aiding in the identification of histocytic and myeloid lineage cells
Clinical References: 1. Sanchez-Espiridion B, Martin-Moreno AM, Montalban C, et al:

Immunohistochemical markers for tumor associated macrophages and survival in advanced classical
Hodgkin's lymphoma. Haematologica 2012;97:1080-1084 2. Tan KL, Scott DW, Hong F, et al:
Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma. A Correlative
Study from the E2496 Intergroup Trial. Blood 2012;120(18):3280-3287 3. Mehra N, Schnatiwinkel C,
Ergon L, et al: Comparison of multiplexed imaging mass cytometry in FFPE tissue to monoplex
immunohistochemistry. Tumor Biology 2018;78(13):3037
CDKP1 CD68 (KP1) Immunostain, Tissue, Technical Component Only

70486 Clinical Information: In normal tissues, CD68 KP-1 stains the cytoplasm of the granulocytes and
myeloid progenitors in the bone marrow, monocytes and macrophages, and osteoclasts. KP-1 reacts
against a carbohydrate moiety of CD68. Although CD68 KP-1 is primarily used as a histiocytic marker, it
is not specific for histiocytes. It can also be expressed in malignant melanoma, granular cell tumors,
peripheral nerve sheath tumors, malignant fibrous histiocytoma, and other mesenchymal neoplasms, and
rare carcinomas.
Useful For: Aids in the identification of histocytic and myeloid lineage cells
Clinical References: 1 Sanchez-Espiridion B, Martin-Moreno AM, Montalban C, et al:

Hodgkin's lymphoma. Haematologica 2012;97:1080-1084 2. Tan KL, Scott DW, Hong F, et al:
Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma. A Correlative
Study from the E2496 Intergroup Trial. Blood 2012;120(18):3280-3287 3. Mehra N, Schnatiwinkel C,
Ergon L, et al: Comparison of multiplexed imaging mass cytometry in FFPE tissue to monoplex
immunohistochemistry. Tumor Biology 2018;78(13):3037
PGM1 CD68 (PG-M1) Immunostain, Technical Component Only

70536 Clinical Information: In normal tissues, CD68 PG-M1 stains monocytes, macrophages and, to a
lesser extent, neutrophils in a cytoplasmic granular staining pattern. It has greater specificity for
monocytes and macrophages than does KP-1 but its immunohistochemical staining pattern in
non-hematolymphoid tumors has not been studied as extensively as CD68 KP-1. Diagnostically, CD68
PG-M1 is usually applied to cases of acute leukemia to demonstrate monocytic differentiation and to
cases of hematolymphoid neoplasms that are suspected to represent histiocytic sarcomas.
Useful For: Identification of monocytic differentiation Phenotyping hematolymphoid neoplasms that

are suspected to represent histiocytic sarcomas
Clinical References: 1. Sanchez-Espiridion B, Martin-Moreno AM, Montalban C, et al:

Hodgkin's lymphoma. Haematologica. 2012;97:1080-1084 2. Tan KL, Scott DW, Hong F, et al:
Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma. A correlative
study from the E2496 intergroup trial. Blood. 2012;120(18):3280-3287 3. Wobser M, Roth S, Reinartz
T, Rosenwald A, Goebeler M, Geissinger E: CD68 expression is a discriminative feature of indolent
cutaneous CD8-positive lymphoid proliferation and distinguishes this lymphoma subtype from other
CD8-positive cutaneous lymphomas. Br J Dermatol. 2015 Jun;172(6):1573-1580. doi:
10.1111/bjd.13628

70399 Clinical Information: Cluster of differentiation 7 (CD7) is expressed normally on all T cells and
natural killer cells. Expression of CD7 can be aberrantly lost in T-cell lymphomas, providing support
for a diagnosis of T-cell lymphoma.
Useful For: Identification of T cells and natural killer cells

available upon request, call 855-516-8404. Interpretation of this test should be performed in the context
of the patient's clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Chu PG, Arber DA, Weiss LM: Expression of T/NK-cell and plasma cell
antigens in non hematopoietic epithelioid neoplasms. An Immunohistochemical Study of 447 Cases.
Am J Clin Pathol 2003;120:64-70 2. Dunphy CH: Applications of flow cytometry and
immunohistochemistry to diagnostic hematopathology. Arch Pathol Lab Med 2004;128:1004-1022 3.
Higgins RA, Blankenship JE, Kinney MC: Application of immunohistochemistry in the diagnosis of
non-Hodgkin and Hodgkin lymphoma. Archives of Pathology and Laboratory Medicine
2008;132(3):441-461

70398 Clinical Information: The transferrin receptor, cluster of differentiation 71 (CD71), is highly
expressed on the surface of cells of the erythroid lineage and mediates the uptake of transferrin-iron
complexes. Transferrin receptor expression levels are highest in early erythroid precursors through the
intermediate normoblast phase, expression then decreases through the reticulocyte phase.
Useful For: Assessment of erythroid lineage

Clinical References: 1. Luchini C, Parcesepe P, Nottegar A, et al: CD71 in gestational pathology:

A versatile immunohistochemical marker with new possible applications. Appl Immunohistochem Mol
Morph.2016 Mar;24(3):215-220 2. Menon V, Thomas R, Elgueta C, et al: Comprehensive cell surface
antigen analysis identifies transferrin receptor protein-1 (CD71) as a negative selection marker for
human neuronal cells. Stem Cells. 2019 Oct;37(10):1293-1306 3. Chan KT, Choi MY, Lai KK, et al:
Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell
carcinoma. Oncol Rep. 2014 Mar;31(3):1296-1304
CD79 CD79a Immunostain, Technical Component Only

70418 Clinical Information: Cluster of differentiation 79a (CD79a) stains the cytoplasm and membrane of
B lymphocytes and megakaryocytes. CD79a is a protein expressed on the surface of B lymphocytes at all
stages of maturation, from B-lymphocyte precursors through plasma cells. Its function is to transduce the
signal of antigen binding to immunoglobulin into the cytoplasm of the B lymphocyte initiating
intracellular signaling. Antibodies to CD79a are diagnostically useful to demonstrate B-cell lineage of
acute lymphoblastic leukemia, malignant lymphomas and chronic lymphoproliferative disorders.

Clinical References: 1. Khurana S, Melody ME, Ketterling RP, et al: Molecular and phenotypic
characterization of an early T-cell precursor acute lymphoblastic lymphoma harboring PICALM-MLLT10
fusion with aberrant expression of B-cell antigens. Cancer Genet. 2020;240:40-44. doi:
10.1016/j.cancergen.2019.11.002 2. Menter T, Lundberg P, Wenzel F, et al: RUNX1 mutations can lead
to aberrant expression of CD79a and PAX5 in acute myelogenous leukemias: A potential diagnostic
pitfall. Pathobiology. 2019;86(2-3):162-166. doi: 10.1159/000493688 3. Matnani RG, Stewart RL,
Pulliam J, Jennings CD, Kesler M: Peripheral T-cell lymphoma with aberrant expression of CD19, CD20,
and CD79a: Case report and literature review. Case Rep Hematol. 2013;2013:183134. doi:
10.1155/2013/183134

70400 Clinical Information: Cluster of differentiation 8 (CD8) is expressed in a subset of T cells (cytotoxic
T cells). Antibodies to CD8 are useful diagnostically to demonstrate cytotoxic T-lymphocyte lineage of
lymphomas and chronic lymphoproliferative disorders.
Useful For: Identification of cytotoxic T cells

available upon request, call 855-516-8404. Interpretation of this test should be performed in the context of
Clinical References: 1. Tewari N, Zaitoun AM, Arora A, Madhusudan S, Ilyas M, Lobo DN: The
presence of tumour-associated lymphocytes confers a good prognosis in pancreatic ductal
adenocarcinoma: an immunohistochemical study of tissue microarrays. BMC Cancer. 2013 Sep
24;13:436. 2. Oguejiofor K, Hall J, Slater C, et al: Stromal infiltration of CD8 T cells is associated with
improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma. Br J Cancer 2015 Sep
15;113(6):886-893 3. Paulson KG, Iyer JG, Simonson WT, et al: CD8+ lymphocyte intratumoral
infiltration as a stage-independent predictor of Merkel cell carcinoma survival: a population-based study.
Am J Clin Pathol. 2014 Oct;142(4):452-458
CD99 CD99 (MIC-2) Immunostain, Technical Component Only

70508 Clinical Information: Cluster of differentiation 99 (CD99) is the product of the MIC2 gene. It is
expressed in normal tissues including some lymphocytes, pancreatic islet cells, granulosa cells of the
ovary, Sertoli cells of the testis, and ependymal cells of the central nervous system. It is strongly
expressed in Ewing sarcoma/primitive neuroectodermal tumor, distinguishing it from other small round
blue cell tumors of childhood and adolescence.
Useful For: Identification of Ewing sarcoma and primitive neuroectodermal tumors

available upon request, call 855-516-8404. Interpretation of this test should be performed in the context
of the patient's clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Nunez J, Veloda C, Liu Y, Wakely PE Jr, Silverman JF: Utility of an
immunohistochemical panel to distinguish nonductal pancreatic neoplasms in surgical pathology. Am J
Clin Pathol. 2013;140(Suppl 1):A181 doi: 10.1093/ajcp/140.suppl1.181 2. Karikari IO, Mehta AI,
Nimjee S, et al: Primary intradural extraosseous Ewing sarcoma of the spine: Case report and literature
review. Neurosurgery. 2011 Oct;69(4):E995-999. doi: 10.1227/NEU.0b013e318223b7c7 3.
Romero-Rojas AE, Diaz-Perez JA, Ariza-Serrano LM: CD99 is expressed in chordoid glioma and
suggests ependymal origin. Virchows Arch. 2012 Jan;460(1):119-122. doi: 10.1007/s00428-011-1170-2
CDKZ CDKN1C Gene, Full Gene Analysis, Varies

35385 Clinical Information: The CDKN1C gene is an imprinted gene that has been associated with
Beckwith-Wiedemann syndrome (BWS), intrauterine growth restriction, metaphyseal dysplasia, adrenal
hypoplasia congenita, and genital anomalies (IMAGe) syndrome, and Russell-Silver syndrome (RSS).
Imprinting describes a difference in gene expression based on parent of origin. The majority of
autosomal genes exhibit biallelic (maternal and paternal) expression, whereas imprinted genes are
normally expressed from only one parent. CDKN1C is typically expressed on the maternally inherited
allele. Â Beckwith-Wiedemann Syndrome: BWS is a disorder characterized by prenatal and/or
postnatal overgrowth, neonatal hypoglycemia, congenital malformations, and an increased risk for
embryonal tumors. Physical findings are variable and can include abdominal wall defects, macroglossia,
and hemihyperplasia. The predisposition for tumor development is associated with specific tumor types
such as adrenal carcinoma, nephroblastoma (Wilms tumor), hepatoblastoma, and rhabdomyosarcoma. In
infancy, BWS has a mortality rate of approximately 20%. Most cases of BWS are caused by
hypomethylation of LIT1, paternal uniparental disomy of chromosome 11, or hypermethylation of H19.
Approximately 5% to 10% of sporadic BWS cases and approximately 40% of BWS cases with a
positive family history are caused by CDKN1C variants. The appropriate first-tier test in the evaluation
of a possible diagnosis of BWS is BWRS / Beckwith-Wiedemann Syndrome/Russell-Silver Syndrome
Molecular Analysis, Varies. This test may be considered when the results of BWS methylation analysis
are negative, and there is still a strong clinical suspicion of BWS. Â Intrauterine Growth Restriction,
Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies Syndrome: Variants in
the CDKN1C gene have also been associated with IMAGe syndrome). The CDKN1C variants
associated with IMAGe syndrome tend to be missense variants occurring in the PCNA-binding domain
of the gene. Not every individual with a clinical diagnosis of IMAGe syndrome will have an identifiable
CDKN1C variant. Â Russell-Silver Syndrome: RSS is a rare genetic condition with an incidence of
approximately 1 in 100,000. RSS is characterized by pre- and postnatal growth retardation with normal
head circumference, characteristic facies, fifth finger clinodactyly, and asymmetry of the face, body,
and/or limbs. Less commonly observed clinical features include cafe au lait spots, genitourinary
anomalies, motor, speech, cognitive delays, and hypoglycemia. Â RSS is a genetically heterogeneous
condition that is associated with genetic and epigenetic alterations at chromosome 7 and the
chromosome 11p15.5 region. The majority of cases of RSS are sporadic, although familial cases have
been reported. The etiology of sporadic cases of RSS includes: hypomethylation of IC1 (H19), maternal
uniparental disomy (UPD) of chromosome 7, 11p15.5 duplications (rare), and chromosome 7
duplications (rare). CDKN1C variants have recently been identified as a cause of RSS in some families.
This test may be considered when results of RSS methylation analysis and UPD 7 studies are negative
and there is still a strong clinical suspicion of RSS.
Useful For: Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome following a normal

result on methylation analysis Â Confirming a clinical diagnosis of intrauterine growth restriction,
metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) syndrome Â
Confirming a clinical diagnosis of Russell-Silver syndrome following a normal result on methylation
analysis and uniparental disomy (UPD) 7 studies.
significance.
Reference Values:
May;17(5):405-424 2. DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP, Feinberg AP:
Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann Syndrome with
cancer and birth defects. Am J Hum Genet. 2002;70:604-611 3. Choufani S, Shuman C, Weksberg R:
Beckwith-Wiedemann Syndrome. Am J Med Genet. 2010;154C:343-354 4. Romanelli V, Belinchon A,
Benito-Sanz S, et al: CDKN1C (p57[Kip2]) analysis in Beckwith-Wiedemann syndrome (BWS) patients:
Genotype-phenotype correlations, novel mutations, and polymorphisms. Am J Med Genet A.
2010;152A:1390-1397 5. Lam WWK, Hatada I, Ohishi S, et al: Analysis of germline CDKNIC
(p57[Kip2]) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel
genotype-phenotype correlation. J Med Genet. 1999;36:518-523 6. Arboleda VA, Lee H, Parnaik R, et al:
Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet.
2012;44(7):788-792
CDX2 CDX2 Immunostain, Technical Component Only

70401 Clinical Information: Caudaltype homeobox 2 (CDX2) is a transcription factor belonging to the
caudal type homeobox gene family. It is involved in regulating the proliferation and differentiation of
intestinal epithelial cells.
Useful For: Identification of carcinoma of intestinal origin

the stain. If an interpretation is required, order PATHC / Pathology Consultation for a full diagnostic
request, call 855-516-8404. Interpretation of this test should be performed in the context of the patient's
Clinical References: 1. Cecchini MJ, Walsh JC, Parfitt J, et al: CDX2 and Muc2
immunohistochemistry as prognostic markers in stage II colon cancer. Hum Pathol. 2019 Aug;90:70-79.
doi: 10.1016/j.humpath.2019.05.005 2. Chiesa-Vottero A: CDX2, SATB2, GATA3, TTF1, and PAX8
immunohistochemistry in Krukenberg tumors. Int J Gynecol Pathol. 2020 Mar;39(2):170-177. doi:
10.1097/PGP.0000000000000582 3. Masood MA, Loya A, Yusuf MA: CDX2 as a prognostic marker in
gastric cancer. Acta Gastroenterol Belg. 2016 Apr-Jun;79(2):197-200
CEBPA CEBPA Mutations, Gene Sequencing, Varies

60444 Clinical Information: Acute myeloid leukemia (AML) with an altered CCAAT/enhancer-binding
protein alpha (CEBPA) gene is a diagnostic category in the current World Health Organization (WHO)
classification of hematopoietic neoplasms.(1) In addition, CEBPA variants on both alleles (so-called
double variant status) is considered a good prognostic feature in adults with newly diagnosed AML who
have a normal karyotype or do not contain an alternate diagnostic genetic abnormality.(2,3) Thus,
evaluation for CEBPA variants is necessary for accurate diagnosis in the current classification system
and contributes prognostic information for a large group of AML patients.
Useful For: Initial evaluation of acute myeloid leukemia, both for assigning an appropriate
diagnostic subclassification and as an aid for determining prognosis This test is not intended to be used
for disease monitoring.
Interpretation: The results will be given as positive or negative for CEBPA variant; if positive, the
variant will be described, and single or double variant status will be indicated.
Reference Values:
Clinical References: 1. Swerdlow S, Campo E, Harris N, et al: WHO Classification of Tumours of

Haematopoietic and Lymphoid Tissues. 4th ed. WHO Press; 2008:109-145 2. Wouters B, Lowenberg B,
Erpelinck-Verschueren C, et al: Double CEBPA mutations, but not single CEBPA mutations, define a
subset of acute myeloid leukemia with a distinctive expression profile that is uniquely associated with a
favorable outcome. Blood. 2009;113:3088-3091 3. Pabst T, Eyholzer M, Fos J, et al: Heterogeneity
within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations
are associated with favourable prognosis. Br J Cancer. 2009;100:1343-1346 4. Pulikkan JA, Tenen DG,
Behre G: C/EBP alpha deregulation as a paradigm for leukemogenesis. Leukemia 2017;31:2279-2285
FRCE Cedar Red (Juniperus virginiana) IgE

57952 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10-0.34 Equivocal/Borderline 1
0.35-0.69 Low Positive 2 0.70-3.49 Moderate Positive 3 3.50-17.49 High Positive 4 5 6 17.50-49.99
50.0-99.99 >99.99 Very High Positive Very High Positive Very High Positive
Reference Values:
<0.35 kU/L
CEDR Cedar, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cedar Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
CELY Celery, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to celery Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
CELI Celiac Associated HLA-DQ Alpha 1 and DQ Beta 1 DNA

88906 Typing, Blood
Clinical Information: Celiac disease (gluten-sensitive enteropathy) is mediated by T lymphocytes
in patients with genetic susceptibility. This genetic association is with certain HLA genes in the class II
region (DQ alpha 1, DQ beta 1).
Useful For: Assessing risk of celiac disease

Interpretation: Most (90%-95%) patients with celiac disease have 1 or 2 copies of HLA-DQ2
haplotype (see below), while the remainder have HLA-DQ8 haplotype. Rare exceptions to these
associations have been occasionally seen. In one study of celiac disease, only 0.7% of patients with
celiac disease lacked the HLA alleles mentioned above. Results are reported as permissive,
nonpermissive, or equivocal gene pairs. It is important to realize that these genes are also present in
about 20% of people without celiac disease. Therefore, the mere presence of these genes does not prove
the presence of celiac disease or that genetic susceptibility to celiac disease is present. The HLA-DQ
molecule is composed of 2 chains: DQ alpha (encoded by HLA-DQA1 gene) and DQ beta (encoded by
HLA-DQB1 gene). HLA-DQ typing can be performed by serological or molecular methods. Currently
most laboratories perform typing by molecular methods. HLA-DQ2 and DQ8 as typed by serology are
usually based on the molecular typing of the DQB1 chain only. The current molecular method allows
typing for both the DQB1 and DQA1 chains and this has shown that there are different haplotypes of
HLA-DQ2 and DQ8. Typing of these haplotypes is important in celiac disease as they carry different
risk association. There are 2 common haplotypes of DQ2: 1. DQA1*05:01 with DQB1*02:01 also
called DQ2.5 in celiac literature 2. DQA1*02:01 with DQB1*02:02 also called DQ2.2 in celiac
literature A single haplotype (heterozygote) of DQ2.5 is permissive for presence of celiac genes.
However, only a double haplotype (homozygous) of DQ2.2 is permissive for presence of celiac genes.
There are few reports where a single haplotype of DQ2.2 is considered to be an equivocal risk. In some
cases, the DQ2.2 haplotype maybe present with a DQ7.5 haplotype (DQA1*05:05 with DQB1*03:01).
In this case, a DQ2.5 molecule can be formed by the combination of DQB1*02:02 from one
chromosome and DQA1*05:05 from the other chromosome. These cases fall in the same category as the
DQ2.5 heterozygote. There are 3 common haplotypes of DQ8: 1. DQA1*03:01 with DQB1*03:02 2.
DQA1*03:02 with DQB1*03:02 3. DQA1*03:03 with DQB1*03:02 Any single haplotype
(heterozygote) of DQ8 is permissive for celiac. Therefore, the gene pairs permissive for celiac are: 1.
Heterozygote (single copy) Â -DQA1*05:XX with DQB1*02:01 Â -DQA1*05:XX with DQB1*02:02
Â -DQA1*03:XX with DQB1*03:02 2. Homozygous (2 copies) Â -DQA1*02:01 with DQB1*02:02
Gene pairs equivocal for celiac are 1. Heterozygote (single copy) Â -DQA1*02:01 with DQB1*02:02 2.
Rare allele's types of DQ2 and DQ8 other than those listed above All other gene pair combinations are
considered nonpermissive for celiac. There are reports that specific HLA-DQ2 and DQ8 combinations
may confer different risks for the development of celiac disease.(1) A recent publication from our group
demonstrated that risk gradient of tissue transglutaminase (tTG) IgA positivity depends on specific
HLA-DQ2 and DQ8 combinations.(2) For more information, see Tissue Transglutaminase IgA
positivity.
Reference Values:
Clinical References: 1. Pietzak MM, Schofield TC, McGinniss MJ, Nakamura RM. Stratifying risk
for celiac disease in a large at-risk United States population by using HLA alleles. Clin Gastroenterol
Hepatol. 2009 Sep;7(9):966-71. doi: 10.1016/j.cgh.2009.05.028 2. Choung RS, Mills JR, Snyder MR,
Murray JA, Gandhi MJ: Celiac disease risk stratification based on HLA-DQ heterodimer (HLA-DQA1
approximately DQB1) typing in a large cohort of adults with suspected celiac disease. Hum Immunol.
2020 Feb-Mar;81(2-3):59-64. doi: 10.1016/j.humimm.2020.01.006. Available at
https://libraryguides.mayo.edu/ld.php?content_id=67330486 3. Polvi A, Arranz E, Fernandez-Arequero
M, et al: HLA-DQ2-negative celiac disease in Finland and Spain. Hum Immunol. 1998
Mar;59(3):169-175 4. Husby S, Murray JA, Katzka DA: AGA Clinical Practice Update on Diagnosis and
Monitoring of Celiac Disease-Changing Utility of Serology and Histologic Measures: Expert Review.
Gastroenterology. 2019 Mar;156(4):885-889. doi: 10.1053/j.gastro.2018.12.010 5. Raiteri A, Granito A,
Giamperoli A, Catenaro T, Negrini G, Tovoli F: Current guidelines for the management of celiac disease:
A systematic review with comparative analysis. World J Gastroenterol. 2022 Jan 7;28(1):154-175. doi:
10.3748/wjg.v28.i1.154
CDCOM Celiac Disease Comprehensive Cascade, Serum and Whole

89201 Blood
Clinical Information: Celiac disease (gluten-sensitive enteropathy, celiac sprue) results from an
immune-mediated inflammatory process following ingestion of wheat, rye, or barley proteins that occurs
in genetically susceptible individuals.(1) The inflammation in celiac disease occurs primarily in the
mucosa of the small intestine, which leads to villous atrophy. Common clinical manifestations related to
gastrointestinal inflammation include abdominal pain, malabsorption, diarrhea, and/or constipation.
Clinical symptoms of celiac disease are not restricted to the gastrointestinal tract. Other common
manifestations of celiac disease include failure to grow (delayed puberty and short stature), iron
deficiency, recurrent fetal loss, osteoporosis, chronic fatigue, recurrent aphthous stomatitis (canker sores),
dental enamel hypoplasia, and dermatitis herpetiformis. Patients with celiac disease may also present with
neuropsychiatric manifestations, including ataxia and peripheral neuropathy, and are at increased risk for
development of non-Hodgkin lymphoma. The disease is also associated with other clinical disorders
including thyroiditis, type I diabetes mellitus, Down syndrome, and IgA deficiency. Individuals with
family members who have celiac disease are at increased risk of developing the disease.(2) Genetic
susceptibility is related to specific human leukocyte antigen (HLA) markers. More than 97% of
individuals with celiac disease in the United States have DQ2 and/or DQ8 HLA markers compared to
approximately 40% of the general population. For this reason, HLA-DQ2 and HLA-DQ8 are considered
genetic risk factors for celiac disease and are required, but not sufficient, for the disease process to occur.
A definitive diagnosis of celiac disease requires a jejunal biopsy demonstrating villous atrophy.(3) Given
the invasive nature and cost of the biopsy, serologic and genetic laboratory tests may be used to identify
individuals with a high probability of having celiac disease. Because no single laboratory test can be
relied upon completely to establish a diagnosis of celiac disease, individuals with positive laboratory
results may be referred for small intestinal biopsy, thereby decreasing the number of unnecessary invasive
procedures (see Celiac Disease Comprehensive Cascade Test Algorithm). In terms of serology, celiac
disease is associated with a variety of autoantibodies, including endomysial antibody, tissue
transglutaminase (tTG), and deamidated gliadin antibodies.(4) Although the IgA isotype of these
antibodies usually predominates in celiac disease, individuals may also produce IgG isotypes, particularly
if the individual is IgA deficient. The most sensitive and specific serologic test is tTG IgA isotype, in
individuals who produce sufficient total IgA. For individuals who are IgA deficient, testing for tTG and
deamidated gliadin IgG antibodies is required. The treatment for celiac disease is maintenance of a
gluten-free diet. In most patients who adhere to this diet, concentrations of associated autoantibodies
decline, which is sometimes also accompanied by reconstitution of the small intestinal villi. In most
patients, an improvement in clinical symptoms is observed. For evaluation purposes, all serologic tests
ordered for the diagnosis of celiac disease should be performed while the patient is on a gluten-containing
diet. Once a patient has initiated the gluten-free diet, serologic testing may be repeated to assess the
response to treatment. In some patients, it may take up to 1 year for antibody titers to normalize.
Persistently elevated results suggest poor adherence to the gluten-free diet or the possibility of refractory
celiac disease. It should be noted that HLA typing is not required to establish a diagnosis of celiac disease.
Consider ordering CDSP / Celiac Disease Serology Cascade, Serum if HLA typing is not desired or has
been previously performed. See Celiac Disease Diagnostic Testing Algorithm for the recommended
approach to a patient suspected of celiac disease. An algorithm is available for monitoring the patient's
response to treatment, see Celiac Disease Routine Treatment Monitoring Algorithm
Useful For: Evaluating patients suspected of having celiac disease, including patients with
compatible symptoms, patients with atypical symptoms, and individuals at increased risk (family
history, previous diagnosis with associated disease) Comprehensive algorithmic evaluation including
human leukocyte antigen typing
Interpretation: Immunoglobulin A: Total IgA levels below the age-specific reference range suggest
either a selective IgA deficiency or a more generalized immunodeficiency. For individuals with a low or
high IgA level, additional clinical and laboratory evaluation is recommended. Some individuals may
have a partial IgA deficiency in which the IgA levels are detectable but fall below the age-adjusted
reference range. For these individuals both IgA and IgG isotypes for tissue transglutaminase (tTG) and
deamidated gliadin antibodies are recommended for the evaluation of celiac disease; tTG IgA, tTG IgG,
deamidated gliadin IgA, and deamidated gliadin IgG antibody assays are performed in this cascade. For
individuals who have selective IgA deficiency with undetectable levels of IgA, only -tTG IgG and
-deamidated gliadin IgG antibody assays are performed. HLA-DQ Typing: Approximately 90% to 95%
of patients with celiac disease have the HLA-DQ2 allele; most of the remaining patients with celiac
disease have the HLA-DQ8 allele. Individuals who do not carry either of these alleles are unlikely to
have celiac disease. However, individuals with these alleles may not, during their lifetime, develop
celiac disease. Therefore, the presence of DQ2 or DQ8 does not conclusively establish a diagnosis of
celiac disease. Individuals with DQ2 and/or DQ8 alleles, in the context of positive serology and
compatible clinical symptoms, should be referred for small intestinal biopsy. HLA typing may be
especially helpful for those patients who have begun to follow a gluten-free diet prior to a confirmed
diagnosis of celiac disease. tTG IgA/IgG Antibodies: Individuals positive for tTG antibodies of the IgA
isotype likely have celiac disease and small intestinal biopsy is recommended. For individuals with
selective IgA deficiency, testing for tTG antibodies of the IgG isotype is performed. In these
individuals, a positive tTG IgG antibody result suggests a diagnosis of celiac disease. However, just as
with the tTG IgA antibody, a biopsy should be performed to confirm the diagnosis. Negative tTG IgA
and/or IgG antibody serology does not exclude a diagnosis of celiac disease, as antibody levels decrease
over time in patients who have been following a gluten-free diet. Deamidated Gliadin IgA/IgG
Antibodies: Positivity for deamidated gliadin antibodies of the IgA isotype is suggestive of celiac
disease, and small intestinal biopsy is recommended. For individuals with selective IgA deficiency,
testing for deamidated gliadin antibodies of the IgG isotype is performed. In these individuals, a
positive deamidated gliadin IgG antibody result suggests a diagnosis of celiac disease. However, just as
with the deamidated gliadin IgA antibody, a biopsy should be performed to confirm the diagnosis.
Negative deamidated gliadin IgA and/or IgG antibody serology does not exclude a diagnosis of celiac
disease, as antibody levels decrease over time in patients who have been following a gluten-free diet.
Endomysial Antibody, IgA: Positivity for endomysial antibodies (EMA) of the IgA isotype is
suggestive of celiac disease, and small intestinal biopsy is recommended. For individuals with selective
IgA deficiency, evaluation of EMA antibodies is not indicated. Negative EMA antibody serology does
not exclude a diagnosis of celiac disease, as antibody levels decrease over time in patients who have
been following a gluten-free diet.
Reference Values:
IMMUNOGLOBULIN A (IgA)
0-<5 months: 7-37 mg/dL
15-<24 months: 36-79 mg/dL
2-<4 years: 27-246 mg/dL
4-<7 years: 29-256 mg/dL
7-<10 years: 34-274 mg/dL
10-<13 years: 42-295 mg/dL
13-<16 years: 52-319 mg/dL
16-<18 years: 60-337 mg/dL
> or =18 years: 61-356 mg/dL
HLA-DQ TYPING
Presence of DQ2 or DQ8 alleles associated with celiac disease
Clinical References: 1. Rubin JE, Crowe SE: Celiac disease. Ann Int Med. 2020
Jan;172(1):ITC1-ITC16 2. Lebwohl B, Rubio-Tapia A: Epidemiology, presentation, and diagnosis of
celiac disease. Gastroenterol. 2021 Jan;160(1):63-75 3. Rubio-Tapia A, Hill ID, Kelly, CP, et al:
American College Gastroenterology clinical guidelines: Diagnosis and management of celiac disease. Am
J Gastroenterol. 2013 May;108(5):656-676 4. Penny HA, Raju SA, Sanders DS: Progress in the
serology-based diagnosis and management of adult celiac disease. Exp Rev Gastroenterol Hepatol. 2020
Mar;14(3):147-154
CDGF Celiac Disease Gluten-Free Cascade, Serum and Whole Blood

89200 Clinical Information: Celiac disease (gluten-sensitive enteropathy, celiac sprue) results from an
immune-mediated inflammatory process following ingestion of wheat, rye, or barley proteins that occurs
in genetically susceptible individuals.(1) The inflammation in celiac disease occurs primarily in the
mucosa of the small intestine, which leads to villous atrophy. Common clinical manifestations related to
gastrointestinal inflammation include abdominal pain, malabsorption, diarrhea, and/or constipation.
Clinical symptoms of celiac disease are not restricted to the gastrointestinal tract. Other common
manifestations of celiac disease include failure to grow (delayed puberty and short stature), iron
deficiency, recurrent fetal loss, osteoporosis, chronic fatigue, recurrent aphthous stomatitis (canker sores),
dental enamel hypoplasia, and dermatitis herpetiformis. Patients with celiac disease may also present with
neuropsychiatric manifestations, including ataxia and peripheral neuropathy, and are at increased risk for
development of non-Hodgkin lymphoma. The disease is also associated with other clinical disorders
including thyroiditis, type I diabetes mellitus, Down syndrome, and IgA deficiency. Individuals with
family members who have celiac disease are at increased risk of developing the disease. Genetic
susceptibility is related to specific human leukocyte antigen (HLA) markers. More than 97% of
individuals with celiac disease in the United States have DQ2 and/or DQ8 HLA markers, compared with
approximately 40% of the general population. For this reason, HLA-DQ2 and HLA-DQ8 are considered
genetic risk factors for celiac disease and are required, but not sufficient, for the disease process to occur.
A definitive diagnosis of celiac disease requires a jejunal biopsy demonstrating villous atrophy.(3) Given
the invasive nature and cost of the biopsy, serologic and genetic laboratory tests may be used to identify
individuals with a high probability of having celiac disease. Because no single laboratory test can be
relied upon completely to establish a diagnosis of celiac disease, individuals with positive laboratory
results should be referred for small intestinal biopsy, thereby decreasing the number of unnecessary
invasive procedures (see Celiac Disease Comprehensive Cascade Test Algorithm). In terms of serology,
celiac disease is associated with a variety of autoantibodies, including endomysial, tissue transglutaminase
(tTG), and deamidated gliadin antibodies.(4) Although the IgA isotype of these antibodies usually
predominates in celiac disease, individuals may also produce IgG isotypes, particularly if the individual is
IgA deficient. The most sensitive and specific serologic test is tTG IgA isotype, in individuals who
produce sufficient total IgA. For individuals who are IgA deficient, testing for tTG and deamidated
gliadin IgG antibodies is required. The treatment for celiac disease is maintenance of a gluten-free diet. In
most patients who adhere to this diet, concentrations of associated autoantibodies decline, which is
sometimes also accompanied by reconstitution of the small intestinal villi. In most patients, an
improvement in clinical symptoms is observed. For evaluation purposes, all serologic tests ordered for the
diagnosis of celiac disease should be performed while the patient is on a gluten-containing diet. Once a
patient has initiated the gluten-free diet, serologic testing may be repeated to assess the response to
treatment. In some patients, it may take up to 1 year for antibody titers to normalize. Persistently elevated
results suggest poor adherence to the gluten-free diet or the possibility of refractory celiac disease. It
should be noted that HLA typing is not required to establish a diagnosis of celiac disease. Consider
ordering CDSP / Celiac Disease Serology Cascade, Serum if HLA typing is not desired or has been
previously performed. See Celiac Disease Diagnostic Testing Algorithm for the recommended approach
to a patient suspected of celiac disease. An algorithm is available for monitoring the patient's response to
treatment, see Celiac Disease Routine Treatment Monitoring Algorithm
Useful For: Evaluating patients suspected of having celiac disease who are currently (or were
recently) on a gluten-free diet
Interpretation: HLA-DQ Typing: Approximately 90% to 95% of patients with celiac disease have
the HLA-DQ2 allele; most of the remaining patients with celiac disease have the HLA-DQ8 allele.
Individuals who do not carry either of these alleles are unlikely to have celiac disease. For these
individuals, no further serologic testing is required. However, individuals with these alleles may not,
during their lifetime, develop celiac disease. Therefore, the presence of DQ2 or DQ8 does not
conclusively establish a diagnosis of celiac disease. For individuals with DQ2 and/or DQ8 alleles, in the
context of positive serology and compatible clinical symptoms, small intestinal biopsy is recommended.
Immunoglobulin A: Total IgA levels below the age-specific reference range suggest either a selective
IgA deficiency or a more generalized immunodeficiency. For individuals with a low or high IgA level,
additional clinical and laboratory evaluation is recommended. Some individuals may have a partial IgA
deficiency in which the IgA levels are detectable but fall below the age-adjusted reference range. For
these individuals, both IgA and IgG isotypes for tissue transglutaminase (tTG) and deamidated gliadin
antibodies are recommended for the evaluation of celiac disease. tTG IgA/IgG Antibodies: Individuals
positive for tTG antibodies of the IgA and/or IgG isotype may have celiac disease and small intestinal
biopsy is recommended. For individuals with selective IgA deficiency, testing for tTG antibodies of the
IgG isotype is indicated. In these individuals, a positive tTg IgG antibody result suggests a diagnosis of
celiac disease. However, just as with the tTG IgA antibody, a biopsy should be performed to confirm
the diagnosis. Negative tTG IgA and/or IgG antibody serology does not exclude a diagnosis of celiac
disease, as antibody levels decrease over time in patients who have been following a gluten-free diet.
Deamidated GliadinÂ IgA/IgG Antibodies: Positivity for deamidated gliadin antibodies of the IgA
and/or IgG isotype is suggestive of celiac disease, and small intestinal biopsy is recommended. For
individuals with selective IgA deficiency, testing for deamidated gliadin antibodies of the IgG isotype is
indicated. In these individuals, a positive deamidated gliadin IgG antibody result suggests a diagnosis of
celiac disease. However, just as with the deamidated gliadin IgA antibody, a biopsy should be
performed to confirm the diagnosis. Negative deamidated gliadin IgA and/or IgG antibody serology
does not exclude a diagnosis of celiac disease, as antibody levels decrease over time in patients who
have been following a gluten-free diet.
Reference Values:
HLA-DQ TYPING
Presence of DQ2 or DQ8 alleles associated with celiac disease
Clinical References: 1. Rubin JE, Crowe SE: Celiac disease. Ann Int Med. 2020
Jan;172(1):ITC1-ITC16 2. Lebwohl B, Rubio-Tapia A: Epidemiology, presentation, and diagnosis of
celiac disease. Gastroenterology. 2021 Jan;160(1):63-75 3. Rubio-Tapia A, Hill ID, Kelly, CP, et al:
American College Gastroenterology clinical guidelines: Diagnosis and management of celiac disease.
Am J Gastroenterol. 2013 May;108(5):656-676 4. Penny HA, Raju SA, Sanders DS: Progress in the
serology-based diagnosis and management of adult celiac disease. Exp Rev Gastroenterol Hepatol. 2020
Mar;14(3):147-154
CDSP Celiac Disease Serology Cascade, Serum

89199 Clinical Information: Celiac disease (gluten-sensitive enteropathy, celiac sprue) results from an
immune-mediated inflammatory process following ingestion of wheat, rye, or barley proteins that
occurs in genetically susceptible individuals.(1) The inflammation in celiac disease occurs primarily in
the mucosa of the small intestine, which leads to villous atrophy. Common clinical manifestations
related to gastrointestinal inflammation include abdominal pain, malabsorption, diarrhea, and/or
constipation. Clinical symptoms of celiac disease are not restricted to the gastrointestinal tract. Other
common manifestations of celiac disease include failure to grow (delayed puberty and short stature),
iron deficiency, recurrent fetal loss, osteoporosis, chronic fatigue, recurrent aphthous stomatitis (canker
sores), dental enamel hypoplasia, and dermatitis herpetiformis. Patients with celiac disease may also
present with neuropsychiatric manifestations, including ataxia and peripheral neuropathy, and are at
increased risk for development of non-Hodgkin lymphoma. The disease is also associated with other
clinical disorders including thyroiditis, type I diabetes mellitus, Down syndrome, and IgA deficiency.
Individuals with family members who have celiac disease are at increased risk of developing the
disease.(2) Genetic susceptibility is related to specific human leukocyte antigen (HLA) markers. More
than 97% of individuals with celiac disease in the United States have DQ2 and/or DQ8 HLA markers,
compared with approximately 40% of the general population. For this reason, HLA-DQ2 and
HLA-DQ8 are considered genetic risk factors for celiac disease and are required, but not sufficient, for
the disease process to occur. A definitive diagnosis of celiac disease requires a jejunal biopsy
demonstrating villous atrophy.(3) Given the invasive nature and cost of the biopsy, serologic and
genetic laboratory tests may be used to identify individuals with a high probability of having celiac
disease. Because no single laboratory test can be relied upon completely to establish a diagnosis of
celiac disease, individuals with positive laboratory results may be referred for small intestinal biopsy,
thereby decreasing the number of unnecessary invasive procedures (see Celiac Disease Comprehensive
Cascade Test Algorithm). In terms of serology, celiac disease is associated with a variety of
autoantibodies, including endomysial antibody, tissue transglutaminase (tTG), and deamidated gliadin
antibodies.(4) Although the IgA isotype of these antibodies usually predominates in celiac disease,
individuals may also produce IgG isotypes, particularly if the individual is IgA deficient. The most
sensitive and specific serologic test is tTG IgA isotype, in individuals who produce sufficient total IgA.
For Individuals who are IgA deficient, testing for tTG and deamidated gliadin IgG antibodies is
required. The treatment for celiac disease is maintenance of a gluten-free diet. In most patients who
adhere to this diet, concentrations of associated autoantibodies decline, which is sometimes also
accompanied by reconstitution of the small intestinal villi. In most patients, an improvement in clinical
symptoms is observed. For evaluation purposes, all serologic tests ordered for the diagnosis of celiac
disease should be performed while the patient is on a gluten-containing diet. Once a patient has initiated
the gluten-free diet, serologic testing may be repeated to assess the response to treatment. In some
patients, it may take up to 1 year for antibody titers to normalize. Persistently elevated results suggest
poor adherence to the gluten-free diet or the possibility of refractory celiac disease. See Celiac Disease
Diagnostic Testing Algorithm for the recommended approach to a patient suspected of celiac disease.
An algorithm is available for monitoring the patient's response to treatment, see Celiac Disease Routine
Treatment Monitoring Algorithm
Useful For: Evaluating patients suspected of having celiac disease, including patients with compatible
symptoms, patients with atypical symptoms, and individuals at increased risk (family history, previous
diagnosis with associated disease, positivity for HLA-DQ2 and/or DQ8)
Interpretation: Immunoglobulin A: Total IgA levels below the age-specific reference range suggest
either a selective IgA deficiency or a more generalized immunodeficiency. For individuals with a low or
high IgA level, additional clinical and laboratory evaluation is recommended. Some individuals may have
a partial IgA deficiency in which the IgA levels are detectable but fall below the age-adjusted reference
range. For these individuals, both IgA and IgG isotypes for tissue transglutaminase (tTG) and deamidated
gliadin antibodies are recommended for the evaluation of celiac disease; tTG IgA, tTG IgG, deamidated
gliadin IgA, and deamidated gliadin IgG antibody assays are performed in this cascade. For individuals
who have selective IgA deficiency or undetectable levels of IgA, only tTG IgG and deamidated gliadin
IgG antibody assays are performed. tTG IgA/IgG Antibodies: Individuals positive for tTG antibodies of
the IgA isotype likely have celiac disease and a small intestinal biopsy is recommended. For individuals
with selective IgA deficiency, testing for tTG antibodies of the IgG isotype is performed. In these
individuals, a positive tTG IgG antibody result suggests a diagnosis of celiac disease. However, just as
with the tTG IgA antibody, a biopsy should be performed to confirm the diagnosis. Negative tTG IgA
and/or IgG antibody serology does not exclude a diagnosis of celiac disease, as antibody levels decrease
over time in patients who have been following a gluten-free diet. Deamidated Gliadin IgA/IgG
Antibodies: Positivity for deamidated gliadin antibodies of the IgA isotype is suggestive of celiac disease;
small intestinal biopsy is recommended. For individuals with selective IgA deficiency, testing for
deamidated gliadin antibodies of the IgG isotype is performed. In these individuals, a positive deamidated
gliadin IgG antibody result suggests a diagnosis of celiac disease. However, just as with the deamidated
gliadin IgA antibody, a biopsy should be performed to confirm the diagnosis. Negative deamidated
gliadin IgA and/or IgG antibody serology does not exclude a diagnosis of celiac disease, as antibody
levels decrease over time in patients who have been following a gluten-free diet. Endomysial IgA
Antibodies: Positivity for endomysial antibodies (EMA) of the IgA isotype is suggestive of celiac disease,
and small intestinal biopsy is recommended. For individuals with selective IgA deficiency, evaluation of
EMA is not indicated. Negative EMA serology does not exclude a diagnosis of celiac disease as antibody
levels decrease over time in patients who have been following a gluten-free diet.
Reference Values:
Immunoglobulin A (IgA)
15-<24 months: 36-79 mg/dL
2-3 years: 27-246 mg/dL
4-6 years: 29-256 mg/dL
7-9 years: 34-274 mg/dL
10-14 years: 42-295 mg/dL
13-15 years: 52-319 mg/dL
16-17 years: 60-337 mg/dL
> or =18 years: 61-356 mg/dL
Clinical References: 1. Rubin JE, Crowe SE: Celiac disease. Ann Intern Med. 2020 Jan
7;172(1):ITC1-ITC16 2. Lebwohl B, Rubio-Tapia A: Epidemiology, presentation, and diagnosis of
celiac disease. Gastroenterology. 2021 Jan;160(1):63-75 3. Rubio-Tapia A, Hill ID, Kelly CP,
Calderwood AH, Murray JA, American College of Gastroenterology: ACG Clinical Guidelines:
Diagnosis and management of celiac disease. Am J Gastroenterol. 2013 May;108(5):656-676 4. Penny
HA, Raju SA, Sanders DS: Progress in the serology-based diagnosis and management of adult celiac
disease. Exp Rev Gastroenterol Hepatol. 2020 Mar;14(3):147-154
NCSPC Cell Concentration (Bill Only)

BFCC Cell Count and Differential, Body Fluid

608873 Clinical Information: Body fluids, other than the commonly analyzed urine and blood, include
synovial, pleural, peritoneal, and pericardial fluids. These fluids may be present in increased volumes
and may contain increased numbers of normal and abnormal cells in a variety of disease states.
Useful For: Aiding in the diagnosis of joint disease, systemic disease, inflammation, malignancy,
infection, and trauma
Interpretation: Trauma and hemorrhage may result in increased red blood cells (RBC) and white
blood cells (WBC); RBC predominate. WBC are increased in inflammatory and infectious processes:
-Neutrophils predominate in bacterial infections -Lymphocytes predominate in viral infections
-Macrophages may be increased in inflammatory and infectious processes -Eosinophils may be
increased in parasitic or fungal infections
Reference Values:
TOTAL NUCLEATED CELLS
Synovial fluid: <150/mcL
Peritoneal/pleural/pericardial fluid: <500/mcL
NEUTROPHILS
Synovial Fluid: <25%
Peritoneal/pleural/pericardial fluid: <25%
LYMPHOCYTES
Synovial fluid: <75%
MONOCYTES/MACROPHAGES
Synovial fluid: <70%
Clinical References: 1. Kjeldsberg CR, Hussong, JW: Body Fluid Analysis. ASCP Press; 2015 2.
Dyken PR, Shirley S, Trefz J, El Gammel T: Comparison of cyto-centrifugation and sedimentation
techniques for CSF cyto-morphology. Acta Cytol. 1980 Mar-Apr;24(2):167-170 3. Sheth KV:
Cerebrospinal and body fluid cell morphology through a hematologist's microscope, workshop presented
at the ASCP-CAP Joint Spring Meeting, San Diego, March 1981 4. Schumacher AH, Reginato A: Atlas
of Synovial Fluid Analysis and Crystal Identification. Lea and Febiger; 1991
BRAFB Cell-Free DNA BRAF V600, Blood

65100 Clinical Information: This test uses DNA extracted from the peripheral blood to evaluate for the
presence of BRAF V600E and V600K alterations. A positive result indicates the presence of an activating
BRAF alteration and may be useful for guiding the treatment of individuals with melanoma. Targeted
cancer therapies are defined as antibody or small molecule drugs that block the growth and spread of
cancer by interfering with specific cell molecules involved in tumor growth and progression. Multiple
targeted therapies have been approved by the FDA for treatment of specific cancers. Molecular genetic
profiling is often needed to identify targets amenable to targeted therapies and to minimize treatment costs
and therapy-associated risks.
Useful For: An alternative to invasive tissue biopsies for the determination of BRAF V600E and
V600K alterations Identification of patients with melanoma who are most likely to benefit from targeted
therapies This test is not intended for serial monitoring of patients with malignant melanoma, evaluating
patients with other malignancies, or as a screening test to identify cancer.

Clinical References: 1. Sanmamed MJ, Fernandez-Landazuri S, Rodriguez C, et al: Quantitative
cell-free circulating BRAFV600E mutation analysis by use of droplet digital PCR in the follow-up of
patients with melanoma being treated with BRAF inhibitors. Clin Chem 2015;61(1):297-304 2.
Schwarzenbach H, Hoon DS, Pantel K: Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev
Cancer 2011;11(6):426-437 3. Johnson DB, Sosman JA: Update on the targeted therapy of melanoma.
Curr Treat Options Oncol 2013;(2):280-292 4. McArthur GA, Chapman PB, Robert C, et al: Safety and
efficacy of vemurafenib in BRAF (V600E) and BRAF (V600K) mutation-positive melanoma (BRIM-3):
extended follow-up of a phase 3, randomized, open-label study. Lancet Oncol 2014 Mar;15(3):323-332
T790M Cell-Free DNA EGFR T790M Mutation Analysis, Blood

113410 Clinical Information: EGFR-targeted tyrosine kinase inhibitors (eg, gefitinib and erlotinib) have
been approved by the FDA for use in treating patients with non-small cell lung cancer (NSCLC) who
previously failed to respond to traditional chemotherapy. However, the EGFR T790M mutation is
associated with acquired resistance to tyrosine kinase inhibitor (TKI) therapy in about 60% of patients
with disease progression after initial response to erlotinib, gefitinib, or afatinib. Recent data suggest that
patients with metastatic NSCLC and the T790M mutation may benefit from osimertinib, an
FDA-approved oral TKI that inhibits both EGFR-activating mutations and the T790M mutation.
Useful For: Determination of EGFR T790M mutation status in blood specimens as an alternative to
invasive tissue biopsies Identification of patients with non-small cell lung cancer who harbor a T790M
mutation and may benefit from specific EGFR-targeted therapies

Clinical References: 1. Schwarzenbach H, Hoon DS, Pantel K: Cell-free nucleic acids as
biomarkers in cancer patients. Nat Rev Cancer 2011;11(6):426-437 2. Ettinger DS, Wood DE, Aisner DL,
et al: Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J
Natl Compr Canc Netw. 2017;15(4):504-535 3. Janne PA, Yang JC, Kim DW, et al: AZD9291 in EGFR
inhibitor-resistant non-small--cell lung cancer. N Engl J Med. 2015;372(18):1689-1699
KRASD Cell-Free DNA KRAS 12, 13, 61,146, Blood
68003 Clinical Information: Approximately 30% to 50% of colorectal cancers (CRC) have mutations in
KRAS. Most occur in hotspot regions in codons 12, 13, 61, and 146. These mutations lead to
constitutive activation of the RAS/MAPK pathway downstream of epidermal growth factor receptor
(EGFR), limiting the effectiveness of anti-EGFR therapies, such as cetuximab and panitumumab, which
inhibit ligand-mediated activation of EGFR. Therefore, identification and quantitation of these
mutations is critical in selecting the appropriate therapy. This test uses DNA extracted from peripheral
blood to evaluate for the presence of KRAS (G12A, G12C, G12D, G12R, G12S, G12V, G13D, Q61K,
Q61L, Q61R, Q61H, and A146T) mutations. A positive result indicates the presence of an activating
KRAS mutation and may be useful for guiding the treatment of individuals with colorectal cancer.
Useful For: As an alternative to invasive tissue biopsies for the determination of KRAS 12, 13,
61,146 (G12A, G12C, G12D, G12R, G12S, G12V, G13D, Q61K, Q61L, Q61R, Q61H, and A146T)
mutation status Selection of patients with colorectal cancer who are most likely to benefit from
epidermal growth factor receptor (EGFR)-targeted therapies

Clinical References: 1. Schwarzenbach H, Hoon DS, Pantel K: Cell-free nucleic acids as
biomarkers in cancer patients. Nat Rev Cancer 2011;11(6):426-437 2. Allegra CJ, Rumble BR,
Hamilton SR, et al: Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to
Predict Response to Anti-Epodermal Growth Factor Receptor Monoclonal Antibody Therapy: ASCO
Provisional Clinical Opinion update 2015. J Clin Oncol 2016 Jan 10;34(2):179-185 3. Olmedillas Lopez
S, Garcia-Olmo DC, Garcia-Arranz M, et al: KRAS G12V Mutation Detection by Droplet Digital PCR
in Circulating Cell-Free DNA of Colorectal Cancer Patients. Int J Mol Sci 2016;17:484
PIK3B Cell-Free DNA PIK3CA Test, Blood

614802 Clinical Information: More than 70% of breast cancers are hormone receptor (HR) positive and
human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-). Approximately 40% of
patients with HR+/HER2- advanced breast cancer have activating mutations in the gene PIK3CA,
inducing hyperactivation of the alpha isoform (p110 alpha) of phosphatidylinositol 3-kinase, a key
upstream component of the PI3K pathway. Mutations in PIK3CA are associated with tumor growth,
resistance to endocrine therapy, and a poor overall prognosis. Patients with HR+/HER2- advanced
breast cancer identified to have a PIK3CA mutation may be eligible for treatment with targeted kinase
inhibitor therapy (eg, alpelisib). This test uses circulating tumor DNA extracted from blood to evaluate
for the presence of 10 clinically actionable PIK3CA mutations: E542K (c.1624G>A) E542K
(c.1633G>A) E545D (c.1635G>T) E545G (c.1634A>G) E545A (c.1634A>C) H1047Y (c.3139C>T)
C420R (c.1285C>T) Q546E (c.1636C>G) H1047L (c.3140A>T) H1047R (c.3140A>G)
Useful For: Identification of hormone receptor positive and human epidermal growth factor receptor
2 negative (HR+/HER2-) advanced breast cancer tumors that may be eligible for treatment with targeted
kinase inhibitor therapy (eg, alpelisib).
Interpretation: The interpretation of molecular biomarker results includes an overview of the results
and the associated diagnostic, prognostic, and therapeutic implications.
Reference Values:
Clinical References: 1. Bachman KE, Argani P, Samuels Y, et al: The PIK3CA gene is mutated
with high frequency in human breast cancers. Cancer Biol Ther. 2004 Aug;3(8):772-775 2. Andre F,
Ciruelos E, Rubovszky G, et al: Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced
breast cancer. N Engl J Med. 2019 May 16;380(20):1929-1940 3. Andre F, Ciruelos EM, Juric D, et al:
Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth
factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann
Oncol. 2021 Feb;32(2):208-217
CNSA Central Nervous System Consultation, Autopsy, Varies

70644 Clinical Information: Difficult neurological abnormalities, including congenital anomalies,
sometimes require the assistance of a neuropathologist. This evaluation is offered to provide the careful
dissection and diagnostic experience that may be needed for unusual or rare neuropathological cases.
Useful For: Evaluation of congenital neurological disease Â Evaluation of neurodegenerative disease

Â Evaluation of cases with a complex neurological or neurosurgical history Â Evaluation of sudden
unexplained death Â This test is not intended for cases under litigation without preauthorization.
Interpretation: This request will be processed as a consultation. Appropriate stains will be performed,
and a diagnostic interpretation provided.
Reference Values:
Clinical References: 1. Collins KA, Powers JM: Autopsy procedures for the brain, spinal cord, and
neuromuscular system. In: Collins KA, Hutchins GM, eds. Autopsy Performance and Reporting. 2nd ed.
College of American Pathologists; 2003:chap 20 2. Crain BJ, Mirra SS: The autopsy in cases of
Alzheimer's Disease and other dementias. In: Collins KA, Hutchins GM, eds. Autopsy Performance and
Reporting. 2nd ed. College of American Pathologists; 2003:chap 21
CMA Centromere Antibodies, IgG, Serum

9278 Clinical Information: Centromere antibodies occur primarily in patients with the calcinosis, Raynaud
phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasis (CREST) syndrome variant of
systemic sclerosis (scleroderma). CREST syndrome is characterized by the following clinical features:
calcinosis, Raynaud phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia.(1)
Centromere antibodies were originally detected by their distinctive pattern of fine-speckled nuclear
staining on cell substrates used in the fluorescent antinuclear antibody test.(2) In subsequent studies,
centromere antibodies were found to react with several centromere proteins of 18 kDa, 80 kDa, and 140
kDa named as CENP-A, CENP-B, and CENP-C, respectively.(3) Several putative epitopes associated
with these autoantigens have been described. The CENP-B antigen is believed to be the primary
autoantigen and is recognized by all sera that contain centromere antibodies.
Useful For: Evaluating patients with clinical signs and symptoms compatible with systemic sclerosis
including skin involvement, Raynaud phenomenon, and arthralgias Aiding in the diagnosis of calcinosis,
Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasis (CREST) syndrome
Interpretation: In various reported clinical studies, centromere antibodies occur in 50% to 96% of
patients with calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasis
(CREST) syndrome. A positive test for centromere antibodies is strongly associated with CREST
syndrome. The presence of detectable levels of centromere antibodies may antedate the appearance of
diagnostic clinical features of CREST syndrome by several years.
Reference Values:
<1.0 U (negative)
Clinical References: 1. White B: Chapter 64: Systemic sclerosis. In Clinical Immunology Principles
and Practice. Second edition. Edited by R Rich, T Fleisher, W Shearer, et al. St. Louis, Mosby-Year
Book, 2001, pp 64.1-64.10 2. Tan EM, Rodnan GP, Garcia I, et al: Diversity of antinuclear antibodies in
progressive systemic sclerosis. Anti-centromere antibody and its relationship to CREST syndrome.
Arthritis Rheum 1980;23:617-625 3. Kallenberg CG: Anti-centromere antibodies (ACA). Clin Rheum
1990;9:136-139
CEAC Cephalosporium acremonium, IgE, Serum
Useful For: Establishing a diagnosis of an allergy to Cephalosporium acremonium Defining the

allergen responsible for eliciting signs and symptoms Identifying allergens: -Responsible for allergic
disease and/or anaphylactic episode -To confirm sensitization prior to beginning immunotherapy -To

Reference Values:
0 Negative

apply to all ages.
CTSU Ceramide Trihexosides and Sulfatides, Random, Urine

606147 Clinical Information: Urinary excretion of ceramide trihexosides (CT) can be suggestive of Fabry
disease, while excretion of sulfatide with or without CT can be suggestive of metachromatic
leukodystrophy, multiple sulfatase deficiency, mucolipidosis II (I-cell disease), or saposin B deficiency.
Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of the enzyme
alpha-galactosidase A (alpha-Gal A). Affected individuals accumulate glycosphingolipids in the
lysosomes throughout the body, particularly in the kidney, heart, and brain. Severity and onset of
symptoms are dependent on the amount of residual enzyme activity. Symptoms may include
acroparesthesias (pain crises), multiple angiokeratomas, reduced or absent sweating, corneal opacity,
renal insufficiency leading to end-stage renal disease, and cardiac and cerebrovascular disease. There
are renal and cardiac variant forms of Fabry disease that may be underdiagnosed. Female patients who
are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely
affected, and they may have alpha-Gal A activity in the normal range. Regardless of the severity of
symptoms, individuals with Fabry disease, may show an increased excretion of CT in urine.
Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder most
commonly caused by a deficiency of the arylsulfatase A enzyme. Various sulfatides accumulate in the
brain, nervous system, and visceral organs including the kidney and gallbladder and are excreted in the
urine. Based on age of onset, the 3 clinical forms of MLD are late-infantile, juvenile, and adult, with
late-infantile being the most common. All result in progressive neurologic changes and leukodystrophy
demonstrated on magnetic resonance imaging. Symptoms may include hypotonia, clumsiness,
diminished reflexes, slurred speech, behavioral problems, and personality changes. Individuals with
MLD show an increased urinary excretion of sulfatides without CT. Saposin B deficiency is a rare
condition with clinical features that mimic MLD; however, individuals with saposin B deficiency have
normal arylsulfatase A activity. Individuals with saposin B deficiency typically have an increased
urinary excretion of both sulfatides and CT. Low arylsulfatase A activity has been found in some
clinically normal parents and other relatives of MLD patients. Individuals with this "pseudodeficiency"
have been recognized with increasing frequency among patients with other apparently unrelated
neurologic conditions as well as among the general population. This has been associated with a fairly
common alternation in the arylsulfatase A gene (ARSA), which leads to low expression of the enzyme
(5%-20% of normal). These individuals do not have metachromatic deposits in peripheral nerve tissues,
and their urine sulfatides content is normal. Multiple sulfatase deficiency (MSD) is a rare autosomal
recessive disorder caused by a defect in SUMF1, which is required for post-translational activation of
the family of 17 sulfatase enzymes, including arylsulfatase A. The clinical features of MSD resemble
those of late-infantile MLD. Dysmorphic features similar to the mucopolysaccharidoses and ichthyosis
as seen in steroid sulfatase deficiency are also common. Individuals with MSD typically have an
increased urinary excretion of sulfatides as well as increased urinary glycosaminoglycans (MPSQU /
Mucopolysaccharides Quantitative, Random, Urine). Mucolipidosis II, also known as I-cell disease, is a
rare autosomal recessive disorder with features of both mucopolysaccharidoses and sphingolipidoses.
I-cell disease is a progressive disorder characterized by congenital or early infantile manifestations
including coarse facial features, short stature, skeletal anomalies, cardio- and hepatomegaly, and
developmental delays. Individuals with I-cell disease have abnormal oligosaccharide profiles (OLIGU /
Oligosaccharide Screen, Random, Urine) and may show an increased urinary excretion of both CT and
sulfatides.
Useful For: Identifying patients with Fabry disease Identifying patients with metachromatic
leukodystrophy Identifying patients with saposin B deficiency Identifying patients with multiple sulfatase
deficiency Identifying patients with mucolipidosis II (I-cell disease)
Interpretation: The pattern of ceramide trihexosides or sulfatide excretion will be described. A normal
pattern of excretion suggests absence of these diseases (see Cautions). Evidence of ceramide trihexoside
accumulation suggests decreased or deficient alpha-galactosidase activity, see Fabry Disease Testing
Algorithm. Evidence of sulfatide accumulation suggests decreased or deficient arylsulfatase A activity.
Follow-up with the specific enzyme assay is recommended: -ARSAW / Arylsulfatase A, Leukocytes
-ARSU / Arylsulfatase A, 24 Hour, Urine To exclude multiple sulfatase deficiency (MSD), determination
of iduronate-2-sulfatase activity is recommended. -I2SW / Iduronate-2-Sulfatase, Blood -I2SBS /
Iduronate-2-Sulfatase, Blood Spot Evidence of both ceramide trihexoside and sulfatide accumulation
suggests a diagnosis of mucolipidosis II (I-cell disease) or saposin B deficiency. Follow-up testing to
rule-out I-cell disease may include molecular analysis of the GNPTAB gene or measurement of serum
hydrolases (NAGS / Hexosaminidase A and Total Hexosaminidase, Serum) Molecular genetic testing is
required to confirm saposin B deficiency. Lysosomal Storage Disorders Diagnostic Algorithm, Part 2
Reference Values:
Clinical References: 1. Desnick RJ, Ioannou YA, Eng CM: Alpha-Galactosidase A deficiency:
Fabry disease. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online
Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Accessed July 29, 2021.
Available at https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225546984 2. Kuchar
L, Ledvinova J, Hrebicek M, et al: Prosaposin deficiency and saposin B deficiency (activator-deficient
metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and
carrying novel PSAP gene mutations. Am J Med Genet A. 2009 Feb 15;149A(4):613-621 3. Mehta A,
Hughes DA: Fabry disease. In: Pagon RA, Adam MP, Ardinger HH, eds. GeneReviews [Internet].
University of Washington; Seattle; 2002. Updated January 5, 2017. Accessed July 29, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK1828 4. Schlotawa L, Ennemann EC, Radhakrishnan K, et al: SUMF1
mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in
multiple sulfatase deficiency. Eur J Hum Genet. 2011 Mar;19(3):253-261 5. Gieselmann V, Ingeborg K:
Metachromatic leukodystrophy. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA,
eds.The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed July
29, 2021.Available at http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225546629
6. Leroy JG, Cathey SS, Friez MJ: GNPTAB-related disorders. In: Adam MP, Ardinger HH, Pagon RA,
eds. GeneReviews [Internet]. University of Washington; Seattle; 2008. Updated August 29. 2019.
Accessed July 29, 2021. Available at www.ncbi.nlm.nih.gov/books/NBK1828
SFINC Cerebrospinal Fluid (CSF) IgG Index, Spinal Fluid

2762 Clinical Information: Elevation of IgG in the cerebrospinal fluid (CSF) of patients with
inflammatory diseases of the central nervous system (CNS) such as multiple sclerosis (MS),
neurosyphilis, acute inflammatory polyradiculoneuropathy, subacute sclerosing panencephalitis may
beÂ due to local (intrathecal) synthesis of IgG. Elevations of CSF IgG or the CSF/serum IgG ratio may
also occur as a result of permeability of the blood brain barrier, and hence, a correction using albumin
measurements in CSF and serum is appropriate. The CSF index is the CSF IgG to CSF albumin ratio
compared to the serum IgG to serum albumin ratio. The CSF index is, therefore, an indicator of the
relative amount of CSF IgG compared to serum. Any increase in the index is a reflection of IgG
production in the CNS. The IgG synthesis rate is a mathematical manipulation of the CSF index data
and can also be used as a marker for CNS inflammatory diseases. The test is commonly ordered with
oligoclonal banding or immunoglobulin kappa free light chains in CSF to aid in the diagnosis of
demyelinating conditions.
Useful For: Aiding in the diagnosis of multiple sclerosis and other central nervous system
inflammatory conditions
Interpretation: Cerebrospinal fluid (CSF) IgG synthesis rate indicates the rate of increase in the
daily CSF production of IgG in milligrams per day. A result greater than 12 mg/24 hours is elevated. A
CSF index greater than 0.85 is elevated and indicative of increased synthesis of IgG.
Reference Values:
Only orderable as part of a profile. For more information see SFIG / Cerebrospinal Fluid (CSF) IgG
Index Profile, Serum and Spinal Fluid.
CSF index: 0.00-0.85

CSF IgG: 0.0-8.1 mg/dL
CSF albumin: 0.0-27.0 mg/dL
CSF IgG/albumin: 0.00-0.21
CSF IgG synthesis rate: 0-12 mg/24 hours
Clinical References: 1. Tourtellotte WW, Walsh MJ, Baumhefner RW, et al: The current status of
multiple sclerosis intra-blood-brain-barrier IgG synthesis. Ann NY Acad Sci. 1984;436:52-67 2.
Bloomer LC, Bray PF: Relative value of three laboratory methods in the diagnosis of multiple sclerosis.
Clin Chem. 1981;27:2011-2013 3. Hische EA, van der Helm HJ: Rate of synthesis of IgG within the
blood-brain barrier and the IgG index compared in the diagnosis of multiple sclerosis. Clin Chem.
1987;33:113-114 4. Thompson AJ, Banwell BL, Barkhof F, et al: Diagnosis of multiple sclerosis: 2017
revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-73. doi:
10.1016/S1474-4422(17)30470-2 5. Gurtner KM, Shosha E, Bryant SC, et al: CSF free light chain
identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes.
Clin Chem Lab Med. 2018 Jun 27;56(7):1071-1080. doi: 10.1515/cclm-2017-0901 6. Rifai N, Horvath
AR, Wittwer CT, eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed.
Elsevier; 2018
SFIG Cerebrospinal Fluid IgG Index Profile, Serum and Spinal Fluid
610783 Clinical Information: Elevation of IgG in the cerebrospinal fluid (CSF) of patients with
inflammatory diseases of the central nervous system (CNS) such as multiple sclerosis (MS),
neurosyphilis, acute inflammatory polyradiculoneuropathy, subacute sclerosing panencephalitis may be
due to local (intrathecal) synthesis of IgG. The CSF index is the CSF IgG to CSF albumin ratio compared
to the serum IgG to serum albumin ratio. The CSF index is, therefore, an indicator of the relative amount
of CSF IgG compared to serum. Any increase in the index is a reflection of IgG production in the CNS.
The IgG synthesis rate is a mathematical manipulation of the CSF index data and can also be used as a
marker for CNS inflammatory diseases. The test is commonly ordered with oligoclonal banding or
immunoglobulin kappa free light chains in CSF to aid in the diagnosis of demyelinating conditions.
Useful For: Aiding in the diagnosis of multiple sclerosis and other central nervous system
inflammatory conditions
Interpretation: Cerebrospinal fluid (CSF) IgG synthesis rate indicates the rate of increase in the daily
CSF production of IgG in milligrams per day. A result greater than 12 mg/24h is elevated. A CSF index
greater than 0.85 is elevated and indicative of increased synthesis of IgG.
Reference Values:
CSF index: 0.00-0.85
CSF IgG: 0.0-8.1 mg/dL
CSF albumin: 0.0-27.0 mg/dL
Serum IgG
0-4 months: 100-334 mg/dL
5-8 months: 164-588 mg/dL
9-14 months: 246-904 mg/dL
15-23 months: 313-1,170 mg/dL
2-3 years: 295-1,156 mg/dL
4-6 years: 386-1,470 mg/dL
7-9 years: 462-1,682 mg/dL
10-12 years: 503-1,719 mg/dL
13-15 years: 509-1,580 mg/dL
16-17 years: 487-1,327 mg/dL
> or =18 years: 767-1,590 mg/dL
Serum albumin
> or =12 months: 3,500-5,000 mg/dL
CSF IgG/albumin: 0.00-0.21
Serum IgG/albumin: 0.0-0.4
CSF IgG synthesis rate: 0-12 mg/24 hours
Clinical References: 1. Tourtellotte WW, Walsh MJ, Baumhefner RW, Staugaitis SM, Shapshak P:
The current status of multiple sclerosis intra-blood-brain-barrier IgG synthesis. Ann NY Acad Sci.
1984;436:52-67 2. Bloomer LC, Bray PF: Relative value of three laboratory methods in the diagnosis of
multiple sclerosis. Clin Chem. 1981 Dec;27(12):2011-2013 3. Hische EA, van der Helm HJ: Rate of
synthesis of IgG within the blood-brain barrier and the IgG index compared in the diagnosis of multiple
sclerosis. Clin Chem. 1987 Jan;33(1):113-114 4. Thompson AJ, Banwell BL, Barkhof F, et al: Diagnosis
of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-73.
doi: 10.1016/S1474-4422(17)30470-2 5. Gurtner KM, Shosha E, Bryant SC, et al: CSF free light chain
identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes. Clin
Chem Lab Med. 2018 Jun 27;56(7):1071-1080. doi: 10.1515/cclm-2017-0901 6. Rifai N, Norvath AR,
Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 6th ed. Elsevier; 2018
CTXWB Cerebrotendinous Xanthomatosis, Blood

113444
Clinical Information: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder
of bile acid synthesis resulting from the deficiency of the mitochondrial enzyme, sterol 27-hydrolase.
Sterol 27-hydrolase facilitates the first step of sterol degradation in the formation of bile acids;
consequently patients with CTX will experience increased storage of the sterol, cholestenol, and
ketosterol bile acid precursors (7-alpha-hydroxy-4-cholesten-3-one [7a-C4] and
7-alpha,12-alpha-dihydroxycholest-4-en-3-one [7a12aC4]) in multiple tissues throughout the body with
a resulting deficiency of the bile acid, chenodeoxycholic acid (CDCA). CTX is caused by variants in the
CYP27A1 gene. Patients with CTX can present with a constellation of findings including infantile onset
diarrhea, childhood onset cataracts, development of tendon/cerebral xanthomas in adolescence and early
adulthood, early onset osteoporosis, as well as a broad array of neuropsychological manifestations such
as intellectual disability, dementia, psychiatric symptoms, ataxia, pyramidal signs, dystonia, and muscle
weakness. Patients may occasionally present with cholestatic liver disease, which may present as
jaundice, poor growth, and hepatosplenomegaly. Intrafamilial variability exists, and some heterozygous
carriers may experience a higher incidence of cardiac disorders or gallstones. Treatment with CDCA
normalizes bile acid synthesis and suppresses cholestenol biosynthesis, with improvement of clinical
symptoms and arrest of disease progression. Supplementation with beta-hydroxy
beta-methylglutaryl-CoA (HMG-CoA) inhibitors and coenzyme Q10 has been proposed. The
availability of effective therapy makes early diagnosis and treatment of patients with CTX essential.
The estimated incidence of CTX is 1 in 50,000 individuals of Northern European ancestry and as high
as 1 in 440 in the Druze population of Israel. The diagnostic evaluation of patients with suspected CTX
may reveal abnormalities on brain magnetic resonance imaging (such as cerebellar atrophy, decrease in
volume of grey and white matter, and abnormal white matter signal) in addition to the biochemical and
clinical abnormalities. The biochemical diagnosis of CTX can be confirmed by molecular genetic
analysis of the CYP27A1 gene (included in: NPPAN / Peripheral Neuropathy Genetic Panels by
Next-Generation Sequencing [NGS], Blood).
Useful For: Evaluating patients with a clinical suspicion of cerebrotendinous xanthomatosis (CTX)
Monitoring of individuals with CTX on chenodeoxycholic acid (CDCA) therapy This test is not useful
for the identification of carriers This test is not useful for the evaluation of bile acid malabsorption
Interpretation: An elevation of 7-alpha-hydroxy-4-cholesten-3-one (7a-C4) and

7-alpha,12-alpha-dihydroxycholest-4-en-3-one (7a12aC4) is strongly suggestive of cerebrotendinous
xanthomatosis.
Reference Values:
7-ALPHA-HYDROXY-4-CHOLESTEN-3-ONE (7a-C4)
Cutoff: < or =0.750 nmol/mL
7-ALPHA,12-ALPHA-DIHYDROXYCHOLEST-4-en-3-ONE (7a12aC4)
Clinical References: 1. Mignarri A, Magni A, Del Puppo M, et al: Evaluation of cholesterol

metabolism in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2016 Jan:39(1):75-83 2. Nie S,
Chen G, Cao X, Zhang Y: Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis,
clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2014 Nov 26;9:179 3.
DeBarber AE, Luo J, Star-Weinstock M, et al: A blood test for cerebrotendinous xanthomatosis with
potential for disease detection in newborns. J. Lipid Res. 2014 Jan:55(1):146-154 4. Federico A, Dotti
MT, Gallus GN: Cerebrotendinous xanthomatosis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds.
GeneReviews [Internet]. University of Washington, Seattle; 2003. Updated April 14, 2016. Accessed
November 20, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1409/
CTXBS Cerebrotendinous Xanthomatosis, Blood Spot

65630 Clinical Information: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder
of bile acid synthesis resulting from the deficiency of the mitochondrial enzyme, sterol 27-hydrolase.
Sterol 27-hydrolase facilitates the first step of sterol degradation in the formation of bile acids;
consequently, patients with CTX will experience increased storage of the sterol, cholestenol, and
ketosterol bile acid precursors (7-alpha-hydroxy-4-cholesten-3-one [7a-C4] and 7-alpha,12
alphaâ€“dihydroxycholest-4-en-3-one (7a12aC4)) in multiple tissues throughout the body with a
resulting deficiency of the bile acid, chenodeoxycholic acid (CDCA). CTX is caused by variants in the
adulthood, early onset osteoporosis, as well as a broad array of neuropsychological manifestations such
as intellectual disability, dementia, psychiatric symptoms, ataxia, pyramidal signs, dystonia, and muscle
jaundice, poor growth, and hepatosplenomegaly. Intrafamilial variability exists, and some heterozygous
beta-methylglutaryl-CoA inhibitors and coenzyme Q10 has been proposed. The availability of effective
therapy makes early diagnosis and treatment of patients with CTX essential. The estimated incidence of
CTX is 1 in 50,000 individuals of Northern European ancestry and as high as 1 in 440 in the Druze
population of Israel. The diagnostic evaluation of patients with suspected CTX may reveal
abnormalities on brain magnetic resonance imaging (such as cerebellar atrophy, decrease in volume of
grey and white matter, and abnormal white matter signal) in addition to the biochemical and clinical
abnormalities. The biochemical diagnosis of CTX can be confirmed by molecular genetic analysis of
the CYP27A1 gene (included in: NPPAN / Peripheral Neuropathy Genetic Panels by Next-Generation
Sequencing [NGS], Blood).
using dried blood spot specimens Monitoring individuals with CTX on chenodeoxycholic acid therapy
This test is not useful for the identification of carriers This test is not useful for the evaluation of bile acid
malabsorption
Interpretation: An elevation of 7-alpha-hydroxy-4-cholesten-3-one) and 7-alpha,12

alpha-dihydroxycholest-4-en-3-one is strongly suggestive of cerebrotendinous xanthomatosis
Reference Values:
7-ALPHA,12-ALPHA-DIHYDROXYCHOLEST-4-en-3-ONE (7a12aC4)

metabolism in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2016 Jan:39(1):75-83 2. Nie S,
Guiqin C, Xuebing C, Zhang Y: Cerebrotendinous xanthomatosis: a comprehensive review of
pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2014 Nov
26;9:179 3. DeBarber AE, Luo J, Star-Weinstock M, et al: A blood test for cerebrotendinous
xanthomatosis with potential for disease detection in newborns. J. Lipid Res. 2014 Jan:55(1):146-154 4.
Federico A, Dotti MT, Gallus GN: Cerebrotendinous xanthomatosis. In: Adam MP, Ardinger HH, Pagon
RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2003. Updated April 14, 2016.
Accessed November 20, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1409/
CTXP Cerebrotendinous Xanthomatosis, Plasma

65631 Clinical Information: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of
bile acid synthesis resulting from the deficiency of the mitochondrial enzyme, sterol 27-hydrolase. Sterol
27-hydrolase facilitates the first step of sterol degradation in the formation of bile acids; consequently,
patients with CTX will experience increased storage of the sterol, cholestenol, and ketosterol bile acid
precursors (7-alpha-hydroxy-4-cholesten-3-one [7a-C4] and
7-alpha,12-alphaâ€“dihydroxycholest-4-en-3-one [7a12aC4]) in multiple tissues throughout the body with
a resulting deficiency of the bile acid, chenodeoxycholic acid (CDCA). CTX is caused by variants in the
adulthood, early onset osteoporosis, as well as a broad array of neuropsychological manifestations such as
intellectual disability, dementia, psychiatric symptoms, ataxia, pyramidal signs, dystonia, and muscle
jaundice, poor growth, and hepatosplenomegaly. Intrafamilial variability exists and some heterozygous
beta-methylglutaryl-CoA (HMG-CoA) inhibitors and coenzyme Q10 has been proposed. The availability
of effective therapy makes early diagnosis and treatment of patients with CTX essential. The estimated
incidence of CTX is 1 in 50,000 individuals of Northern European ancestry and as high as 1 in 440 in the
Druze population of Israel. The diagnostic evaluation of patients with suspected CTX may reveal
abnormalities on brain magnetic resonance imaging (such as cerebellar atrophy, decrease in volume of
grey and white matter, and abnormal white matter signal) in addition to the biochemical and clinical
abnormalities. The biochemical diagnosis of CTX can be confirmed by molecular genetic analysis of the
CYP27A1 gene (included in: NPPAN / Peripheral Neuropathy Genetic Panels, Next-Generation
Sequencing (NGS), Blood).
using plasma specimens Monitoring of individuals with CTX on chenodeoxycholic acid (CDCA)
therapy This test is not useful for the identification of carriers This test is not useful for the evaluation of
bile acid malabsorption
Interpretation: An elevation of 7-alpha-hydroxy-4-cholesten-3-one (7a-C4) and

7-alpha,12-alpha-dihydroxycholest-4-en-3-one (7a12aC4) is strongly suggestive of cerebrotendinous
xanthomatosis.
Reference Values:
7-ALPHA,12 ALPHAâ€“DIHYDROXYCHOLEST-4-en-3-ONE (7a12aC4)


metabolism in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2016 Jan;39(1):75-83 2. Nie S,
Chen G, Cao X, Zhang Y: Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis,
clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2014 Nov 26;9:179 3.
DeBarber AE, Luo J, Star-Weinstock M, et al: A blood test for cerebrotendinous xanthomatosis with
potential for disease detection in newborns. J Lipid Res. 2014 Jan;5591):146-154 4. Federico A, Dotti
MT, Gallus GN: Cerebrotendinous xanthomatosis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds.
GeneReviews [Internet]. University of Washington, Seattle;
FCZAC Certolizumab and Anti-Certolizumab Antibody, DoseASSURE

75563 CTZ
Useful For: Provides certolizumab drug concentration and anti-certolizumab antibodies in order to
optimize treatment and facilitate clinical decision-making. This assay may be helpful in any patient on
certolizumab therapy for Crohn's disease, psoriasis, or other autoimmune condition.
Reference Values:
Certolizumab:
Quantitation Limit: <1.0 ug/mL
Results of 1 ug/mL or higher indicate detection of certolizumab
Anti-Certolizumab Antibody:
Quantitation Limit: <40 ng/mL
Results of 40 ng/mL or higher indicate detection of anti-certolizumab pegol antibodies.

CERS Ceruloplasmin, Serum
614504 Clinical Information: Ceruloplasmin is a positive acute-phase reactant and a copper-binding protein
that accounts for over 95% of serum copper in normal adults. Ceruloplasmin is measured primarily to
assist with a diagnosis of Wilson disease. Other indications include Menkes disease, dietary copper
insufficiency, and risk of cardiovascular disease. Wilson disease is a rare inherited disorder of copper
transport that results in low serum copper and ceruloplasmin and accumulation of copper in various
tissues. The pathological accumulation of copper in the liver, brain, cornea, and kidney causes cirrhosis,
neuropsychiatric symptoms, Kayser-Fleischer rings, and hematuria/proteinuria, respectively. See Wilson
Disease Testing Algorithm in Special Instructions for appropriate use of clinical findings, serum
biomarkers, genetic tests, and tissue biopsies when working up suspected cases. Menkes disease is an
X-linked disorder in which dietary copper is absorbed from the gastrointestinal tract but cannot be
transported, so copper is not available to the liver for incorporation into ceruloplasmin. Dietary
ceruloplasmin deficiency may be due to inadequate dietary copper intake, long-term parenteral nutrition
without copper supplementation, malabsorption, penicillamine therapy, or a combination of these.
Useful For: Investigation of patients with possible Wilson disease

Interpretation: Low concentrations of ceruloplasmin are consistent with Wilson disease and warrant
further investigation according to the recommended algorithm; see Wilson Disease Testing Algorithm in
Special Instructions. Ceruloplasmin is a positive acute-phase reactant. Increases in serum ceruloplasmin
have been reported during pregnancy, in women taking oral contraceptives, in hepatitis, pneumonia,
tuberculosis, rheumatoid arthritis, myocardial infarction, various forms of anemia, and many obscure
neurological disorders.
Reference Values:
Males:
0-8 weeks: 7.4-23.7 mg/dL
9 weeks-5 months: 13.5-32.9 mg/dL
6-11 months: 13.7-38.9 mg/dL
12 months-7 years: 21.7-43.3 mg/dL
8-13 years: 20.5-40.2 mg/dL
14-17 years: 17.0-34.8 mg/dL
> or =18 years: 19.0-31.0 mg/dL
Females:
0-8 weeks: 7.4-23.7 mg/dL
9 weeks-5 months: 13.5-32.9 mg/dL
6-11 months: 13.7-38.9 mg/dL
12 months-7 years: 21.7-43.3 mg/dL
8-13 years: 20.5-40.2 mg/dL
14-17 years: 20.8-43.2 mg/dL
> or = 18 years: 20.0-51.0 mg/dL
Clinical References: 1. Wilson Tang WH, Wu Y, Hartiala J, et al: Clinical and genetic association
of serum ceruloplasmin with cardiovascular risk. Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):516-522
2. Dadu RT, Dodge R, Nambi V, et al: Ceruloplasmin and heart failure in the Atherosclerosis Risk in
Communities study. Circ Heart Fail. 2013 Sep 1;6(5):936-943 3. Cox DW, Tumer Z, Roberts EA: Copper
transport disorders: Wilson's disease and Menkes disease. Inborn Metabolic Disease. Fernandes J,
Sandubray JM, VandenBerghe F, eds. Springer-Verlag; 2000:385-391 4. Sontakke AN, More U: Changes
in serum ceruloplasmin levels with commonly used methods of contraception. Indian J Clin Biochem.
2004 Jan:19(1):102-104 5. Schilsky ML: Wilson disease: Diagnosis, treatment, and follow-up. Clin Liver
Dis. 2017 Nov;21(4):755-767 6. Hermann W: Classification and differential diagnosis of Wilson's
disease. Ann Transl Med. 2019 Apr;7(Suppl 2):S63
CFTRZ CFTR Gene, Full Gene Analysis, Varies
35388 Clinical Information: Cystic fibrosis (CF), in the classic form, is a severe autosomal recessive
disorder characterized by a varied degree of chronic obstructive lung disease and pancreatic enzyme
insufficiency. Clinical diagnosis is generally made based on these features, combined with a positive
sweat chloride test or positive nasal potential difference. CF can also have an atypical presentation and
may manifest as congenital bilateral absence of the vas deferens (CBAVD), chronic idiopathic
pancreatitis, bronchiectasis, or chronic rhinosinusitis. Several states have implemented newborn
screening for CF, which identifies potentially affected individuals by measuring immunoreactive
trypsinogen in a dried blood specimen collected on filter paper. If a clinical diagnosis of CF has been
made, molecular testing for common CF mutations is available. To date, over 1,500 mutations have
been described within the CF gene, named cystic fibrosis transmembrane conductance regulator
(CFTR). The most common mutation, deltaF508, accounts for approximately 67% of the mutations
worldwide and approximately 70% to 75% in the North American Caucasian population. Most of the
remaining mutations are rather rare, although some show a relatively higher prevalence in certain ethnic
groups or in some atypical presentations of CF, such as isolated CBAVD. The recommended approach
for confirming a CF diagnosis or detecting carrier status begins with molecular tests for the common CF
mutations (eg, CFP / Cystic Fibrosis Mutation Analysis, 106-Mutation Panel, Varies). This test, CFTR
Gene, Full Gene Analysis, Varies may be ordered if 1 or both disease-causing mutations are not
detected by the targeted mutation analysis. Full gene analysis, through sequencing and dosage analysis
of the CFTR gene, is utilized to detect private mutations. Together, full gene analysis of the CFTR gene
and deletion/duplication analysis identify over 98% of the sequence variants in the coding region and
splice junctions. Of note, FDA guidance has indicated that CFTR potentiator or combination chemical
chaperone/potentiator therapies may improve clinical outcomes for patients with a clinical diagnosis of
CF and at least 1 copy of a small subset of mutations. If one of the mutations associated with an
FDA-approved therapy is identified, this information will be included in the interpretive report. See
Cystic Fibrosis Molecular Diagnostic Testing Algorithm in Special Instructions for additional
information.
Useful For: Follow-up testing to identify mutations in individuals with a clinical diagnosis of cystic
fibrosis (CF) and a negative targeted mutation analysis for the common mutations Identification of
mutations in individuals with atypical presentations of CF (eg, congenital bilateral absence of the vas
deferens or pancreatitis) Identification of mutations in individuals where detection rates by targeted
mutation analysis are low or unknown for their ethnic background Identification of patients who may
respond to cystic fibrosis transmembrane conductance regulator (CFTR) potentiator therapy This is not
the preferred genetic test for carrier screening or initial diagnosis. For these situations, order CFP /
Cystic Fibrosis Mutation Analysis, 106-Mutation Panel, Varies
known significance.
Reference Values:
May;17(5):405-424 2. Rosenstein BJ, Zeitlin PL: Cystic fibrosis. Lancet 1998 Jan
24;351(9098):277-282 3. Strom CM, Huang D, Chen C, et al: Extensive sequencing of the cystic
fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a
comprehensive test. Genet Med 2003 Jan-Feb;5(1):9-14 4. De Boeck K, Munck A, Walker S, et al:
Efficacy and safety of ivacaftor in patients with Cystic Fibrosis and the G551D gating mutation. J Cyst
Fibros 2014 Dec;13(6):674-680 doi: 10.1016/j.jcf.2014.09.005 5. Currier RJ, Sciortino S, Liu R, et al:
Genomic sequencing in cystic fibrosis newborn screening: what works best, two-tier predefined CFTR
mutation panels or second-tier CFTR panel followed by third-tier sequencing? Genet Med 2017
Oct;19(10):1159-1163
G162 CGO Custom Gene Panel (LPGD) (Bill Only)
CHGL Chaetomium globosum, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to Chaetomium globosum Defining the allergen
and/or anaphylactic episode - To confirm sensitization prior to beginning immunotherapy - To investigate
the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens Testing for IgE

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
FAMCE Cheese American IgE

57914
Interpretation: Class IgE (kU/L) Comment 0 <0.35 Below Detection 1 0.35 Ã¢â‚¬â€œ 0.69 Low
Reference Values:
<0.35 kU/L
FCCGG Cheese Cheddar IgG

Reference Values:
FSCE Cheese Swiss IgE

Reference Values:
<0.35 kU/L
CCHZ Cheese, Cheddar, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cheddar cheese Defining the allergen

Reference Values:
0 Negative

apply to all ages.
MCHZ Cheese, Mold, IgE, Serum

immune response to allergen that may be associated with allergic disease. The allergens chosen for testing
often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical
manifestations. In individuals predisposed to develop allergic disease, the sequence of sensitization and
clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in
infants and children <5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by
respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant
allergens (dust mite, mold, and pollen inhalants).
Useful For: May be useful to establish the diagnosis of an allergic disease and to define the allergens
responsible for eliciting signs and symptoms May be useful to identify allergens that may be responsible
for allergic disease or anaphylactic episode, to confirm sensitization to particular allergens prior to
beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom
allergens, drugs, or chemical allergens

Reference Values:
0 Negative

apply to all ages.
CHER Cherry, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cherry Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
CTRE Chestnut Tree, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to chestnut tree Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CNUT Chestnut, Sweet, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to sweet chestnut Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
CHXP Chick Pea, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to chick pea Defining the allergen responsible for

Reference Values:
Class IgE KU/L Interpretation
0 Negative

apply to all ages.
CDROP Chicken Droppings, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to chicken droppings Defining the allergen

Reference Values:

0 Negative

apply to all ages.
2017:1057-1070
CHCK Chicken Feathers, IgE, Serum
Useful For: Establishing a diagnosis of an allergy to chicken feathers Defining the allergen

Reference Values:
0 Negative

apply to all ages.
FCHXG Chicken IgG

Reference Values:
CSPR Chicken Serum Proteins, IgE, Serum
Useful For: Establishing the diagnosis of an allergy to chicken serum proteins Defining the allergen

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CHIC Chicken, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to chicken Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
CHIKG Chikungunya IgG, Antibody, Serum

63868 Clinical Information: Chikungunya virus (ChikV) is a single-stranded RNA alphavirus and a
member of the Togaviridae family of viruses. The name Chikungunya is derived from the language of
the Makonde ethnic groups in southeast Africa and means "that which bends" or "stooped walk." This is
in reference to the hunched-over appearance of infected individuals due to the characteristically painful
and incapacitating arthralgia caused by the virus. ChikV is endemic throughout Africa, India, and more
recently the Caribbean islands. In 2014, the first case of autochthonous or local transmission in the
United States occurred in Florida.Â Humans are the primary reservoir for ChikV and Aedes species
mosquitos are the primary vectors for transmission. Unlike other mosquito-borne viruses such as West
Nile virus (WNV) and Dengue, the majority of individuals who are exposed to ChikV become
symptomatic, with the most severe manifestations observed at the extremes of age and in those with
suppressed immunity. Once exposed to ChikV, individuals develop lasting immunity and protection
from reinfection. Prior to development of symptoms, the incubation period ranges, on average, from 3
to 7 days. Infected patients typically present with sudden onset high fever, incapacitating joint pain, and
often a maculopapular rash lasting anywhere from 3 to 10 days. Notably, symptom relapse can occur in
some individuals 2 to 3 months following resolution of initial symptoms. Currently, there are no
licensed vaccines and treatment is strictly supportive care.
Useful For: Aiding in the diagnosis of recent infection with Chikungunya virus detecting IgG
antibodies in patients with recent travel to endemic areas and a compatible clinical syndrome
Interpretation: IgM and IgG Negative: -No serologic evidence of exposure to Chikungunya virus.
Repeat testing on a new specimen collected in 5 to 10 days is recommended if clinical suspicion
persists. IgM and IgG Positive: -IgM and IgG antibodies to Chikungunya virus detected, suggesting
recent or past infection. IgM antibodies to Chikungunya virus may remain detectable for 3 to 4 months
post-infection. IgM Positive, IgG Negative: -IgM antibodies to Chikungunya virus detected, suggesting
recent infection. Repeat testing in 5 to 10 days is recommended to demonstrate anti-Chikungunya virus
IgG seroconversion to confirm current infection.Â IgM Negative, IgG Positive: -IgG antibodies to
Chikungunya virus detected, suggesting past infection. IgM and/or IgG Borderline: -Repeat testing in
10 to 14 days is recommended.
Reference Values:
Only orderable as part of a profile. For more information see CHIKV / Chikungunya IgM and IgG,
Antibody, Serum.
Clinical References: Pan American Health Organization. Preparedness and Response for
Chikungunya virus. Introduction into the Americas. Washington, DC, PAHO 2011
CHIKV Chikungunya IgM and IgG, Antibody, Serum

member of the Togaviridae family of viruses. The name Chikungunya is derived from the language of the
Makonde ethnic groups in southeast Africa and means "that which bends" or "stooped walk." This is in
reference to the hunched-over appearance of infected individuals due to the characteristically painful and
incapacitating arthralgia caused by the virus. ChikV is endemic throughout Africa, India, and more
recently the Caribbean islands. In 2014, the first case of autochthonous or local transmission in the United
States occurred in Florida. Humans are the primary reservoir for ChikV and Aedes species mosquitos are
the primary vectors for transmission. Unlike other mosquito-borne viruses such as West Nile virus
(WNV) and Dengue, the majority of individuals who are exposed to ChikV become symptomatic, with
the most severe manifestations observed at the extremes of age and in those with suppressed immunity.
Once exposed to ChikV, individuals develop lasting immunity and protection from reinfection. Prior to
development of symptoms, the incubation period ranges, on average, from 3 to 7 days. Infected patients
typically present with sudden onset high fever, incapacitating joint pain, and often a maculopapular rash
lasting anywhere from 3 to 10 days. Notably, symptom relapse can occur in some individuals 2 to 3
months following resolution of initial symptoms. Currently, there are no licensed vaccines and treatment
is strictly supportive care.
Useful For: Aiding in the diagnosis of recent infection with Chikungunya virus in patients with recent
travel to endemic areas and a compatible clinical syndrome
Repeat testing on a new specimen collected in 5 to 10 days is recommended if clinical suspicion persists.
IgM and IgG Positive: -IgM and IgG antibodies to Chikungunya virus detected, suggesting recent or past
infection. IgM antibodies to Chikungunya virus may remain detectable for 3 to 4 months post-infection.
IgM Positive, IgG Negative: -IgM antibodies to Chikungunya virus detected, suggesting recent infection.
Repeat testing in 5 to 10 days is recommended to demonstrate anti-Chikungunya virus IgG
seroconversion to confirm current infection. IgM Negative, IgG Positive: -IgG antibodies to Chikungunya
virus detected, suggesting past infection. IgM and/or IgG Borderline: -Repeat testing in 10 to 14 days is
recommended.
Reference Values:
IgM: Negative
IgG: Negative
Chikungunya virus. Introduction into the Americas. PAHO 2011
CHIKM Chikungunya IgM, Antibody, Serum

Current 63867
Clinical Information: Chikungunya virus (ChikV) is a single-stranded RNA alphavirus and a
from reinfection. Prior to development of symptoms, the incubation period ranges, on average, from 3
Useful For: Aiding in the diagnosis of recent infection with Chikungunya virus detecting IgM
antibodies in patients with recent travel to endemic areas and a compatible clinical syndrome
Repeat testing on a new specimen collected in 5 to 10 days is recommended if clinical suspicion
persists. IgM and IgG Positive: -IgM and IgG antibodies to Chikungunya virus detected, suggesting
recent or past infection. IgM antibodies to Chikungunya virus may remain detectable for 3 to 4 months
post-infection. IgM Positive, IgG Negative: -IgM antibodies to Chikungunya virus detected, suggesting
recent infection. Repeat testing in 5 to 10 days is recommended to demonstrate anti-Chikungunya virus
IgG seroconversion to confirm current infection.Â IgM Negative, IgG Positive: -IgG antibodies to
Chikungunya virus detected, suggesting past infection. IgM and/or IgG Borderline: -Repeat testing in
10 to 14 days is recommended.
Reference Values:
Antibody, Serum.
CHIKI Chikungunya Interpretation

from reinfection. Prior to development of symptoms, the incubation period, ranges, on average, from 3
Useful For: Interpretation of testing that aids in the diagnosis of recent infection with Chikungunya
virus in patients with recent travel to endemic areas and a compatible clinical syndrome
Repeat testing on a new specimen collected in 5 to 10 days is recommended if clinical suspicion persists.
IgM and IgG Positive: -IgM and IgG antibodies to Chikungunya virus detected, suggesting recent or past
infection. IgM antibodies to Chikungunya virus may remain detectable for 3 to 4 months post-infection.
IgM Positive, IgG Negative: -IgM antibodies to Chikungunya virus detected, suggesting recent infection.
Repeat testing in 5 to 10 days is recommended to demonstrate anti-Chikungunya virus IgG
seroconversion to confirm current infection.Â IgM Negative, IgG Positive: -IgG antibodies to
Chikungunya virus detected, suggesting past infection. IgM and/or IgG Borderline: -Repeat testing in 10
to 14 days is recommended.
Reference Values:
Antibody, Serum.
CHIKS Chikungunya Virus, PCR, Molecular Detection, Serum

603833 Clinical Information: Chikungunya virus (CHIK) is an RNA virus of the genus Alphavirus, family
Togaviridae, and is transmitted mainly through the bite of infected mosquitoes in the genus Aedes (A
aegypti and A albopictus). This is the same mosquito that transmits dengue, yellow fever, and Zika
viruses. Most people infected with chikungunya virus will develop some symptoms, most commonly
fever and joint pain. There is no specific antiviral treatment for chikungunya virus infection. Most cases
of disease have occurred in Africa, Asia, Europe, and the Indian and Pacific Oceans, but transmission of
CHIK has been identified in Caribbean countries and South American regions, as well as foci in the
southern United States. Infection with chikungunya virus may be suspected based on symptoms (fever,
joint pain, and headache) and recent history of travel. A diagnosis of CHIK infection can be confirmed
through laboratory tests on serum or cerebrospinal fluid. This assay is designed to detect only species of
clinical significance and is to be used for patients with a clinical history and symptoms consistent with
chikungunya infection.
Useful For: Qualitative detection of chikungunya virus in serum after early symptom onset (ideally <7
days) This test is not recommended for screening healthy patients.
Interpretation: A positive test result indicates the presence of chikungunya virus RNA in the
specimen. A negative test result with a positive internal control indicates that chikungunya virus RNA is
not detectable in the specimen. A negative test result with a negative internal control is considered
evidence of PCR inhibition or reagent failure. A new specimen should be collected for testing if clinically
indicated.
Reference Values:
Negative
Clinical References: 1. Lanciotti RS, Kosoy OL, Laven JJ, et.al: Chikungunya virus in US travelers
returning from India, 2006. Emerg Infect Dis 2007 May;13(5):764-767. Available at www.cdc.gov/eid 2.
Johnson BW, Russell BJ, Goodman CH: Laboratory Diagnosis of Chikungunya Virus Infections and
Commercial Sources for Diagnostic Assays. J Infect Dis 2016 Dec 15;214(suppl 5):S471-S474. Available
at https://doi.org/10.1093/infdis/jiw274 3. Morrison TE: Reemergence of chikungunya virus. J Virol 2014
Oct;88(20):11644-11647
CHIKC Chikungunya Virus, PCR, Molecular Detection, Spinal Fluid

603832 Clinical Information: Chikungunya virus (CHIK) is an RNA virus of the genus Alphavirus, family
Togaviridae, and is transmitted mainly through the bite of infected mosquitoes in the genus Aedes (A
aegypti and A albopictus). This is the same mosquito that transmits dengue, yellow fever, and Zika
viruses. Most people infected with chikungunya virus will develop some symptoms, most commonly
fever and joint pain. There is no specific antiviral treatment for chikungunya virus infection. Most cases
of disease have occurred in Africa, Asia, Europe, and the Indian and Pacific Oceans, but transmission of
CHIK has been identified in Caribbean countries and South American regions, as well as foci in the
southern United States. Infection with chikungunya virus may be suspected based on symptoms (fever,
joint pain, and headache) and recent history of travel. A diagnosis of CHIK infection can be confirmed
through laboratory tests on serum or cerebrospinal fluid. This assay is designed to detect only species of
clinical significance and is to be used for patients with a clinical history and symptoms consistent with
chikungunya infection.
Useful For: Qualitative detection of chikungunya virus in cerebrospinal fluid (CSF) after early
symptom onset (ideally <7 days) This test is not recommended for screening healthy patients.
Interpretation: A positive test result indicates the presence of chikungunya virus RNA in the
specimen. A negative test result with a positive internal control indicates that chikungunya virus RNA is
not detectable in the specimen. A negative test result with a negative internal control is considered
evidence of PCR inhibition or reagent failure. A new specimen should be collected for testing if
clinically indicated.
Reference Values:
Negative
Clinical References: 1. Lanciotti RS, Kosoy OL, Laven JJ, et.al: Chikungunya virus in US
travelers returning from India, 2006. Emerg Infect Dis 2007 May;13(5):764-767. Available at
www.cdc.gov/eid 2. Johnson BW, Russell BJ, Goodman CH: Laboratory Diagnosis of Chikungunya
Virus Infections and Commercial Sources for Diagnostic Assays. J Infect Dis 2016 Dec 15;214(suppl
5):S471-S474. Available at https://doi.org/10.1093/infdis/jiw274 3. Morrison TE: Reemergence of
chikungunya virus. J Virol 2014 Oct;88(20):11644-11647
CHILI Chili Pepper, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to chili pepper Defining the allergen responsible

Reference Values:

0 Negative

apply to all ages.
2017:1057-1070
CHIMU Chimerism Transplant No Cell Sort, Varies

62983 Clinical Information: Patients who have had donor hematopoietic cells infused for the purpose of
engraftment (ie, bone marrow transplant recipients) may have their blood or bone marrow monitored for
an estimate of the percentage of donor and recipient cells present. This can be done by first identifying
unique features of the donor's and the recipient's DNA prior to transplantation and then examining the
recipient's blood or bone marrow after the transplantation procedure has occurred. The presence of both
donor and recipient cells (chimerism) and the percentage of donor cells are indicators of transplant
success. Short tandem repeat (STR) sequences are used as identity markers. STRs are di-, tri-, or
tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is variability
in STR length among people and the STR lengths remain stable throughout life, making them useful as
identity markers. Polymerase chain reaction is used to amplify selected STR regions from germline DNA
of both donor and recipient. The lengths of the amplified fragment are evaluated for differences
(informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood or bone
marrow can again be evaluated for the informative STR regions to identify chimerism and estimate the
proportions of donor and recipient cells in the specimen.
Useful For: Determining the relative amounts of donor and recipient cells in a specimen An indicator
of bone marrow transplant success
Interpretation: An interpretive report will be provided, which defines unique features of the donor's
cells. It is most useful to observe a trend in chimerism levels. Clinically critical results should be
confirmed with 1 or more subsequent specimens.
Reference Values:
Clinical References: 1. Antin JH, Childs R, Filipovich AH, et al: Establishment of complete and
mixed donor chimerism after allogenic lymphohematopoietic transplantation: recommendations from a
workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the
American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2001;7:473-485
2. Tang X, Alatrash G, Ning J, et al: Increasing chimerism following allogeneic stem cell transplantation
is associated with longer survivial time. Biol Blood Marrow Transplant. 2014 August;20(8):1139-1144.
doi: 10.1016/j.bbmt.2014.04.003 3. Ludeman MJ, Zhong C, Mulero JJ, et al: Developmental validation of
GlobalFiler PCR amplification kit: a 6-dye multiplex assay designed for amplification of casework
samples. Int J Legal Med. 2018 Nov;132(6):1555-1573. doi: 10.1007/s00414-018-1817-5 4. Tyler J,
Kumer L, Fisher C, Casey H, Shike H: Personalized chimerism test that uses selection of short tandem
repeat or quantitative PCR depending on patient's chimerism status. J Mol Diagn. 2019
May;21(3):483-490. doi: 10.1016/j.jmoldx.2019.01.007 5. Lion T, Watzinger F, Preuner S, et al: The
EuroChimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell
transplantation. Leukemia. 2012 Aug;26(8):1821-1828. doi: 10.1038/leu.2012.66
CHIMS Chimerism Transplant Sorted Cells, Varies
tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is
variability in STR length among people and the STR lengths remain stable throughout life, making them
useful as identity markers. Polymerase chain reaction is used to amplify selected STR regions from
germline DNA of both donor and recipient. The lengths of the amplified fragment are evaluated for
differences (informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood
or bone marrow can again be evaluated for the informative STR regions to identify chimerism and
estimate the proportions of donor and recipient cells in the specimen.
Useful For: Determining the relative amounts of donor and recipient cells in a specimen in sorted
cell fractions An indicator of bone marrow transplant success
Interpretation: An interpretive report will be provided, which includes whether chimerism is

detected or not and, if detected, the approximate percentage of donor and recipient cells. Sorted cell
analysis permits more detailed evaluation of chimeric status in T-cell and myeloid cell fractions, which
can be helpful in clinical management. It is most useful to observe a trend in chimerism levels.
Clinically critical results should be confirmed with 1 or more subsequent specimens.
Reference Values:
workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the
American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant.
2001;7:473-485 2. Tang X, Alatrash G, Ning J, et al: Increasing chimerism following allogeneic stem
cell transplantation is associated with longer survivial time. Biol Blood Marrow Transplant. 2014
August;20(8):1139-1144. doi: 10.1016/j.bbmt.2014.04.003 3. Ludeman MJ, Zhong C, Mulero JJ, et al:
Developmental validation of GlobalFiler PCR amplification kit: a 6-dye multiplex assay designed for
amplification of casework samples. Int J Legal Med. 2018 Nov;132(6):1555-1573. doi:
10.1007/s00414-018-1817-5 4. Tyler J, Kumer L, Fisher C, Casey H, Shike H: Personalized chimerism
test that uses selection of short tandem repeat or quantitative PCR depending on patient's chimerism
status. J Mol Diagn. 2019 May;21(3):483-490. doi: 10.1016/j.jmoldx.2019.01.007 5. Lion T, Watzinger
F, Preuner S, et al: The EuroChimerism concept for a standardized approach to chimerism analysis after
allogeneic stem cell transplantation. Leukemia. 2012 Aug;26(8):1821-1828. doi: 10.1038/leu.2012.66
CHIDB Chimerism-Donor, Varies

tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is
variability in STR length among people and the STR lengths remain stable throughout life, making them
useful as identity markers. Polymerase chain reaction is used to amplify selected STR regions from
germline DNA of both donor and recipient. The lengths of the amplified fragment are evaluated for
differences (informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood
or bone marrow can again be evaluated for the informative STR regions to identify chimerism and
estimate the proportions of donor and recipient cells in the specimen. This test evaluates the donor
specimen prior to the recipient bone marrow transplant.
Useful For: Evaluating the donor cells prior to bone marrow transplant Determining the relative
amounts of donor and recipient cells in a specimen. An indicator of bone marrow transplant success
Interpretation: An interpretive report will be provided, which includes whether chimerism is detected
or not and, if detected, the approximate percentage of donor and recipient cells. Sorted cell analysis
permits more detailed evaluation of chimeric status in T-cell and myeloid cell fractions, which can be
helpful in clinical management. It is most useful to observe a trend in chimerism levels. Clinically critical
results should be confirmed with 1 or more subsequent specimens.
Reference Values:
workshop at the 2001 Tandem Meetings. Biol Blood Marrow Transplant. 2001;7:473-485 2. Tang X,
Alatrash G, Ning J, et al: Increasing chimerism following allogeneic stem cell transplantation is
associated with longer survivial time. Biol Blood Marrow Transplant. 2014 August;20(8):1139-1144. doi:
10.1016/j.bbmt.2014.04.003 3. Ludeman MJ, Zhong C, Mulero JJ, et al: Developmental validation of
GlobalFiler PCR amplification kit: a 6-dye multiplex assay designed for amplification of casework
samples. Int J Legal Med. 2018 Nov;132(6):1555-1573. doi: 10.1007/s00414-018-1817-5 4. Tyler J,
Kumer L, Fisher C, et al: Personalized chimerism test that uses selection of short tandem repeat or
quantitative PCR depending on patient's chimerism status. J Mol Diagn. 2019 May;21(3):483-490. doi:
10.1016/j.jmoldx.2019.01.007 5. Lion T, Watzinger F, Preuner S, et al: The EuroChimerism concept for a
standardized approach to chimerism analysis after allogeneic stem cell transplantation. Leukemia. 2012
Aug;26(8):1821-1828. doi: 10.1038/leu.2012.66
CHRGB Chimerism-Recipient Germline (Pretransplant), Varies

tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is variability
in STR length among people and the STR lengths remain stable throughout life, making them useful as
identity markers. Polymerase chain reaction is used to amplify selected STR regions from germline DNA
of both donor and recipient. The lengths of the amplified fragment are evaluated for differences
(informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood or bone
marrow can again be evaluated for the informative STR regions to identify chimerism and estimate the
proportions of donor and recipient cells in the specimen. This test evaluates the recipient specimen prior
to bone marrow transplant.
Useful For: Evaluating the recipient cells prior to bone marrow transplant
Interpretation: An interpretive report will be provided, which includes whether chimerism is detected
or not and, if detected, the approximate percentage of donor and recipient cells. Sorted cell analysis
permits more detailed evaluation of chimeric status in T-cell and myeloid cell fractions, which can be
helpful in clinical management. It is most useful to observe a trend in chimerism levels. Clinically critical
results should be confirmed with 1 or more subsequent specimens.
Reference Values:
workshop at the 2001 Tandem Meetings. Biol Blood Marrow Transplant 2001;7:473-485 2. Tang X,
Alatrash G, Ning J, et al: Increasing chimerism following allogeneic stem cell transplantation is
associated with longer survivial time. Biol Blood Marrow Transplant. 2014 August;20(8):1139-1144.
doi: 10.1016/j.bbmt.2014.04.003 3. Tyler J, Kumer L, Fisher C, et al: Personalized chimerism test that
uses selection of short tandem repeat or quantitative PCR depending on patient's chimerism status. J
Mol Diagn. 2019 May;21(3):483-490. doi: 10.1016/j.jmoldx.2019.01.007 4. Lion T, Watzinger F,
Preuner S, et al: The EuroChimerism concept for a standardized approach to chimerism analysis after
allogeneic stem cell transplantation. Leukemia. 2012 Aug;26(8):1821-1828. doi: 10.1038/leu.2012.66
SCLAM Chlamydia Serology, Serum

8142 Clinical Information: Members of the family Chlamydiaceae are small, nonmotile, gram-negative,
obligate intracellular organisms that grow in the cytoplasm of host cells. Two genera of clinical
importance are Chlamydia, which includes Chlamydia trachomatis, and Chlamydophila, which includes
Chlamydophila pneumoniae and Chlamydophila psittaci. These organisms share many features of
bacteria and are susceptible to antibiotic therapy. They are also similar to viruses, requiring living cells
for multiplication. The chlamydial life cycle can be divided into 2 distinct phases: an extracellular,
nonreplicating, infectious stage and an obligate intracellular, replicating, noninfectious stage. The
infectious form, or elementary body (EB), attaches to the target cell membrane and enters the cell via a
phagosome. After cell entry, the EB reorganizes into reticulate particles (forming inclusion bodies) and
binary fission begins. After 18 to 24 hours, reticulate particles condense to form EBs. These new EBs
are released, beginning another infection cycle. C psittaci is the causative agent of psittacosis, a disease
characterized by pneumonia, headache, altered mentation, and hepatosplenomegaly. Psittacosis is
acquired by airborne transmission from infected birds. C pneumoniae (formerly known as Taiwan acute
respiratory agent: TWAR and, more recently, as Chlamydia pneumoniae) causes pneumonia in humans.
It is unique because it is a primary pathogen of humans, is spread from human to human, and apparently
has no animal or bird host. Chlamydophila pneumoniae is responsible for approximately 10% of
pneumonia cases. C trachomatis has been implicated in a wide variety of infections in humans. It is a
common cause of nongonococcal urethritis and cervicitis, and many systemic complications of
chlamydial infections have been described. In females, this organism is a cause of pelvic inflammatory
disease, salpingitis, and endometritis. In males, epididymitis and Reiter syndrome occur.
Lymphogranuloma venereum is a sexually transmitted infection caused by C trachomatis. It presents
with a transient primary genital lesion followed by suppurative regional lymphadenopathy.
Occasionally, severe proctitis or proctocolitis may develop. C trachomatis also causes ophthalmologic
infections, such as trachoma (rare in the United States), adult inclusion conjunctivitis and inclusion
conjunctivitis in neonates. These disorders have traditionally been diagnosed by cytologic detection or
culture. However, molecular detection methods (CTRNA / Chlamydia trachomatis by Nucleic Acid
Amplification [HOLOGIC], Varies) may now represent a more sensitive diagnostic approach.
Fitz-Hugh-Curtis syndrome (perihepatitis) has been associated with chlamydiae.
Useful For: Aiding in the clinical diagnosis of chlamydial infections This test is not intended for
medical-legal use.
Interpretation: IgG: Chlamydophila pneumoniae > or =1:512 IgG endpoint titers of 1:512 or more
are considered presumptive evidence of current infection. <1:512 and > or =1:64 A single specimen
endpoint titer ofÂ from 1:64 to 1:512 should be considered evidence of infection at an undetermined
time. A second specimen drawn 10 to 21 days after the original draw should be tested in parallel with
the first. If the second specimen exhibits a titer 1:512 or more or a 4-fold increase over that of the initial
specimen, current (acute) infection is indicated. Unchanging titers from 1:64 to 1:512 suggest past
infection. <1:64 IgG endpoint titers below 1:64 suggest that the patient does not have a current
infection. These antibody levels may be found in patients with either no history of chlamydial infection
or those with past infection whose antibody levels have dropped below detectable levels.
Chlamydophila pneumoniae antibody is detectable in 25% to 45% of adults tested. Chlamydophila
psittaci and Chlamydia trachomatis > or =1:64 IgG endpoint titers of 1:64 or more are considered
presumptive evidence of current infection. <1:64 IgG endpoint titers below 1:64 suggest that the patient
does not have a current infection. These antibody levels may be found in patients with either no history
of chlamydial infection or those with past infection whose antibody levels have dropped below
detectable levels. IgM Chlamydophila pneumoniae, Chlamydophila psittaci, and Chlamydia trachomatis
> or =1:10 IgM endpoint titers of 1:10 or more are considered presumptive evidence of infection. <1:10
IgM endpoint titers below 1:10 suggest that the patient does not have a current infection. These
antibody levels may be found in patients with either no history of chlamydial infection or those with
past infection whose antibody levels have dropped below detectable levels.
Reference Values:
Chlamydophila pneumoniae
IgG: <1:64
IgM: <1:10
Chlamydophila psittaci
IgG: <1:64
IgM: <1:10
Chlamydia trachomatis
IgG: <1:64
IgM: <1:10
Clinical References: 1. Movahed MR: Infection with Chlamydia pneumoniae and atherosclerosis: a
review. J South Carolina Med Assoc. 1999;95:303-308 2. Smith T: Chlamydia. In: Schmidt N, Emmons
R, eds. Diagnostic procedures for viral, rickettsial and chlamydial infections. 6th ed. APHA; 1989:
1165-1198 3. Sheffield PA, Moore DE, Voigt LF, et al: The association between Chlamydia trachomatis
serology and pelvic damage in women with tubal ectopic gestations. Fertil Steril. 1993;60:970-975 4.
Batteiger BE, Tang M: Chlamydia trachomatis (trachoma and urogenital infections). In: Bennett JE, Dolin
R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed.
Elsevier; 2020:2301-2319 5. Schlossberg D: Psittacosis (due to Chlamydia psittaci). In: Bennett JE, Dolin
R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed.
Elsevier; 2020:2320-2322 6. Hammerschlag MR, Kohlhoff SA, Gaydos CA: Chlamydia pneumoniae. In:
Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of
MCTGC Chlamydia trachomatis and Neisseria gonorrhoeae,

43721 Miscellaneous Sites, Nucleic Acid Amplification, Varies
Clinical Information: Chlamydia is caused by the obligate intracellular bacterium Chlamydia
trachomatis and is the most prevalent sexually transmitted bacterial infection in the United States.(1,2) In
2010, 1.3 million documented cases were reported to the CDC.(2) Given that 3 out of 4 infected women
and 1 out of 2 infected men will be asymptomatic initially, the actual prevalence of disease is thought to
be much greater than reported. The organism causes genitourinary infections in women and men and may
be associated with dysuria as well as vaginal, urethral, or rectal discharge. In women, complications
include pelvic inflammatory disease, salpingitis, and infertility. Approximately 25% to 30% of women
who develop acute salpingitis become infertile.(2) Complications among men are rare but include
epididymitis and sterility. Rarely, genital chlamydial infection can cause arthritis with associated skin
lesions and ocular inflammation (Reiter syndrome). C trachomatis can be transmitted from the mother
during delivery and is associated with conjunctivitis and pneumonia. Finally, C trachomatis may cause
hepatitis and pharyngitis in adults. Once detected, the infection is easily treated by a short course of
antibiotic therapy. Annual chlamydia screening is now recommended for all sexually active women age
25 years and younger and for older women with risk factors for infection, such as a new sex partner or
multiple sex partners. The CDC also recommends that all pregnant women be given a screening test for
Chlamydia infection.(2) Repeat testing for test-of-cure is not recommended after treatment with a
standard treatment regimen unless patient compliance is in question, reinfection is suspected, or the
patient's symptoms persist. Repeat testing of pregnant women, 3 weeks after completion of therapy, is
also recommended to ensure therapeutic cure.(2) Gonorrhea is caused by the bacterium Neisseria
gonorrhoeae. It is also a very common sexually transmitted infection (STI), with 301,174 cases of
gonorrhea reported to CDC in 2009.(2,3) Many infections in women are asymptomatic and the true
prevalence of gonorrhea is likely much higher than reported. The organism causes genitourinary
infections in women and men and may be associated with dysuria as well as vaginal, urethral, or rectal
discharge. Complications include pelvic inflammatory disease in women and gonococcal epididymitis and
prostatitis in men. Gonococcal bacteremia, pharyngitis, and arthritis may also occur. Infection in men is
typically associated with symptoms that would prompt clinical evaluation. Given the risk for
asymptomatic infection in women, screening is recommended for women at increased risk of infection
(eg, women with previous gonorrhea or other STI, inconsistent condom use, new or multiple sex partners,
and women in certain demographic groups such as those in communities with high STI prevalence).(2,3)
The CDC currently recommends dual antibiotic treatment due to emerging antimicrobial resistance.(2)
Culture was previously considered to be the gold standard test for diagnosis of C trachomatis and N
gonorrhoeae infections.(2) However, organisms are labile in vitro, therefore, precise specimen collection,
transportation, and processing conditions are required to maintain organism viability, which is necessary
for successful culturing. In comparison, nucleic acid amplification testing (NAAT) provides superior
sensitivity and specificity and is now the recommended method for diagnosis in most cases.(4-6)
Immunoassays and non-amplification DNA tests are also available for C trachomatis and N gonorrhoeae
detection, but these methods are significantly less sensitive and less specific than NAAT.(2) Improved
screening rates and increased sensitivity of NAAT testing have resulted in an increased number of
accurately diagnosed cases of both chlamydia and gonorrhea.(2-6) Improved detection rates result from
both the increased performance of the assay and the patients' easy acceptance of urine testing. Early
identification of infection enables sexual partners to seek testing and/or treatment as soon as possible and
reduces the risk of disease spread. Prompt treatment reduces the risk of infertility in women.
Useful For: Detection of Chlamydia trachomatis and Neisseria gonorrhoeae in non-FDA-approved

specimen types This test is not intended for use in medico-legal applications. This test is not useful for
the detection of Chlamydia pneumoniae.
Interpretation: A positive result indicates that rRNA of Chlamydia trachomatis and/or Neisseria
gonorrhoeae is present in the specimen tested and strongly supports a diagnosis of
chlamydial/gonorrheal infection. A negative result indicates that rRNA for C trachomatis and/or N
gonorrhoeae was not detected in the specimen. The predictive value of an assay depends on the
prevalence of the disease in any particular population. In settings with a high prevalence of sexually
transmitted disease, positive assay results have a high likelihood of being true positives. In settings with
a low prevalence of sexually transmitted disease, or in any setting in which a patient's clinical signs and
symptoms or risk factors are inconsistent with gonococcal or chlamydial urogenital infection, positive
results should be carefully assessed and the patient retested by other methods (eg, culture for N
gonorrhoeae), if appropriate. A negative result does not exclude the possibility of infection. If clinical
indications strongly suggest gonococcal or chlamydial infection, additional specimens should be
collected for testing. A result of indeterminate indicates that a new specimen should be collected. This
test has not been shown to cross react with commensal (nonpathogenic) Neisseria species present in the
oropharynx.
Reference Values:
Negative
Clinical References: 1. Centers for Disease Control and Prevention. 2014. Recommendations for
the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae, 2014. MMWR
Morb Mortal Wkly Rep. 2014;63:1-18 2. Centers for Disease Control and Prevention: Sexually
Transmitted Diseases Treatment Guidelines, 2015. MMWR Morb Mortal Wkly Rep. 2015 Jun
5;64(RR-03):1-137. 3. Centers for Disease Control and Prevention. 2002. Reporting of
laboratory-confirmed chlamydial infection and gonorrhea by providers affiliated with three large
Managed Care Organizations-United States, 1995-1999. MMWR Morb Mortal Wkly Rep.
2002;51:256-259 4. Crotchfelt KA, Pare B, Gaydos C, Quinn TC: Detection of Chlamydia trachomatis
by the GEN-PROBE AMPLIFIED Chlamydia trachomatis Assay (AMP CT) in urine specimens from
men and women and endocervical specimens from women. J Clin Microbiol. 1998 Feb;36(2):391-394
5. Gaydos CA, Quinn TC, Willis D, et al: Performance of the APTIMA Combo 2 assay for detection of
Chlamydia trachomatis and Neisseria gonorrhoeae in female urine and endocervical swab specimens. J
Clin Microbiol. 2003 Jan;41(1):304-309 6. Chernesky MA, Jang DE: APTIMA transcription-mediated
amplification assays for Chlamydia trachomatis and Neisseria gonorrhoeae. Expert Rev Mol Diagn.
2006 Jul;6(4):519-525
CGRNA Chlamydia trachomatis and Neisseria gonorrhoeae, Nucleic

61553 Acid Amplification, Varies
trachomatis and is the most prevalent sexually transmitted bacterial infection (STI) in the United
States.(1,2) In 2010, 1.3 million documented cases were reported to the CDC.(2) Given that 3 out of 4
infected women and 1 out of 2 infected men will be asymptomatic initially, the actual prevalence of
disease is thought to be much greater than reported.(2) The organism causes genitourinary infections in
women and men and may be associated with dysuria as well as vaginal, urethral, or rectal discharge. In
women, complications include pelvic inflammatory disease, salpingitis, and infertility. Approximately
25% to 30% of women who develop acute salpingitis become infertile.(2) Complications among men are
rare but include epididymitis and sterility. Rarely, genital chlamydial infection can cause arthritis with
associated skin lesions and ocular inflammation (Reiter syndrome). C trachomatis can be transmitted from
the mother during delivery and is associated with conjunctivitis and pneumonia in the newborn. Finally, C
trachomatis may cause hepatitis and pharyngitis in adult. Once detected, the infection is easily treated by a
short course of antibiotic therapy.(2) Annual Chlamydia screening is now recommended for all sexually
active women age 25 years and younger and for older women with risk factors for infection, such as a
new sex partner or multiple sex partners.(2) The CDC also recommends that all pregnant women be given
a screening test for chlamydia infection.(2) Repeat testing for test-of-cure is not recommended after
treatment with a standard treatment regimen unless patient compliance is in question, reinfection is
suspected, or the patient's symptoms persist. Repeat testing of pregnant women, 3 weeks after completion
of therapy, is also recommended to ensure therapeutic cure.(2) Gonorrhea is caused by the bacterium
Neisseria gonorrhoeae. It is also a very common STI, with 301,174 cases of gonorrhea reported to CDC in
2009.(1,2) Like Chlamydia, many infections in women are asymptomatic, and the true prevalence of
gonorrhea is likely much higher than reported.(1,2) The organism causes genitourinary infections in
women and men and may be associated with dysuria as well as vaginal, urethral, or rectal discharge.
Complications include pelvic inflammatory disease in women and gonococcal epididymitis and prostatitis
in men. Gonococcal bacteremia, pharyngitis, and arthritis may also occur. Infection in men is typically
associated with symptoms that would prompt clinical evaluation. Given the risk for asymptomatic
infection in women, screening is recommended for women at increased risk of infection (eg, women with
previous gonorrhea or other STI, inconsistent condom use, new or multiple sex partners, and women in
certain demographic groups such as those in communities with high STI prevalence.)(2) The CDC
currently recommends dual antibiotic treatment due to emerging antimicrobial resistance.(2) Culture was
previously considered to be the gold standard test for diagnosis of C trachomatis and N gonorrhoeae
infections. However, these organisms are labile in vitro, therefore, precise specimen collection,
Immunoassays and non-amplification DNA tests are also available for C trachomatis and N gonorrhoeae
detection, but these methods are significantly less sensitive and less specific than NAAT.(2-5) Improved
screening rates and increased sensitivity of NAAT testing have resulted in an increased number of
accurately diagnosed cases.(2-5) Improved detection rates result from both the increased performance of
the assay and the patients' easy acceptance of urine testing. Early identification of infection enables sexual
partners to seek testing and/or treatment as soon as possible and reduces the risk of disease spread. Prompt
treatment reduces the risk of infertility in women.
Useful For: Detection of Chlamydia trachomatis or Neisseria gonorrhoeae This test is not intended for
use in medico-legal applications. This test is not useful for the detection of Chlamydia pneumoniae.
Interpretation: A positive result indicates that rRNA of Chlamydia trachomatis or Neisseria

gonorrhoeae is present in the specimen tested and strongly supports a diagnosis of chlamydial or
gonorrheal infection. A negative result indicates that rRNA for C trachomatis or N gonorrhoeae was not
detected in the specimen. The predictive value of an assay depends on the prevalence of the disease in any
particular population. In settings with a high prevalence of sexually transmitted disease, positive assay
results have a high likelihood of being true-positives. In settings with a low prevalence of sexually
transmitted disease, or in any setting in which a patient's clinical signs and symptoms or risk factors are
inconsistent with gonococcal or chlamydial urogenital infection, positive results should be carefully
assessed and the patient retested by other methods (eg, culture for N gonorrhoeae), if appropriate. A
negative result does not exclude the possibility of infection. If clinical indications strongly suggest
gonococcal or chlamydial infection, additional specimens should be collected for testing. A result of
indeterminate indicates that a new specimen should be collected.
Reference Values:
Chlamydia trachomatis
Negative
Neisseria gonorrhoeae
Negative
Clinical References: 1. Centers for Disease Control and Prevention. 2002. Reporting of
2002;51:256-259 2. Centers for Disease Control and Prevention: Sexually Transmitted Diseases
Treatment Guidelines, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(RR-03):1-137 3. Crotchfelt KA,
Pare B, Gaydos C, Quinn TC: Detection of Chlamydia trachomatis by the GEN-PROBE AMPLIFIED
Chlamydia trachomatis Assay (AMP CT) in urine specimens from men and women and endocervical
specimens from women. J Clin Microbiol. 1998 Feb;36(2):391-394 4. Gaydos CA, Quinn TC, Willis D,
et al: Performance of the APTIMA Combo 2 assay for detection of Chlamydia trachomatis and
Neisseria gonorrhoeae in female urine and endocervical swab specimens. J Clin Microbiol. 2003
Jan;41(1):304-309 5. Chernesky MA, Jang DE: APTIMA transcription-mediated amplification assays
for Chlamydia trachomatis and Neisseria gonorrhoeae. Expert Rev Mol Diagn. 2006 Jul;6(4):519-525
MCRNA Chlamydia trachomatis, Miscellaneous Sites, Nucleic Acid

61554 Amplification, Varies
trachomatis and is the most prevalent sexually transmitted bacterial infection in the United States.(1,2)
In 2010, 1.3 million documented cases were reported to the CDC.(2) Given that 3 out of 4 infected
women and 1 out of 2 infected men will be asymptomatic initially, the actual prevalence of disease is
thought to be much greater than reported. The organism causes genitourinary infections in women and
men and may be associated with dysuria as well as vaginal, urethral, or rectal discharge. In women,
complications include pelvic inflammatory disease, salpingitis, and infertility. Approximately 25% to
30% of women who develop acute salpingitis become infertile.(2) Complications among men are rare
but include epididymitis and sterility. Rarely, genital chlamydial infection can cause arthritis with
associated skin lesions and ocular inflammation (Reiter syndrome). C trachomatis can be transmitted
from the mother during delivery and is associated with conjunctivitis and pneumonia. Finally, C
trachomatis may cause hepatitis and pharyngitis in adults. Once detected, the infection is easily treated
by a short course of antibiotic therapy. Annual chlamydia screening is now recommended for all
sexually active women age 25 years and younger and for older women with risk factors for infection,
such as a new sex partner or multiple sex partners. The CDC also recommends that all pregnant women
be given a screening test for Chlamydia infection.(2) Repeat testing for test-of-cure is not recommended
after treatment with a standard treatment regimen unless patient compliance is in question, reinfection is
suspected, or the patient's symptoms persist. Repeat testing of pregnant women, 3 weeks after
completion of therapy, is also recommended to ensure therapeutic cure.(2) Culture was previously
considered to be the gold standard test for diagnosis of C trachomatis infection.(2) However, organisms
are labile in vitro, therefore, precise specimen collection, transportation, and processing conditions are
required to maintain organism viability, which is necessary for successful culturing. In comparison,
nucleic acid amplification testing (NAAT) provides superior sensitivity and specificity and is now the
recommended method for diagnosis in most cases.(3-5) Immunoassays and non-amplification DNA
tests are also available for C trachomatis detection, but these methods are significantly less sensitive and
less specific than NAAT.(2) Improved screening rates and increased sensitivity of NAAT testing have
resulted in an increased number of accurately diagnosed cases.(2) Early identification of infection
enables sexual partners to seek testing and treatment as soon as possible and reduces the risk of disease
spread. Prompt treatment reduces the risk of infertility in women.
Useful For: Detection of Chlamydia trachomatis in non-FDA-approved specimen types This test is not
intended for use in medico-legal applications. This test is not useful for the detection of Chlamydia
pneumoniae.
Interpretation: A positive result indicates the presence of rRNA Chlamydia trachomatis. This assay
does detect plasmid-free variants of C trachomatis. A negative result indicates that rRNA for C
trachomatis was not detected in the specimen. The predictive value of an assay depends on the prevalence
of the disease in any particular population. In settings with a high prevalence of sexually transmitted
disease, positive assay results have a high likelihood of being true positives. In settings with a low
prevalence of sexually transmitted disease, or in any setting in which a patient's clinical signs and
symptoms or risk factors are inconsistent with chlamydial urogenital infection, positive results should be
carefully assessed and the patient retested by other methods, if appropriate.
Reference Values:
Negative
Clinical References: 1. Centers for Disease Control and Prevention. 2014. Recommendations for the
laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae, 2014. MMWR Morb
Mortal Wkly Rep. 2014;63:1-18 2. Centers for Disease Control and Prevention: Sexually Transmitted
Diseases Treatment Guidelines, 2015. MMWR Morb Mortal Wkly Rep. 2015 Jun 5;64(RR-03):1-137 3.
Crotchfelt KA, Pare B, Gaydos C, Quinn TC: Detection of Chlamydia trachomatis by the GEN-PROBE
AMPLIFIED Chlamydia trachomatis Assay (AMP CT) in urine specimens from men and women and
endocervical specimens from women. J Clin Microbiol. 1998 Feb;36(2):391-394 4. Gaydos CA, Quinn
TC, Willis D, et al: Performance of the APTIMA Combo 2 assay for detection of Chlamydia trachomatis
and Neisseria gonorrhoeae in female urine and endocervical swab specimens. J Clin Microbiol. 2003
Jan;41(1):304-309 5. Chernesky MA, Jang DE: APTIMA transcription-mediated amplification assays for
Chlamydia trachomatis and Neisseria gonorrhoeae. Expert Rev Mol Diagn. 2006 Jul;6(4):519-525
CTRNA Chlamydia trachomatis, Nucleic Acid Amplification, Varies

61551 Clinical Information: Chlamydia is caused by the obligate intracellular bacterium Chlamydia
trachomatis and is the most prevalent sexually transmitted bacterial infection (STI) in the United
States.(1,2) In 2010, 1.3 million documented cases were reported to the Centers for Disease Control and
Prevention (CDC).(2) Given that 3 out of 4 infected women and 1 out of 2 infected men will be
asymptomatic initially, the actual prevalence of disease is thought to be much greater than reported. The
organism causes genitourinary infections in women and men and may be associated with dysuria as well
as vaginal, urethral, or rectal discharge. In women, complications include pelvic inflammatory disease,
salpingitis, and infertility. Approximately 25% to 30% of women who develop acute salpingitis become
infertile.(2) Complications among men are rare but include epididymitis and sterility. Rarely, genital
chlamydial infection can cause arthritis with associated skin lesions and ocular inflammation (Reiter
syndrome). C trachomatis can be transmitted from the mother during delivery and is associated with
conjunctivitis and pneumonia in the newborn. Finally, C trachomatis may cause hepatitis and pharyngitis
in adults. Once detected, the infection is easily treated by a short course of antibiotic therapy. Annual
chlamydia screening is now recommended for all sexually active women age 25 years and younger and
for older women with risk factors for infection, such as a new sex partner or multiple sex partners. The
CDC also recommends that all pregnant women be given a screening test for Chlamydia infection.(2)
Repeat testing for test-of-cure is not recommended after treatment with a standard treatment regimen
unless patient compliance is in question, reinfection is suspected, or the patient's symptoms persist.
Repeat testing of pregnant women, 3 weeks after completion of therapy, is also recommended to ensure
therapeutic cure.(2) Culture was previously considered to be the gold standard test for diagnosis of C
trachomatis infection.(2) However, organisms are labile in vitro and precise specimen collection,
Immunoassays and non-amplification DNA tests are also available for C trachomatis detection, but these
methods are significantly less sensitive and less specific than NAAT.(2) Improved screening rates and
increased sensitivity of NAAT testing have resulted in an increased number of accurately diagnosed
cases.(2) Improved detection rates result from both the increased performance of the assay. Early
identification of infection enables sexual partners to seek testing and/or treatment as soon as possible and
reduces the risk of disease spread. Prompt treatment reduces the risk of infertility in women.
Useful For: Detection of Chlamydia trachomatis This test is not intended for use in medico-legal
applications. This test is not useful for the detection of Chlamydia pneumoniae.
Interpretation: A positive result indicates the presence of rRNA Chlamydia trachomatis. A negative
result indicates that rRNA for C trachomatis was not detected in the specimen. The predictive value of
an assay depends on the prevalence of the disease in any particular population. In settings with a high
prevalence of sexually transmitted disease, positive assay results have a high likelihood of being
true-positives. In settings with a low prevalence of sexually transmitted disease, or in any setting in
which a patient's clinical signs and symptoms or risk factors are inconsistent with chlamydial urogenital
infection, positive results should be carefully assessed and the patient retested by other methods, if
appropriate.
Reference Values:
Negative
Clinical References: 1. Centers for Disease Control and Prevention. 2002. Reporting of
2002;51:256-259 2. Centers for Disease Control and Prevention: Sexually Transmitted Diseases
Treatment Guidelines, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(RR-03):1-137 3. Crotchfelt KA,
Pare B, Gaydos C, Quinn TC: Detection of Chlamydia trachomatis by the GEN-PROBE AMPLIFIED
Chlamydia trachomatis Assay (AMP CT) in urine specimens from men and women and endocervical
specimens from women. J Clin Microbiol. 1998 Feb;36(2):391-394 4. Gaydos CA, Quinn TC, Willis D,
et al: Performance of the APTIMA Combo 2 assay for detection of Chlamydia trachomatis and
Neisseria gonorrhoeae in female urine and endocervical swab specimens. J Clin Microbiol. 2003
Jan;41(1):304-309 5. Chernesky MA, Jang DE: APTIMA transcription-mediated amplification assays
for Chlamydia trachomatis and Neisseria gonorrhoeae. Expert Rev Mol Diagn. 2006 Jul;6(4):519-525
CDP Chlordiazepoxide and Metabolite, Serum

8610 Clinical Information: Chlordiazepoxide (Librium) is a benzodiazepine widely used in the
treatment of anxiety, alcohol withdrawal symptoms, and as a premedication for anesthesia. The
mechanism of action of all benzodiazepines remains unclear. However, it is known that
benzodiazepines facilitate gamma-amino butyric acid (GABA)-mediated neurotransmission in the brain.
Benzodiazepines most likely facilitate the inhibitory presynaptic or postsynaptic reactions of GABA.
Chlordiazepoxide is metabolized to long-acting metabolites in the liver to the active metabolite
nordiazepam (desmethyldiazepam) and the clearance of the drug is reduced considerably in the elderly
and in patients with hepatic disease. Therapeutic assessment should include measurement of both the
parent drug (chlordiazepoxide) and the active metabolite (nordiazepam). Since chlordiazepoxide has a
wide therapeutic index and toxicity is dose-dependent, routine drug monitoring is not indicated in all
patients.
Useful For: Monitoring chlordiazepoxide therapy Assessing toxicity

Interpretation: Chlordiazepoxide and nordiazepoxide combined concentrations above 5000 ng/mL
have been associated with toxicity.
Reference Values:
Therapeutic concentration:
Chlordiazepoxide: 400-3,000 ng/mL
Nordiazepam: 100-500 ng/mL
Clinical References: 1. Langman, LJ, Bechtel L, Meier BM, Holstege CP, Clinical toxicology. In:
Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics.
6th ed. Elsevier; 2018:832-887 2. Burtis CA, Ashwood ER, Bruns DE, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. WB Saunders Company; 2011:1109-1188 3. Hiemke C, Baumann
P, Bergemann N, et al: AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry:
Update 2011. Pharmacopsychiatry. 2011;44:195-235
CLU Chloride, 24 Hour, Urine

614058 Clinical Information: Chloride is the major extracellular anion. Its precise function in the body is not
well understood; however, it is involved in maintaining osmotic pressure, proper body hydration, and
electric neutrality. In the absence of acid-base disturbances, chloride concentrations in plasma will
generally follow those of sodium. Since urine is the primary mode of elimination of ingested chloride,
urinary chloride excretion during steady state conditions will reflect ingested chloride, which
predominantly is in the form of sodium chloride. However, under certain clinical conditions, the renal
excretion of chloride may not reflect intake. For instance, during states of extracellular volume depletion,
urine chloride (and sodium) excretion is reduced.
Useful For: Indication of fluid balance and acid-base homeostasis using a 24-hour urine collection
Interpretation: Urine sodium and chloride excretion are similar, and, under steady-state conditions,
both the urinary sodium and chloride excretion reflect the intake of sodium chloride. During states of
extracellular volume depletion, low values indicate appropriate renal reabsorption of these ions, whereas
elevated values indicate inappropriate excretion (renal wasting). Urinary sodium and chloride excretion
may be dissociated during metabolic alkalosis with volume depletion where urine sodium excretion may
be high (due to renal excretion of sodium bicarbonate), while urine chloride excretion remains
appropriately low.
Reference Values:
> or =18 years: 34-286 mmol/24 hours
Reference values have not been stablished for patients who are less than 18 years of age.
Reference values apply to 24-hour collection.
Clinical References: 1. Delaney MP, Lamb EJ: Kidney disease. In: Rifai N, Horvath AR, Wittwer
CT, eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier;
2018:1308-1309 2. Kamel KS, Ethier JH, Richardson RM, Bear RA, Halperin ML: Urine electrolytes and
osmolality: when and how to use them. Am J Nephrol. 1990;10(2):89-102
CL_F Chloride, Feces

606755 Clinical Information: The concentration of electrolytes in fecal water and their rate of excretion are
dependent upon 3 factors: -Normal daily dietary intake of electrolytes -Passive transport from serum and
other vascular spaces to equilibrate fecal osmotic pressure with vascular osmotic pressure -Electrolyte
transport into fecal water due to exogenous substances and rare toxins (eg, cholera toxin) Fecal osmolality
is normally in equilibrium with vascular osmolality, and sodium is the major effector of this
equilibrium.(1) Fecal osmolality is normally 2 x (sodium + potassium) unless there are exogenous factors
inducing a change in composition, such as the presence of other osmotic agents (magnesium sulfate,
saccharides) or drugs inducing secretions, such as phenolphthalein or bisacodyl. Chronic diarrhea with
elevations in fecal chloride concentrations are caused by congenital chloridorrhea. This is a rare condition
associated with a genetic defect in a protein responsible for transport of chloride ions across the mucosal
membranes in the lower intestinal tract in exchange for bicarbonate ions. It plays an essential part in
intestinal chloride absorption, therefore variants in this gene have been associated with congenital
chloride diarrhea.(2. Acquired chloridorrhea is a rare condition that has been described as causing profuse,
chloride-rich diarrhea and a surprising contraction metabolic alkalosis rather than metabolic acidosis often
associated with typical diarrhea. Contributors to acquired chloridorrhea include chronic intestinal
inflammation and reduction of chloride/bicarbonate transporter expression in genetically susceptible
persons post-bowel resection and ostomy placement. Acquired chloridorrhea is rare but may be an
under-recognized condition in post-bowel resection patients.(3)
Useful For: Workup of cases of chronic diarrhea Evaluation of suspected chloridorrhea

Interpretation: Fecal chloride may be low (<20 mmol/L) in sodium sulfate-induced diarrhea.(4)
Markedly elevated fecal chloride concentration in infants (>60 mmol/L) and adults (>100 mmol/L) is
associated with congenital and secondary chloridorrhea.(5)
Reference Values:
Clinical References: 1. Steffer KJ, Santa Ana CA, Cole JA, Fordtran JS: The practical value of
comprehensive stool analysis in detecting the cause of idiopathic chronic diarrhea. Gastroenterol Clin
North Am 2012;41:539-560 2. Makela S, Kere J, Holmberg C, Hoglund P: SLC26A3 mutations in
congenital chloride diarrhea. Hum Mutat. 2002 Dec;20(6):425-438. doi: 10.1002/humu.10139/ 3. Ali
OM, Shealy C, Saklayen M: Acute pre-renal failure: acquired chloride diarrhea after bowel resection.
Clin Kidney J. 2012;5(4):356-358. doi: 10.1093/ckj/sfs082 4. Eherer AJ, Fordtran JS: Fecal osmotic gap
and pH in experimental diarrhea of various causes. Gastroenterology. 1992;103:545-551 5. Casprary
WF: Diarrhea associated with carbohydrate malabsorption. Clin Gastroenterol. 1986;15:631-655
RCHLU Chloride, Random, Urine

610607 Clinical Information: Chloride is the major extracellular anion. Its precise function in the body is
not well understood; however, it is involved in maintaining osmotic pressure, proper body hydration,
and electric neutrality. In the absence of acid-base disturbances, chloride concentrations in plasma will
generally follow those of sodium. Since urine is the primary mode of elimination of ingested chloride,
urinary chloride excretion during steady state conditions will reflect ingested chloride, which
predominantly is in the form of sodium chloride. However, under certain clinical conditions, the renal
excretion of chloride may not reflect intake. For instance, during states of extracellular volume
depletion, urine chloride (and sodium) excretion is reduced.
Useful For: An indicator of fluid balance and acid-base homeostasis

Interpretation: Urine sodium and chloride excretion are similar and, under steady state conditions,
both the urinary sodium and chloride excretion reflect the intake of sodium chloride. During states of
extracellular volume depletion, low values indicate appropriate renal reabsorption of these ions, whereas
elevated values indicate inappropriate excretion (renal wasting). Urinary sodium and chloride excretion
may be dissociated during metabolic alkalosis with volume depletion where urine sodium excretion may
be high (due to renal excretion of sodium bicarbonate) while urine chloride excretion remains
appropriately low.
Reference Values:
No established reference values
Random urine chloride may be interpreted in conjunction with serum chloride, using both values to
calculate fractional excretion of chloride.
The calculation for fractional excretion (FE) of chloride (Cl) is

FE(Cl) =(Cl [urine] x Creat [serum])/(Cl [serum] x Creat [urine]) x100
CT, eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. 2018:1308-1309 2.
Toffaletti J: Electrolytes. In: Dufour DR, Rifai N, eds. Professional Practice in Clinical Chemistry: A
Review.Â AACC Press; 1993 3. Kamel KS, Ethier JH, Richardson RM, et al: Urine electrolytes and
osmolality: when and how to use them. Am J Nephrol. 1990;10:89-102
CL Chloride, Serum
8460 Clinical Information: Chloride is the major anion in the extracellular water space; its physiological
significance is in maintaining proper body water distribution, osmotic pressure, and normal anion-cation
balance in the extracellular fluid compartment. Chloride is increased in dehydration, renal tubular acidosis
(hyperchloremia metabolic acidosis), acute renal failure, metabolic acidosis associated with prolonged
diarrhea and loss of sodium bicarbonate, diabetes insipidus, adrenocortical hyperfunction, salicylate
intoxication, and with excessive infusion of isotonic saline or extremely high dietary intake of salt.
Hyperchloremia acidosis may be a sign of severe renal tubular pathology. Chloride is decreased in
overhydration, chronic respiratory acidosis, salt-losing nephritis, metabolic alkalosis, congestive heart
failure, Addisonian crisis, certain types of metabolic acidosis, persistent gastric secretion and prolonged
vomiting, aldosteronism, bromide intoxication, syndrome of inappropriate antidiuretic hormone secretion,
and conditions associated with expansion of extracellular fluid volume.
Useful For: Evaluation of water, electrolyte, and acid-base status

Interpretation: In normal individuals, serum chloride values vary little during the day, although there
is a slight decrease after meals due to the diversion of chloride to the production of gastric juice.
Reference Values:
1-17 years: 102-112 mmol/L
Reference values have not been established for patients who are under 12 months of age.
Clinical References: Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood. WB

Saunders Company, Philadelphia, PA, 1994
FCHPZ Chlorpromazine (Thorazine)

FCHCG Chocolate/Cacao IgG

Reference Values:
FCCK Cholecystokinin (CCK)

90162 Clinical Information: Cholecystokinin is a 33 amino acid peptide having a very similar structure to
Gastrin. Cholecystokinin is present in several different sized forms including a 58 peptide Pro-CCK and
22, 12, and 8 peptide metabolites. The octapeptide retains full activity of the 33 peptide molecule.
Cholecystokinin has an important physiological role in the regulation of pancreatic secretion, gallbladder
contraction and intestinal motility. Cholecystokinin levels are elevated by dietary fat especially in
diabetics. Elevated levels are seen in hepatic cirrhosis patients. Cholecystokinin is found in high levels in
the gut, in the brain and throughout the central nervous system.
Reference Values:
Up to 80 pg/mL
CHLGP Cholestasis Gene Panel, Varies
608018 Clinical Information: Cholestasis is a decrease in or obstruction of bile flow that results in
jaundice, pruritus, hepatomegaly, and splenomegaly. Cholestasis can be the primary clinical symptom
due to progressive familial intrahepatic cholestasis (PFIC) or one of a number of symptoms due to a
variety of genetic disorders that cause multisystem disease. Many forms of cholestasis are multifactorial
in origin occurring due to the presence of both risk-associated alleles and environmental circumstances.
This panel is not intended to diagnose multifactorial cholestasis and risk-associated alleles will not be
reported unless requested. PFIC is a group of disorders caused by bile secretion or transport defects that
result in intrahepatic cholestasis in infancy or childhood. There are 5 types of PFIC that are molecularly
defined: FIC1 (ATP8B1 gene), PFIC2 (ABCB11 gene), PFIC3 (ABCB4 gene), PFIC4 (TJP2 gene), and
PFIC5 (NR1H4 gene). PFICs 1, 2, and 4 have normal to mild elevations of gamma-glutamyltransferase
(GGT). PFIC 3 results in significantly elevated serum GGT, whereas PFIC5 causes low to normal GGT
levels. PFIC can present with cholestasis in neonates, but most commonly manifests around 3 months of
age for those with PFIC2, the most common type. Studies of infants and children with cholestasis have
shown that 12% to 13% have molecularly confirmed PFIC. Disease progression results in liver failure
and hepatocellular carcinoma. Liver transplantation is an effective treatment, though less effective for
multisystemic PFIC1 than for other types. However, there is significant mortality, as 87% of patients
with untreated PFIC will not survive. A variety of other genetic disorders can also result in cholestasis,
such as Alagille syndrome (JAG1 and NOTCH2 genes), alpha-1-antitrypsin deficiency (SERPINA1
gene), arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome (VPS33B and VIPAS39
genes), citrullinemia (SLC25A13 gene), congenital defects of bile acid synthesis (HSD3B7 and
AKR1D1 genes), familial hypercholanemia (BAAT gene), neonatal ichthyosis-sclerosing cholangitis
syndrome (CLDN1 gene), and Crigler-Najjar syndrome types I or II or Gilbert syndrome (UGT1A1). In
addition, peroxisomal disorders (PEX genes) and mitochondrial disorders can include cholestatic liver
disease among other features. A comprehensive gene panel is a rapid and reliable first-tier test to
establish a diagnosis for patients with monogenic cholestasis
Useful For: Establishing a molecular diagnosis for patients with monogenic cholestasis Identifying
variants within genes known to be associated with primary, monogenic cholestasis, allowing for
predictive testing of at-risk family members
known significance.
Reference Values:
May;17(5):405-424 2. Baker A, Kerkar N, Todorova L, et al: Systematic review of progressive familial
intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2019;43(1):20-36 3. Chowdhury J, Wolkoff
AW, Chowdhury N, Arias IM: Hereditary jaundice and disorders of bilirubin metabolism. In: Valle D,
Antonarakis S, Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of
Inherited Disease. McGraw-Hill; 2019 Accessed January 07, 2020. Available at
http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225541453
CHLBF Cholesterol, Body Fluid

606915 Clinical Information: Serum cholesterol is measured to determine the concentration of circulating
lipoprotein particles when screening for cardiovascular disease. The concentration is affected by genetic
and lifestyle factors. Cholesterol concentrations in serous effusions increase due to exudative processes
that cause cell lysis or increased vascular permeability. Measurement of cholesterol in body fluids is
used for the diagnosis of a cholesterol effusion or cholesterol-rich pseudochylous effusion.
Pseudochylous effusions contain low triglycerides and high cholesterol and occur from chronic pleural
effusions such as rheumatic pleurisy and tuberculosis. Malignant effusions may become enriched with
cholesterol due to increased synthesis and release from neoplastic cells or lymphatic obstruction.(1)
Pleural fluid: Chylothorax is the name given to pleural effusions containing chylomicrons with
accordingly high triglyceride and low cholesterol concentrations, which occurs when chyle accumulates
from a disruption of the thoracic duct caused mainly by malignancy or trauma.(2) Pseudochylous
effusions accumulate gradually through the breakdown of cellular lipids in long-standing effusions such
as rheumatoid pleuritis, tuberculosis, or myxedema, and by definition the effluent contains high
concentrations of cholesterol, while chylous effusions contain high concentrations of triglycerides in the
form of chylomicrons.(3) Differentiation of pseudochylothorax from chylothorax is important as their
milky or opalescent appearance is similar; however, therapeutic management strategies differ.
Measurement of pleural fluid cholesterol has also been investigated in multiple studies for the purpose
of differentiating exudates from transudates.(4) Most of these studies concluded that cholesterol
performs as well as measurement of lactate dehydrogenase and total protein applying Light's criteria,
but does not add much value beyond that. Peritoneal fluid: Ascites is the pathologic accumulation of
excess fluid in the peritoneal cavity. Cholesterol analysis in peritoneal fluid may be a useful index to
separate malignant ascites from nonmalignant, often cirrhotic ascites. Studies report concentrations
ranging from greater than 32 to 70 mg/dL are greater than 88% sensitive and greater than 80% specific
for malignant ascites, outperforming cytology.(4)
Useful For: Aiding in the diagnosis of a cholesterol effusion or cholesterol-rich pseudochylous

effusion in body fluids Distinguishing between chylous and pseudochylous pleural effusions
Distinguishing between malignant and nonmalignant ascites
Interpretation: Pleural fluid cholesterol concentrations between 45 to 65 mg/dL are consistent with
exudative effusions. Cholesterol concentrations above 200 mg/dL suggest a pseudochylous effusion.(2)
Peritoneal fluid cholesterol concentrations between 32 to 70 mg/dL suggest a malignant cause of
ascites.(4)
Reference Values:
Clinical References: 1. Gulyas M, Kaposi AD, Elek G, Szollar LG, Hjerpe A: Value of
carcinoembryonic antigen (CEA) and cholesterol assays of ascitic fluid in cases of inconclusive cytology.
J Clin Pathol. 2001 Nov;54(11):831-5. doi: 10.1136/jcp.54.11.831 2. Hooper C, Lee YC, Maskell N: BTS
Pleural Guideline Group. Investigation of a unilateral pleural effusion in adults: British Thoracic Society
Pleural Disease Guideline 2010. Thorax. 2010 Aug;65 Suppl 2:ii4-17. doi: 10.1136/thx.2010.136978 3.
Staats BA, Ellefson RD, Budahn LL, et al: The lipoprotein profile of chylous and nonchylous pleural
effusions. Mayo Clin Proc. 1980;55(11):700-704 4. Block DR, Algeciras-Schimnich A: Body fluid
analysis: clinical utility and applicability of published studies to guide interpretation of today's laboratory
testing in serous fluids. Crit Rev Clin Lab Sci. 2013;50:107-124. doi: 10.3109/10408363.2013.844679
HDCH Cholesterol, High-Density Lipoprotein (HDL), Serum

8429 Clinical Information: High-density lipoprotein cholesterol (HDL-C) is associated with lower risk of
cardiovascular disease. Excess cholesterol is actively pumped into HDL to be carried in the blood
circulation and cleared by the liver in a process known as reverse cholesterol transport. For these reasons,
HDL-C is often referred to as "good" cholesterol. HDL-C is rarely measured in isolation and most often
ordered along with total cholesterol and triglycerides. Measuring HDL-C and total cholesterol enables
calculation of non-HDL cholesterol (total cholesterol-HDL-C). Non-HDL cholesterol is the combination
of low-density lipoprotein cholesterolÂ and very-low density lipoprotein cholesterol. Non-HDL
cholesterol is directly associated with risk for cardiovascular disease and referred to as "bad" cholesterol.
Useful For: Measurement of serum high-density lipoprotein concentrations for managing

atherosclerotic cardiovascular disease risk
Interpretation: Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular
disease. HDL-C can be increased by the same lifestyle changes that reduce risk for cardiovascular disease:
physical activity, smoking cessation, and eating healthier. However, medications that specifically increase
HDL levels have failed to reduce cardiovascular disease. Extremely low HDL values (<20 mg/dL) may
indicate liver disease or inherited dyslipidemia.
Reference Values:
The National Lipid Association and the National Cholesterol Education Program have set the following
guidelines for lipids in a context of cardiovascular risk for adults 18 years old and older:
HDL CHOLESTEROL
Males
> or =40 mg/dL
Females
> or =50 mg/dL
The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children
and Adolescents has set the following guidelines for lipids in a context of cardiovascular risk for
children 2-17 years of age:
HDL CHOLESTEROL
Low HDL: <40 mg/dL
Borderline Low: 40-45 mg/dL
Acceptable: >45 mg/dL
Reference values have not been established for patients who are younger than 24 months of age.
Clinical References: 1. Grundy SM, Stone NJ, Bailey AL, et al:

patient-centered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol. 2014
Blood Institute: Expert panel on integrated guidelines for cardiovascular health and risk reduction in
children and adolescents: Summary report. Pediatrics. 2011 Dec;128 Suppl 5(Suppl 5):S213-S256. doi:
10.1542/peds.2009-2107C
CLDL1 Cholesterol, Low-Density Lipoprotein (LDL), Calculated,

617023 Serum
Clinical Information: Lipoprotein cholesterol measurements are essential in managing risk for
atherosclerotic cardiovascular disease (ASCVD). Atherosclerosis is defined by a buildup of plaque
within arterial walls. ASCVD includes coronary heart disease, strokes, and peripheral artery disease.
ASCVD develops over decades and is often asymptomatic until the patient experiences a
life-threatening event such as a heart attack, stroke, or aneurysm. Low-density lipoprotein cholesterol
(LDL-C) is the primary lipoprotein responsible for atherogenic plaque. Very low-density lipoprotein
cholesterol (VLDL-C) is also atherogenic and the combination of LDL-C and VLDL-C is called
non-high-density lipoprotein (HDL) cholesterol. Serum LDL-C and non-HDL cholesterol are directly
associated with risk for ASCVD and often referred to as "bad" cholesterol. HDL-C is often referred to
as "good" cholesterol because HDL-C concentrations are inversely related to ASCVD risk. Adjusted
LDL-C calculations, like the Sampson/NIH equation, are endorsed by multiple guidelines as being more
accurate when triglycerides are greater than 150 mg/dL and/or LDL-C is less than 70 mg/dL.
Useful For: Calculation of low-density lipoprotein cholesterol using total cholesterol,

non-high-density lipoprotein (HDL) cholesterol, HDL cholesterol, and triglyceride concentrations
Managing atherosclerotic cardiovascular disease risk

disease risk. Establishing appropriate treatment strategies and lipid goals require that blood lipid values
be considered in context with other risk factors including, age, sex, smoking status, and medical history
of hypertension, diabetes, and cardiovascular disease. Low-density lipoprotein cholesterol results of 190
mg/dL or above in adults (> or =160 mg/dL in children) are severely elevated and may indicate familial
hypercholesterolemia.
Reference Values:
Only orderable as part of a profile. For more information see LPSC1 / Lipid Panel, Serum
guidelines for lipids in a context of cardiovascular risk for adults 18 years old and older:
LDL CHOLESTEROL
Borderline High: 130-159 mg/dL
High: 160-189 mg/dL
Very High: > or =190 mg/dL
and Adolescents has set the following guidelines for lipids in a context of cardiovascular risk for children
2 to 17 years old:
LDL CHOLESTEROL
Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-e1143 2.
Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered
management of dyslipidemia: Part 1-executive summary. J Clin Lipidol. 2014;8(5):473-488. doi:
10.1016/j.jacl.2014.07.007 3. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk
Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on
integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary
report. Pediatrics. 2011 Dec;128 Suppl 5(Suppl 5):S213-S256. doi: 10.1542/peds.2009-2107C 4. Sampson
M, Ling C, Sun Q, et al: A new equation for calculation of low-density lipoprotein cholesterol in patients
with normolipidemia and/or hypertriglyceridemia. JAMA Cardiol. 2020 May 1;5(5):540-548
NHDCH Cholesterol, Non-High-Density Lipoprotein (HDL), Calculated,

29871 Serum
Clinical Information: Lipoprotein cholesterol measures are essential in managing risk for
atherosclerotic cardiovascular disease (ASCVD). Atherosclerosis is defined by a buildup of plaque within
arterial walls. ASCVD includes coronary heart disease, strokes, and peripheral artery disease. ASCVD
develops over decades and is often asymptomatic until the patient experiences a life-threatening event
such as a heart attack, stroke, or aneurysm. Non-high-density lipoprotein cholesterol (HDL-C) is defined
by the calculation of total cholesterol-HDL-C. Non-HDL cholesterol is the combination of low-density
lipoprotein cholesterol (LDL-C) and very-low density lipoprotein cholesterol (VLDL-C). Non-HDL
cholesterol is directly associated with risk for cardiovascular disease and referred to as â€œbadâ€•
cholesterol. Multiple trials have demonstrated that non-HDL cholesterol is as good or better than LDL-C
at predicting cardiovascular disease risk. Non-HDL cholesterol is not influenced by triglyceride
concentrations or fasting.
Useful For: Calculation of non-high-density lipoprotein cholesterol for the work up of cardiovascular
risk Managing atherosclerotic cardiovascular disease risk
disease (ASCVD) risk. Establishing appropriate treatment strategies and lipid goals require blood lipid
values be considered in context with other risk factors including, age, sex, smoking status, and medical
history of hypertension, diabetes, and cardiovascular disease. For non-high-density lipoprotein
cholesterol results of 220 mg/dL or above, a possible inherited hyperlipidemia diagnosis should be
considered.
Reference Values:
Only orderable as part of a profile. For more information see LPSC1 / Lipid Panel, Serum.
The National Lipid Association and the National Cholesterol Education Program have set the
following guidelines for lipids in a context of cardiovascular risk for adults 18 years old and older:
NON-HDL CHOLESTEROL
High: 190-219 mg/dL
Very High: > or =220 mg/dL
and Adolescents has set the following guidelines for lipids in a context of cardiovascular risk for
children 2-17 years old:
NON-HDL CHOLESTEROL
Clinical References: 1. Grundy SM, Stone NJ, Bailey AL, et al:

patient-centered management of dyslipidemia: part 1-executive summary. J Clin Lipidol. 2014
Blood Institute: Expert panel on integrated guidelines for cardiovascular health and risk reduction in
children and adolescents: Summary report. Pediatrics. 2011 Dec;128 Suppl 5 (Suppl 5):S213-S256. doi:
10.1542/peds.2009-2107C
CHOL Cholesterol, Total, Serum

8320 Clinical Information: Cholesterol is a lipid that is synthesized in most tissues and actively
absorbed from the diet. There is a strong association between serum cholesterol concentrations and
cardiovascular disease. Cholesterol is carried in the blood by lipoproteins. Some lipoproteins carry a
stronger risk of cardiovascular disease while others are associated with reduced cardiovascular risk.
Total cholesterol concentration includes the sum of all "good" and "bad" cholesterol. Therefore, total
cholesterol is recommended to be interpreted in context of a lipid panel that includes high-density
lipoprotein cholesterol and triglyceride measures. Low levels of cholesterol can be seen in disorders that
include hyperthyroidism, malabsorption, and deficiencies of apolipoproteins.
Useful For: Evaluation of cardiovascular risk

Interpretation: The National Lipid Association and the National Cholesterol Education Program
(NCEP) have set the following guidelines for total cholesterol: Desirable: <200 mg/dL Borderline High:
200 to 239 mg/dL High: > or =240 mg/dL The recommended clinical decision points of 200 mg/dL and
240 mg/dL total cholesterol correspond to the 50th percentile and 90th percentile of healthy U.S. adults,
respectively. Values in hyperthyroidism usually are in the lower normal range; malabsorption values
may be below 100 mg/dL, while apolipoprotein B deficiency values usually are below 80 mg/dL.
Reference Values:
guidelines for lipids in a context of cardiovascular disease for adults 18 years old and older:
TOTAL CHOLESTEROL
and Adolescents has set the following guidelines for lipids in a context of cardiovascular disease for
children 2 to 17 years of age:
TOTAL CHOLESTEROL
Reference values have not been established for patients who younger than 24 months of age.
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the
management of blood cholesterol: a report of the American College of Cardiology/American Heart
Association Task Force on clinical practice guidelines. circulation. 2019 Jun 18;139(25):e1082-e1143.
doi: 10.1161/CIR.0000000000000625 2. Jacobson TA, Ito MK, Maki KC, et al: National Lipid
Association recommendations for patient-centered management of dyslipidemia: Part 1-executive
summary. J Clin Lipidol. 2014;8(5):473-488. doi: 10.1016/j.jacl.2014.07.007 3. Expert Panel on
Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents:
Summary report. Pediatrics. 2011 Dec;128 Suppl 5(Suppl 5):S213-S256. doi: 10.1542/peds.2009-2107C
CHLE Cholesteryl Esters, Serum

606888 Clinical Information: Cholesterol in the blood serum is normally 60% to 80% esterified with fatty
acids, largely as a result of the action of the enzyme lecithin-cholesterol acyltransferase (LCAT), which
circulates in the blood in association with the high-density lipoproteins. Familial deficiency of LCAT is
uncommon, usually occurring individuals of northern Europe descent, and is associated with erythrocyte
abnormalities (target cells) and decreased (20% or less) esterification of serum cholesterol. This is
associated with early atherosclerosis, corneal opacification, hyperlipidemia, and mild hemolytic anemia.
Persons with liver disease may have impaired formation of LCAT and, therefore, an acquired LCAT
deficiency and reduced cholesterol ester concentration.
Useful For: Establishing a diagnosis of lecithin-cholesterol acyltransferase deficiency Evaluating the

extent of metabolic disturbance by bile stasis or liver disease
Interpretation: In patients with lecithin-cholesterol acyltransferase deficiency, the concentration of

unesterified cholesterol in serum may increase 2 to 5 times the normal value, resulting in a decrease in
esterified serum cholesterol to 20% or less of the total serum cholesterol.
Reference Values:
> or =18 years: 60-80% of total cholesterol
Clinical References: 1. Meikle PJ, Mundra PA, Wong G, et al: Circulating lipids are associated with
alcoholic liver cirrhosis and represent potential biomarkers for risk assessment. PLoS One. 2015 Jun
24;10(6):e0130346. doi: 10.1371/journal.pone.0130346 2. Leach NV, Dronca E, Vesa SC, et al: Serum
homocysteine levels, oxidative stress and cardiovascular risk in non-alcoholic steatohepatitis. Eur J Intern
Med. 2014 Oct;25(8):762-767. doi: 10.1016/j.ejim.2014.09.007 3. Santamarina-Fojo S, Hoeg JM,
Assmann G, Brewer B: Lecithin cholesterol acyltransferase deficiency and fish eye disease. In: Valle DL,
Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of
Inherited Disease. McGraw-Hill; 2019. Accessed June 8, 2021. Available at
FCNAB Chromatin (Nucleosomal) Antibody

Reference Range: <1.0 Negative AI
CRCOF Chromium and Cobalt, Synovial Fluid

606424 Clinical Information: Per FDA recommendations, orthopedic surgeons should consider measuring
and following serial chromium (Cr) and cobalt (Co) concentrations in EDTA anticoagulated whole
blood in symptomatic patients with metal-on-metal hip implants as part of their overall clinical
evaluation. However, a recent publication(1) has shown synovial fluid measurements were superior to
whole blood and serum Cr and Co concentrations in predicting local tissue destruction in failed hip
arthroplasty constructs. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica,
LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside are typically made of Cr, Co, and
molybdenum. This list of products is incomplete, and the products' compositions change occasionally;
see each prostheses' product information for composition details. Cr: Cr is a naturally-occurring element
widely distributed in the environment. It exists in several valence states with the 3 main forms being
Cr(0), Cr(III), and Cr(VI). Cr(III) is an essential trace element that enhances the action of insulin.
Deficiency leads to impaired growth, reduced life span, corneal lesions, and alterations in
carbohydrates, lipid, and protein metabolism. Cr is widely used in manufacturing processes to make
various metal alloys such as stainless steel. It is also used in many consumer products including wood
treated with copper dichromate, leather tanned with chromic sulfate, and metal-on-metal hip
replacements. The general population is most likely to be exposed to trace levels of Cr, as Cr(III) is
naturally occurring in foods, such as fruits, vegetables, nuts, beverages, and meats. The highest potential
occupational exposure occurs in the metallurgy and tanning industries, where workers may be exposed
to high air concentrations. Co: Co is a naturally-occurring, hard, grey element widely distributed in the
environment. It is used to produce alloys in the manufacturing of aircraft engines, cutting tools, and
some artificial hip and knee joint prosthesis devices. Co is an essential cofactor in vitamin B12, which is
necessary for neurological function, brain function, and the formation of blood. For most people, food is
the largest source of Co intake. However, more than a million workers are potentially exposed to Co
and its compounds, with the greatest exposure in mining processes, cemented tungsten-carbide industry,
Co powder industry, and alloy production industry. Co is not highly toxic, but large doses will produce
adverse clinical manifestations. Acute symptoms include pulmonary edema, allergy, nausea, vomiting,
hemorrhage, and renal failure. Chronic exposure to Co-containing hard metal (dust or fume) can result
in a serious lung disease called "hard metal lung disease," which is a type of pneumoconiosis (lung
fibrosis). Furthermore, inhalation of Co particles can cause respiratory sensitization, asthma, shortness
of breath, and decreased pulmonary function. Even though the primary route of occupational exposure
to Co is the respiratory tract, skin contact is also important because dermal exposures to hard metal and
cobalt salts can result in significant systemic uptake. Sustained exposures can cause skin sensitization,
which may result in eruptions of contact dermatitis. In cases of suspected toxicity, blood, serum, or
urine concentrations of Co can be checked. Vitamin B12 should be used to assess nutritional status.
Useful For: Monitoring metallic prosthetic implant wear and local tissue destruction in failed hip
arthroplasty constructs This test is not useful for assessment of vitamin B12 activity.
Interpretation: Chromium: Based on an internal study, synovial fluid chromium concentrations of

16.9 ng/mL or above were more likely due to a metal reaction (eg, adverse local tissue reaction
[ALTR]/adverse reaction to metal debris [ARMD]) versus a nonmetal reaction in patients undergoing
metal-on-metal revision (sensitivity of 92.3% and specificity of 92.6%). Cobalt: Based on an internal
study, synovial fluid cobalt concentrations of 19.8 ng/mL or above were more likely due to a metal
reaction (eg, ALTR/ ARMD) versus a nonmetal reaction in patients undergoing metal-on-metal revision
(sensitivity of 92.3% and specificity of 96.3%).
Reference Values:
CHROMIUM:
0-17 years: Not established
> or =18 years: <16.9 ng/mL
COBALT:
Clinical References: 1. Houdek MT, Taunton MJ, Wyles CC, Jannetto PJ, Lewallen DG, Berry DJ.
Synovial fluid metal ion levels are superior to blood metal ion levels in predicting an adverse local tissue
reaction in failed total hip arthroplasty. J Arthroplasty. 2021 Sep;36(9):3312-3317.e1. doi:
10.1016/j.arth.2021.04.034 2. Eltit F, Assiri A, Garbuz D, et al: Adverse reactions to metal on
polyethylene implants: Highly destructive lesions related to elevated concentration of cobalt and
chromium in synovial fluid. J Biomed Mater Res A. 2017 Jul;105(7):1876-1886. doi:
10.1002/jbm.a.36057 3. Lass R, Grubl A, Kolb A, et al: Comparison of synovial fluid, urine, and serum
ion levels in metal-on-metal total hip arthroplasty at minimum follow-up of 18 years. J Orthop Res. 2014
Sept;32(9):1234-1240. doi: 10.1002/jor.22652 4. De Pasquale D, Stea S, Squarzoni S, et al:
Metal-on-metal hip prostheses: Correlation between debris in the synovial fluid and levels of cobalt and
chromium ions in the bloodstream. Int Orthop. 2014 Mar;38(3):469-475. doi: 10.1007/s00264-013-2137-5
CRUO Chromium Occupational Exposure, Random, Urine

65719 Clinical Information: Chromium (Cr) has an atomic mass of 51.996, atomic number 24, and
valences ranging from 2(-) to 6(+). Hexavalent chromium, Cr(6+), and trivalent chromium, Cr(3+), are
the 2 most prevalent forms. Cr(3+) is the only oxidation state present under normal physiologic
conditions. Cr(6+) is widely used in industry to make chromium alloys including stainless steel pigments
and electroplated coatings. Cr(6+), a known carcinogen, is rapidly metabolized to Cr(3+). Cr(3+) is the
only form present in human urine.
Useful For: Screening for occupational exposure

Interpretation: The National Institute for Occupational Safety and Health (NIOSH) draft document on
occupational exposure reviews the data supporting use of urine to assess chromium exposure.(1) They
recommend a Biological Exposure Index of 10 mcg/g creatinine and 30 mcg/g creatinine for the increase
in urinary chromium concentrations during a work shift and at the end of shift at the end of the workweek,
respectively (Section 3.3.1).
Reference Values:
> or =18 years: The American Conference of Governmental Industrial Hygienists (ACGIH) Biological
Exposure Index (BEI) for daily occupational exposure to hexavalent chromium in urine is an increase of
10.0 mcg/L between pre-shift and post-shift urine collections. The ACGIH BEI for long- and short-term
hexavalent chromium in urine is an end-of-shift concentration of >24.9 mcg/L at the end of the work
week.
Clinical References: 1. Centers for Disease Control and Prevention: National Institute for
Occupational Safety and Health (NIOSH) criteria for a recommended standard occupational exposure to
hexavalent chromium. September 2013. Accessed November 06, 2020. Available at
www.cdc.gov/niosh/docs/2013-128/pdfs/2013_128.pdf
CRU Chromium, 24 Hour, Urine

8593
Clinical Information: Chromium (Cr) exists in valence states ranging from 2(-) to 6(+). Hexavalent
chromium (Cr[6+]) and trivalent chromium (Cr[3+]) are the 2 most prevalent forms. Cr(6+) is used in
industry to make chromium alloys including stainless steel, pigments, and electroplated coatings.
Cr(6+), a known carcinogen, is immediately converted to Cr(3+) upon exposure to biological tissues.
Cr(3+) is the only chromium species found in biological specimens. Urine chromium concentrations are
likely to be increased above the reference range in patients with metallic joint prosthesis. Prosthetic
devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards
Company, Tricon, and Whiteside typically are made of chromium, cobalt, and molybdenum. This list of
products is incomplete, and these products change occasionally; see prosthesis product information for
each device for composition details.
Useful For: Screening for occupational exposure to chromium Monitoring metallic prosthetic
implant wear
Interpretation: Chromium is principally excreted in the urine. Urine levels correlate with exposure.
Results greater than the reference range indicate either recent exposure to chromium or specimen
contamination during collection. Prosthesis wear is known to result in increased circulating
concentration of metal ions. Modest increase (8-16 mcg/24 hour) in urine chromium concentration is
likely to be associated with a prosthetic device in good condition. Urine concentrations greater than 20
mcg/24 hours in a patient with chromium-based implant suggest significant prosthesis wear. Increased
independently predict prosthesis wear or failure. The National Institute for Occupational Safety and
Health (NIOSH) draft document on occupational exposure reviews the data supporting use of urine to
assess chromium exposure. They recommend a Biological Exposure Index of 10 mcg/g creatinine and
30 mcg/g creatinine for the increase in urinary chromium concentrations during a work shift and at the
end of shift at the end of the workweek, respectively. A test for this specific purpose (CROMU /
Chromium for Occupational Monitoring, Random, Urine) is available.
Reference Values:
> or =18 years: 0.1-1.2 mcg/24 hours
Clinical References: 1. Vincent JB: Elucidating a biological role for chromium at a molecular
level. Acc Chem Res. 2000 July;33(7):503-510 2. The National Institute for Occupational Safety and
Health (NIOSH): NIOSH Criteria Document: Criteria for a Recommendation Standard for an
Occupational Exposure to Hexavalent Chromium. September 2013 Available at
www.cdc.gov/niosh/docs/2013-128/pdfs/2013_128.pdf 3. Keegan GM, Learmonth ID, Case CP: A
systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium
exposures from industry and surgical implants. Crit Rev Toxicol. 2008;38:645-674
CRWB Chromium, Blood

65601 Clinical Information: Chromium (Cr) is a naturally occurring element widely distributed in the
environment. Chromium exists in several valence states with the 3 main forms being Cr(0), Cr(III), and
Cr(VI). Cr(III) is an essential trace element that enhances the action of insulin. Deficiency leads to
impaired growth, reduced life span, corneal lesions, and alterations in carbohydrates, lipid, and protein
metabolism. Chromium is widely used in manufacturing processes to make various metal alloys such as
stainless steel. It is also used in many consumer products including: wood treated with copper
dichromate, leather tanned with chromic sulfate, and metal-on-metal hip replacements. The general
population is most likely to be exposed to trace levels of chromium in the food that is eaten. Low levels
of Cr(III) occur naturally in a variety of foods, such as fruits, vegetables, nuts, beverages, and meats.
The highest potential occupational exposure occurs in the metallurgy and tanning industries, where
workers may be exposed to high air concentrations. Per FDA recommendations, orthopedic surgeons
should consider measuring and following serial chromium concentrations in EDTA anticoagulated
whole blood in symptomatic patients with metal-on-metal hip implants as part of their overall clinical
evaluation. Blood Cr concentrations are likely to be increased above the reference range in patients with
metallic joint prosthesis. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica,
LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside typically are made of chromium,
cobalt, and molybdenum. This list of products is incomplete, and these products change occasionally;
see prosthesis product information for each device for composition details.
Useful For: Monitoring exposure to chromium using whole blood specimens Monitoring metallic
prosthetic implant wear
Interpretation: Results greater than the reference range indicate exposure to chromium (Cr) (see
Cautions about specimen collection). Prosthesis wear is known to result in increased circulating
concentration of metal ions. Increased blood trace element concentrations in the absence of corroborating
clinical information do not independently predict prosthesis wear or failure.
Reference Values:
Clinical References: 1. Vincent JB: Elucidating a biological role for chromium at a molecular level.
Acc Chem Res. 2000 July;33(7):503-510 2. Centers for Disease Control and Prevention: National
Institute for Occupational Safety and Health (NIOSH) criteria for a recommended standard occupational
exposure to hexavalent chromium. September 2013. Accessed November 06, 2020. Available at
www.cdc.gov/niosh/docs/2013-128/pdfs/2013_128.pdf 3. Keegan GM, Learmonth ID, Case CP: A
systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium
exposures from industry and surgical implants. Crit Rev Toxicol. 2008;38:645-674 4. Tower SS:
Arthroprosthetic cobaltism: Neurological and cardiac manifestations in two patients with metal-on-metal
arthroplasty: A case report. J Bone Joint Surg Am. 2010 Dec;92(17):2847-2851 5. US Food and Drug
Administration: Information about Soft Tissue Imaging and Metal Ion Testing. Updated March 15, 2019.
Accessed March 2, 2021. Available at:
www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHipI
mplants/ucm331971.htm 6. US Department of Health and Human Services, Agency for Toxic Substances
and Disease Registry: Toxicology profile for chromium. September 2012. Accessed March 2, 2021.
Available at www.atsdr.cdc.gov/ToxProfiles/tp7.pdf 7. Rifai N, Horwath AR, Wittwer CT, eds: Tietz
CRS Chromium, Serum

8638 Clinical Information: Chromium (Cr) exists in valence states ranging from 2(-) to 6(+). Hexavalent
chromium (Cr[+6]) and trivalent chromium (Cr[+3]) are the 2 most prevalent forms. Cr(+6) is used in
industry to make chromium alloys including stainless steel, pigments, and electroplated coatings. Cr(+6),
a known carcinogen, is immediately converted to Cr(+3) upon exposure to biological tissues. Cr(+3) is the
only chromium species found in biological specimens. Serum Cr concentrations are likely to be increased
above the reference range in patients with metallic joint prosthesis. Prosthetic devices produced by Depuy
Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside
typically are made of chromium, cobalt, and molybdenum. This list of products is incomplete, and these
products change occasionally; see prosthesis product information for each device for composition details.
Useful For: Screening for occupational exposure Monitoring metallic prosthetic implant wear
Interpretation: Results greater than the flagged value indicate clinically significant exposure to
chromium (Cr) (see Cautions about specimen collection). The reported units of measurement for
chromium of ng/mL is equivalent to mcg/L. Prosthesis wear is known to result in an increased circulating
concentration of metal ions. A modest increase (0.3-0.6 ng/mL) in serum Cr concentration is likely to be
associated with a prosthetic device in good condition. Serum concentrations above 1 ng/mL in a patient
with a Cr-based implant suggest significant prosthesis wear. Increased serum trace element concentrations
in the absence of corroborating clinical information do not independently predict prosthesis wear or
failure. However, the FDA recommends testing chromium in EDTA anticoagulated whole blood in
symptomatic patients with metal-on-metal implants.
Reference Values:
<0.3 ng/mL
When collected by a phlebotomist experienced in ultra-clean collection technique and handled according
to the instructions in Trace Metals Analysis Specimen Collection and Transport in Special Instructions,
we have observed the concentration of chromium in serum to be <0.3 ng/mL. However, the majority of
specimens submitted for analysis from unexposed individuals contain 0.3 ng/mL to 0.9 ng/mL of
chromium. Commercial evacuated blood collection tubes not designed for trace-metal specimen collection
yield serum containing 2.0 ng/mL to 5.0 ng/mL chromium derived from the collection tube.
Clinical References: 1. Vincent JB: Elucidating a biological role for chromium at a molecular
level. Acc Chem Res 2000 July;33(7):503-510 2. NIOSH Hexavalent Chromium Criteria Document
Update. September 2008; Available at www.cdc.gov/niosh/topics/hexchrom/ 3. Keegan GM, Learmonth
ID, Case CP: A systematic comparison of the actual, potential, and theoretical health effects of cobalt
and chromium exposures from industry and surgical implants. Crit Rev Toxicol 2008;38:645-674 4.
Tower SS: Arthroprosthetic cobaltism: Neurological and cardiac manifestations in two patients with
metal-on-metal arthroplasty: A case report. J Bone Joint Surg Am 2010;92:1-5
CRSY Chromium, Synovial Fluid

606353 Clinical Information: Chromium (Cr) is a naturally-occurring element widely distributed in the
environment. It exists in several valence states with the 3 main forms being Cr(0), Cr(III), and Cr(VI).
Cr(III) is an essential trace element that enhances the action of insulin. Deficiency leads to impaired
growth, reduced life span, corneal lesions, and alterations in carbohydrates, lipid, and protein
metabolism. Cr is widely used in manufacturing processes to make various metal alloys such as
stainless steel. It is also used in many consumer products including wood treated with copper
dichromate, leather tanned with chromic sulfate, and metal-on-metal hip replacements. Per FDA
recommendations, orthopedic surgeons should consider measuring and following serial chromium
concentrations in EDTA anticoagulated whole blood in symptomatic patients with metal-on-metal hip
implants as part of their overall clinical evaluation. However, a recent publication(1) has shown
synovial fluid measurements were superior to whole blood and serum Cr concentrations in predicting
local tissue destruction in failed hip arthroplasty constructs. Prosthetic devices produced by Depuy
Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and
Whiteside are typically made of Cr, cobalt, and molybdenum. This list of products is incomplete, and
the products' compositions change occasionally; see each prostheses' product information for
composition details. The general population is most likely to be exposed to trace levels of Cr, as Cr(III)
is naturally occurring in foods, such as fruits, vegetables, nuts, beverages, and meats. The highest
potential occupational exposure occurs in the metallurgy and tanning industries, where workers may be
exposed to high air concentrations. In cases of suspected toxicity, blood, serum, or urine concentrations
of chromium can be checked.
arthroplasty constructs This test is not useful for assessment of potential chromium toxicity.
Interpretation: Based on an internal study, synovial fluid chromium concentrations of 16.9 ng/mL
or above were more likely due to a metal reaction (eg, adverse local tissue reaction [ALTR]/adverse
reaction to metal debris [ARMD]) versus a nonmetal reaction in patients undergoing metal-on-metal
revision (sensitivity of 92.3% and specificity of 92.6%).
Reference Values:
Clinical References: 1. Houdek MT, Taunton MJ, Wyles CC, Jannetto PJ, Lewallen DG, Berry
DJ: Synovial fluid metal ion levels are superior to blood metal ion levels in predicting an adverse local
tissue reaction in failed total hip arthroplasty. J Arthroplasty. 2021 Sep;36(9):3312-3317.e1. doi:
ion levels in metal-on-metal total hip arthroplasty at minimum follow-up of 18 years. J Orthop Res.
2014 Sept;32(9):1234-1240. doi: 10.1002/jor.22652 4. De Pasquale D, Stea S, Squarzoni S, et al:
chromium ions in the bloodstream. Int Orthop. 2014 Mar;38(3):469-475. doi:
10.1007/s00264-013-2137-5
CRCRU Chromium/Creatinine Ratio, Random, Urine

607758 Clinical Information: Chromium (Cr) has an atomic mass of 51.996, atomic number 24, and
valences ranging from 2(-) to 6(+). Hexavalent chromium, Cr(6+), and trivalent chromium, Cr(3+), are
the 2 most prevalent forms. Cr(3+) is the only oxidation state present under normal physiologic
conditions. Cr(6+) is widely used in industry to make chromium alloys including stainless steel pigments
and electroplated coatings. Cr(6+), a known carcinogen, is rapidly metabolized to Cr(3+). Cr(3+) is the
only form present in human urine.
Useful For: Detecting chromium exposure

Interpretation: Chromium is principally excreted in the urine. Results greater than the reference range
indicate either recent exposure to chromium or specimen contamination during collection. The National
Institute for Occupational Safety and Health (NIOSH) document on occupational exposure reviews the
data supporting use of urine to assess chromium exposure. The biological exposure indices (BEI) for total
chromium in urine measured at the end of the shift at the end of the workweek is 25 mcg/L. The BEI for
the increase in total chromium during a shift is 10 mcg/L. A test for this specific purpose (CROMU /
Chromium for Occupational Monitoring, Random, Urine) is available.
Reference Values:
>17 years: <0.8 mcg/g Creatinine
Clinical References: 1. U.S. Department of Health and Human Services, Agency for Toxic
Substances and Disease Registry. Toxicology profile for chromium. September 2012. Accessed
11/06/2020. Available at www.atsdr.cdc.gov/ToxProfiles/tp7.pdf 2. Rifai N, Horwath AR, Wittwer CT,
eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2017 3. Centers
for Disease Control and Prevention: National Institute for Occupational Safety and Health (NIOSH)
criteria for a recommended standard occupational exposure to hexavalent chromium. September 2013.
Accessed 11/06/2020. Available at www.cdc.gov/niosh/docs/2013-128/pdfs/2013_128.pdf 4. Gianello G,
Masci O, Carelli G, Vinci F, Castellino N: Occupational exposure to chromium-an assessment of
environmental pollution levels and biological monitoring of exposed workers. Ind Health. 1998
Jan;36(1):74-77. doi: 10.2486/indhealth.36.74.
CH9 Chromogenic Factor IX Activity Assay, Plasma

65029 Clinical Information: Factor IX (FIX) is a vitamin K-dependent serine protease synthesized in the
liver and participates in the intrinsic coagulation pathway. Its biological half-life is 18 to 24 hours.
Congenital FIX deficiency is inherited as an X-linked recessive bleeding disorder (hemophilia B). Severe
deficiency (<1%) characterized by hemarthroses, deep tissue bleeding, excessive bleeding with trauma,
and ecchymoses. Typically, these patients are tested using a 1-stage clotting assay. However, new
treatment options using long-acting glycoPEGylated replacement products are being approved for clinical
use. Pharmacokinetic studies for these products indicate ideal monitoring of patients should be performed
by the 2-stage chromogenic assay.
Useful For: Monitoring coagulation factor replacement therapy of selected extended half-life
coagulation factor replacements Aiding in the diagnosis of hemophilia B using a 2-stage assay, especially
when a 1-stage assay was normal
Interpretation: Factor IX deficiency may be acquired (eg, vitamin K deficiency, warfarin

anticoagulation effect, liver disease, or a consumptive coagulopathy) or congenital (hemophilia B).
Optimal laboratory monitoring of selected extended half-life factor IX replacement therapy (eg,
glycoPEGylated factor FIX) may be achieved with the chromogenic factor IX assay. Elevated factor IX
levels may be associated with acute or chronic inflammation, excess factor IX replacement therapy, or as
a result of a rare genetic variant, factor IX Padua.
Reference Values:
65-140%
Chromogenic Factor IX activity generally correlates with the one-stage FIX activity. In full
term/premature neonates, infants, children, and adolescents the one-stage FIX activity* is similar to
adults. However, no similar data for chromogenic FIX activity are available. (Appel JTH 2012;
10:2254)
Processing in Special Instructions.
Clinical References: 1. Bowyer AE, Hillarp A, Ezban M, et al: Measuring factor IX activity of
noacog beta pegol with commercially available one-stage clotting and chromogenic assay kits: a
two-center study. J Thromb Haemost 2016 Jul;14(7 1428-1435 doi: 10.1111/jth.13348 2. Kitchen S,
Signer-Romero K, Key NS: Current laboratory practices in the diagnosis and management of
haemophilia: a global assessment. Haemophilia 2015 Jul;21(4)550-557 3. Sorensen MH, Anderson S,
Ezban M: Factor IX-deficient plasma spiked with N9-GP behaves similarly to N9-GP
post-administration clinical samples in N9-GP ELISA and FIX activity assays. Haemophilia 2015
Nov;21(6):832-836 4. Dodt J, Hubbard AR, Wicks SJ, et al: Potency determination of factor VIII and
factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators.
Haemophilia 2015 Jul;21(4):543-549 5. Wilmot HV, Hogwood J, Gray E: Recombinant factor IX:
discrepancies between one-stage clotting and chromogenic assays. Haemophilia 2014
Nov;20(6):891-897
CHF8 Chromogenic Factor VIII Activity Assay, Plasma

610419 Clinical Information: Factor VIII (FVIII) is synthesized in the endothelial cells of the liver and,
perhaps, in other tissues. It is a coagulation cofactor that circulates bound to von Willebrand factor and
is part of the intrinsic coagulation pathway. The biological half-life is 9 to 18 hours (average is 12
hours). Congenital FVIII deficiency is inherited in a recessive X-linked manner and results in
hemophilia A, which has an incidence of 1 in 10,000 live male births. Patients with severe deficiency
(<1%) experience spontaneous bleeding episodes (eg, hemarthrosis, deep-tissue bleeding, etc), whereas
patients with moderate or mild deficiency (>1%) typically experience post-trauma or surgical bleeding.
FVIII activity assays (FVIII:C) are performed to diagnose hemophilia A and to monitor FVIII
replacement therapy. FVIII:C assays are typically 1-stage clotting assays. However, there is a subset of
patients with mild hemophilia A who have shown discrepantly low results when measured with the
2-stage (chromogenic) assay, indicating that testing patients with a mild bleeding history with both a 1-
and 2-stage assay would aid in diagnosis. In addition, there are new treatment options using long-acting
glycoPEGylated products. Pharmacokinetic studies are showing that ideal monitoring of patients should
be performed by the 2-stage chromogenic assay.
Useful For: Monitoring coagulation factor replacement therapy of selected extended half-life
coagulation factor replacements Aiding in the diagnosis of hemophilia A using a 2-stage assay,
especially when the 1-stage assay was normal
Interpretation: Factor VIII deficiency may be seen in congenital hemophilia A, acquired

(autoimmune) hemophilia A, or von Willebrand disease (congenital and acquired). Laboratory artifacts
that may result in artificially reduced factor VIII include samples collected in EDTA, instead of citrate,
or heparin contamination of the plasma sample. Elevated factor VIII may be seen in acute or chronic
inflammatory states or excess factor VIII replacement therapy.
Reference Values:
55.0-200.0%
Chromogenic Factor VIII activity generally correlates with the one-stage FVIII activity. In full
term/premature neonates, infants, children, and adolescents the one-stage FVIII activity* is similar to
adults. However, no similar data for chromogenic FVIII activity are available.(Appel JTH
2012;10:2254)
Clinical References: 1. Rodgers SE, Duncan EM, Sobieraj-Teague M, Lloyd JV: Evaluation of three
automated chromogenic FVIII kits for the diagnosis of mild discrepant haemophilia A. Int J Lab Hematol.
2009 Apr;31(2):180-188 2. Kitchen S, Beckman H, Katterle Y, et al: BAY 81-8973, a full-length
recombinant factor VIII: results from an International comparative laboratory field study. Haemophilia.
2016 May;22(3):e192-199. doi: 10.1111/hae.12925 3. Peyvandi F, Oldenburg J, Friedman KD: A critical
appraisal of one-stage and chromogenic assays of factor VIII activity. J Thromb Haemost. 2016
Feb;14(2):248-261 4. Dodt J, Hubbard AR, Wicks SJ, et al: Potency determination of factor VIII and
factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators.
Haemophilia. 2015 Jul;21(4):543-549
CH8BI Chromogenic Factor VIII Inhibitor Bethesda Profile

606844 Interpretation
Clinical Information: Factor VIII (FVIII) inhibitors are IgG antibodies directed against coagulation
FVIII that typically result in development of potentially life-threatening hemorrhage. These antibodies
may be alloimmune: developing in patients with congenital FVIII deficiency (hemophilia A) in response
to therapeutic infusions of factor VIII concentrate or autoimmune: occurring in patients without
hemophilia (not previously factor VIII deficient) either spontaneously or during pregnancy or in
association with autoimmune diseases.
Useful For: Interpretation of CHF8P / Chromogenic Factor VIII Inhibitor Bethesda Profile, Plasma
Detecting the presence and titer of a specific factor inhibitor directed against coagulation factor VIII This
test is not useful for detecting the presence of inhibitors directed against other clotting factors and will not
detect the presence of lupus anticoagulants.
Interpretation: The interpretive report will include assay information, background information, and
conclusions based on the test results.
Reference Values:
Only orderable as part of a profile. For more information see CHF8P / Chromogenic Factor VIII Inhibitor
Bethesda Profile, Plasma.
Clinical References: 1. Peyvandi F, Oldenburg J, Friedman KD: A critical appraisal of one-stage

and chromogenic assays of factor VIII activity. J Thromb Haemost. 2016 Feb;14(2):248-261 2.
Verbruggen B, van Heerde WL, Laros-van Gorkom BA: Improvements in factor VIII inhibitor detection:
From Bethesda to Nijmegen. Semin Thromb Hemost. 2009 Nov;35(8):752-759 3. Miller C, Platt S, Rice
A, Kelly F, Soucie JM, Hemophilia Inhibitor Research Study Investigators: Validation of
Nijmegen-Bethesda assay modifications to allow inhibitor measurement during replacement therapy and
facilitate inhibitor surveillance. J Thromb Haemost. 2012;10:1055-1061
CHF8P Chromogenic Factor VIII Inhibitor Bethesda Profile, Plasma

610420 Clinical Information: Factor VIII (FVIII) inhibitors are IgG antibodies directed against coagulation
FVIII that typically result in development of potentially life-threatening hemorrhage. These antibodies
may be alloimmune: developing in patients with congenital FVIII deficiency (hemophilia A) in response
to therapeutic infusions of factor VIII concentrate or autoimmune: occurring in patients without
hemophilia (not previously factor VIII deficient) either spontaneously, during pregnancy, or in association
with autoimmune diseases.
Useful For: Detecting the presence and titer of a specific factor inhibitor directed against coagulation
factor VIII for patients on emicizumab (Hemlibra) Detecting the presence and titer of an inhibitor
directed against factor VIII This test is not useful for detecting the presence of inhibitors directed
against other clotting factors and will not detect the presence of lupus anticoagulants.

Reference Values:
CHROMOGENIC Factor VIII Activity Assay
Adults: 55.0-200.0%
Normal, full-term newborn infants or healthy premature infants usually have normal or elevated factor
VIII.*
BETHESDA TITER
< or =0.5 Bethesda Units
Clinical References: 1. Peyvandi F, Oldenburg J, Friedman KD: A critical appraisal of one-stage

and chromogenic assays of factor VIII activity. J Thromb Haemost. 2016 Feb;14(2):248-261 2.
Verbruggen B, van Heerde WL, Laros-van Gorkom BA: Improvements in factor VIII inhibitor
detection: From Bethesda to Nijmegen. Semin Thromb Hemost. 2009 Nov;35(8):752-759 3. Miller CH,
Platt SJ, Rice AS, Kelly F, Soucie JM: Hemophilia Inhibitor Research Study Investigators: Validation
of Nijmegen-Bethesda assay modifications to allow inhibitor measurement during replacement therapy
and facilitate inhibitor surveillance. J Thromb Haemost. 2012 Jun;10(6):1055-1061
CH8B Chromogenic Factor VIII Inhibitor Bethesda Titer, Plasma

606843 Clinical Information: Factor VIII inhibitors are IgG antibodies directed against coagulation FVIII
that typically result in development of potentially life-threatening hemorrhage. These antibodies may be
alloimmune: developing in patients with congenital FVIII deficiency (hemophilia A) in response to
therapeutic infusions of factor VIII concentrate or autoimmune: occurring in nonhemophiliac patients
(not previously factor VIII deficient) either spontaneously, during pregnancy, or in association with
autoimmune diseases.
Useful For: Detecting the presence and titer of a specific factor inhibitor directed against coagulation
factor VIII This test is not useful for detecting the presence of inhibitors directed against other clotting
factors and will not detect the presence of lupus anticoagulants.
Interpretation: The interpretive report will include assay information, background information, and
conclusions based on the test results.
Reference Values:
Only orderable as part of a profile. For more information see CH8BP / Chromogenic Factor VIII
Inhibitor Bethesda Profile, Plasma.
< or =0.5 Bethesda Units
Clinical References: 1. Verbruggen B, van Heerde WL, Laros-van Gorkom BA: Improvements in
Factor VIII Inhibitor Detection: From Bethesda to Nijmegen. Semin Thromb Hemost 2009
Nov;35(8):752-759 2. Miller C, Platt S, Rice A, et al: Validation of Nijmegen-Bethesda assay
modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor
surveillance. J Thromb Haemost 2012;10:1055-1061
CGAK Chromogranin A, Serum

34641 Clinical Information: Chromogranin A (CGA) is a 439-amino acid protein with a molecular
weight of 48 to 60 kDa, depending on glycosylation and phosphorylation status. It is a member of the
granin family of proteins and polypeptides. Granins are widespread in endocrine, neuroendocrine,
peripheral, and central nervous tissues, where they are found in secretory granules alongside the
tissue-specific secretion products. The role of granins within the granules is to maintain the regulated
secretion of these signaling molecules. This includes: -Facilitating the formation of secretory granules
-Calcium- and pH-mediated sequestration and resolubilization of hormones or neurotransmitters
-Regulation of neuropeptide and peptide hormone processing through modulation of prohormone
convertase activity In addition, granins contain multiple protease and peptidase cleavage sites and, upon
intra- or extracellular cleavage, give rise to a series of daughter peptides with distinct extracellular
functions. Some of these have defined functions, such as pancreastatin, vasostatin, and catestatin, while
others are less well characterized.(1) Because of its ubiquitous distribution within neuroendocrine
tissues, CGA can be a useful diagnostic marker for neuroendocrine neoplasms, including carcinoids,
pheochromocytomas, neuroblastomas, medullary thyroid carcinomas (MTC), some pituitary tumors,
functioning and nonfunctioning islet cell tumors, and other amine precursor uptake and decarboxylation
(APUD) tumors. It can also serve as a sensitive means for detecting residual or recurrent disease in
treated patients.(2-4) Carcinoid tumors in particular almost always secrete CGA along with a variety of
specific modified amines, chiefly serotonin (5-hydroxytryptamine: 5-HT) and peptides.(1-4) Carcinoid
tumors are subdivided into foregut carcinoids, arising from respiratory tract, stomach, pancreas or
duodenum (approximately 15% of cases); midgut carcinoids, occurring within jejunum, ileum, or
appendix (approximately 70% of cases); and hindgut carcinoids, which are found in the colon or rectum
(approximately 15% of cases). Carcinoids display a spectrum of aggressiveness with no clear
distinguishing line between benign and malignant. In advanced tumors, morbidity and mortality relate
as much, or more, to the biogenic amines and peptide hormones secreted, as to local and distant spread.
The symptoms of this carcinoid syndrome consist of flushing, diarrhea, right-sided valvular heart
lesions, and bronchoconstriction. Serum CGA and urine 5-hydroxyindolacetic acid (5-HIAA) are
considered the most useful biochemical markers and are first-line tests in disease surveillance of most
patients with carcinoid tumors.(2-4) Serum CGA measurements are used in conjunction with, or
alternative to, measurements of serum or whole blood serotonin, urine serotonin and 5-HIAA, and
imaging studies. This includes the differential diagnosis of isolated symptoms suggestive of carcinoid
syndrome, in particular flushing. Finally, a number of tumors that are not derived from classical
endocrine or neuroendocrine tissues, but contain cells with partial neuroendocrine differentiation, such
as small-cell carcinoma of the lung or prostate carcinoma, may also display elevated CGA levels. The
role of CGA measurement is not well defined in these tumors, with the possible exception of prognostic
information in advanced prostate cancer.(5)
Useful For: Follow-up or surveillance of patients with known or treated carcinoid tumors An adjunct
in the diagnosis of carcinoid tumors An adjunct in the diagnosis of other neuroendocrine tumors,
including pheochromocytomas, medullary thyroid carcinomas, functioning and nonfunctioning islet cell
and gastrointestinal amine precursor uptake and decarboxylation tumors, and pituitary adenomas A
possible adjunct in outcome prediction and follow-up in advanced prostate cancer
Interpretation: Follow-up/Surveillance: Urine 5-hydroxyindolacetic acid (5-HIAA) and serum

chromogranin A (CGA) increase in proportion to carcinoid tumor burden. Because of the linear
relationship of CGA to tumor burden, its measurement also provides prognostic information. Most mid-
and hindgut tumors secrete CGA even if they do not produce significant amounts of serotonin or serotonin
metabolites (5-HIAA). Guidelines recommend 3 to 12 monthly measurements of CGA or 5-HIAA in
follow-up of midgut carcinoids.(2,3) Patients with foregut tumors can also be monitored with CGA or
5-HIAA measurements, if they were positive for these markers at initial diagnosis. Hindgut tumors
usually do not secrete serotonin and consequently, only CGA monitoring is recommended.(1-4) As is
typical for tumor marker use in follow-up and surveillance, a 40% to 50% change in serum CGA
concentrations should be considered potentially clinically significant in the absence of confounding
factors (see Cautions). Much smaller changes in CGA concentrations might be considered significant if
they occur over several serial measurements and are all in the same direction. Adjunct in Diagnosis of
Carcinoid Tumors: CGA is elevated in most patients (approximately 90%) with symptomatic or advanced
carcinoids (carcinoid syndrome), usually to levels several times the upper limit of the reference interval.
Serum CGA measurements are particularly suited for diagnosing hindgut tumors, being elevated in nearly
all cases, even though serotonin and 5-HIAA are often normal. CGA is also elevated in 80% to 90% of
patients with symptomatic foregut and midgut tumors. To achieve maximum sensitivity in the initial
diagnosis of suspected carcinoid tumors, serum CGA, serotonin in serum or blood, and 5-HIAA in urine
should all be measured. In most cases, if none of these 3 analytes are elevated, carcinoids can usually be
excluded as a cause of symptoms suggestive of carcinoid syndrome. For some cases, additional tests such
as urine serotonin measurement will be required. An example would be a foregut tumor that does not
secrete CGA and only produces 5-hydroxytryptophan (5-HTP) rather than serotonin. In this case,
circulating chromogranin, serotonin, and urine 5-HIAA levels would not be elevated. However, the
kidneys can convert 5-HTP to serotonin, leading to high urine serotonin levels. Adjunct in the Diagnosis
of Other Neuroendocrine Tumors: In patients with suspected neuroendocrine tumors other than
carcinoids, CGA is often elevated alongside any specific amine and peptide hormones or
neurotransmitters that may be produced. The CGA elevations are less pronounced than in carcinoid
tumors, and measurement of specific tumor secretion products is considered of greater utility. However,
CGA measurements can occasionally aid in diagnosis of these tumors if specific hormone measurements
are inconclusive. This is the case in particular with pheochromocytoma and neuroblastoma, where CGA
levels may be substantially elevated and can, therefore, provide supplementary and confirmatory
information to measurements of specific hormones. In particular, CGA measurements might provide
useful diagnostic information in patients with mild elevations in catecholamines and metanephrines;(6)
such mild elevations often represent false-positive test results. Possible Adjunct in Outcome Prediction
and Follow-up of Prostate Cancer: Prostate cancers often contain cells with partial neuroendocrine
differentiation. These cells secrete CGA. The amounts secreted are insufficient in most cases to make this
a useful marker for prostate cancer diagnosis. However, if patients with advanced prostate cancer are
found to have elevated CGA levels, this indicates the tumor contains a significant neuroendocrine cell
subpopulation. Such tumors are often resistant to antiandrogen therapy and have a worse prognosis. These
patients should be monitored particularly closely.(5)
Reference Values:
<93 ng/mL
Clinical References: 1. Bartolomucci A, Possenti R, Mahata SK, et al: The extended granin
family: Structure, function, and biomedical implications. Endocr Rev. 2011;32:755-797 2. Boudreaux
JP, Klimstra DS, Hassan MM, et al: The NANETS Consensus Guideline for the diagnosis and
management of neuroendocrine tumors-Well-differentiated neuroendocrine tumors of the jejunum,
ileum, appendix, and cecum. Pancreas. 2010;39:753-766 3. Anthony LB, Stosberg JR, Klimstra DS, et
al: The NANETS Consensus Guideline for the diagnosis and management of neuroendocrine tumors -
Well-differentiated NETs of the distal colon and rectum. Pancreas. 2010;39:767-774 4. Kullke MH,
Benson AB, Bergsland E, et al: National Comprehensive Cancer Network Clinical Practice Guidelines
in Oncology (NCCN Guidelines): NCCN Guidelines Version 1.Â Neuroendocrine Tumors. 2012:1-94.
Accessed March 20, 2012. Available at
www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf 5. Tricoli JV, Schoenfeldt M,
Conley BA: Detection of prostate cancer and predicting progression: Current and future diagnostic
markers. Clin Cancer Res. 2004;10:3943-3953 6. Algeciras-Schimnich A, Preissner CM, Young WF, et
al: Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the
diagnostic accuracy of plasma fractionated metanephrines for pheochromocytomas. J Clin Endocrinol
Metab. 2008;93:91-95 7. Korse CM, Muller M, Taal BG: Discontinuation of proton pump inhibitors
during assessment of chromogranin A levels in patients with neuroendocrine tumors. Br J Cancer.
2011;32:1173-1175 8. Bech PR, Ramachandran R, Dhillo WS, et al: Quantifying the effects of renal
impairment on plasma concentrations of the neuroendocrine neoplasia biomarkers chromogranin A,
chromogranin B, and cocaine- and amphetamine-regulated transcript. Clin Chem. 2012;58:941-943
CHRO Chromogranin Immunostain, Technical Component Only

70402 Clinical Information: Chromogranin A is widely expressed in neuronal tissues and in secretory
granules of human endocrine cells such as parathyroid gland, adrenal medulla, anterior pituitary gland,
Langerhans islets of the pancreas, and C-cells of the thyroid. It is useful for the identification of tumors
with neuroendocrine differentiation such as pituitary adenomas, islet cell tumors, pheochromocytomas,
medullary thyroid carcinomas, Merkel cell tumors, and carcinoids.
Useful For: Aiding in the identification of tumors with neuroendocrine differentiation
Clinical References: 1. Zhang D, Xie C, Wang R, et al: Effective preparation of a monoclonal

antibody against human chromogranin A for immunohistochemical diagnosis. BMC Biotechnology. 2018
May;18(1):25 2. Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki,KI:
Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms.
Ann Transl Med. 2018 Jun;6(12):252 3. Gkolfinopoulos S, Tsapakidis K, Papadimitriou K, Papamichael
D, Kountourakis P: Chromogranin A as a valid marker in oncology: Clinical application or false hopes?
World J Methodol. 2017 Mar 26;7(1):9-15
CMAFF Chromosomal Microarray (CMA) Familial Testing, FISH

35263 Clinical Information: Chromosomal microarray (CMA) is a method for detecting copy number
changes (gains or losses) across the entire genome. When copy number changes are identified in a patient,
parental studies are sometimes necessary to assess their clinical significance. Changes that are inherited
from clinically normal parents are less likely to be clinically significant in the patient and de novo changes
are more likely to be pathogenic. To identify familial copy number changes in parents of previously tested
patients, fluorescence in situ hybridization testing is utilized. the parental results will provide the context
for interpretation of the patient's CMA results.
Useful For: Determining the inheritance pattern of copy number changes previously identified by
chromosomal microarray analysis in a patient and aiding in the clinical interpretation of the pathogenicity
of the copy number change

Reference Values:
Clinical References: 1. Shaffer LG, Kashork CD, Saleki R, et al: Targeted genomic microarray
analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr.
2006 Jul;149(1):98-102 2. Baldwin EL, Lee JY, Blake DM, et al: Enhanced detection of clinically
relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray. Genet Med.
2008 May;10:415-429
CMAPC Chromosomal Microarray, Autopsy, Products of Conception, or

63042 Stillbirth, Varies
Clinical Information: Chromosomal abnormalities may result in malformed fetuses, spontaneous
abortions, or neonatal deaths. Estimates of the frequency of chromosome abnormalities in spontaneously
aborted fetuses range from 15% to 60%. Chromosomal microarray (CMA) studies of products of
conception, a stillborn infant, or neonate (autopsy) may provide useful information concerning the cause
of fetal loss. In addition, CMA may provide information regarding the recurrence risk for future
pregnancy loss and risk of having subsequent children with chromosome anomalies. This is particularly
useful information if there is a family history of 2 or more miscarriages or when fetal malformations are
evident. CMA is a high-resolution method for detecting copy number changes (gains or losses) across the
entire genome in a single assay and is sometimes called a molecular karyotype. This CMA test utilizes
more than 1.9 million copy number probes and approximately 750,000 single nucleotide polymorphism
probes for the detection of copy number changes and regions with absence of heterozygosity.
Identification of regions of excess homozygosity on a single chromosome could suggest uniparental
disomy that may warrant further clinical investigation when observed on chromosomes with known
imprinting disorders. In addition, the detection of excess homozygosity on multiple chromosomes may
suggest consanguinity.
Useful For: Prenatal diagnosis of copy number changes (gains or losses) across the entire genome
Diagnosing chromosomal causes for fetal death Determining recurrence risk of future pregnancy losses
Determining the size, precise breakpoints, gene content, and any unappreciated complexity of
abnormalities detected by other methods such as conventional chromosome and fluorescence in situ
hybridization (FISH) studies Determining if apparently balanced abnormalities identified by previous
conventional chromosome studies have cryptic imbalances, since a proportion of such rearrangements
that appear balanced at the resolution of a chromosome study are actually unbalanced when analyzed by
higher-resolution chromosomal microarray Assessing regions of homozygosity related to uniparental
disomy or identical by descent
Interpretation: Copy number variants are classified based on known, predicted, or possible
While many copy number changes observed by chromosomal microarray testing can readily be
characterized as pathogenic or benign, there are limited data available to support definitive classification
of a subset into either of these categories, making interpretation of these variants challenging. In these
situations, a number of considerations are taken into account to help interpret results including the size
and gene content of the imbalance, as well as whether the change is a deletion or duplication. Parental
testing may also be necessary to further assess the potential pathogenicity of a copy number change. In
such situations, the inheritance pattern and clinical and developmental history of the transmitting parent
will be taken into consideration. All copy number variants within the limit of detection classified as
pathogenic or likely pathogenic will be reported regardless of size. This includes but is not limited to
incidental findings currently recommended for reporting by the American College of Medical Genetics
and Genomics.(1) Copy number changes with unknown significance will be reported when at least one
protein-coding gene is involved in a deletion greater than 1 megabase (Mb) or a duplication greater than
2 Mb. The detection of excessive homozygosity may suggest the need for additional clinical testing to
confirm uniparental disomy (UPD) or to test for variants in genes associated with autosomal recessive
disorders consistent with the patient's clinical presentation that are present in regions of homozygosity.
Regions with absence of heterozygosity (AOH) of unknown significance will be reported when greater
than 5 Mb (terminal) and 10 Mb (interstitial) on UPD-associated chromosomes. Whole genome AOH
will be reported when greater than 5% of the genome. The continual discovery of novel copy number
variation and published clinical reports means that the interpretation of any given copy number change
may evolve with increased scientific understanding.
Reference Values:
Clinical References: 1. Kalia, S., Adelman, K., Bale, S. et al: Recommendations for reporting of
secondary findings in clinical exome and genome sequencing. 2016 update (ACMG SF v2.0): a policy
statement of the American College of Medical Genetics and Genomics. Genet Med. 2017
Feb;19(2):249-255. doi: 10.1038/gim.2016.190 2. American College of Obstetricians and Gynecologists
Committee on Genetics: Committee Opinion No. 581: the use of chromosomal microarray analysis in
prenatal diagnosis. Obstet Gynecol. 2013 Dec;122(6):1374-1377. doi:
10.1097/01.AOG.0000438962.16108.d1 3. Society for Maternal-Fetal Medicine (SMFM), Dugoff L,
Norton ME, Kuller JA: The use of chromosomal microarray for prenatal diagnosis. Am J Obstet
Gynecol. 2016 Oct;215(4):B2-B9. doi: 10.1016/j.ajog.2016.07.016 4. Sahoo T, Dzidic N, Strecker MN,
et al: Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: Outcomes,
benefits, and challenges. Genet Med. 2017 Jan;19(1):83-89. doi: 10.1038/gim.2016.69 5. Rosenfeld JA,
Tucker ME, Escobar LF, et al: Diagnostic utility of microarray testing in pregnancy loss. Ultrasound
Obstet Gynecol. 2015 Oct;46(4):478-486. doi: 10.1002/uog.14866
CMAMT Chromosomal Microarray, Autopsy/Products of

62667 Conception/Stillbirth, Tissue
Clinical Information: Chromosomal abnormalities may result in malformed fetuses, spontaneous
abortions, or neonatal deaths. Estimates of the frequency of chromosome abnormalities in spontaneously
aborted fetuses range from 15% to 60%. Chromosomal microarray (CMA) studies of products of
conception (POC), a stillborn infant, or a neonate (autopsy) may provide useful information concerning
the cause of miscarriage or fetal loss. In addition, CMA may provide information regarding the recurrence
risk for future pregnancy loss and risk of having subsequent children with chromosome anomalies. This is
particularly useful information if there is a family history of 2 or more miscarriages or when fetal
malformations are evident. CMA is a high-resolution method for detecting copy number changes (gains or
losses) across the entire genome in a single assay and is sometimes called a molecular karyotype. This
CMA test utilizes over 220,000 markers for the detection of copy number changes and regions with
absence of heterozygosity. The detection of excess homozygosity on multiple chromosomes may suggest
consanguinity. Homozygosity involving the entire genome is indicative of a complete molar pregnancy.
Useful For: Diagnosis of congenital copy number changes in products of conception, including
aneuploidy (ie, trisomy or monosomy) and structural abnormalities Diagnosing chromosomal causes for
fetal death Determining recurrence risk of future pregnancy losses Determining the size, precise
breakpoints, gene content, and any unappreciated complexity of abnormalities detected previously by
other methods such as conventional chromosome and fluorescence in situ hybridization (FISH) studies
Determining if apparently balanced abnormalities identified by previous conventional chromosome
studies have cryptic imbalances, since a proportion of such rearrangements that appear balanced at the
resolution of a chromosome study are actually unbalanced when analyzed by higher-resolution
chromosomal microarray
While many copy number changes observed by chromosomal microarray testing can readily be
characterized as pathogenic or benign, there are limited data available to support definitive classification
of a subset into either of these categories, making interpretation of these variants challenging. In these
situations, a number of considerations are taken into account to help interpret results including the size
and gene content of the imbalance, as well as whether the change is a deletion or duplication. Parental
testing may also be necessary to further assess the potential pathogenicity of a copy number change. In
such situations, the inheritance pattern and clinical and developmental history of the transmitting parent
will be taken into consideration. All copy number variants within the limit of detection classified as
pathogenic or likely pathogenic will be reported regardless of size. This includes, but is not limited to,
incidental findings currently recommended for reporting by the American College of Medical Genetics
and Genomics (ACMG).(1) Copy number changes with unknown significance will be reported when at
least one protein-coding gene is involved in a deletion greater than 1 megabase (Mb) or a duplication
greater than 2 Mb. The detection of excessive homozygosity may suggest the need to test for variants in
genes associated with autosomal recessive disorders consistent with the patient's clinical presentation that
are present in regions of homozygosity. Homozygosity will be reported when involving greater than 20%
of the genome. Homozygosity involving the entire genome is indicative of a complete molar pregnancy.
The continual discovery of novel copy number variation and published clinical reports means that the
interpretation of any given copy number change may evolve with increased scientific understanding.
Reference Values:
Clinical References: 1. Kalia S, Adelman K, Bale S, et al: Recommendations for reporting of

statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249-255 2.
American College of Obstetricians and Gynecologists Committee on Genetics: Committee opinion No.
581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol.
2013;122:1374-1377 3. Wapner RJ, Martin CL, Levy B, et al: Chromosomal microarray versus
karyotyping for prenatal diagnosis. N Engl J Med. 2012;367:2175-2184 4. Armengol L, Nevado J,
Serra-Juhe C, et al: Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis.
Hum Genet. 2012;131:513-523 5. Laurino MY, Bennett RL, Saraiya DS, et al: Genetic evaluation and
counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic
Counselors. J Genet Couns. 2005;14:165-181 6. Reddy UM, Page GP, Saade GR, et al: Karyotype versus
microarray testing for genetic abnormalities after stillbirth. N Engl J Med. 2012;367:2185-2193
CMACB Chromosomal Microarray, Congenital, Blood

35247 Clinical Information: Aneuploidy or unbalanced chromosome rearrangements are often found in
patients with intellectual disability, developmental delay, autism, dysmorphic features, or congenital
anomalies. Some chromosomal abnormalities are large enough to be detected with conventional
chromosome analysis. However, many pathogenic rearrangements are below the resolution limits of
chromosome analysis (approximately 5 megabases). Chromosomal microarray (CMA) is a
high-resolution method for detecting copy number changes (gains or losses) across the entire genome in
a single assay and is sometimes called a molecular karyotype. This CMA test utilizes greater than 1.9
million copy number probes and approximately 750,000 single nucleotide polymorphism probes for the
detection of copy number changes and regions of excessive homozygosity. Identification of regions of
excessive homozygosity on a single chromosome could suggest uniparental disomy (UPD), which may
warrant further clinical investigation when observed on chromosomes with known imprinting disorders
associated with UPD. In addition, the detection of excessive homozygosity on multiple chromosomes
may suggest consanguinity and, therefore, could be useful in determining candidate genes for further
testing for autosomal recessive disorders. An online research opportunity called GenomeConnect
(genomeconnect.org) is available for the recipients of genetic test results. This patient registry collects
deidentified genetic and health information to advance knowledge of genetic variants. For more
information see GenomeConnect Patient Portal.
Useful For: First-tier, postnatal testing for individuals with multiple anomalies that are not specific to
well-delineated genetic syndromes, apparently nonsyndromic developmental delay or intellectual
disability, or autism spectrum disorders as recommended by the American College of Medical Genetics
and Genomics Follow-up testing for individuals with unexplained developmental delay or intellectual
disability, autism spectrum disorders, or congenital anomalies with a previously normal conventional
chromosome study Determining the size, precise breakpoints, gene content, and any unappreciated
complexity of abnormalities detected by other methods such as conventional chromosome and
fluorescence in situ hybridization studies Determining if apparently balanced abnormalities identified
by previous conventional chromosome studies have cryptic imbalances, since a proportion of such
rearrangements that appear balanced at the resolution of a chromosome study are actually unbalanced
when analyzed by higher-resolution chromosomal microarray Assessing regions of homozygosity
related to uniparental disomy or identity by descent
Interpretation: When interpreting results, the following factors need to be considered: Copy number
variation is found in all individuals, including patients with abnormal phenotypes and normal
populations. Therefore, determining the clinical significance of a rare or novel copy number change can
be challenging. Parental testing may be necessary to further assess the potential pathogenicity of a copy
number change. While most copy number changes observed by chromosomal microarray testing can
readily be characterized as pathogenic or benign, there are limited data available to support definitive
classification of a subset into either of these categories. In these situations, a number of considerations
are taken into account to help interpret results including the size and gene content of the imbalance,
whether the change is a deletion or duplication, the inheritance pattern, and the clinical and/or
developmental history of a transmitting parent. All copy number variants within the limit of detection
classified as pathogenic or likely pathogenic will be reported regardless of size. This includes but is not
limited to incidental findings currently recommended for reporting by the American College of Medical
Genetics and Genomics (ACMG).(1) Copy number changes with unknown significance will be reported
when at least one protein-coding gene is involved in a deletion greater than 200 kilobases (kb) or a
duplication greater than 1 megabase (Mb). The detection of excessive homozygosity may suggest the
need for additional clinical testing to confirm uniparental disomy (UPD) or to test for variants in genes
associated with autosomal recessive disorders consistent with the patient's clinical presentation that are
present in regions of homozygosity. Interstitial regions with absence of heterozygosity (AOH) of
unknown significance will be reported when greater than 10 Mb on UPD-associated chromosomes, and
greater than 15 Mb on non-imprinted chromosomes. Terminal AOH will be reported when greater than
5 Mb. Whole genome AOH will be reported when greater than 2% of the genome. The continual
discovery of novel copy number variation and published clinical reports means that the interpretation of
any given copy number change may evolve with increased scientific understanding. Families benefit
from hearing genetic information multiple times and in multiple ways. A referral to a clinical genetics
professional is appropriate for individuals and families to discuss the results of chromosomal microarray
testing.
Reference Values:
Clinical References: 1. Kalia SS, Adelman K, Bale SJ, et al: Recommendations for reporting of
statement of the American College of Medical Genetics and Genomics. Genet Med. 2017
Feb;19(2):249-255. doi: 10.1038/gim.2016.190 2. Manning M, Hudgins L, Professional Practice and
Guidelines Committee: Array-based technology and recommendations for utilization in medical genetics
practice for detection of chromosomal abnormalities. Genet Med. 2010 Nov;12(11):742-745. doi:
10.1097/GIM.0b013e3181f8baad 3. Miller DT, Adam MP, Aradhya S, et al: Consensus statement:
Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental
disabilities or congenital anomalies. Am J Hum Genet. 2010 May;86(5):749-764. doi:
10.1016/j.ajhg.2010.04.006 4. Kearney HM, Thorland EC, Brown KK, et al: American College of
Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy
number variants. Genet Med. 2011 Jul;13(7)680-685. doi: 10.1097/GIM.0b013e3182217a3a 5. Kearney
HM, Kearney JB, Conlin LK: Diagnostic implications of excessive homozygosity detected by SNP-based
microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clin Lab Med.
2011 Dec;31(4):595-613. doi: 10.1016/j.cll.2011.08.003 6. Marcou CA, Pitel B, Hagen CE, et al: Limited
diagnostic impact of duplications <1 Mb of uncertain clinical significance: a 10-year retrospective
analysis of reporting practices at the Mayo Clinic. Genet Med. 2020 Dec;22(12):2120-2124. doi:
10.1038/s41436-020-0932-0
CMAH Chromosomal Microarray, Hematologic Disorders, Varies

35899 Clinical Information: The importance of identifying chromosome abnormalities in hematologic
disorders is well established and often provides important diagnostic, prognostic, and therapeutic
information critical to proper patient management. Although many chromosomal abnormalities are large
enough to be detected with conventional chromosome analysis, many others are below its limits of
resolution, and conventional chromosome analysis does not detect copy-neutral loss of heterozygosity.
Chromosomal microarray (CMA) improves the diagnostic yield to identify genetic changes that are not
detected by conventional chromosome analysis or fluorescence in situ hybridization (FISH) studies. CMA
utilizes greater than 1.9 million copy number probes and approximately 750,000 single nucleotide
polymorphism probes to detect copy number changes and regions of copy-neutral loss of heterozygosity.
CMA analysis is appropriate to identify gain or loss of chromosome material throughout the genome at a
resolution of 30 to 60 kilobases. CMA can do the following: -Define the size, precise breakpoints, and
gene content of copy number changes to demonstrate the complexity of abnormalities -Characterize
unidentified chromosome material, marker chromosomes, and DNA amplification detected by
conventional chromosome and FISH studies -Determine if apparently balanced chromosome
rearrangements identified by conventional chromosome studies have cryptic imbalances -Assess regions
of copy-neutral loss of heterozygosity, which is common in neoplasia and often masks homozygous
mutations involving tumor suppressor genes The limit of detection is dependent on size of the
abnormality, type of abnormality (deletion or duplication) and DNA quality. When a deletion or
duplication exceeds the reporting limits, mosaicism can confidently be detected as low as 25% and may
be lower if the abnormality is large and DNA quality is good.
Useful For: Detection and characterization of clonal copy number imbalance and loss of
heterozygosity associated with hematologic neoplasms Assisting in the diagnosis and classification of
certain hematologic neoplasms Evaluating the prognosis for patients with certain hematologic neoplasms
Interpretation: The interpretive report describes copy number changes and any loss of heterozygosity
that may be associated with the neoplastic process. Abnormal clones with subclonal cytogenetic evolution
will be discussed if identified. The continual discovery of novel copy number variation and published
clinical reports means that the interpretation of any given copy number change may evolve with increased
scientific understanding. Although the presence of a clonal abnormality usually indicates a neoplasia, in
some situations it may reflect a benign or constitutional genetic change. If a genetic change is identified
that is likely constitutional and clearly pathogenic (eg, XYY), consultation with a Clinical Geneticist may
be suggested. The absence of an abnormal clone may be the result of specimen collection from a site that
is not involved in the neoplasm or may indicate that the disorder is caused by a point mutation that is not
detectable by chromosomal microarray (CMA). CMA, fluorescence in situ hybridization (FISH), and
conventional cytogenetics are to some extent complementary methods. In some instances, additional FISH
or conventional cytogenetic studies will be recommended to clarify interpretive uncertainties.
Reference Values:
Clinical References: 1. Cooley L, Lebo M, Li M, et al: American College of Medical Genetics

and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in
neoplastic disorders. Genet Med. 2013 Jun;15(6):484-494 2. Dougherty M, Wilmoth D, Tooke L, et al:
Implementation of high resolution single nucleotide polymorphism array analysis as a clinical test for
patients with hematologic malignancies. Cancer Genetics. 2011 Jan;204(1):26-38 3. Schwartz, S:
Clinical Utility of Single Nucleotide Polymorphism Arrays. Clin Lab Med. 2011 Dec;31(4):581-594 4.
Braggio E, Kay N, VanWier S, et al: Longitudinal genome-wide analysis of patients with chronic
lymphocytic leukemia reveals complex evolution of clonal architecture at disease progression and at the
time of relapse. Leukemia. 2012 Jul;26(7):1698-1701
CMAP Chromosomal Microarray, Prenatal, Amniotic Fluid/Chorionic

35898 Villus Sampling
Clinical Information: Chromosomal abnormalities cause a wide range of disorders associated with
birth defects and intellectual disability. Many of these disorders can be diagnosed prenatally by analysis
of chorionic villi or amniocytes. The most common reasons for performing cytogenetic studies for
prenatal diagnosis include advanced maternal age, abnormal prenatal screen, a previous child with a
chromosome abnormality, abnormal fetal ultrasound, or a family history of a chromosome abnormality.
Chromosomal microarray (CMA) is a high-resolution method for detecting copy number changes (gains
or losses) across the entire genome in a single assay and is sometimes called a molecular karyotype. The
American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine
recommend the chromosomal microarray as a replacement for the fetal karyotype in patients with a
pregnancy demonstrating one or more major structural abnormalities on ultrasound when undergoing
invasive prenatal diagnosis.(1) This CMA test utilizes more than 1.9 million copy number probes and
approximately 750,000 single nucleotide polymorphism probes for the detection of copy number
changes and regions with absence of heterozygosity. Identification of regions of excessive
homozygosity on a single chromosome could suggest uniparental disomy, which may warrant further
clinical investigation when observed on chromosomes with known imprinting disorders. In addition, the
detection of excessive homozygosity on multiple chromosomes may suggest consanguinity.
Useful For: Prenatal diagnosis of copy number changes (gains or losses) across the entire genome
Determining the size, precise breakpoints, gene content, and any unappreciated complexity of
abnormalities detected by other methods such as conventional chromosome and fluorescence in situ
hybridization (FISH) studies Determining if apparently balanced abnormalities identified by previous
conventional chromosome studies have cryptic imbalances, since a proportion of such rearrangements
that appear balanced at the resolution of a chromosome study are actually unbalanced when analyzed by
higher-resolution chromosomal microarray Assessing regions of homozygosity related to uniparental
disomy or identity by descent
When interpreting results, it is important to realize that copy number variation is found in all
individuals, including patients with abnormal phenotypes and normal populations. Therefore,
determining the clinical significance of a rare or novel copy number change can be challenging. Parental
testing may be necessary to further assess the potential pathogenicity of a copy number change. While
most copy number changes observed by chromosomal microarray testing can readily be characterized as
pathogenic or benign, there are limited data available to support definitive classification of a subset into
either of these categories. In these situations, a number of considerations are taken into account to help
interpret results including the size and gene content of the imbalance, whether the change is a deletion
or duplication, the inheritance pattern, and the clinical and developmental history of a transmitting
parent. All copy number variants within the limit of detection classified as pathogenic or likely
pathogenic will be reported regardless of size. This includes but is not limited to incidental findings
currently recommended for reporting by the American College of Medical Genetics and Genomics
(ACMG).(2) Copy number changes with unknown significance will be reported when at least one
protein-coding gene is involved in a deletion greater than 1 megabase (Mb) or a duplication greater than
2 Mb. The detection of excessive homozygosity may suggest the need for additional clinical testing to
confirm uniparental disomy (UPD) or to test for variants in genes associated with autosomal recessive
disorders consistent with the patient's clinical presentation that are present in regions of homozygosity.
Regions with absence of heterozygosity (AOH) of unknown significance will be reported when greater
than 5 Mb (terminal) and 10 Mb (interstitial) on UPD-associated chromosomes. Whole genome AOH
will be reported when greater than 5% of the genome. The continual discovery of novel copy number
may evolve with increased scientific understanding.
Reference Values:
Clinical References: 1. American College of Obstetricians and Gynecologists Committee on

Genetics. Committee opinion no. 581: the use of chromosomal microarray analysis in prenatal diagnosis.
Obstet Gynecol. 2013 Dec;122(6):1374-1377. doi: 10.1097/01.AOG.0000438962.16108.d1 2. Kalia, S.,
Adelman, K., Bale, S. et al: Recommendations for reporting of secondary findings in clinical exome and
genome sequencing. 2016 update (ACMG SF v2.0): a policy statement of the American College of
Medical Genetics and Genomics. Genet Med. 2017 Feb;19(2):249-255. doi: 10.1038/gim.2016.190 3.
Wapner RJ, Martin CL, Levy B, et al: Chromosomal microarray versus karyotyping for prenatal
diagnosis. N Engl J Med. 2012 Dec;367(23):2175-2184. doi: 10.1056/NEJMoa1203382 4. Armengol L,
Nevado J, Serra-Juhe C, et al: Clinical utility of chromosomal microarray analysis in invasive prenatal
diagnosis. Hum Genet. 2012 Mar;131(3):513-523. doi: 10.1007/s00439-011-1095-5 5. Breman A, Pursley
AN, Hixson P, et al: Prenatal chromosomal microarray analysis in a diagnostic laboratory; experience
with >1000 cases and review of the literature. Prenat Diagn. 2012 Apr;32(4):351-361. doi:
10.1002/pd.3861 6. South ST, Lee C, Lamb AN, et al: ACMG Standards and Guidelines for constitutional
cytogenomic microarray analysis, including postnatal and prenatal applications: Revision 2013. Genet
Med. 2013 Nov;15(11):903-909. doi: 10.1038/gim.2013.129
CMAPT Chromosomal Microarray, Tumor, Formalin-Fixed

35901 Paraffin-Embedded
Clinical Information: The importance of identifying chromosome abnormalities in malignant
neoplasms is well established, and often provides important diagnostic, prognostic, and therapeutic
detected by conventional chromosome analysis or fluorescence in situ hybridization (FISH) studies. CMA
utilizes copy number probes and single nucleotide polymorphism probes to detect copy number changes
and regions of copy-neutral loss of heterozygosity. CMA analysis is appropriate to identify gain or loss of
chromosome material throughout the genome at a resolution of 50 to 100 kilobases. CMA can: -Define
the size, precise breakpoints, and gene content of copy number changes to demonstrate the complexity of
abnormalities -Characterize unidentified chromosome material, marker chromosomes, and DNA
amplification detected by conventional chromosome and FISH studies -Determine if apparently balanced
chromosome rearrangements identified by conventional chromosome studies have cryptic imbalances
-Assess regions of copy-neutral loss of heterozygosity, which is common in neoplasia and often masks
homozygous mutations involving tumor suppressor genes The limit of detection is dependent on size of
the abnormality, type of abnormality (deletion or duplication) and DNA quality. When a deletion or
Useful For: Genomic characterization of tumor for copy number imbalances and loss of
heterozygosity Assisting in the diagnosis and classification of malignant neoplasms Evaluating the
prognosis for patients with malignant tumors
Interpretation: The interpretive report describes copy number changes and any loss of
heterozygosity that may be associated with the neoplastic process. Abnormal clones with subclonal
cytogenetic evolution will be discussed if identified. The continual discovery of novel copy number
may evolve with increased scientific understanding. Although the presence of a clonal abnormality
usually indicates a neoplasia, in some situations it may reflect a benign or constitutional genetic change.
If a genetic change is identified that is likely constitutional and clearly pathogenic (eg, XYY), follow-up
with a medical genetics consultation may be suggested. The absence of an abnormal clone may be the
result of specimen collection from a site that is not involved in the neoplasm, or may indicate that the
disorder is caused by a point mutation that is not detectable by chromosomal microarray (CMA). CMA,
fluorescence in situ hybridization (FISH), and conventional cytogenetics are to some extent
complementary methods. In some instances, additional FISH or conventional cytogenetic studies will be
recommended to clarify interpretive uncertainties. See Cytogenetic Analysis of Glioma in Special
Instructions for common questions and answers.
Reference Values:
Clinical References: 1. Cooley L, Lebo M, Li M, et al: American College of Medical Genetics

and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in
neoplastic disorders. Genet Med. 2013;15:484-494. doi: 10.1038/gim.2013.49 2. Ciriello G, Miller ML,
Aksoy BA, Senbabaoglu Y, Schultz N, Sander C: Emerging landscape of oncogenic signatures across
human cancers. Nat Genet. 2013 Sep 26;45(10):1127-1133. doi: 10.1038/ng.2762 3. Wang Y, Cottman
M, Schiffman JD: Molecular inversion probes: a novel microarray technology and its application in
cancer research. Cancer Genet. 2012 Jul-Aug;205(7-8):341-355. doi: 10.1016/j.cancergen.2012.06.005
CMAT Chromosomal Microarray, Tumor, Fresh or Frozen using

35900 Affymetrix Cytoscan HD
Clinical Information: The importance of identifying chromosome abnormalities in malignant
neoplasms is well established, and often provides important diagnostic, prognostic, and therapeutic
detected by conventional chromosome analysis or fluorescence in situ hybridization (FISH) studies.
CMA utilizes greater than 1.9 million copy number probes and approximately 750,000 single nucleotide
polymorphism probes to detect copy number changes and regions of copy-neutral loss of
heterozygosity. CMA analysis is appropriate to identify gain or loss of chromosome material throughout
the genome at a resolution of 30 to 60 kilobases. CMA can: -Define the size, precise breakpoints, and
gene content of copy number changes to demonstrate the complexity of abnormalities -Characterize
unidentified chromosome material, marker chromosomes, and DNA amplification detected by
conventional chromosome and FISH studies -Determine if apparently balanced chromosome
rearrangements identified by conventional chromosome studies have cryptic imbalances -Assess regions
of copy-neutral loss of heterozygosity, which is common in neoplasia and often masks homozygous
mutations involving tumor suppressor genes The limit of detection is dependent on size of the
abnormality, type of abnormality (deletion or duplication) and DNA quality. When a deletion or
Useful For: Genomic characterization of tumor for copy number imbalances and loss of heterozygosity
Assisting in the diagnosis and classification of malignant neoplasms, including hematolymphoid
malignancies Evaluating the prognosis for patients with malignant tumors
Interpretation: The interpretive report describes copy number changes and any loss of heterozygosity
that may be associated with the neoplastic process. Abnormal clones with subclonal cytogenetic evolution
will be discussed if identified. The continual discovery of novel copy number variation and published
clinical reports means that the interpretation of any given copy number change may evolve with increased
scientific understanding. Although the presence of a clonal abnormality usually indicates a neoplasia, in
some situations it may reflect a benign or constitutional genetic change. If a genetic change is identified
that is likely constitutional and clearly pathogenic (eg, XYY), follow-up with a medical genetic
consultation may be suggested. The absence of an abnormal clone may be the result of specimen
collection from a site that is not involved in the neoplasm, or may indicate that the disorder is caused by a
point mutation that is not detectable by chromosomal microarray (CMA). CMA, fluorescence in situ
hybridization (FISH), and conventional cytogenetics are to some extent complementary methods. In some
instances, additional FISH or conventional cytogenetic studies will be recommended to clarify interpretive
uncertainties.
Reference Values:
Clinical References: 1. Cooley L, Lebo M, Li M, et al: American College of Medical Genetics and
Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in
neoplastic disorders. Genet Med. 2013;15:484-494. doi: 10.1038/gim.2013.49 2. Ciriello G, Miller ML,
Aksoy BA, Senbabaoglu Y, Schultz N, Sander C: Emerging landscape of oncogenic signatures across
human cancers. Nat Genet. 2013 Sep 26;45(10):1127-1133. doi: 10.1038/ng.2762
CHRAF Chromosome Analysis, Amniotic Fluid

35243 Clinical Information: Chromosome analysis for prenatal diagnosis is appropriate in pregnancies with
abnormal maternal screening, advanced maternal age, and features suggestive of or concerns for
aneuploidy syndromes, including Down syndrome, Turner syndrome, Klinefelter syndrome, trisomy 13
syndrome, and trisomy 18 syndrome. Chromosomal abnormalities are the cause of a wide range of
disorders associated with birth defects and congenital diseases. Many of these disorders can be diagnosed
prenatally by analysis of amniocytes. This method permits diagnosis of chromosome abnormalities during
the second trimester of pregnancy or later. A chromosomal microarray (CMAP / Chromosomal
Microarray, Prenatal, Amniotic Fluid/Chorionic Villus Sampling) is recommended, rather than
chromosomal analysis, to detect clinically relevant gains or losses of chromosomal material in
pregnancies with 1 or more major structural abnormalities. Chromosomal microarray can also be
considered, rather than chromosome analysis, for patients undergoing invasive prenatal diagnostic testing
with a structurally normal fetus.
Useful For: Prenatal diagnosis of chromosome abnormalities, including aneuploidy (ie, trisomy or
monosomy) and balanced rearrangements
Interpretation: Cytogenetic studies on amniotic fluid are considered nearly 100% accurate for the
detection of large fetal chromosome abnormalities. However, subtle or cryptic abnormalities involving
microdeletions usually can be detected only with the use of targeted FISH testing. Approximately 3% of
amniotic fluid specimens analyzed are found to have chromosome abnormalities. Some of these
chromosome abnormalities are balanced and may not be associated with birth defects. A normal
karyotype does not rule out the possibility of birth defects, such as those caused by submicroscopic
cytogenetic abnormalities, molecular mutations, and other environmental factors (ie, teratogen exposure).
For these reasons, clinicians should inform their patients of the technical limitations of chromosome
analysis prior to performing the amniocentesis. It is recommended that a qualified professional in Medical
Genetics communicate all results to the patient.
Reference Values:
Genetics: Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal
diagnosis. Obstet Gynecol 2013;122:1374-1377 2. Society for Maternal-Fetal Medicine (SMFM): The
use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215:B2-B9 3.
Committee Opinion, 640: Cell-free DNA screening for fetal aneuploidy. American College of
Obstetricians and Gynecologists Committee on Genetics. Obstet Gynecol 2015;123:e31-e37 4. Wilson
KL, Czerwinski JL, Hoskovec JM, et al: NSGC practice guideline: prenatal screening and diagnostic
testing options for chromosome aneuploidy. J Genet Couns 2013;22:4-15
CHRCV Chromosome Analysis, Chorionic Villus Sampling

35251 Clinical Information: Although not used as widely as amniocentesis, the use of chorionic villus
sampling (CVS) for chromosome analysis is an important procedure for the prenatal diagnosis of
chromosome abnormalities. CVS can be collected by either transcervical or transabdominal techniques.
The medical indications for performing chromosome studies on CVS are similar to amniocentesis, and
may include advanced maternal age, abnormal first-trimester screen, and family history of a
chromosome abnormality. A chromosomal microarray (CMAP / Chromosomal Microarray, Prenatal) is
recommended, rather than chromosomal analysis, to detect clinically relevant gains or losses of
chromosomal material in pregnancies with one or more major structural abnormalities. Chromosomal
microarray can also be considered, rather than chromosome analysis, for patients undergoing invasive
prenatal diagnostic testing with a structurally normal fetus.
Useful For: Prenatal diagnosis of chromosome abnormalities, including aneuploidy (ie, trisomy or
monosomy) and balanced rearrangements This test is not appropriate as a first-tier test for detecting
gains or losses of chromosomal material in pregnancies with 1 or more major structural abnormalities.
Interpretation: Cytogenetic studies on chorionic villus specimen (CVS) are considered more than
99% reliable for the detection of most fetal chromosome abnormalities. However, subtle or cryptic
abnormalities involving microdeletions usually can be detected only with the use of targeted FISH
testing. Approximately 3% of CSVs analyzed are found to have chromosome abnormalities. Some of
these chromosome abnormalities are balanced and may not be associated with birth defects. A normal
karyotype does not rule out the possibility of birth defects, such as those caused by submicroscopic
cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). For
these reasons, clinicians should inform their patients of the technical limitations of chromosome
analysis before the procedure is performed, so that patients may make an informed decision about
pursuing the procedure. Limitations: -False-chromosome mosaicism may occur due to artifact of culture
-True mosaicism may be missed due to statistical sampling error -Presence of chromosome
abnormalities in placental cells that do not occur in the cells of the fetus (confined placental mosaicism)
-Subtle structural chromosome abnormalities can occasionally be missed It is recommended that a
qualified professional in Medical Genetics communicate all results to the patient.
Reference Values:

Genetics: Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal
diagnosis. Obstet Gynecol 2013;122:1374-1377 2. Society for Maternal-Fetal Medicine (SMFM): The
use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215:B2-B9 3.
Committee Opinion, 640: Cell-free DNA screening for fetal aneuploidy. American College of
Obstetricians and Gynecologists Committee on Genetics. Obstet Gynecol 2015;123:e31-e37 4. Wilson
KL, Czerwinski JL, Hoskovec JM, et al: NSGC practice guideline: prenatal screening and diagnostic
testing options for chromosome aneuploidy. J Genet Couns 2013;22:4-15
FCLPD Chromosome Analysis, CLL/LPD

CHRCB Chromosome Analysis, Congenital Disorders, Blood
35248 Clinical Information: Chromosome analysis is appropriate for individuals with clinical features
including infertility, multiple miscarriages, delayed puberty, ambiguous genitalia, amenorrhea, or
individuals with clinical features suggestive of an aneuploidy syndrome, including Down syndrome,
Turner syndrome, Klinefelter syndrome, Trisomy 13 syndrome, and Trisomy 18 syndrome. A
chromosomal microarray study (CMACB / Chromosomal Microarray, Congenital, Blood) is
recommended as the first-tier test (rather than a congenital chromosome study) to detect clinically
relevant gains or losses of chromosomal material for individuals with multiple anomalies not specific to
well-delineated genetic syndromes, individuals with apparently nonsyndromic developmental delay or
intellectual disability, and individuals with autism spectrum disorders. Chromosome analysis may be
appropriate for this patient population if microarray has been performed with normal results. Some
chromosome rearrangements are balanced (no gain or loss of material) and, therefore, not detectable by
chromosomal microarray. In rare situations these rearrangements may interrupt gene functioning and have
the potential to cause abnormal clinical features. Limitations: A normal karyotype (46,XX or 46,XY with
no apparent chromosome abnormality) does not eliminate the possibility of abnormal clinical features
such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and
environmental factors (ie, teratogen exposure). Chromosomal mosaicism may be missed due to statistical
sampling error (rare) and subtle structural chromosome abnormalities can occasionally be missed.
Useful For: Diagnosis of congenital chromosome abnormalities, including aneuploidy, structural

abnormalities, and balanced rearrangements
Interpretation: When interpreting results, the following factors need to be considered: -Some
chromosome abnormalities are balanced (no apparent gain or loss of genetic material) and may not be
associated with birth defects. However, balanced abnormalities often cause infertility and, when inherited
in an unbalanced fashion, may result in birth defects in the offspring. -A normal karyotype (46,XX or
46,XY with no apparent chromosome abnormality) does not eliminate the possibility of birth defects such
as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental
factors (ie, teratogen exposure). It is recommended that a qualified professional in Medical Genetics
communicate all abnormal results to the patient.
Reference Values:
Clinical References: 1. Manning M, Hudgins L, Professional Practice and Guidelines Committee:

Array-based technology and recommendations for utilization in medical genetics practice for detection of
chromosomal abnormalities. Genet Med 2010;12(11):742-745 2. Laurino MY, Bennett RL, Saraiya DS, et
al: Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the
National Society of Genetic Counselors. J Genet Couns 2005;14:165-181 3. Sheets KB, Crissman BG,
Feist CD, et al: Practice guidelines for communicating a prenatal or postnatal diagnosis of Down
syndrome: recommendations of the national society of genetic counselors. J Genet Couns
2011;20:432-441
CHRHB Chromosome Analysis, Hematologic Disorders, Blood

35308 Clinical Information: Chromosomal abnormalities play a central role in the pathogenesis, diagnosis,
and monitoring of treatment of many hematologic disorders. Whenever possible, it is best to do
chromosome studies for neoplastic hematologic disorders on bone marrow. Bone marrow studies are more
sensitive and the chances of finding metaphases are about 95%, compared with only a 60% chance for
blood studies. When it is not possible to collect bone marrow, chromosome studies on blood may be
useful. When blood cells are cultured in a medium without mitogens, the observation of any
chromosomally abnormal clone may be consistent with a neoplastic process. Conventional chromosome
studies of B-cell disorders are not always successful because B lymphocytes do not proliferate well in cell
culture. The agent CpG 7909 (CpG) is a synthetic oligodeoxynucleotide that binds to the Toll-like
receptor 9 (TLR9) present on B cells, causing B-cell activation. In the laboratory setting, CpG may be
used as a mitogen to stimulate B cells in patient specimens, thus allowing identification of chromosome
abnormalities. CpG stimulation reveals an abnormal karyotype in approximately 80% of patients with of
chronic lymphocytic leukemia, and the karyotype is complex in 20% to 25% of cases. Several studies
have reported that increased genetic complexity revealed by CpG-stimulated chromosome studies confers
a less favorable time to first treatment, treatment response, and overall survival. For more information, see
Multiple Myeloma: Laboratory Screening.
Useful For: Assisting in the classification and follow-up of certain malignant hematological
disorders when bone marrow is not available This test is not useful for congenital disorders.
Interpretation: The presence of an abnormal clone usually indicates a malignant neoplastic process.
The absence of an apparent abnormal clone in blood may result from a lack of circulating abnormal
cells and not from an absence of disease. On rare occasions, the presence of an abnormality may be
associated with a congenital abnormality and thus, not related to a malignant process. When this
situation is suspected, consultation with a Clinical Geneticist is recommended.
Reference Values:
Clinical References: 1. Dewald GW, Ketterling RP, Wyatt WA, Stupca PJ: Cytogenetic studies in
neoplastic hematologic disorders. In: McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed.
Williams and Wilkens; 2002:658-685 2. Rigolin GM, Cibien F, Martinelli S, et al: Chromosome
aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic
leukemia with "normal" FISH: correlations with clinicobiological parameters. Blood. 2012 Mar
8;119(10):2310-2313
CHRBM Chromosome Analysis, Hematologic Disorders, Bone Marrow

35245 Clinical Information: Chromosomal abnormalities play a central role in the pathogenesis,
diagnosis, and treatment monitoring of many hematologic disorders. Cytogenetic studies on bone
marrow may be helpful in many malignant hematologic disorders as the observation of a
chromosomally abnormal clone may be consistent with a neoplastic process. Certain chromosome
abnormalities may help classify a malignancy. As examples, the Philadelphia (Ph) chromosome, also
referred to as der(22)t(9;22)(q34;q11.2), is usually indicative of chronic myeloid leukemia (CML) or
acute leukemia; t(8;21)(q22;q22) defines a specific subset of patients with acute myeloid leukemia; and
t(8;14)(q24.1;q32) is associated with Burkitt lymphoma. Cytogenetic studies are also used to monitor
patients with hematologic neoplasia and may identify disease progression, such as the onset of blast
crisis in CML, which is often characterized by trisomy 8, isochromosome 17q, and multiple Ph
chromosomes. Conventional chromosome studies of B-cell disorders are not always successful because
B lymphocytes do not proliferate well in cell culture. The agent CpG 7909 (CpG) is a synthetic
oligodeoxynucleotide that binds to the Toll-like receptor 9 (present on B cells, causing B-cell activation.
In the laboratory setting, CpG may be used as a mitogen to stimulate B cells in patient specimens, thus
allowing identification of chromosome abnormalities. CpG stimulation reveals an abnormal karyotype
in approximately 80% of patients with chronic lymphocytic leukemia, and the karyotype is complex in
20% to 25% of cases. Several studies have reported that increased genetic complexity revealed by
CpG-stimulated chromosome studies confers a less favorable time to first treatment, treatment response,
and overall survival.
Useful For: Assisting in the diagnosis and classification of certain malignant hematological disorders
Evaluating the prognosis in patients with certain malignant hematologic disorders Monitoring effects of
treatment Monitoring patients in remission
Interpretation: To ensure the best interpretation, it is important to provide some clinical information
to verify the appropriate type of cytogenetic study is performed. The following factors are important
when interpreting the results: -Although the presence of an abnormal clone usually indicates a
malignant neoplastic process, in rare situations, the clone may reflect a benign condition. -The absence
of an abnormal clone may be the result of specimen collection from a site that is not involved in the
neoplasm or may indicate that the disorder is caused by submicroscopic abnormalities that cannot be
identified by chromosome analysis. -On rare occasions, the presence of an abnormality may be
associated with a constitutional abnormality that is not related to a malignant neoplastic process.
Follow-up with a medical genetics consultation is recommended. -On occasion, bone marrow
chromosome studies are unsuccessful. If clinical information has been provided, there may be a
fluorescence in situ hybridizationÂ study option that could be performed.
Reference Values:
Clinical References: 1. Mellors PW, Binder M, Ketterling RH, et al: Metaphase cytogenetics and
plasma cell proliferation index for risk stratification in newly diagnosed multiple myeloma. Blood Adv.
2020 May 26;4(10):2236-2244 2. Dewald GW, Ketterling RP, Wyatt WA, Stupca PJ: Cytogenetic studies
in neoplastic hematologic disorders. In: McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed.
Williams and Wilkens; 2002:658-685 3. Rigolin GM, Cibien F, Martinelli S, et al: Chromosome
aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia
with "normal" FISH: correlations with clinicobiological parameters. Blood. 2012 Mar
8;119(10):2310-2313
COGBL Chromosome Analysis, Hematologic Disorders, Children's

113532 Oncology Group Enrollment Testing, Blood
Clinical Information: Clonal chromosomal abnormalities play a central role in the pathogenesis,
diagnosis, and treatment monitoring of pediatric hematologic malignancies. Whenever possible, it is best
to do chromosome studies for neoplastic hematologic disorders on bone marrow. Bone marrow studies are
more sensitive and the chances of finding metaphases are about 95%, compared with only a 60% chance
for blood studies. When it is not possible to collect bone marrow, chromosome studies on blood may be
useful. When blood cells are cultured in a medium without mitogens, the observation of any
chromosomally abnormal clone may be consistent with a neoplastic process. Characteristic chromosome
rearrangements and copy number patterns may help classify a pediatric hematologic malignancy. For
example, t(1;19)(q23;p13.3) is typically observed in B-cell acute lymphoblastic leukemia/lymphoma and
t(8;21)(q22;q22) defines a specific subset of patients with acute myeloid leukemia; while
t(7;14)(q35;q11.2) is associated with T-lymphoblastic leukemia/lymphoma. Confirmation of classic gene
fusions associated with the above translocations together with evaluation for other recurrent abnormalities
are available within the appropriate Children's Oncology Group (COG) fluorescence in situ hybridization
(FISH) panels; COGBF / B-Lymphoblastic Leukemia/Lymphoma, Children's Oncology Group
Enrollment Testing, FISH, Varies; COGTF / T-Cell Acute Lymphoblastic Leukemia (T-ALL), Children's
Oncology Group Enrollment Testing, FISH, Varies; and COGMF / Acute Myeloid Leukemia (AML),
Children's Oncology Group Enrollment Testing, FISH, Varies. Some rearrangements identified by
chromosomal analysis may be extremely rare but are known, recurrent entities for which the Mayo Clinic
Genomics Laboratory has the most extensive catalogue of FISH testing to confirm the corollary gene
fusions. Metaphase FISH confirmation of classic translocations which are cryptic and not visually
detectable by chromosome analysis [ie, t(12;21)] associated with ETV6/RUNX1 fusion) is performed as
required by COG and is included as part of the electronic case submission by the Mayo Clinic Genomics
Laboratory to COG for central review. Additional cytogenetic techniques such as chromosomal
microarray (CMAH / Chromosomal Microarray, Hematologic Disorders, Varies) may be helpful to
resolve questions related to ploidy (hyperdiploid clone vs doubled hypodiploid clone) or to resolve certain
clonal structural rearrangements such as the presence or absence of intrachromosomal amplification of
chromosome 21 (iAMP21).
Useful For: Evaluation of pediatric blood specimens for chromosomal abnormalities associated with
hematologic malignancies for diagnostic and prognostic purposes in patients being considered for
enrollment in Children's Oncology Group clinical trials and research protocols This test is not useful for
congenital disorders.
Interpretation: The presence of an abnormal clone usually indicates a malignant neoplastic process.
The absence of an apparent abnormal clone in blood may result from a lack of circulating abnormal cells
and not from an absence of disease. On rare occasions, the presence of an abnormality may be associated
with a congenital abnormality and, thus, not related to a malignant process. When this situation is
suspected, follow-up with a medical genetics consultation is recommended.
Reference Values:
Williams and Wilkens; 2002: 658-685 2. Rigolin GM, Cibien F, Martinelli S, et al: Chromosome
aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic
leukemia with "normal" FISH: correlations with clinicobiological parameters. Blood. 2012 Mar
8;119(10):2310-2313 3. Swerdlow SH, Campo E, Harris NL, et al, eds: WHO Classification of
Tumours of Haematopoietic and Lymphoid Tissues. IARC Press; 2017 4. Arber DA, Borowitz MJ,
Cessna M, et al: Initial Diagnostic Workup of Acute Leukemia: Guideline from the College of
American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017
Oct;141(10):1342-1393
COGBM Chromosome Analysis, Hematologic Disorders, Children's

113531 Oncology Group Enrollment Testing, Bone Marrow
Clinical Information: Clonal chromosome abnormalities in bone marrow (or peripheral blood or
tissue if bone marrow is not available) play a central role in the pathogenesis, diagnosis, and treatment
monitoring of pediatric hematologic malignancies. Characteristic chromosome rearrangements and copy
number patterns may help classify a pediatric hematologic malignancy. For example, t(1;19)(q23;p13.3)
is typically observed in B-cell acute lymphoblastic leukemia/lymphoma and t(8;21)(q22;q22) defines a
specific subset of patients with acute myeloid leukemia; while t(7;14)(q35;q11.2) is associated with
T-lymphoblastic leukemia/lymphoma. Confirmation of classic gene fusions associated with the above
translocations together with evaluation for other recurrent abnormalities are available within the
appropriate Children's Oncology Group (COG) fluorescence in situ hybridization (FISH) panels;
COGBF / B-Lymphoblastic Leukemia/Lymphoma, Children's Oncology Group Enrollment Testing,
FISH, Varies; COGTF / T-Cell Acute Lymphoblastic Leukemia (T-ALL), Children's Oncology Group
Enrollment Testing, FISH, Varies; and COGMF / Acute Myeloid Leukemia (AML), Children's
Oncology Group Enrollment Testing, FISH, Varies. Some rearrangements identified by chromosomal
analysis may be extremely rare but are known recurrent entities for which the Mayo Clinic Genomics
Laboratory has the most extensive catalogue of FISH testing to confirm the corollary gene fusions.
Metaphase FISH confirmation of classic translocations that are cryptic and not visually detectable by
chromosome analysis [ie, t(12;21) associated with ETV6/RUNX1 fusion] is performed as required by
COG and is included as part of the electronic case submission by the Mayo Clinic Genomics Laboratory
to COG for central review. Additional cytogenetic techniques such as chromosomal microarray (CMAH
/ Chromosomal Microarray, Hematologic Disorders, Varies) may be helpful to resolve questions related
to ploidy (hyperdiploid clone vs doubled hypodiploid clone) or to resolve certain clonal structural
(iAMP21). If the expert cytogeneticist at Mayo Clinic reviewing this test's case feels microarray assay
may be of benefit, the client will be contacted. For children in whom disease relapse or a secondary
myeloid neoplasm is a concern and enrollment in a new COG protocol is being considered; this test is
appropriate for bone marrow chromosome analysis.
Useful For: Evaluation of pediatric bone marrow specimens for chromosomal abnormalities
associated with hematologic malignancies for diagnostic and prognostic purposes in patients being
considered for enrollment in Children's Oncology Group clinical trials and research protocols using
bone marrow specimens
Interpretation: The following factors are important when interpreting the results: -Although the
presence of an abnormal clone usually indicates a malignant neoplastic process, in rare situations, the
clone may reflect a benign condition. -The absence of an abnormal clone may be the result of specimen
collection from a site that is not involved in the neoplasm or may indicate that the disorder is caused by
submicroscopic abnormalities that cannot be identified by chromosome analysis. -On rare occasions, the
presence of an abnormality may be associated with a constitutional abnormality that is not related to a
malignant neoplastic process. Follow-up with a medical genetics consultation is recommended. -On
occasion, bone marrow chromosome studies are unsuccessful. If clinical information has been provided,
we may have a fluorescence in situ hybridization study option that could be performed.
Reference Values:
Williams and Wilkens; 2002:658-685 2. De Haas V, Ismaila N, Advani A, et al: Initial diagnostic
work-up of acute leukemia: ASCO Clinical Practice Guideline Endorsement of the College of American
Pathologists and American Society of Hematology Guideline. J Clin Oncol. 2019 Jan 20;37(3):239-253 3.
Swerdlow SH, Campo E, Harris NL, et al, eds: WHO Classification of Tumours of Haematopoietic and
Lymphoid Tissues. IARC Press; 2017 4. Arber DA, Borowitz MJ, Cessna M, et al: Initial diagnostic
workup of acute leukemia: Guideline from the College of American Pathologists and the American
Society of Hematology. Arch Pathol Lab Med. 2017 Oct;141(10):1342-1393
CHFXH Chromosome Analysis, Hematologic Disorders, Fixed Cells

64922 Clinical Information: Chromosomal abnormalities play a central role in the pathogenesis, diagnosis,
and treatment monitoring of many hematologic disorders. Cytogenetic studies on bone marrow may be
helpful in many malignant hematologic disorders as the observation of a chromosomally abnormal clone
may be consistent with a neoplastic process. Certain chromosome abnormalities may help classify a
malignancy. As examples, the Philadelphia (Ph) chromosome, also referred to as
der(22)t(9;22)(q34;q11.2), is usually indicative of chronic myeloid leukemia (CML) or acute leukemia,
t(8;21)(q22;q22) defines a specific subset of patients with acute myeloid leukemia, and t(8;14)(q24.1;q32)
is associated with Burkitt lymphoma. Cytogenetic studies are also used to monitor patients with
hematologic neoplasia and may identify disease progression, such as the onset of blast crisis in CML,
which is often characterized by trisomy 8, isochromosome 17q, and multiple Ph chromosomes.
Useful For: Assisting in the diagnosis and classification of certain malignant hematological disorders
Evaluating the prognosis of patients with certain malignant hematologic disorders Monitoring effects of
treatment Monitoring patients in remission
Interpretation: To ensure the best interpretation, it is important to provide some clinical information
to verify the appropriate type of cytogenetic study is performed. The following factors are important when
interpreting the results: -Although the presence of an abnormal clone usually indicates a malignant
neoplastic process, in rare situations, the clone may reflect a benign condition. -The absence of an
abnormal clone may be the result of specimen collection from a site that is not involved in the neoplasm
or may indicate that the disorder is caused by submicroscopic abnormalities that cannot be identified by
chromosome analysis. -On rare occasions, the presence of an abnormality may be associated with a
congenital abnormality that is not related to a malignant neoplastic process. Follow-up with a medical
genetics consultation is recommended. -On occasion, bone marrow chromosome studies are unsuccessful.
If clinical information has been provided, we may have a FISH study option that could be performed.
Reference Values:
neoplastic hematologic disorders. In Clinical Laboratory Medicine. Second edition. Edited by KD
McClatchey. Baltimore, Williams and Wilkens, 2002, pp 658-685 2. Rigolin GM, Cibien F, Martinelli S,
et al: Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic
lymphocytic leukemia with "normal" FISH: correlations with clinicobiological parameters. Blood 2012
Mar 8;119(10):2310-2313
FCAHM Chromosome Analysis, Hematologic Malignancy

Current 75612
Clinical Information: Chromosome Analysis, Hematologic Malignancy - Cytogenetics of
hematologic disorders attempts to define and interpret chromosomal aberrations that occur in neoplastic
cells associated with leukemia, lymphoma and other hematologic malignancies. Chromosome
abnormalities in cancer cells of patients with malignant hematologic disorders including acute and
chronic myeloid and lymphoid leukemias, myelodysplastic and myeloproliferative disorders,
lymphomas and unexplained anemias may correlate with the diagnosis, prognosis, treatment and
etiology of disease.
Reference Values:
CHRTI Chromosome Analysis, Skin Biopsy

35250 Clinical Information: Chromosomal abnormalities cause a wide range of disorders associated with
birth defects and congenital diseases. Usually, the abnormalities can be demonstrated in peripheral
blood, which is readily available. Chromosome analysis on skin fibroblasts may be indicated when the
results from peripheral blood are inconclusive or in clinical circumstances such as suspected cases of
chromosome mosaicism, confirmation of new chromosome disorders, or some dermatological disorders.
Subtle structural chromosomal anomalies can occasionally be missed. Chromosomal mosaicism may be
missed due to statistical sampling error (rare).
Useful For: Diagnosis of mosaic congenital chromosome abnormalities, including mosaic

aneuploidy and mosaic structural abnormalities Subsequent chromosome analysis when results from
peripheral blood are inconclusive
Interpretation: When interpreting results, the following factors need to be considered: -Some
chromosome abnormalities are balanced (no apparent gain or loss of genetic material) and may not be
associated with birth defects. However, balanced abnormalities often cause infertility and, when
inherited in an unbalanced fashion, may result in birth defects in the offspring. -A normal karyotype
(46,XX or 46,XY with no apparent chromosome abnormality) does not eliminate the possibility of birth
defects such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and
environmental factors (ie, teratogen exposure). It is recommended that a qualified professional in
Medical Genetics communicate all results to the patient.
Reference Values:
Clinical References: 1. The Principals of Clinical Cytogenetics. Second edition. Edited by SL

Gerson, MB Keagle. Totowa, NJ, Humana Press 2005 pp 210 2. Azcona C, Bareille P, Stanhop R:
Lesson of the week: Turner's syndrome mosaicisim in patients with a normal blood lymphocyte
karyotype. BMJ 1999;318:856-857 3. Woods CG, Bankier A, Curry J, et al: Asymmetry and skin
pigmentary anomalies in chromosome mosaicism. J Med Genet 1994;31:694-701 4. Ribeiro Noce T, de
Pina-Neto JM, Happle R: Phylloid pattern of pigmentary disturbance in a case of complex mosaicism.
Am J Med Genet 2001;98:145-147
EOSDF Chronic Eosinophilia, Diagnostic FISH, Varies

609587 Clinical Information: The myeloid/lymphoid neoplasms with eosinophilia and rearrangements of
PDGFRA, PDGFRB, FGFR1 and JAK2 represent a significantly diverse group of hematologic
malignancies. Despite the disparate clinical presentations, which include chronic myeloid neoplasms
(chronic myelomonocytic leukemia, chronic myeloproliferative neoplasms, chronic eosinophilic
leukemia) versus more acute myeloid and lymphoid neoplasms (acute myeloid leukemia, B- and
T-lymphoblastic leukemia/lymphoma and mixed phenotypic acute leukemias), this diagnostic subgroup
shares rearrangements involving 4 specific gene regions: PDGFRA, PDGFRB, FGFR1 and JAK2.
While conventional chromosome studies may detect many of the rearrangements associated with these
gene rearrangements, several are cytogenetically "cryptic," including the most common abnormality
involving PDGFRA activation. This one megabase submicroscopic, intrachromosomal deletion results
in loss of the CHIC2 gene region with subsequent fusion of neighboring genes FIP1L1 and PDGFRA.
In addition to this more common, cryptic deletion, the PDGFRA gene has many translocation partners
described (at least 15) that similarly result in PDGFRA upregulation. The PDGFRB, FGFR1 and JAK2
gene regions similarly have numerous translocation/inversion partners described, at least 50 for
PDGFRB, 10 for FGFR1 and 40 for JAK2. Despite the significant heterogeneity in gene partners, the
identification of PDGFRA, PDGFRB, FGFR1 and JAK2 rearrangements is critical for disease
categorization and potential therapeutic intervention. Both PDGFRA and PDGFRB have the potential
for response to targeted tyrosine kinase inhibitor therapies such as imatinib mesylate. Similarly, JAK2
rearrangements have the potential for response to targeted inhibitor therapy. Rearrangements of FGFR1
are typically more aggressive and less responsive to targeted inhibitors. While not formally included in
the World Health Organization (WHO) categorization of myeloid/lymphoid neoplasms with PDGFRA,
PDGFRB, FGFR1 or JAK2 rearrangements, rearrangements of the ABL1 gene other than with the BCR
locus, can result in similar clinical phenotypes. Thus, the ABL1 gene region has been included in this
fluorescence in situ hybridization (FISH) panel evaluation to appropriate interrogate this gene region,
particularly since these patients may not be identified by conventional karyotype analysis and may
significantly benefit from targeted tyrosine kinase therapies.
in patients with myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement (including
PDGFRA, PDGFRB, FGFR1, JAK2, and ABL1). Supporting the diagnosis of malignancy if a clone is
present An adjunct to conventional chromosome studies.
Reference Values:
Clinical References: Swerdlow SH, Campo E, Harris NL, et al: Myeloid/lymphoid neoplasms with
eosinophilia and gene rearrangement. WHO Classification of Tumours of Haematopoietic and Lymphoid
Tissues. 4th ed. IARC Press; 2017:71-80
EOSMF Chronic Eosinophilia, Specified FISH, Varies

614254 Clinical Information: The myeloid/lymphoid neoplasms with eosinophilia and rearrangements of
PDGFRA, PDGFRB, FGFR1 and JAK2 represent a significantly diverse group of hematologic
malignancies. Despite the disparate clinical presentations, which include chronic myeloid neoplasms
(chronic myelomonocytic leukemia, chronic myeloproliferative neoplasms, chronic eosinophilic
leukemia) versus more acute myeloid and lymphoid neoplasms (acute myeloid leukemia, B- and
T-lymphoblastic leukemia/lymphoma and mixed phenotypic acute leukemias), this diagnostic subgroup
shares rearrangements involving 4 specific gene regions: PDGFRA, PDGFRB, FGFR1 and JAK2. While
conventional chromosome studies may detect many of the rearrangements associated with these gene
rearrangements, several are cytogenetically "cryptic", including the most common abnormality involving
PDGFRA activation. This one megabase submicroscopic, intrachromosomal deletion results in loss of the
CHIC2 gene region with subsequent fusion of neighboring genes FIP1L1 and PDGFRA. In addition to
this more common, cryptic deletion, the PDGFRA gene has many translocation partners described (at
least 15) that similarly result in PDGFRA upregulation. The PDGFRB, FGFR1 and JAK2 gene regions
similarly have numerous translocation/inversion partners described, at least 50 for PDGFRB, 10 for
FGFR1 and 40 for JAK2. Despite the significant heterogeneity in gene partners, the identification of
PDGFRA, PDGFRB, FGFR1 and JAK2 rearrangements is critical for disease categorization and potential
therapeutic intervention. Both PDGFRA and PDGFRB have the potential for response to targeted tyrosine
kinase inhibitor therapies such as imatinib mesylate. Similarly, JAK2 rearrangements have the potential
for response to targeted inhibitor therapy. Rearrangements of FGFR1 are typically more aggressive and
less responsive to targeted inhibitors. While not formally included in the World Health Organization
categorization of myeloid/lymphoid neoplasms with PDGFRA, PDGFRB, FGFR1,or JAK2
rearrangements, rearrangements of the ABL1 gene, other than with the BCR locus, can result in similar
clinical phenotypes. Thus, the ABL1 gene region has been included in this fluorescence in situ
hybridization panel evaluation to appropriate interrogate this gene region, particularly since these patients
may not be identified by conventional karyotype analysis and may significantly benefit from targeted
tyrosine kinase therapies.
seen in patients with myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement (including
PDGFRA, PDGFRB, FGFR1, JAK2, and ABL1) using specified probes set Supporting a diagnosis of
malignancy, when a clone is present An adjunct to conventional chromosome studies
Reference Values:
Clinical References: Swerdlow SH, Campo E, Harris NL, et al: Myeloid/lymphoid neoplasms
with eosinophilia and gene rearrangement. WHO Classification of Tumours of Haematopoietic and
Lymphoid Tissues. 4th ed. IARC Press; 2017:71-80
CRHEP Chronic Hepatitis (Unknown Type), Serum

113119 Clinical Information: Hepatitis B: Hepatitis B virus (HBV) is a DNA virus that is endemic
in approximately 10% of patients. Some of these carriers are asymptomatic; others develop chronic liver
disease including cirrhosis and hepatocellular carcinoma. Hepatitis C: Hepatitis C virus (HCV) is an
RNA virus that is a significant cause of morbidity and mortality worldwide. HCV is transmitted through
contaminated blood or blood products or through other close, personal contacts. It is recognized as the
cause of most cases of post-transfusion hepatitis. HCV shows a high rate of progression (>50%) to
chronic disease. In the United States, HCV infection is quite common, with an estimated 3.5 to 4
million chronic HCV carriers. Cirrhosis and hepatocellular carcinoma are sequelae of chronic HCV.
The following algorithms are available: -Chronic Hepatitis C Treatment and Monitoring Algorithm:
Direct Antiviral Antigen (DAA) Combination -Hepatitis B: Testing Algorithm for Screening,
Diagnosis, and Management -Hepatitis C: Testing Algorithm for Screening and Diagnosis -Viral
Hepatitis Serologic Profiles
Useful For: Diagnosis and evaluation of patients with symptoms of hepatitis with a duration more
than 6 months Distinguishing between chronic hepatitis B and chronic hepatitis C
Interpretation: Interpretation depends on clinical setting. See Viral Hepatitis Serologic Profiles
Chronic Hepatitis B: Hepatitis B surface antigen (HBsAg) is the first serologic marker appearing in the
serum 6 to 16 weeks following hepatitis B viral (HBV) infection. In acute cases, HBsAg usually
disappears 1 to 2 months after the onset of symptoms. Persistence of HBsAg for more than 6 months
indicates development of either a chronic carrier state or chronic HBV infection. Hepatitis B core
antibodies (anti-HBc Ab) appear shortly after the onset of symptoms of HBV infection and soon after
the appearance of HBsAg. The IgM subclass usually falls to undetectable levels within 6 months, and
the IgG subclass may remain for many years. Hepatitis B surface antibody (anti-HBs) usually appears
with the resolution of hepatitis B virus infection after the disappearance of HBsAg. If HBsAg and
anti-HBc (total antibody) are positive and patient's condition warrants, consider testing for hepatitis Be
antigen (HBeAg), anti-HBe, hepatitis B virus DNA (HBV-DNA) or anti-hepatitis D virus (anti-HDV).
Chronic Hepatitis C: Anti-HCV is almost always detectable by the late convalescent and chronic stage
of infection. The serologic tests currently available do not differentiate between acute and chronic
hepatitis C infections.
Reference Values:
HEPATITIS B SURFACE ANTIGEN :
Negative
HEPATITIS B SURFACE ANTIBODY, QUALITATIVE/QUANTITATIVE

Hepatitis B Surface Antibody
Unvaccinated: negative
Vaccinated: positive
Hepatitis B Surface Antibody, Quantitative

Unvaccinated: <5.0 mIU/mL
Vaccinated: > or =12.0 mIU/mL
HEPATITIS B CORE TOTAL ANTIBODIES:

Negative
HEPATITIS C ANTIBODY:
Negative
Clinical References: 1. Wietzke P, Schott P, Braun F, Mihm S, Ramadori G: Clearance of HCV

RNA in a chronic hepatitis C virus-infected patient during acute hepatitis B virus superinfection. Liver.
1999 Aug;19(4):348-353 2. Villari D, Pernice M, Spinella S, et al: Chronic hepatitis in patients with
active hepatitis B virus and hepatitis C virus combined infections: a histological study. Am J
Gastroenterol. 1995 Jun;90(6):955-958 3. Bonino F, Piratvisuth T, Brunetto MR, Liaw YF: Diagnostic
markers of chronic hepatitis B infection and disease. Antivir Ther. 2010;15(Suppl 3):35-44 4. American
Association for the Study of Liver Diseases and Infectious Diseases Society of America: HCV guidance:
Recommendations for testing, managing, and treating hepatitis C. Accessed September 29, 2020.
Available at www.hcvguidelines.org/content 5. Badur S, Akgun A: Diagnosis of hepatitis B infections
and monitoring of treatment. J Clin Virol. 2001 Jun;21(3):229-237 6. LeFebre ML, US Preventive
Services Task Force: Screening for hepatitis B virus infection in nonpregnant adolescents and adults: US
Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Jul 1;161(1):58-66.
doi: 10.7326/M14-1018 7. Jackson K, Locarnini S, Gish R: Diagnostics of hepatitis B virus: Standard of
care and investigational. Clin Liver Dis (Hoboken). 2018 Aug 22;12(1):5-11. doi: 10.1002/cld.729 8.
Coffin CS, Zhou K, Terrault NA: New and old biomarkers for diagnosis and management of chronic
hepatitis B virus infection. Gastroenterology. 2019 Jan;156(2):355-368.e3. doi:
10.1053/j.gastro.2018.11.037 9. WHO Guidelines Development Group: World Health Organization
Guidelines on hepatitis B and C testing. World Health Organization; 2017. Accessed September 29, 2020.
Available at www.who.int/hepatitis/publications/guidelines-hepatitis-c-b-testing/en/ 10. Centers for
Disease Control and Prevention. Testing and public health management of persons with chronic hepatitis
B virus infection. Accessed April 8, 2020. Available at www.cdc.gov/hepatitis/hbv/testingchronic.htm
CHBVS Chronic Hepatitis B Screen, Serum

615268 Clinical Information: Hepatitis B virus (HBV) is endemic throughout the world. The infection is
spread primarily through percutaneous contact with infected blood products (eg, blood transfusion,
sharing of needles by intravenous drug addicts). The virus is also found in various human body fluids, and
it is known to be spread through oral and genital contact. HBV can be transmitted from mother to child
during delivery through contact with blood and vaginal secretions, but it is not commonly transmitted
transplacentally. Hepatitis B surface antigen (HBsAg) is the first serologic marker appearing in the serum
at 6 to 16 weeks following exposure to HBV. In acute infection, HBsAg usually disappears in 1 to 2
months after the onset of symptoms. Persistence of HBsAg for more than 6 months in duration indicates
development of either a chronic carrier state or chronic HBV infection. The following algorithms are
available: -Hepatitis B: Testing Algorithm for Screening, Diagnosis, and Management -HBV
Infection-Monitoring Before and After Liver Transplantation -Viral Hepatitis Serologic Profiles
Useful For: Diagnosis and evaluation of patients at risk for or suspected of having chronic hepatitis
B This test is not offered as a screening or confirmatory test for blood donor specimens. This test is not
useful during "window period" of acute hepatitis B virus infection (ie, after disappearance of hepatitis B
surface antigen [HBsAg] and prior to appearance of hepatitis B surface antibody). This test is not useful
as a stand-alone prenatal screening test of HBsAg status in pregnant women.
Interpretation: A reactive screen result (signal to cutoff ratio; S/Co ratio > or =1.0 but < or =100.0)
confirmed as positive by hepatitis B surface antigen (HBsAg) confirmatory test (see Method
Description) or a positive screen result (S/Co ratio >100.0) is indicative of acute or chronic hepatitis B
virus (HBV) infection, or chronic HBV carrier state. Specimens with reactive screen results but negative
(ie, not confirmed) HBsAg confirmatory test results are likely to contain cross-reactive antibodies from
other infectious or immunologic disorders. Repeat testing at a later date is recommended if clinically
indicated. Confirmed presence of HBsAg is frequently associated with HBV replication and infectivity,
especially when accompanied by the presence of hepatitis B e-antigen or detectable HBV DNA. The
following algorithms are available: -Hepatitis B: Testing Algorithm for Screening, Diagnosis, and
Management -HBV Infection-Monitoring Before and After Liver Transplantation -Viral Hepatitis
Serologic Profiles
Reference Values:
Negative
See Viral Hepatitis Serologic Profiles
Clinical References: 1. Bonino F, Piratvisuth T, Brunetto MR, Liaw YF: Diagnostic markers of
chronic hepatitis B infection and disease. Antivir Ther. 2010;15(3):35-44. doi: 10.3851/IMP1622 2.
Badur S, Akgun A: Diagnosis of hepatitis B infections and monitoring of treatment. J Clin Virol. 2.
Servoss JC, Friedman LS: Serologic and molecular diagnosis of hepatitis B virus. Clin Liver Dis. 2004
May;8(2):267-281. doi: 10.1016/j.cld.2004.02.001 3. Badur S, Akgun A: Diagnosis of hepatitis B
infections and monitoring of treatment. J Clin Virol. 2001 Jun;21(3):229-237. doi:
10.1016/s1386-6532(01)00147-0 4. LeFebre ML: U.S. Preventive Services Task Force: Screening for
hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med. 2014 Jul;1;161(1):58-66. doi: 10.7326/M14-1018 5.
Jackson K, Locarnini S, Gish R: Diagnostics of hepatitis B virus: Standard of care and investigational.
Clin Liver Dis. 2018 Aug 22;12(1):5-11. doi: 10.1002/cld.729 6. Coffin CS, Zhou K, Terrault NA: New
and old biomarkers for diagnosis and management of chronic hepatitis B virus infection.
Gastroenterology. 2019 Jan;156(2):355-368. doi: 10.1053/j.gastro.2018.11.037 7. WHO Guidelines
Development Group: WHO guidelines on hepatitis B and C testing. World Health Organization; 2017.
Accessed July 8, 2021. Available at www.who.int/publications/i/item/9789241549981 8. Centers for
Disease Control and Prevention. Testing and public health management of persons with chronic
hepatitis B virus infection. CDC; Updated October 8, 2019. Accessed April 8, 2020. Available at:
www.cdc.gov/hepatitis/hbv/testingchronic.htm
CHSBP Chronic Hepatitis Profile (Type B), Serum

9023 Clinical Information: Hepatitis B virus (HBV) is a DNA virus that is endemic throughout the
world. The infection is spread primarily through percutaneous contact with infected blood products (eg,
blood transfusion and sharing of needles by drug addicts). The virus is also found in virtually every type
of human body fluid and is known to be spread through oral and genital contact. HBV can be
transmitted from mother to child during delivery through contact with blood and vaginal secretions; it is
not commonly transmitted transplacentally. After a course of acute illness, HBV persists in
approximately 10% of patients. Some of these carriers are asymptomatic; others develop chronic liver
disease including cirrhosis and hepatocellular carcinoma. The following are available: -Hepatitis B:
Testing Algorithm for Screening, Diagnosis, and Management -Viral Hepatitis Serologic Profiles
Useful For: Evaluating patients with confirmed chronic hepatitis B Monitoring hepatitis B viral
infectivity
Interpretation: Hepatitis B surface antigen (HBsAg) is the first serologic marker appearing in the
serum 6 to 16 weeks following hepatitis B viral (HBV) infection. In acute cases, HBsAg usually
disappears 1 to 2 months after the onset of symptoms. Persistence of HBsAg for more than 6 months
indicates development of either chronic carrier state or chronic liver disease. Hepatitis B surface
antibody (anti-HBs) appears with the resolution of HBV infection after the disappearance of HBsAg.
Anti-HBs also appears as the immune response following a course of inoculation with the hepatitis B
vaccine. Hepatitis B core antibody (anti-HBc) appears shortly after the onset of symptoms of HBV
infection and may be the only serologic marker remaining years after exposure to hepatitis B. The
presence of hepatitis Be antigen (HBeAg) correlates with infectivity, the number of viral Dane particles,
the presence of core antigen in the nucleus of the hepatocyte, and the presence of viral DNA polymerase
in serum. Hepatitis Be antibody (anti-HBe) positivity in a carrier is often associated with chronic
asymptomatic infection. If the patient has a sudden exacerbation of disease, consider ordering hepatitis
C virus antibody (anti-HCV) and hepatitis delta virus antibody (anti-HDV). If HBsAg converts to
negative and patient's condition warrants, consider testing for anti-HBs. If HBsAg is positive, consider
testing for anti-HDV. The following are available: -Hepatitis B: Testing Algorithm for Screening,
Diagnosis, and Management -Viral Hepatitis Serologic Profiles
Reference Values:
HEPATITIS B SURFACE ANTIGEN:
Negative
HEPATITIS Be ANTIGEN:
Negative
HEPATITIS Be ANTIBODY: Negative
Interpretation depends on clinical setting. See Viral Hepatitis Serologic Profiles.
Clinical References: 1. Bonino F, Piratvisuth T, Brunetto MR, Liaw YF: Diagnostic markers of
chronic hepatitis B infection and disease. Antivir Ther. 2010;15(3):35-44 2. Servoss JC, Friedman LS:
Serologic and molecular diagnosis of hepatitis B virus. Clin Liver Dis. 2004 May;8(2):267-281 3. Badur
S, Akgun A: Diagnosis of hepatitis B infections and monitoring of treatment. J Clin Virol. 2001
Jun;21(3):229-237 4. LeFevre ML, U.S. Preventive Services Task Force: Screening for hepatitis B virus
infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation
statement. Ann Intern Med. 2014 Jul 1;161(1):58-66. doi:10.7326/M14-1018 5. Jackson K, Locarnini S,
Gish R: Diagnostics of hepatitis B virus: Standard of care and investigational. Clin Liver Dis (Hoboken).
2018 Aug 22;12(1):5-11. doi: 10.1002/cld.729 6. Coffin CS, Zhou K, Terrault NA: New and Old
Biomarkers for Diagnosis and Management of Chronic Hepatitis B Virus Infection. Gastroenterology.
2019 Jan;156(2):355-368. doi: 10.1053/j.gastro.2018.11.037 7. WHO Guidelines Development Group:
World Health Organization guidelines on hepatitis B and C testing. World Health Organization; 2017.
Accessed September 29, 2020. Available at
www.who.int/hepatitis/publications/guidelines-hepatitis-c-b-testing/en/ 8. Centers for Disease Control and
Prevention. Testing and public health management of persons with chronic hepatitis B virus infection.
Accessed April 8, 2020. Available at www.cdc.gov/hepatitis/hbv/testingchronic.htm
CLLMV Chronic Lymphocytic Leukemia (CLL) Monitoring Minimal

65175 Residual Disease (MRD) Detection, Varies
Clinical Information: Chronic lymphocytic leukemia (CLL) is a low-grade, B-cell neoplasm that is
the most common leukemia detected in the western world. It is a disease primarily of adults and may
present as a lymphocytosis, be detected as part of a lymphadenopathy evaluation, or be found incidentally
in an otherwise asymptomatic patient. The diagnosis of CLL is based on a combination of morphologic
features showing primarily small lymphoid cells with coarse chromatin and scant cytoplasm and an
immunophenotype of clonal B-cells with dim immunoglobulin, dim CD20, and coexpression of CD5 and
CD23. New therapeutic approaches in CLL have been increasingly successful with some patients showing
no or only very minimal residual disease (MRD) in their peripheral blood or bone marrow specimens
following a therapeutic course. Immunophenotyping studies are necessary as morphologic features are not
sufficient to detect MRD. The absence of MRD is an important prognostic indicator in these patients.
Useful For: Confirming the presence or absence of minimal residual disease in patients with known
chronic lymphocytic leukemia who are either postchemotherapy or post-bone marrow transplantation
Interpretation: An interpretive report for presence or absence of minimal residual disease (MRD)
for chronic lymphocytic leukemia (CLL) is provided. Individuals without CLL should not have
detectable clonal B cells in the peripheral blood or bone marrow. Patients who have detectable MRD by
this assay are considered to have residual CLL disease.
Reference Values:
This test will be processed as a laboratory consultation. An interpretation of the immunophenotypic

findings and correlation with the morphologic features will be provided by a hematopathologist for
every case.
Clinical References: 1. Hallek M, Cheson BD, Catovsky D, et al: Guidelines for the diagnosis and
treatment of chronic lymphocytic leukemia: a report from the International Workshop on chronic
lymphocytic leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood
2008;111:5446-5456 2. Varghese AM, Rawstron AC, Hillmen P: Eradicating minimal residual disease
in chronic lymphocytic leukemia: should this be the goal of treatment? Curr Hematol Malig Rep
2010;5:35-44 3. Shanafelt TD: Predicting clinical outcome in CLL: how and why. Hematology Am Soc
Hematol Educ Program 2009;421-429 4. Sayala HA, Rawstron AC, Hillmen P: Minimal residual
disease assessment in chronic lymphocytic leukaemia. Best Pract Res Clin Haematol 2007;20:499-512
5. Rawstron AC, Villamor N, Ritgen M, et al: International standardized approach for flow cytometric
residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 2007;21:956-964 6. Moreton
P, Kennedy B, Lucas G, et al: Eradication of minimal residual disease in B-cell chronic lymphocytic
leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol
2005;23:2971-2979
CLLDF Chronic Lymphocytic Leukemia, Diagnostic FISH, Varies

610713 Clinical Information: Chronic lymphocytic leukemia (CLL) is the most common leukemia in
North America. The most common cytogenetic abnormalities in CLL involve chromosomes 6, 11, 12,
13 and 17. These are detected and quantified using the CLL fluorescence in situ hybridization (FISH)
panel. Use of CpG-oligonucleotide mitogen will identify an abnormal CLL karyotype in at least 80% of
cases. This mitogen is added to cultures when chromosome analysis is ordered and the reason for
referral is a B-cell disorder (CHRBM / Chromosome Analysis, Hematologic Disorders, Bone Marrow
and CHRHB / Chromosome Analysis, Hematologic Disorders, Blood). This FISH test detects an
abnormal clone in approximately 70% of patients with indolent disease and in greater than 80% of
patients who require treatment. At least 5% of patients referred for CLL FISH testing have
translocations involving the IGH locus. Fusion of IGH with CCND1 is associated with
t(11;14)(q13;q32), and fusion of IGH with BCL3 is associated with t(14;19)(q32;q13.3). Patients with
t(11;14) usually have the leukemic phase of mantle cell lymphoma. Patients with t(14;19) may have an
atypical form of B-CLL or the leukemic phase of a lymphoma. The prognostic associations for
chromosome abnormalities detected by this FISH assay are, from best to worst: 13q-, normal, +12, 6q-,
11q- and 17p-.
seen in patients with chronic lymphocytic leukemia (CLL) Identifying and tracking known chromosome
abnormalities in patients with CLL and tracking response to therapy Distinguishing patients with 11;14
translocations who have leukemic phase of mantle cell lymphoma from patients who have CLL
Detecting patients with atypical CLL or other forms of lymphoma associated with translocations
between IGH and BCL3
the normal reference range for any given probe set. The absence of an abnormal clone does not rule out
the presence of a neoplastic disorder.
Reference Values:
Clinical References: 1. Dewald GW, Brockman SR, Paternoster SF, et al: Chromosome anomalies
detected by interphase FISH: correlation with significant biological features of B-cell chronic
lymphocytic leukemia. Br J Haematol. 2003;121:287-295 2. Dohner H, Stilgenbauer S, Benner A, et al:
Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000
Dec;343(26):1910-1916 3. Van Dyke DL, Shanafelt TD, Call TG, et al: A comprehensive evaluation of
the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J
Haematol. 2010;148:544-550 4. Shanafelt TD: Predicting clinical outcome in CLL: how and why.
Hematology Am Soc Hematol Educ Program. 2009;421-429 5. Van Dyke DL, Werner L, Rassenti LZ, et
al: The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic
leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol. 2016 Apr;173(1):105-113
CLLMF Chronic Lymphocytic Leukemia, Specified FISH, Varies

610724 Clinical Information: Chronic lymphocytic leukemia (CLL) is the most common leukemia in North
America. The most common cytogenetic abnormalities in CLL involve chromosomes 6, 11, 12, 13, and
17. These are detected and quantified using the CLL fluorescence in situ hybridization (FISH) panel. Use
of CpG-oligonucleotide mitogen will identify an abnormal CLL karyotype in at least 80% of cases. This
mitogen is added to cultures when chromosome analysis is ordered and the reason for testing is a B-cell
disorder (CHRBM / Chromosome Analysis, Hematologic Disorders, Bone Marrow and CHRHB /
Chromosome Analysis, Hematologic Disorders, Blood). This FISH test detects an abnormal clone in
approximately 70% of patients with indolent disease and greater than 80% of patients who require
treatment. At least 5% of patients referred for CLL FISH testing have translocations involving the IGH
locus. Fusion of IGH with CCND1 is associated with t(11;14)(q13;q32), and fusion of IGH with BCL3 is
associated with t(14;19)(q32;q13.3). Patients with t(11;14) usually have the leukemic phase of mantle cell
lymphoma. Patients with t(14;19) may have an atypical form of B-CLL or the leukemic phase of a
lymphoma. The prognostic associations for chromosome abnormalities detected by this FISH assay are,
from best to worst: 13q-, normal, +12, 6q-, 11q-, and 17p-.
in patients with chronic lymphocytic leukemia (CLL) Identifying and tracking known chromosome
abnormalities in patients with CLL and tracking response to therapy Distinguishing patients with 11;14
translocations who have leukemic phase of mantle cell lymphoma from patients who have CLL Detecting
patients with atypical CLL or other forms of lymphoma associated with translocations between IGH and
BCL3
the normal reference range for any given probe set. The absence of an abnormal clone does not rule out
the presence of a neoplastic disorder.
Reference Values:
Clinical References: 1. Dewald GW, Brockman SR, Paternoster SF, et al: Chromosome anomalies
detected by interphase FISH: correlation with significant biological features of B-cell chronic
lymphocytic leukemia. Br J Haematol. 2003;121:287-295 2. Dohner H, Stilgenbauer S, Benner A, et al:
Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000
Dec;343(26):1910-1916 3. Van Dyke DL, Shanafelt TD, Call TG, et al: A comprehensive evaluation of
the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J
Haematol. 2010;148:544-550 4. Shanafelt TD: Predicting clinical outcome in CLL: how and why.
Hematology Am Soc Hematol Educ Program. 2009;421-429 5. Van Dyke DL, Werner L, Rassenti LZ, et
al: The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic
leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol. 2016 Apr;173(1):105-113
CHUB Chub Mackerel, IgE, Serum
Useful For: Establishing a diagnosis of an allergy to chub mackerel Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
CSU Chyluria Screen, Random, Urine

606921 Clinical Information: Chyluria is a medical condition in which chyle is present in the urine. Chyle
is a milky substance composed of lymphatic fluid and chylomicrons formed in the small intestine during
the digestion of fatty foods. Chyluria is most prevalent in tropical areas where it is caused by parasitic
(Wuchereria bancrofti) infections spread by mosquitoes. Parasitic chyluria is so rare as to be nonexistent
in the continental United States. Nonparasitic chyluria causes include traumatic lesions, tumors,
lymphangioma, pregnancy, and granulomatous infections.
Useful For: Aiding in the diagnosis of chyluria (galacturia)

Interpretation: This assay provides information regarding the fat content in urine fluid. Urinary
cholesterol and triglyceride values are normally less than 10 mg/dL. High triglyceride levels in urine
may indicate chyluria.
Reference Values:
No lipoproteins present
Clinical References: 1. Diamond E, Schapira HE: Chyluria-a review of the literature. Urology.
1985;26:427-431 2. Mendu DR, Sternlicht H, Ramanathan LV, et al: Two cases of spontaneous remission
of non-parasitic chyluria. Clin Biochem. 2017;50(15):886-888. doi: 10.1016/j.clinbiochem.2017.05.002
FCHYS Chymotrypsin, Stool

2.3 Ã¢â‚¬â€œ 51.4 U/g
FCING Cinnamon IgG

Reference Values:
CINN Cinnamon, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cinnamon Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
Clinical References: Homburger HA, Hamilton RG: Chapter 55: Allergic diseases. In: McPherson
RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed.
Elsevier; 2017:1057-1070
FCQBA Circulating Immune Complex, C1q Binding

0.0-3.9 ug Eq/mL
Less than or equal to 3.9 ug Eq/mL is considered negative for circulating complement binding immune
complexes.
Circulating immune complexes may be found without any evident pathology and positive results do
not necessarily implicate the immune complex in a disease process.
FCIC3 Circulating Immune Complex, C3 fragments

75772 Interpretation: Many autoimmune disorders, chronic infections and malignancies are associated
with circulating immune complexes. Quantitation of immune complexes assists in staging immunologic
disorders. Detection of circulating immune complexes is not essential to any specific diagnosis.
Circulating immune complexes may be found without any evident pathology and positive results do not
necessarily implicate immune complex-related disease process. Values between 15 and 20 ug Eq/mL
are considered equivocal for the Circulating Immune Complex, C3 fragments assay. Repeat testing
using a new specimen is recommended, if clinically indicated.
Reference Values:
Less than or equal to 15 ug Eq/mL
FCIC Circulating Immune Complexes (CIC)

91497 Interpretation: Circulating immune complexes (CICs) are detectable in a variety of systemic
disorders such as rheumatological, autoimmune, allergic diseases; viral, bacterial infections and
malignancies. Although detection of CICs is neither essential nor specific for any disease, anti-C1q
assay is likely to provide information regarding disease activity in lupus nephritis.
Reference Values:
Negative <20 EU/mL
Borderline/Equivocal 20 Ã¢â‚¬â€œ 25 EU/mL
Positive >25 EU/mL
CITAL Citalopram, Serum

83730 Clinical Information: Citalopram (Celexa) and S-citalopram (escitalopram, Lexapro) are approved
for treatment of depression. Celexa is a racemic mixture containing equal amounts of R- and
S-enantiomer. Metabolites of citalopram (N-desmethylcitalopram) are less active than citalopram and
do not accumulate in serum to clinically significant concentration. Citalopram metabolism is carried out
by cytochrome P450 (CYP) 2C19 and 3A4-5. CYP 2D6 may play a minor role in citalopram
metabolism. Citalopram is known to reduce CYP 2D6 activity. Citalopram clearance is significantly
affected by reduced hepatic function, but only slightly by reduced renal function. A typical Celexa dose
administered to an adult is 40-mg per day. A typical Lexapro dose is 20-mg per day. Citalopram is 80%
protein bound, and the apparent volume of distribution is 12 L/Kg. Bioavailability is 80% and protein
binding is 56% for either form of the drug. Time to peak serum concentration is 4 hours, and the
elimination half-life is 35 hours. Half-life is increased in the elderly. Dosage reductions may be
necessary for patients who are elderly or have reduced hepatic function.
Useful For: Monitoring citalopram therapy Identifying noncompliance, although regular blood level
monitoring is not indicated in most patients Identifying states of altered drug metabolism when used in
conjunction with CYP2C19 and CYP3A4-5 genotyping
Interpretation: Steady-state serum concentrations associated with optimal response to citalopram are
in the range of 50 to 100 ng/mL when the patient is administered the R,S-enantiomeric mixture (Celexa).
The most common toxicities associated with excessive serum concentration are fatigue, impotence,
insomnia, and anticholinergic effects. The toxic range for citalopram is greater than 220 ng/mL.
Reference Values:
Citalopram: 50-110 ng/mL
Escitalopram: 15-80 ng/mL
Clinical References: 1. Hiemke C, Baumann P, Bergemann N, et al: AGNP consensus guidelines

for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011;44:195-235 2.
Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE
Bruns. Elsevier, Mosby, Saunders, 2011
CITR2 Citrate Concentration, Random, Urine

606637 Clinical Information: Urinary citrate is a major inhibitor of kidney stone formation due in part to
binding of calcium in urine. Low urine citrate levels are considered a risk for kidney stone formation.
Several metabolic disorders are associated with low urine citrate. Any condition that lowers renal tubular
pH or intracellular pH may decrease citrate (eg, metabolic acidosis, increased acid ingestion,
hypokalemia, or hypomagnesemia). Low urinary citrate is subject to therapy by correcting acidosis,
hypokalemia, or hypomagnesemia by altering diet or using drugs such as citrate and potassium.
Useful For: Diagnosing risk factors for patients with calcium kidney stones Monitoring results of
therapy in patients with calcium stones or renal tubular acidosis
Interpretation: A low citrate value represents a potential risk for kidney stone formation/growth.
Patients with low urinary citrate and new or growing stone formation may benefit from adjustments in
therapy known to increase urinary citrate excretion. Very low citrate levels suggest investigation for the
possible diagnosis of metabolic acidosis (eg, renal tubular acidosis). For children ages 5 to 18, a ratio of
less than 0.176 mg citrate/ mg creatinine is below the 5% reference range and considered low.(1)
Reference Values:
Only orderable as part of a profile. For more information see CITRA / Citrate Excretion, Random, Urine.
Clinical References: 1. Srivastava T, Winston MJ, Auron A et al: Urine calcium/citrate ratio in
children with hypercalciuric stones. Pediatr Res. 2009;66:85-90 2. Hosking DH, Wilson JW, Liedtke RR,
et al: The urinary excretion of citrate in normal persons and patients with idiopathic calcium urolithiasis
(abstract). Urol Res. 1984;12:26 3. Lieske JC, Wang X: Heritable traits that contribute to nephrolithiasis.
Urolithiasis. 2019 Feb;47(1):5-10 4. Lieske JC, Turner ST, Edeh SN, Smith JA, Kardia SLR: Heritability
of urinary traits that contribute to nephrolithiasis. Clin J Am Soc Nephrol. 2014 May;9(5):943-950. doi:
10.2215/CJN.08210813
CITR Citrate Excretion, 24 Hour, Urine
Several metabolic disorders are associated with low urine citrate. Any condition that lowers renal
tubular pH or intracellular pH may decrease citrate (eg, metabolic acidosis, increased acid ingestion,
hypokalemia, or hypomagnesemia). Low urinary citrate promotes kidney stone formation and growth,
and is subject to therapy by correcting acidosis, hypokalemia, or hypomagnesemia by altering diet or
using drugs such as citrate and potassium.
Useful For: Diagnosing risk factors for patients with calcium kidney stones Monitoring results of
therapy in patients with calcium stones or renal tubular acidosis
Interpretation: Any value less than the mean for 24 hours represents a potential risk for kidney
stone formation and growth. Patients with low urinary citrate and new or growing stone formation, may
benefit from adjustments in therapy known to increase urinary citrate excretion. (See Clinical
Information) Very low levels (<150 mg/24 hours) suggest investigation is needed for the possible
diagnosis of metabolic acidosis (eg, renal tubular acidosis).
Reference Values:
20 years: 150-1,191 mg/24 hours
21 years: 157-1,191 mg/24 hours
22 years: 164-1,191 mg/24 hours
23 years: 171-1,191 mg/24 hours
24 years: 178-1,191 mg/24 hours
25 years: 186-1,191 mg/24 hours
26 years: 193-1,191 mg/24 hours
27 years: 200-1,191 mg/24 hours
28 years: 207-1,191 mg/24 hours
29 years: 214-1,191 mg/24 hours
30 years: 221-1,191 mg/24 hours
31 years: 228-1,191 mg/24 hours
32 years: 235-1,191 mg/24 hours
33 years: 242-1,191 mg/24 hours
34 years: 250-1,191 mg/24 hours
35 years: 257-1,191 mg/24 hours
36 years: 264-1,191 mg/24 hours
37 years: 271-1,191 mg/24 hours
38 years: 278-1,191 mg/24 hours
39 years: 285-1,191 mg/24 hours
40 years: 292-1,191 mg/24 hours
41 years: 299-1,191 mg/24 hours
42 years: 306-1,191 mg/24 hours
43 years: 314-1,191 mg/24 hours
44 years: 321-1,191 mg/24 hours
45 years: 328-1,191 mg/24 hours
46 years: 335-1,191 mg/24 hours
47 years: 342-1,191 mg/24 hours
48 years: 349-1,191 mg/24 hours
49 years: 356-1,191 mg/24 hours
50 years: 363-1,191 mg/24 hours
51 years: 370-1,191 mg/24 hours
52 years: 378-1,191 mg/24 hours
53 years: 385-1,191 mg/24 hours
54 years: 392-1,191 mg/24 hours
55 years: 399-1,191 mg/24 hours
56 years: 406-1,191 mg/24 hours
57 years: 413-1,191 mg/24 hours
58 years: 420-1,191 mg/24 hours
59 years: 427-1,191 mg/24 hours
60 years: 434-1,191 mg/24 hours
>60 years: not established
Clinical References: 1. Hosking DH, Wilson JW, Liedtke RR, Smith LH, Wilson DM: The urinary
excretion of citrate in normal persons and patients with idiopathic calcium urolithiasis. Lab Clin Med.
1985 Dec;106(6):682-689. 2. Lieske JC, Wang X: Heritable traits that contribute to nephrolithiasis.
Urolithiasis. 2019 February; 47(1): 5-10 3. Lieske JC, Turner ST, Edeh SN, Smith JA, Kardia SLR:
Heritability of urinary traits that contribute to nephrolithiasis. Clin J Am Soc Nephrol. 2014
May;9(5):943-950
CITRA Citrate Excretion, Random, Urine

Useful For: Diagnosing risk factors for patients with calcium kidney stones using random urine
specimens Monitoring results of therapy in patients with calcium stones or renal tubular acidosis
Interpretation: A low value represents a potential risk for kidney stone formation/growth. Patients
with low urinary citrate and new or growing stone formation may benefit from adjustments in therapy
known to increase urinary citrate excretion. Very low citrate levels suggest investigation for the possible
diagnosis of metabolic acidosis (eg, renal tubular acidosis). For children ages 5 to 18, a ratio of less than
0.176 mg citrate/ mg creatinine is below the 5% reference range and considered low.(1)
Reference Values:
Clinical References: 1. Srivastava T, Winston MJ, Auron A, Alon US: Urine calcium/citrate ratio in
children with hypercalciuric stones. Pediatr Res. 2009 Jul;66(1):85-90. doi:
10.1203/PDR.0b013e3181a2939e 2. Hosking DH, Wilson JW, Liedtke RR, Smith LH, Wilson DM: The
urinary excretion of citrate in normal persons and patients with idiopathic calcium urolithiasis. J Lab Clin
Med. 1985 Dec;106(6):682-689 3. Lieske JC, Wang X: Heritable traits that contribute to nephrolithiasis.
Urolithiasis. 2019 Feb;47(1):5-10. doi: 10.1007/s00240-018-1095-1 4. Lieske JC, Turner ST, Edeh SN,
Smith JA, Kardia SL: Heritability of urinary traits that contribute to nephrolithiasis. Clin J Am Soc
Nephrol. 2014 May;9(5):943-950
RAT10 Citrate/Creatinine Ratio, Urine

Useful For: Calculating the citrate concentration per creatinine Diagnosing risk factors for patients
with calcium kidney stones Monitoring results of therapy in patients with calcium stones or renal tubular
acidosis
Interpretation: A low citrate value represents a potential risk for kidney stone formation/growth.
Patients with low urinary citrate and new or growing stone formation may benefit from adjustments in
therapy known to increase urinary citrate excretion. Very low citrate levels suggest investigation for the
possible diagnosis of metabolic acidosis (eg, renal tubular acidosis). For children ages 5 to 18, a ratio of
less than 0.176 mg citrate/ mg creatinine is below the 5% reference range and considered low.(1)
Reference Values:
Only orderable as part of a profile. For more information see CITRA / Citrate Excretion, Random,
Urine.
Clinical References: 1. Srivastava T, Winston MJ, Auron A et al: Urine calcium/citrate ratio in
children with hypercalciuric stones. Pediatr Res. 2009;66:85-90 2. Hosking DH, Wilson JW, Liedtke
RR, et al: The urinary excretion of citrate in normal persons and patients with idiopathic calcium
urolithiasis (abstract). Urol Res. 1984;12:26 3. Lieske JC, Wang X: Heritable traits that contribute to
nephrolithiasis. Urolithiasis. 2019 Feb;47(1):5-10 4. Lieske JC, Turner ST, Edeh SN, Smith JA, Kardia
SLR: Heritability of urinary traits that contribute to nephrolithiasis. Clin J Am Soc Nephrol. 2014
May;9(5):943-950. doi: 10.2215/CJN.08210813
CLAD Cladosporium, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Cladosporium Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
CLAM Clam, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to clam Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
CLAUD Claudin-1 Immunostain, Technical Component Only

70403 Clinical Information: Claudin proteins are a family of tight junction-associated proteins that prevent
leakage of ions, water, etc between cells. Differential expression of claudin proteins is seen in various
epithelial cell types. Strong expression of claudin-1 is seen on squamous epithelial cells of the skin.
Claudin-1 may have reduced expression in invasive versus benign breast lesions. In the diagnostic setting,
30% to 50% of soft tissue and intramucosal intestinal perineuriomas are positive for claudin-1. Gastric
intestinal-type adenocarcinoma shows more frequent claudin-1 expression than diffuse gastric
carcinomas.
Useful For: Identification of a number of different soft tissue and epithelial neoplasms
Clinical References: 1. Katzka DA, Tadi R, Smyrk TC, et al: Effects of topical steroids on tight
junction proteins and spongiosis in esophageal epithelia of patients with eosinophilic esophagitis. Clin
Gastroenterol Hepatol. 2014 Nov;12(11):1824-9.e1. doi: 10.1016/j.cgh.2014.02.039 2. Bhat AA, Syed
N, Therachiyil L, et al: Claudin-1, a double-edged sword in cancer. Int J Mol Sci. 2020 Jan;21(2):569.
doi: 10.3390/ijms21020569 3. Moldvay J, Fabian K, Jackel M, et al: Claudin-1 protein expression Is a
good prognostic factor in non-small cell lung cancer, but only in squamous cell carcinoma cases. Pathol
Oncol Res. 2017;23(1):151-156. doi: 10.1007/s12253-016-0115-0
CLDN4 Claudin-4 Immunostain, Technical Component Only

607334 Clinical Information: Claudin-4 is a component of tight junction strands and is expressed on the
membrane of cells of epithelial origin. Claudin-4 has been shown to distinguish carcinoma from
mesothelioma and carcinoma from sarcoma.
Useful For: Distinguishing carcinoma from mesothelioma and sarcoma

Clinical References: 1. Jo VY, Cibas ES, Pinkus GS: Claudin-4 immunohistochemistry is highly
effective in distinguishing adenocarcinoma from malignant mesothelioma in effusion cytology. Cancer
Cytopathol. 2014 Apr;122(4):299-306 2. Ohta Y, Sasaki Y, Saito M, et al: Claudin-4 as a marker for
distinguishing malignant mesothelioma from lung carcinoma and serous adenocarcinoma. Int J Surg
Pathol. 2013 Oct;21(5):493-501 3. Ordonez NG: Value of claudin-4 immunostaining in the diagnosis of
mesothelioma. Am J Clin Pathol. 2013 May;139(5):611-619 4. Schaefer IM, Agaimy A, Fletcher CD,
Hornick JL: Claudin-4 expression distinguishes SWI/SNF complex-deficient undifferentiated
carcinomas from sarcomas. Mod Pathol. 2017 Apr;30(4):539-548
FCLCN CLCN1 DNA Sequencing Test

CLOBZ Clobazam and Metabolite, Serum

65483 Clinical Information: Clobazam is a broad spectrum, antiepileptic drug used for various types of
seizures, Lennox-Gastaut syndrome (a type of childhood onset epilepsy), and migraine prophylaxis.
Clobazam blocks voltage-dependent sodium channels, potentiates gamma-aminobutyric acid (GABA)
activity at some of the GABA receptors, and inhibits potentiation of the glutamate receptor and carbonic
anhydrase enzyme, all of which contribute to its antiepileptic and antimigraine efficacy. In general,
clobazam shows favorable pharmacokinetics with good absorption (1-4 hours for the immediate-release
formulation), low protein binding, and minimal hepatic metabolism. Elimination is predominantly renal,
and it is excreted unchanged in the urine with an elimination half-life of approximately 21 hours. As
with other anticonvulsant drugs eliminated by the renal system, patients with impaired kidney function
exhibit decreased clobazam clearance and a prolonged elimination half-life. Serum concentrations of
other anticonvulsant drugs are not significantly affected by the concurrent administration of clobazam,
with the exception of patients on phenytoin whose serum concentrations can increase after the addition
of clobazam. Other drug-drug interactions include the coadministration of phenobarbital, phenytoin, or
carbamazepine, which can result in decreased clobazam concentrations. In addition, concurrent use of
posaconazole and clobazam may result in the elevation of clobazam serum concentrations. Therefore,
changes in cotherapy with these medications (phenytoin, carbamazepine, posaconazole, or
phenobarbital) may require dose adjustment of clobazam, and therapeutic drug monitoring can be
helpful. The most common adverse drug effects associated with clobazam include weight loss, loss of
appetite, somnolence, dizziness, coordination problems, memory impairment, and paresthesia.
Useful For: Monitoring clobazam therapy

Interpretation: The results of this test should be interpreted in conjunction with the patient's physical
signs, symptoms, and other laboratory test results. Most individuals display optimal response to clobazam
when serum levels of clobazam are between 30 and 300 ng/mL and N-desmethylclobazam are between
300 and 3000 ng/mL. Risk of toxicity is increased when clobazam levels are above 500 ng/mL or
N-desmethlyclobazam levels are above 5000 ng/mL. Some individuals may respond well outside of these
ranges or may display toxicity within the therapeutic range, thus, interpretation should include clinical
evaluation.
Reference Values:
CLOBAZAM
Therapeutic Range: 30-300 ng/mL
N-DESMETHYLCLOBAZAM (NORCLOBAZAM)
Therapeutic Range: 300-3,000 ng/mL
Clinical References: 1. Hiemke C, Bergemann N, Clement HW, et al: Consensus guidelines for
therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018
Jan;51(1-02):9-62 2. Patslos PN, Berry DJ, Bourgeois BF, et al: Antiepileptic drugs-best practice
guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug
monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008 Jul;49(7):1239-1276 3.
Johannessen SI, Tomsom T: Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring
needed? Clin Pharmacokinet. 2006;45(11):1061-1075
CLOM Clomipramine, Serum

80902 Clinical Information: Clomipramine (chlorimipramine, Anafranil) is a tricyclic antidepressant drug
used primarily to treat obsessive-compulsive disorder. Clomipramine is also used to treat panic disorder
and treatment-resistant depression. Clomipramine preferentially blocks synaptic reuptake of serotonin; its
pharmacologically active metabolite, norclomipramine (desmethylchlorimipramine) preferentially blocks
synaptic reuptake of norepinephrine. Clomipramine undergoes significant first-pass hepatic metabolism
(up to 50%), which probably explains the high degree of interindividual variability observed between
administered dose and steady-state serum concentrations of the drug and its metabolite. The serum ratio of
clomipramine to norclomipramine is typically 1:2-2.5. The elimination half-lives of clomipramine and
norclomipramine are 19 to 37 hours and 54 to 77 hours, respectively. When a patient is started on
clomipramine or following an alteration in the dose, 1 to 2 weeks are required to achieve a steady-state
condition. Anticholinergic side effects (ie, dry mouth, excessive sweating, blurred vision, urinary
retention, constipation) frequently accompany treatment. Other side effects may include tremor, nausea,
orthostatic hypotension, dizziness, sexual dysfunction, and sleep disturbances. Signs and symptoms
following overdose are similar to other tricyclic antidepressant drugs: cardiac toxicity (eg, tachycardia,
arrhythmia, impaired conduction, congestive heart failure) is the major concern.
Useful For: Determining whether a poor therapeutic response is attributable to noncompliance
Monitoring serum concentration of clomipramine and norclomipramine to assist in optimizing the
administered dose
Interpretation: Studies investigating the relationship between serum concentrations of clomipramine

and norclomipramine and therapeutic response have yielded conflicting results. However, the
probability of therapeutic failure seems to increase if the sum of the clomipramine and norclomipramine
serum concentrations is <230 ng/mL. Summed serum concentrations of clomipramine and
norclomipramine that exceed 450 ng/mL seem to result in no additional enhancement in therapeutic
response and may predispose the patient to greater risk of adverse side effects. A toxic range has not
been well established at this time.
Reference Values:
CLOMIPRAMINE AND NORCLOMIPRAMINE
Note: Therapeutic ranges are for specimens collected at trough (ie, immediately before next scheduled
CZPS Clonazepam and 7-Aminoclonazepam, Serum

65044 Clinical Information: Clonazepam (5 [2-chlorophenyl]-2, 3-dihydro-7-nitro-1,
4-benzodiazepin-2-one), a benzodiazepine is useful alone or as an adjunct in the treatment of certain
seizures. In addition, it may be useful in patients with panic disorder and restless legs syndrome.
Clonazepam has no definite antiseizure and antipanic mechanism of action, although it is believed to be
related to its capacity to enhance gamma-aminobutyric acid (GABA) activity, which is the major
inhibitory neurotransmitter in the central nervous system. It is able to suppress the spike and wave
discharges in absence seizures and decreases the frequency, duration, amplitude, and spread of
discharge in minor motor seizures. Clonazepam is highly protein bound (approximately 85%). It is
extensively metabolized by hepatic cytochrome P450, family 3, subfamily A (CYP3A) to inactive
metabolites and has a half-life of 30 to 40 hours.
Useful For: Assessing patient compliance Monitoring for appropriate therapeutic level Assessing
clonazepam toxicity
Interpretation: The therapeutic range varies depending on the indication. Some individuals may
respond well outside of these ranges or may display toxicity within the therapeutic range, and thus,
interpretation should include clinical evaluation. The possibility of toxicity is increased when levels
exceed 100 ng/mL.
Reference Values:
Clonazepam
Anticonvulsant: 20-70 ng/mL
Anxiolytic: 4-80 ng/mL
Some individuals may show therapeutic response outside of these ranges or may display toxicity
within the therapeutic range, thus interpretation should include clinical evaluation.
Clinical References: Hiemke C, Baumann P, Bergemann N, et al: AGNP Consensus Guidelines

for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry. 2011;44(6):195-235
FCLON Clonidine (Catapres)

Sedation has been associated with serum clonidine concentrations greater than 1.5 ng/mL
Toxic concentration has not been established.
CDIF Clostridioides difficile Culture, Varies

64354 Clinical Information: Clostridioides difficile (formerly Clostridium difficile) can cause diarrhea and
may cause pseudomembranous colitis. Overgrowth of toxin-producing C difficile in the colon leads to the
production of toxins A and/or B by the organism and consequent diarrhea. C difficile infection should be
suspected in patients with symptoms of diarrhea with risk factors such as current or recent use of
antibiotics, a history of C difficile infection, current or recent hospitalization or placement in a nursing
home or long-term care facility, age older than 65 years, gastric acid suppression, etc. C difficile infection
is the most common cause of diarrhea in hospitalized patients and may lead to serious complications,
including sepsis, bowel perforation, and increased overall mortality (especially in older patients). The
incidence of C difficile infection has risen in the community and in healthcare settings. While culture is
not the preferred means to diagnose C difficile-associated diarrhea, culture for C difficile provides an
isolate suitable for antimicrobial susceptibility testing. Note that this test does not differentiate between
toxin-producing and nontoxigenic strains of C difficile.
Useful For: Providing an isolate suitable for antimicrobial susceptibility testing.

Interpretation: A positive result indicates the presence of viable Clostridioides difficile in feces. A
positive culture may be found with asymptomatic C difficile colonization with a toxin-producing or
non-toxin-producing strain, or with C difficile-associated diarrhea. A negative result indicates the absence
of C difficile growth in culture. Isolation of C difficile does not differentiate between toxin-producing and
non-toxin-producing strains.
Reference Values:
No growth after 1 day of incubation.
Clinical References: 1. Cohen SH, Gerding DN, Johnson S, et al: Clinical practice guidelines for
Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of
America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol.
2010 May;31(5):431-455 2. Lawson PA, Citron DM, Tyrrell KL, Finegold SM: Reclassification of
Clostridium difficile as Clostridioides difficile (Hall and O'Toole 1935) Prevot 1938. Anaerobe. 2016
Aug;40:95-99. doi. 10.1016/j.anaerobe.2016.06.008 3. Oren A, Garrity GM: List of new names and new
combinations previously effectively, but not validly, published. Int J Syst Evol Microbiol. 2016
Nov;66(11):4299-4305. doi 10.1099/ijsem.0.001585
CDFRP Clostridioides difficile Toxin, Molecular Detection, PCR, Feces

35149 Clinical Information: Clostridioides difficile (formerly Clostridium difficile) is the cause of C
difficile-associated diarrhea (CDAD), an antibiotic-associated diarrhea, and pseudomembranous colitis
(PMC). In these disorders bacterial overgrowth of C difficile develops in the colon, typically as a
consequence of antibiotic usage. Clindamycin and broad-spectrum cephalosporins have most frequently
been associated with CDAD and PMC, but almost all antimicrobials may be responsible. Disease is
related to production of toxin A and B. Treatment typically involves withdrawal of the associated
antimicrobials and, if symptoms persist, orally administered and intraluminally active metronidazole,
vancomycin, or fidaxomicin. Intravenous metronidazole may be used if an oral agent cannot be
administered. In recent years, a more severe form of CDAD with increased morbidity and mortality has
been recognized as being caused by an epidemic toxin-hyperproducing strain of C difficile (NAP1 strain).
Many toxin-hyperproducing isolates also contain the binary toxin gene and are resistant to quinolones.
This test does not differentiate between toxin-hyperproducing and nontoxin-hyperproducing strains.
Traditionally, diagnosis relied upon: 1. Clinical and epidemiologic features 2. Culture, which is labor
intensive and time consuming 3. Cytotoxicity assays, which are also labor intensive and time consuming
4. Toxin detection immunoassays, which are insensitive The described polymerase chain reaction assay
detects the regulatory gene (tcdC) responsible for production of toxins A and B. This test is used for rapid
diagnosis of CDAD and PMC enabling prompt treatment that may reduce hospital stays for inpatients
with CDAD.
Useful For: Rapid diagnosis of Clostridioides difficile-associated diarrhea (CDAD) and

pseudomembranous colitis (PMC)
Interpretation: A positive polymerase chain reaction (PCR) result for the presence of the gene
regulating toxin production (tcdC) indicates the presence of Clostridioides difficile and toxin A and/or
B. A negative result indicates the absence of detectable C difficile tcdC DNA, but does not rule-out C
difficile infection and may occur due to inhibition of PCR, sequence variability underlying primers or
probes, or the presence of C difficile DNA in quantities less than the limit of detection of the assay.
Reference Values:
Not applicable
Clinical References: 1. Aichinger E, Schleck CD, Harmsen WS, Nyre LM, Patel R: Nonutility of
repeat laboratory testing for detection of Clostridium difficile by use of PCR or enzyme immunoassay. J
Clin Microbiol. 2008;46:3795-3797 2. Verdoorn BP, Orenstein R, Rosenblatt JE, et al: High prevalence
of tcdC deletion-carrying Clostridium difficile and lack of association with disease severity. Diagn
Microbiol Infect Dis. 2010;66:24-28 3. Karre T, Sloan L, Patel R, Mandrekar J, Rosenblatt J:
Comparison of two commercial molecular assays to a laboratory-developed molecular assay for
diagnosis of Clostridium difficile infection. J Clin Microbiol. 2011;49:725-727 4. Lawson PA, Citron
DM, Tyrrell KL, Finegold SM: Reclassification of Clostridium difficile as Clostridioides difficile (Hall
and O'Toole 1935) Prevot 1938. Anaerobe. 2016 Aug;40:95-99. doi: 10.1016/j.anaerobe.2016.06.008 5.
Oren A, Garrity GM: List of new names and new combinations previously effectively, but not validly,
published. Int J Syst Evol Microbiol. 2016 Sep;66:3761-3764. doi: 10.1099/ijsem.0.001321
CLOV Clove, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to clove Defining the allergen responsible for
Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CLZ Clozapine, Serum

42366 Clinical Information: Clozapine (Clozaril), a tricyclic dibenzodiazepine, is used for the symptomatic
management of psychotic disorders and is considered an atypical antipsychotic drug. It is currently used
primarily for the treatment of patients with schizophrenia or schizoaffective disorders who are at risk for
recurrent suicidal behavior and who have encountered nonresponse or adverse, intolerable extrapyramidal
side effects with more classical antipsychotics (chlorpromazine, haloperidol). Although clozapine was
developed about 30 years ago and the initial results were promising, the development of several fatal
cases of agranulocytosis resulted in the discontinued use of this agent. Seizures, orthostatic hypotension,
and an increased risk of fatal myocarditis have also been associated with the use of clozapine. The use of
clozapine has regained interest for several reasons. Patients who did not respond to treatment with other
antipsychotics improved when clozapine was administered. Also, agranulocytosis, which occurs in
approximately 1% to 2% of patients, can be controlled with close hematologic monitoring. However,
because of the significant risk of agranulocytosis and seizure associated with its use, clozapine should
only be used in patients who have failed to respond adequately to treatment with appropriate courses of
standard drug treatments, either because of insufficient effectiveness or the inability to achieve an
effective dose because of intolerable adverse reactions from those drugs. Treatment is usually started with
dosages of 25 to 75 mg/day with a gradual increase to reach a final dose of 300 to 450 mg/day within
approximately 2 weeks of the initiation of treatment. Once the desired effect is achieved, the dose may be
gradually decreased to keep the patient on the lowest possible effective dose. Patients being treated with
clozapine should be closely monitored during treatment for adverse reactions. Treatment must include
monitoring of white blood cell count and absolute neutrophil count. Clozapine treatment should be
discontinued in patients failing to show an acceptable clinical response. In addition,Â the need for
continuing treatment should be periodically reevaluated in patients exhibiting beneficial clinical
responses. Clozapine is metabolized to desmethylated and N-oxide derivatives. The desmethyl metabolite
(norclozapine) has only limited activity, and N-oxide metabolite is inactive.
Useful For: Monitoring patient compliance An aid to achieving desired serum levels
Interpretation: The effectiveness of clozapine treatment should be based on clinical response and
treatment should be discontinued in patients failing to show an acceptable clinical response.
Reference Values:
CLOZAPINE
Therapeutic range: 350-600 ng/mL
NORCLOZAPINE
Therapeutic range: Not well established
CLOZAPINE + NORCLOZAPINE
Therapeutic range: Not well established
Clinical References: 1. Volpicelli SA, Centorrino F, Puopolo PR, et al: Determination of

clozapine, norclozapine, and clozapine-N-oxide in serum by liquid chromatography. ClinChem. 1993
Aug;39(8):1656-1659 2. Chung MC, Lin SK, Chang WH, Jann MW: Determination of clozapine and
desmethylclozapine in human plasma by high-performance liquid chromatography with ultraviolet
detection. J Chromatogr. 1993 Mar 5;613(1):168-173. doi: 10.1016/0378-4347(93)80212-m 3. Perry PJ,
Miller DD, Arndt SV, Cadoret RJ: Clozapine and norclozapine plasma concentrations and clinical
response of treatment-refractory schizophrenia patients. Am J Psychiatry. 1991 Feb;148(2):231-235.
doi: 10.1176/ajp.148.2.231 4. Physicians' Desk Reference (PDR). 61st ed. Thomson PDR; 2007 5.
Fitton A, Heel RC: Clozapine. A review of its pharmacological properties, and therapeutic use in
schizophrenia. Drugs. 1990 Nov;40(5);722-747. doi: 10.2165/00003495-199040050-00007 6. Clozaril.
Package insert: Novartis Pharmaceuticals; 05/2005 7. Mitchell PB: Therapeutic drug monitoring of
psychotropic medications. Br J Clin Pharmacol. 2001;52(Suppl 1):45S-54S. doi:
10.1046/j.1365-2125.2001.0520s1045.x 8. Hiemke C, Bergemann N, Clement HW, et al: Consensus
Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.
Pharmacopsychiatry. 2018 Jan;51(1-02):9-62. doi: 10.1055/s-0043-116492
CLUS Clusterin Immunostain, Technical Component Only

70404 Clinical Information: In lymph nodes, tonsils, and spleen, clusterin stains the follicular dendritic
cell meshworks. B cells, T cells, and histiocytes are negative. Clusterin is often positive in the tumor
cells of systemic anaplastic large-cell lymphoma and is usually negative in Reed Sternberg cells in
classical Hodgkin lymphoma. It is a sensitive marker for follicular dendritic cell sarcomas.
Useful For: A marker of follicular dendritic cells

Clinical References: 1. Zhang J, Miao C, Xu A: Prognostic role of secretory clusterin in multiple

human malignant neoplasms: A meta-analysis of 26 immunohistochemistry studies. PLoS One. 2016
Aug 17;11(8):e0161150. doi: 10.1371/journal.pone.0161150 2. Tang L, Zhou J, Jiang ZM, Zhang HZ,
Liu L, Chen J: Value of clusterin expression in pathologic diagnosis and histogenesis of giant cell tumor
of tendon sheath. Zhonghua Bing Li Xue Za Zhi. 2012 Mar;41(3):161-167. doi:
10.3760/cma.j.issn.0529-5807.2012.03.004 3. Fu Y, Lai Y, Wang Q, et al: Overexpression of clusterin
promotes angiogenesis via the vascular endothelial growth factor in primary ovarian cancer. Mol Med
Rep. 2013 Jun;7(6):1726-1732. doi: 10.3892/mmr.2013.1436
CMET cMET Immunostain, Technical Component Only

70405 Clinical Information: c-Met, a cell surface receptor tyrosine kinase, regulates cellular proliferation,
migration, and differentiation during development. Increased expression of c-Met has been shown to
correlate with poor prognosis in nonsmall cell carcinomas of the lung.
Useful For: Identification of normal and neoplastic c-Met expressing cells

or second opinion of the case The positive and negative controls are verified as showing appropriate
Clinical References: 1. Wang M, Liang L, Lei X, et al: Evaluation of cMET aberration by

immunohistochemistry and fluorescence in situ hybridization (FISH) in triple negative breast cancers.
Ann Diagn Pathol. 2018 Aug;35:69-76. doi: 10.1016/j.anndiagpath.2018.04.004. 2. Rossi G, Ragazzi M,
Tamagnini I, et al: Does immunohistochemistry represent a robust alternative technique in determining
drugable predictive gene alterations in non-small cell lung cancer? Curr Drug Targets. 2017;18(1):13-26.
doi: 10.2174/1389450116666150330114441 3. Pyo JS, Kang G, Cho WJ, Choi SB: Clinicopathological
significance and concordance analysis of c-MET immunohistochemistry in non-small cell lung cancers: A
meta-analysis. Pathol Res Pract. 2016 Aug;212(8):710-6. doi: 10.1016/j.prp.2016.05.006.
FCMVQ CMV by PCR

Not detected = Negative, no virus detected
Detected = Positive, virus detected
<1000 copies/mL = Positive. Virus detected below 1000 copies/mL
1000 copies/mL to 1,000,000 copies/mL = Positive
>1,000,000 copies/mL = Positive. Virus detected above maximum quantitative range.
This test employs real-time PCR amplification of a Cytomegalovirus-specific conserved genetic target.
A positive result should be coupled with clinical indicators for diagnosis. A Ã¢â‚¬Å“Not detected" result
for this assay does not exclude Cytomegalovirus involvement in a disease process.
FDMZ CNBP DNA Test (DM2)

57859 Clinical Information: Detects CCTG repeat expansions in the Zinc Finger Protein 9 (ZNF9) gene.
Typical Presentation: Individuals with a range of symptoms from cataracts to significant muscle wasting,
cardiac complications, ptosis and myotonia.
Reference Values:
CDS1 CNS Demyelinating Disease Evaluation, Serum

65565 Clinical Information: Neuromyelitis optica (NMO), sometimes called Devic disease or opticospinal
multiple sclerosis (MS) is a severe, relapsing, autoimmune, inflammatory and demyelinating central
nervous system disease (IDD) that predominantly affects optic nerves and spinal cord.(1) The disorder is
now recognized as a spectrum of autoimmunity (termed NMO spectrum disorders: NMOSD).(1-3) Brain
lesions are observed in more than 60% of patients with NMOSD and approximately 10% will be
MS-like.(4) Children tend to have greater brain involvement than adults, and brain lesions are more
symptomatic than is typical for adult patients.(3) The clinical course is characterized by relapses of optic
neuritis or transverse myelitis, or both. Some patients may present with acute disseminated
encephalomyelitis (ADEM). Many patients with NMOSD are misdiagnosed as having MS. More effective
treatments combined with earlier and more accurate diagnosis has led to improved outcomes. Â
Approximately 80% of patients with NMO are seropositive for aquaporin-4 (AQP4)-IgG.(5-7) In the
remaining 20% of patients, myelin oligodendrocyte glycoprotein (MOG)-IgG is detected in up to a
third.(8) The pathogenic target for the remaining patients remains unknown. Detection of MOG-IgG is
diagnostic of central nervous system (CNS) inflammatory demyelination, where the clinical phenotype
(NMOSD, optic neuritis, transverse myelitis, ADEM) may be similar, but the immunopathology
(astrocytopathy vs oligodendrogyopathy) and clinical outcome (worse vs better) is different.(9) Detection
of MOG-IgG also predicts relapse.(10) More importantly, however, is that MOG-IgG seropositive IDDs
are distinct from MS and treated differently.(8, 9) Treatments for IDDs seropositive for MOG-IgG include
corticosteroids and plasmapheresis for acute attacks and mycophenolate mofetil, azathioprine, and
rituximab for relapse prevention. Disease modifying agents, treatments promoted for MS, have been
reported to exacerbate MOG-IgG1 seropositive IDDS. Therefore, early diagnosis and initiation of
appropriate immunosuppressant treatment is important to optimize the clinical outcome by preventing
further attacks. In 2015, Waters and colleagues (11) from Oxford University established a novel cell based
assay for the measurement of IgG1 MOG antibodies based on previous findings that MOG antibodies are
almost exclusively of the IgG1 subclass. They showed that their MOG-IgG1 flow cytometry assay
eliminated false-positives without losing true-positives with low titers. The detection of MOG-IgG1
allowed non MS demyelinating diseases (ADEM, AQp4-IgG negative neuromyelitis optica spectrum
disorder: including ON,TM) to be distinguished from MS.(12) Â Using a similar assay to our MOG-IgG1
flow cytometry assay, Wingerchuk et al demonstrated high specificity of their MOG-IgG1 assay in which
49 patients with MS, 13 healthy control sera, and 37 AQP4-seropositive serum samples were all negative
at a dilution of 1:20. Of 58 patients fulfilling 2006 Wingerchuk criteria for NMO, 21 (36%) tested
negative for AQP4-IgG MOG-IgG1 was detected by cell based assay in 8 (38%) of these cases. (13) Â
Testing of 1,109 consecutive sera sent for AQP4-IgG testing,(11) revealed 40 AQP4-IgG and 65
MOG-IgG1 positive cases. None were positive for both. The clinical diagnoses obtained in 33 MOG-IgG1
positive patients included 4 NMO, 1 ADEM and 11 optic neuritis (n = 11). All 7 patients with probable
MS were MOG-IgG1 negative. This study provides Class II evidence that the presence of serum
MOG-IgG1 distinguishes non-MS central nervous system (CNS) demyelinating disorders from MS
(sensitivity 24%, 95% confidence interval [CI] 9%-45%; specificity 100%, 95% CI 88%-100%). Â The
assay validated here, was developed using the MOG construct provided by Dr Waters(11) and the
validation was based on a blinded comparison with the Oxford assay. Comparison was also made with the
Euroimmun fixed cell-based kit assay.(14) Â A recent longitudinal analysis with 2 year follow-up
suggested that persistence of MOG-IgG is associated with relapses thus warranting relapse
preventing.(10) Detection of MOG-IgG1 allows distinction from MS and is generally indicative of a
relapsing disease, mandating initiation of immunosuppression, even after the first attack in some, thereby
reducing attack frequency and disability in the future.
Useful For: Diagnosis of inflammatory demyelinating diseases (IDDs) with similar phenotype to
neuromyelitis optica spectrum disorder (NMOSD), including optic neuritis (single or bilateral) and
transverse myelitis Diagnosis of autoimmune myelin oligodendrocyte glycoprotein (MOG)-opathy
Diagnosis of neuromyelitis optica (NMO) Distinguishing NMOSD, acute disseminated
encephalomyelitis (ADEM), optic neuritis, and transverse myelitis from multiple sclerosis early in the
course of disease Diagnosis of ADEM Prediction of a relapsing disease course
Interpretation: A positive value for aquaporin-4 (AQP4)-IgG is consistent with an autoimmune

astrocytopathy/neuromyelitis optica spectrum disorder (NMOSD) and justifies initiation of appropriate
immunosuppressive therapy at the earliest possible time. This allows early initiation and maintenance of
optimal therapy. Recommend follow-up in 3 to 6 months if NMOSD is suspected. A positive value for
myelin oligodendrocyte glycoprotein (MOG)-IgG is consistent with an neuromyelitis optica
(NMO)-like phenotype, and in the setting of acute disseminated encephalomyelitis (ADEM), optic
neuritis (ON) and transverse myelitis (TM) indicates an autoimmune oligodendrogliopathy with
potential for relapsing course. Identification of MOG-IgG allows distinction from multiple sclerosis
(MS) and may justify initiation of appropriate immunosuppressive therapy (not MS disease-modifying
agents) at the earliest possible time. This allows early initiation and maintenance of optimal therapy.
Recommend follow-up in 3 to 6 months as persistence of MOG-IgG seropositivity predicts a relapsing
course. Detection of both antibodies is rare and unusual. AQP4-IgG and MOG-IgG are not found in MS
or healthy subjects.
Reference Values:
MOG FACS, S
Negative
NMO/AQP4 FACS, S
Negative
Clinical References: 1. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al: The spectrum of
neuromyelitis optica. Lancet Neurol 2007;6(9):805-815 2. Apiwattanakul M, Popescu BF, Matiello M, et
al: Intractable vomiting as the initial presentation of neuromyelitis optica. Ann Neurol
2010;68(5):757-761 3. McKeon A, Lennon VA, Lotze T, et al. CNS aquaporin-4 autoimmunity in
children. Neurology 2008;71(2):93-100 4. Pittock SJ, Weinshenker BG, Lucchinetti CF, et al:
Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol
2006;63(7):964-968 5. Fryer JP, Lennon VA, Pittock SJ, et al: AQP4 autoantibody assay performance in
clinical laboratory service. Neurol Neuroimmunol Neuroinflamm 2014;1(1):e11 6. Waters PJ, McKeon A,
Leite MI, et al: Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays.
Neurology 2012;78(9):665-671; discussion 669 7. Lennon VA, Wingerchuk DM, Kryzer TJ, et al: A
serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet
2004;364(9451):2106-2112 8. Peschl P, Bradl M, Hoftberger R, et al: Myelin Oligodendrocyte
Glycoprotein: Deciphering a Target in Inflammatory Demyelinating Diseases. Front Immunol 2017;8:529
9. Pittock SJ, Lucchinetti CF. Neuromyelitis optica and the evolving spectrum of autoimmune
aquaporin-4 channelopathies: a decade later. Ann N Y Acad Sci 2015 10. Hyun JW, Woodhall MR, Kim
SH, et al: Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory
diseases. J Neurol Neurosurg Psychiatry 2017 11. Waters P, Woodhall M, O'Connor KC, et al: MOG
cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol
Neuroinflamm 2015;2(3):e89 12. Reindl M, Jarius S, Rostasy K, Berger T: Myelin oligodendrocyte
glycoprotein antibodies: How clinically useful are they? Curr Opin Neurol 2017;30(3):295-301 13.
Wingerchuk DM, Banwell B, Bennett JL, et al: International consensus diagnostic criteria for
neuromyelitis optica spectrum disorders. Neurology 2015;85(2):177-189 14. Jarius S, Ruprecht K, Kleiter
I, et al: MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency,
syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and
origin. J Neuroinflammation 2016;13(1):279
F_2 Coagulation Factor II Activity Assay, Plasma

9121 Clinical Information: Factor II (prothrombin) is a vitamin K-dependent serine protease synthesized
in liver. It participates in the final common pathway of coagulation, as the substrate for the
prothrombinase enzyme complex. Prothrombin is the precursor of thrombin (IIa), which converts
fibrinogen to fibrin. Plasma biological half-life is about 3 days. Deficiency of factor II may cause
prolonged prothrombin time and activated partial thromboplastin time. Deficiency may result in a
bleeding diathesis.
Useful For: Diagnosing a congenital deficiency (rare) of coagulation factor II Evaluating acquired
deficiencies associated with liver disease or vitamin K deficiency, oral anticoagulant therapy, and
antibody-induced deficiencies (eg, in association with lupus-like anticoagulant) Determining warfarin
treatment stabilization in patients with nonspecific inhibitors (ie, lupus anticoagulant) Determining degree
of anticoagulation with warfarin to correlate with level of protein S Investigation of prolonged
prothrombin time or activated partial thromboplastin time
Interpretation: Liver disease, vitamin K deficiency, or warfarin anticoagulation can cause decreased
factor II activity. Patients that are homozygous generally have levels of less than 25% activity. Patient that
are heterozygous generally have levels of less than 50% activity. Normal newborn infants may have levels
of 25% to 50%.
Reference Values:
Adults: 75-145%
Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =25%)
which may remain below adult levels for > or =180 days postnatal.*
Processing
Clinical References: 1. Lancellotti S, De Cristofaro R: Congenital prothrombin deficiency. Semin
Thromb Hemost. 2009 Jun;35(4):367-381. doi: 10.1055/s-0029-1225759 2. Peyvandi F, Bolton-Maggs
PH, Batorova A, De Moerloose P: Rare bleeding disorders. Haemophilia. 2012 Jul;18 Suppl 4:148-153.
doi: 10.1111/j.1365-2516.2012.02841.x 3. Girolami A, Scandellari R, Scapin M, Vettore S: Congenital
bleeding disorders of the vitamin K-dependent clotting factors. Vitam Horm. 2008;78:281-374. doi:
10.1016/S0083-6729(07)00014-3 4. Brenner B, Kuperman AA, Watzka M, Oldenburg J: Vitamin
K-dependent coagulation factors deficiency. Semin Thromb Hemost. 2009 Jun;35(4):439-446. doi:
10.1055/s-0029-1225766
F_9 Coagulation Factor IX Activity Assay, Plasma

9065 Clinical Information: Factor IX is a vitamin K-dependent serine protease synthesized in the liver
and participates in the intrinsic coagulation pathway. Its biological half-life is 18 to 24 hours.
Congenital deficiency inherited as an X-linked recessive bleeding disorder (hemophilia B). Severe
deficiency (<1%) characterized by hemarthroses, deep tissue bleeding, excessive bleeding with trauma
and ecchymoses. Acquired deficiency associated with liver disease, vitamin K deficiency, warfarin
therapy and inhibitors (rare).
Useful For: Diagnosing deficiencies, particularly hemophilia B (Christmas disease) Assessing the
impact of liver disease on hemostasis Investigation of a prolonged activated partial thromboplastin time
Interpretation: Acquired deficiency is more common than congenital. Mild hemophilia B: 5% to

50% activity Moderate hemophilia B: 1% to 5% activity Severe hemophilia B: <1% activity
Reference Values:
< or =6 months: Normal, full-term newborn infants or healthy premature infants may have decreased
levels (> or =20%) which may not reach adult levels for > or =180 days postnatal.* (Literature derived)
>6 months: 65-140%
Processing.
Clinical References: 1. Barrowcliffe TW, Raut S, Sands D, Hubbard AR: Coagulation and
chromogenic assays of factor VIII activity: general aspects, standardization, and recommendations.
Semin Thromb Hemost. 2002 Jun;28(3):247-256 2. Franchini M, Lippi G, Favaloro EJ: Acquired
inhibitors of coagulation factors: part II. Semin Thromb Hemost. 2012 Jul;38(5):447-453 3. Carcao
MD: The diagnosis and management of congenital hemophilia. Semin Thromb Hemost. 2012
Oct;38(7):727-734
FACTV Coagulation Factor V Activity Assay, Plasma

9054 Clinical Information: Factor V is a vitamin K-independent protein synthesized in the liver and in
other tissues (endothelium, megakaryocytes/platelets). In its thrombin-activated form (factor Va), it
serves as an essential cofactor in the prothrombinase enzyme complex, which converts prothrombin to
thrombin (the prothrombinase complex consists of the enzyme, activated factor X, factor Va cofactor, a
phospholipid surface, and calcium). Deficiency of factor V may cause prolonged prothrombin time and
activated partial thromboplastin time and may result in a bleeding diathesis. Plasma biological half-life
varies from 12 to 36 hours. Platelets contain 20% to 25% of the factor V in blood. Factor V (also known
as labile factor) is highly susceptible to proteolytic inactivation, with the potential for spuriously
decreased assay results.
Useful For: Diagnosing congenital deficiencies (rare) of coagulation factor V Evaluating acquired
deficiencies associated with liver disease, factor V inhibitors, myeloproliferative disorders, and
intravascular coagulation and fibrinolysis Investigation of prolonged prothrombin time or activated
partial thromboplastin time
Interpretation: Acquired deficiencies are much more common than congenital. Patients that are
congenitally deficient homozygous generally have activity levels less than or equal to10% to 20%.
Patients that are congenitally deficient heterozygous generally have activity levels less than or equal to
50%. Congenital deficiency may occur in combined association with factor VIII deficiency.
Reference Values:
>1 month: 70%-165%
<1 month: Normal, full-term and premature newborn infants may have mildly decreased levels (> or
=30% to 35%) which reach adult levels within 21 days postnatal.
Processing
Clinical References: 1. Girolami A, Scandellari R, Scapin M, Vettore S: Congenital bleeding

disorders of the vitamin K-dependent clotting factors. Vitam Horm. 2008;78:281-374 2. Brenner B,
Kuperman AA, Watzka M, Oldenburg J: Vitamin K-dependent coagulation factors deficiency. Semin
Thromb Hemost. 2009 Jun;35(4):439-446 3. Asselta R, Peyvandi F: Factor V deficiency. Semin Thromb
Hemost. 2009 Jun;35(4):382-389 4. Lippi G, Favaloro EJ, Montagnana M, et al: Inherited and acquired
factor V deficiency. Blood Coagul Fibrinolysis. 2011 Apr;22(3):160-166 5. Spreafico M, Peyvandi F:
Combined FV and FVIII deficiency. Haemophilia. 2008 Nov;14(6):1201-1208 6. Kottke-Marchant K, ed:
Laboratory Hematology Practice. Wiley Blackwell Publishing; 2012
F_7 Coagulation Factor VII Activity Assay, Plasma

9055 Clinical Information: Factor VII is a vitamin K-dependent serine protease synthesized in the liver. It
is a component of the extrinsic coagulation scheme, measured by the prothrombin time. Plasma biological
half-life is about 3 to 6 hours. Deficiency may result in a bleeding diathesis.
Useful For: Diagnosing congenital deficiency of coagulation factor VII Evaluating acquired
deficiencies associated with liver disease, oral anticoagulant therapy, and vitamin K deficiency
Determining degree of anticoagulation with warfarin to correlate with level of protein C Investigation of a
prolonged prothrombin time
Interpretation: Liver disease, vitamin K deficiency, or warfarin anticoagulation can cause decreased
factor VII activity. Patients that are homozygous have levels usually less than 20% activity. Patient that
are heterozygous generally have levels of 50% activity or less. Newborn infants usually have levels 25%
or more.
Reference Values:
Adults: 65-180%
Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =20%)
which increase within the first postnatal week but may not reach adult levels for > or =180 days
postnatal.*
Processing

disorders of the vitamin K-dependent clotting factors. Vitam Horm. 2008;78:281-374. doi:
10.1016/S0083-6729(07)00014-3 2. Brenner B, Kuperman AA, Watzka M, Oldenburg J: Vitamin
K-dependent coagulation factors deficiency. Semin Thromb Hemost. 2009 Jun;35(4):439-446. doi:
10.1055/s-0029-1225766 3. Mariani G, Bernardi F: Factor VII deficiency. Semin Thromb Hemost. 2009
Jun;35(4):400-406. doi: 10.1055/s-0029-1225762 4. Franchini M, Marano G, Pupells S, et al: Rare
congenital bleeding disorders. Ann Transl Med. 2018 Sep;6(17):331. doi: 10.21037/atm.2018.08.34
F8A Coagulation Factor VIII Activity Assay, Plasma

9070 Clinical Information: Factor VIII is synthesized in the liver and, perhaps, in other tissues. It is a
coagulation cofactor that circulates bound to von Willebrand factor and is part of the intrinsic coagulation
pathway. The biological half-life is 9 to 18 hours (average is 12 hours). Congenital factor VIII deficiency
is the cause of hemophilia A, which has an incidence of 1 in 10,000 and is inherited in a recessive
sex-linked manner on the X chromosome. Severe deficiency (<1%) characteristically demonstrates as
hemarthrosis, deep-tissue bleeding, excessive bleeding with trauma, and ecchymoses. Factor VIII may be
decreased in von Willebrand disease. Acquired deficiency states also occur. Antibodies specific for factor
VIII are the most commonly occurring specific inhibitors of coagulation factors and can produce serious
bleeding disorders (acquired hemophilia). Spuriously decreased results may occur as factor VIII is highly
susceptible to proteolytic inactivation.
Useful For: Diagnosing hemophilia A Diagnosing von Willebrand disease when measured with the
von Willebrand factor (VWF) antigen and VWF activity Diagnosing acquired deficiency states
Investigation of prolonged activated partial thromboplastin time Monitoring infusions of factor VIII
replacement during interventional procedures and prophylactic infusions This test is not useful for
inferring carrier status in suspected female carriers of hemophilia A, unless it is 50% of normal (<28%
activity in adults).
Interpretation: Mild hemophilia A: 5% to 50% activity Moderate hemophilia A: 1% to 5% activity

Severe hemophilia A: <1% activity Congenital deficiency may also occur in combined association with
factor V deficiency. Liver disease usually causes an increase of factor VIII activity. Acquired
deficiencies of factor VIII have been associated with myeloproliferative or lymphoproliferative
disorders (acquired von Willebrand disease: VWD), inhibitors of factor VIII (autoantibodies,
postpartum conditions, etc), and intravascular coagulation and fibrinolysis. Levels may be decreased
with von Willebrand factor in VWD.
Reference Values:
Adults: 55-200%
Normal, full-term newborn infants or healthy premature infants typically have levels greater than or
equal to 40%.*
*See Pediatric Hemostasis References in Coagulation Guidelines for Specimen Handling and
ProcessingÂ in Special Instructions.
Clinical References: 1. Spreafico M, Peyvandi F: Combined FV and FVIII deficiency.

Haemophilia. 2008 Nov;14(6):1201-1208 2. Barrowcliffe TW, Raut S, Sands D, Hubbard AR:
Coagulation and chromogenic assays of factor VIII activity: general aspects, standardization, and
recommendations. Semin Thromb Hemost. 2002 Jun;28(3):247-256 3. Franchini M, Lippi G, Favaloro
EJ: Acquired inhibitors of coagulation factors: part II. Semin Thromb Hemost. 2012 Jul;38(5):447-453
4. Carcao MD: The diagnosis and management of congenital hemophilia. Semin Thromb Hemost. 2012
Oct;38(7):727-734
F8IS Coagulation Factor VIII Inhibitor Screen, Plasma

7289 Clinical Information: Specific factor inhibitors are antibodies that are found most often in response
to the use of factor VIII concentrate by patients congenitally deficient in factor VIII (hemophilia A).
Factor VIII inhibitors can also develop in non-hemophiliac patients (not previously factor VIII
deficient), most commonly in the following: the elderly, postpartum patients, and patients with
autoimmune disease. Testing will include coagulation factor VIII activity assay with dilutions to
evaluate assay inhibition, and if the factor VIII assay activity is decreased, an inhibitor screen to look
for specific factor VIII inhibition. If specific inhibition is apparent, it will be titered.
Useful For: Detecting the presence of a specific factor inhibitor directed against coagulation factor
VIII
Interpretation: An interpretive report will be provided when testing is completed.

Reference Values:
8INHE / Factor VIII Inhibitor Evaluation, Plasma
AVWPR / von Willebrand Disease Profile, Plasma
Negative
Clinical References: 1. Bowie EJW, Thompson JH Jr, Didisheim P, Owen CA Jr: Mayo Clinic
Laboratory Manual of Hemostasis. WB Saunders Company, 1971 pp 111-115 2. Kasper CK: Treatment of
factor VIII inhibitors. Prog Hemost Thromb 1989;9:57-86 3. Peerschke EI, Castellone DD,
Ledford-Kraemer M, et al: Laboratory assessment of FVIII inhibitor titer. Am J Clin Pathol
2009;131(4):552-558 4. Pruthi RK, Nichols WL: Autoimmune factor VIII inhibitors. Curr Opin Hematol
1999;6(5):314-322 5. Laboratory Hematology Practice. Edited by K Kottke-Marchant. Wiley Blackwell
Publishing, 2012
F_10 Coagulation Factor X Activity Assay, Plasma

9066 Clinical Information: Factor X is a vitamin K-dependent serine protease that is synthesized in the
liver. Its biological half-life is 24 to 48 hours. Factor X participates in both intrinsic and extrinsic
pathways of coagulation (final common pathway) by serving as the enzyme (factor Xa) in the
prothrombinase complex. Congenital factor X deficiency is rare. Acquired deficiency associated with
liver disease, warfarin therapy, vitamin K deficiency, systemic amyloidosis and inhibitors (rare).
Deficiency may cause prolonged prothrombin time and activated partial thromboplastin time.
Useful For: Diagnosing deficiency of coagulation factor X, congenital or acquired Evaluating

hemostatic function in liver disease Investigation of prolonged prothrombin time or activated partial
thromboplastin time
Interpretation: Acquired deficiency is more common than congenital deficiency. Homozygotes:

<25% Heterozygotes: 25% to 50%
Reference Values:
Adults: 70-150%
Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or
=15-20%) which may not reach adult levels for > or =180 days postnatal.*

disorders of the vitamin K-dependent clotting factors. Vitam Horm 2008;78:281-374 2. Brenner B,
Kuperman AA, Watzka M, Oldenburg J: Vitamin K-dependent coagulation factors deficiency. Semin
Thromb Hemost 2009 Jun;35(4):439-446 3. Menegatti M, Peyvandi F: Factor X deficiency. Semin
Thromb Hemost 2009 Jun;35(4):407-415 4. Girolami A, Ruzzon E, Tezza F, et al: Congenital FX
deficiency combined with other clotting defects or with other abnormalities: a critical evaluation of the
literature. Haemophilia 2008;14(2):323-328 5. Girolami A, Scarparo P, Scandellari R, Allemand E:
Congenital factor X deficiencies with a defect only or predominantly in the extrinsic or in the intrinsic
system: a critical evaluation. Am J Hematol 2008;83(8):668-671
FXCH Coagulation Factor X Chromogenic Activity Assay, Plasma

89042 Clinical Information: The antithrombotic effect of oral vitamin K antagonists (eg, warfarin) is
mediated by reduction in the plasma activity of vitamin K-dependent procoagulant factors II
(prothrombin) and X. The intensity of oral anticoagulation therapy with vitamin K antagonists must be
monitored and adjusted to a narrow therapeutic range; undermedicating increases the risk of thrombosis,
while overmedicating increases the risk of bleeding. Such therapy typically is monitored with the
prothrombin time/international normalized ratio (INR) system. Lupus anticoagulants (LAC) are
autoantibodies that interfere with phospholipid-dependent clotting tests and most commonly cause
prolongation of the activated partial thromboplastin time (APTT). LAC can be associated with a
prothrombotic disorder termed the antiphospholipid syndrome. LAC occasionally may cause prolongation
of the baseline prothrombin time, rendering the INR system inaccurate for monitoring the intensity of oral
anticoagulant therapy. LAC-induced prolongation of the prothrombin time is most commonly seen with
recombinant human tissue factor thromboplastins (ie, prothrombin time reagents) with a low international
sensitivity index (ISI) such as Innovin or RecombiPlasTin 2G (ISI = 1.0). The chromogenic factor X
activity is an alternative assay for monitoring oral anticoagulant therapy. This assay is unaffected by LAC
because the assay end point is not a phospholipid-dependent clotting time. Argatroban is a parenteral
direct thrombin inhibitor that is approved for treatment of heparin-induced thrombocytopenia (HIT), an
antibody-mediated prothrombotic disorder. Argatroban therapy prolongs the prothrombin time, which also
renders the INR inaccurate for monitoring the warfarin effect while transitioning from Argatroban to oral
anticoagulant therapy. The chromogenic coagulation factor X activity assay may be used as an alternative
to the INR for monitoring and adjusting the warfarin dose during this transition.
Useful For: Monitoring warfarin anticoagulant therapy, especially in patients whose plasma contains
lupus anticoagulants that interfere with baseline prothrombin time/international normalized ratio and in
patients receiving the drug Argatroban who are being transitioned to warfarin This assay should not be
used for monitoring heparin, or oral direct factor Xa inhibitors such as rivaroxaban (Xarelto), apixaban
(Eliquis), or edoxaban (Savaysa).
Interpretation: A chromogenic factor X activity of approximately 20% to 40% corresponds to the

usual warfarin international normalized ratio range (ie, 2.0-3.0).
Reference Values:
> or =18 years of age: 60%-140%
Chromogenic Factor X activity generally correlates with the one-stage factor X activity. In full term or
premature neonates, infants, and children, the one-stage factor X activity* is lower than adult reference
range and progressively rises to the adult reference range by adolescence. However, no similar data for
the chromogenic factor X activity have been published.
Clinical References: 1. Austin JH, Stearns CR, Winkler AM, et al: Use of the chromogenic factor
X assay in patients transitioning from Argatroban to warfarin therapy. Pharmacotherapy
2012;32(6):493-501 2. McGlasson DL, Romick BG, Rubal BJ: Comparison of a chromogenic factor x
assay with international normalized ratio for monitoring oral anticoagulation therapy. Blood Coagul
Fibrinolysis 2008;19:513-517 3. Moll S, Ortel TL: Monitoring warfarin therapy in patients with lupus
anticoagulants. Ann Intern Med 1997;127:177-185 4. Robert A, Le Querrec A, Delahousse B, et al:
Control of oral anticoagulation in patients with antiphospholipid syndrome--influence of the lupus
anticoagulant on International Normalized Ratio. Thromb Haemost 1998;80:99-103
F_11 Coagulation Factor XI Activity Assay, Plasma

9067 Clinical Information: Factor XI is synthesized in the liver. Its biological half-life is 60 to 80 hours.
Factor XI is a component of intrinsic coagulation pathway which, when activated, activates factor IX to
IXa. Factor XI deficiency may cause prolonged partial thromboplastin time. Deficiency associated with
mild bleeding diathesis, but there is poor correlation between activity level and clinical bleeding. A
relatively high incidence of congenital deficiency occurs among Ashkenazi Jewish descent (hemophilia
C).
Useful For: Diagnosing deficiency of coagulation factor XI Investigating prolonged activated partial
thromboplastin time
Interpretation: Acquired deficiency is associated with liver disease and rarely inhibitors. Patients
that are homozygous: <20% activity Patients that are heterozygous: 20% to 60% activity
Reference Values:
Adults: 55-150%
Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or
=10%) which may not reach adult levels for > or =180 days postnatal.*
Processing.
Clinical References: 1. He R, Chen D, He S: Factor XI: hemostasis, thrombosis, and antithrombosis.
Thromb Res. 2012 May;129(5):541-550 2. Martin-Salces M, Jimenez-Yuste V, Alvarez MT, Quintana M,
Hernandez-Navarro F: Review: Factor XI deficiency: review and management in pregnant women. Clin
Appl Thromb Hemost. 2010;16(2):209-213 3. Seligsohn U: Factor XI in haemostasis and thrombosis:
past, present and future. Thromb Haemost. 2007 Jul;98(1):84-89 4. Santoro R, Prejano S, Iannaccaro P:
Factor XI deficiency: a description of 34 cases and literature review. Blood Coagul Fibrinolysis. 2011
Jul;22(5):431-435
F_12 Coagulation Factor XII Activity Assay, Plasma

9069 Clinical Information: Factor XII is synthesized in the liver. Its biological half-life is 40 to 50 hours.
Factor XII is a component of the contact activation system and is involved in both intrinsic pathway and
fibrinolytic system. Factor XII deficiency is often discovered when activated partial thromboplastin time
is found to be unexpectedly long. The deficiency causes no known bleeding disorder. An association
between severe factor XII deficiency and thrombosis risk has been proposed, but not proven.
Useful For: Diagnosing deficiency of coagulation factor XII Determining cause of prolonged activated
partial thromboplastin time
Interpretation: Acquired deficiency is associated with liver disease, nephritic syndrome, and chronic
granulocytic leukemia. Congenital homozygous deficiency: 20% activity Congenital heterozygous
deficiency: 20% to 50% activity
Reference Values:
Adults: 55-180%
Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =15%
to 20%) which may not reach adult levels for > or =180 days postnatal.*
Clinical References: Renne T, Schmaier AH, Nickel KF, et al: In vivo roles of factor XII. Blood.
2012 Nov 22;120(22):4296-4303
CMMPP Cobalamin, Methionine, and Methylmalonic Acid Pathways,

606103 Plasma
Clinical Information: Homocysteine, methylmalonic acid (MMA), methylcitric acid, methionine,
cysteine, and cystathionine can be used to evaluate patients for inborn errors of methionine, cobalamin,
and propionate metabolism. Homocysteine is an intermediary in the sulfur-amino acid metabolism
pathways, linking the methionine cycle to the folate cycle. Inborn errors of metabolism that lead to
homocysteinemia or homocystinuria include cystathionine beta-synthase deficiency (homocystinuria) and
various defects of methionine remethylation. Homocystinuria is an autosomal recessive disorder caused
by a deficiency of the enzyme cystathionine beta-synthase. The incidence of homocystinuria is
approximately 1 in 200,000 to 335,000 live births. Classical homocystinuria is characterized by a normal
presentation at birth followed by failure to thrive and developmental delay. Untreated homocystinuria can
lead to ophthalmological problems, developmental delay, seizures, thromboembolic episodes, and skeletal
abnormalities. The biochemical phenotype is characterized by increased plasma concentrations of
methionine and homocysteine along with decreased concentrations of cystine. Elevated levels of MMA
result from inherited defects of enzymes involved in MMA metabolism or inherited or acquired
deficiencies of vitamin B12. Enzymatic deficiencies of propionyl-CoA carboxylase and
methylmalonyl-CoA mutase are associated with propionic academia (PA) and methylmalonic acidemia
mut(0/-) type (MMAmut), respectively. The clinical phenotype includes vomiting, hypotonia, lethargy,
apnea, hypothermia, and coma. The biochemical phenotype for MMAmut includes elevations of
propionyl carnitine, methylmalonic acid, and methylcitric acid. Patients with PA will have elevations of
propionyl carnitine and methylcitric acid with normal MMA concentrations as the enzymatic defect is
upstream of methylmalonic-CoA mutase. Inherited conditions of cobalamin (Cbl) absorption and
transport are caused by variants in several genes encoding Cbl binding factors and transmembrane
transporters and receptors. In addition, inside the cell, Cbl undergoes several steps of modification until it
reaches a divergent point beyond which 2 separate paths lead to the formation of the 2 active components
of this cofactor: a) adenosylcobalamin (AdoCbl), a cofactor for methylmalonyl-CoA mutase; and b)
methylcobalamin (MeCbl), a cofactor for methionine synthase, remethylating homocysteine to
methionine. Defects of AdoCbl and MeCbl metabolism after the point where the synthetic pathways
separate lead to isolated deficiencies of methylmalonyl-CoA mutase (elevations of propionyl carnitine,
MMA, and methylcitric acid) or methionine synthase (elevated homocysteine with low/low normal
methionine) respectively. Defects prior to this point are associated with deficiencies of both enzymes and
lead to elevation of all markers (propionyl carnitine, MMA, methylcitric acid, and homocysteine).
Acquired cobalamin (vitamin B12) deficiency can be a result of pernicious anemia, vegan diet,
malabsorption, and decreased intrinsic factor excretion (secondary to gastrectomy) and can be
distinguished from most inherited defects (particularly intracellular deficiencies) with the identification of
decreased levels of vitamin B12. Elderly patients with cobalamin deficiency may present with
megaloblastic anemia, peripheral neuropathy, ataxia, loss of position and vibration senses, memory
impairment, depression, and dementia in the absence of anemia. Other conditions such as renal
insufficiency, hypovolemia, and bacterial overgrowth of the small intestine also contribute to the possible
causes of mild methylmalonic acidemia and aciduria. Additional testing with homocysteine and MMA
determinations may help distinguish between vitamin B12 and folate deficiency states.
Useful For: Screening and monitoring patients suspected of or confirmed with an inherited disorder
of methionine, cobalamin, or propionate metabolism using plasma specimens Evaluating individuals
with suspected deficiency of vitamin B12
Interpretation: An interpretive report will be provided. When abnormal results are detected, a
detailed interpretation is given, including an overview of the results and of their significance, a
correlation to available clinical information, elements of differential diagnosis, recommendations for
additional biochemical testing, and in vitro confirmatory studies (complementation studies, molecular
analysis), and a phone number to reach one of the laboratory directors in case the referring physician
has additional questions. Abnormal results are not sufficient to conclusively establish a diagnosis of a
particular disease. To verify a preliminary diagnosis based on the analysis, independent biochemical
(eg, complementation studies) or molecular genetic analyses are required.
Reference Values:
Age Total homocysteine Methylmalonic 2-Methylcitric Total Methionine Cystathionine

(nmol/mL) acid (nmol/mL) acid (nmol/mL) cysteine (nmol/mL) (nmol/mL)
(nmol/mL)
Female Male Female Male
0-11 3.1-8.3 3.2-9.7 0.08-0.32 0.02-0.35 142.8-258.8 14.7-43.1 14.5-42.3 0.07-0.38

months
12-23 3.2-8.3 3.3-9.6 0.08-0.31 0.02-0.35 143.7-258.7 14.7-43.1 14.5-42.2 0.07-0.38
months
24-35 3.2-8.2 3.3-9.6 0.08-0.31 0.02-0.35 144.8-258.6 14.7-43.0 14.5-42.1 0.07-0.38

months
3 years 3.2-8.2 3.3-9.6 0.08-0.31 0.02-0.35 146.0-258.5 14.7-43.0 14.5-42.0 0.07-0.38
4 years 3.3-8.2 3.4-9.5 0.08-0.30 0.02-0.35 148.2-258.4 14.7-42.8 14.5-41.8 0.07-0.38
5 years 3.4-8.1 3.5-9.4 0.08-0.30 0.02-0.35 150.6-258.3 14.8-42.7 14.5-41.6 0.07-0.38
6 years 3.5-8.1 3.6-9.4 0.08-0.29 0.02-0.35 153.2-258.3 14.8-42.5 14.5-41.4 0.07-0.38
7 years 3.5-8.1 3.7-9.4 0.08-0.29 0.02-0.35 155.8-258.4 14.8-42.2 14.5-41.1 0.07-0.38
8 years 3.6-8.2 3.8-9.3 0.08-0.28 0.02-0.35 158.5-258.7 14.9-42.0 14.6-40.9 0.07-0.37
9 years 3.7-8.2 3.9-9.4 0.09-0.28 0.02-0.35 161.0-259.1 14.9-41.7 14.6-40.7 0.07-0.37
10 years 3.8-8.3 4.1-9.4 0.09-0.28 0.02-0.35 163.5-259.7 15.0-41.4 14.7-40.6 0.07-0.37
11 years 3.9-8.4 4.3-9.4 0.09-0.28 0.02-0.35 165.9-260.5 15.1-41.0 14.8-40.4 0.07-0.37
12 years 3.9-8.6 4.4-9.5 0.09-0.27 0.02-0.35 168.4-261.4 15.1-40.7 14.9-40.3 0.07-0.37
13 years 4.0-8.7 4.6-9.6 0.09-0.27 0.02-0.35 170.9-262.4 15.2-40.3 15.1-40.1 0.07-0.36
14 years 4.1-8.8 4.8-9.7 0.09-0.27 0.02-0.35 173.6-263.6 15.3-39.9 15.3-40.0 0.07-0.36
15 years 4.2-8.9 5.0-9.8 0.09-0.27 0.02-0.35 176.4-264.7 15.4-39.5 15.5-39.9 0.07-0.36
16 years 4.2-9.1 5.2-9.9 0.09-0.27 0.02-0.35 179.3-265.9 15.5-39.1 15.8-39.7 0.07-0.35
17 years 4.3-9.2 5.4-10.0 0.09-0.27 0.02-0.35 182.2-267.1 15.6-38.7 16.1-39.6 0.07-0.35
18 years 4.3-9.3 5.6-10.1 0.08-0.27 0.02-0.35 184.9-268.3 15.7-38.2 16.4-39.4 0.07-0.35
19 years 4.4-9.5 5.7-10.3 0.08-0.26 0.02-0.35 187.4-269.4 15.7-37.8 16.7-39.3 0.07-0.34
20 years 4.4-9.6 5.9-10.5 0.08-0.26 0.02-0.35 189.5-270.5 15.8-37.3 17.0-39.1 0.07-0.34
21 years 4.4-9.8 6.0-10.6 0.08-0.26 0.02-0.35 191.2-271.7 15.9-36.8 17.3-38.9 0.07-0.33
22 years 4.4-9.9 6.1-10.8 0.08-0.27 0.02-0.35 192.5-272.8 15.9-36.3 17.6-38.7 0.07-0.33
23 years 4.4-10.1 6.2-11.0 0.08-0.27 0.02-0.35 193.5-274.1 15.9-35.8 17.9-38.5 0.07-0.33

24 years 4.4-10.3 6.2-11.1 0.08-0.27 0.02-0.35 194.2-275.4 15.9-35.3 18.1-38.3 0.07-0.32
25 years 4.4-10.4 6.3-11.3 0.08-0.28 0.02-0.35 194.8-277.0 15.9-34.8 18.2-38.1 0.07-0.32
26 years 4.4-10.6 6.3-11.4 0.08-0.28 0.02-0.35 195.3-278.6 15.9-34.3 18.4-37.9 0.07-0.32
27 years 4.3-10.8 6.4-11.6 0.08-0.28 0.02-0.35 196.0-280.5 16.0-33.8 18.5-37.7 0.07-0.31
28 years 4.3-11.0 6.4-11.7 0.08-0.29 0.02-0.35 196.7-282.4 16.0-33.4 18.7-37.5 0.07-0.31
29 years 4.3-11.2 6.4-11.8 0.08-0.29 0.02-0.35 197.7-284.3 16.0-33.0 18.8-37.3 0.07-0.31
30 years 4.3-11.4 6.4-11.9 0.08-0.30 0.02-0.35 198.8-286.3 16.1- 32.6 18.9-37.1 0.07-0.30
31 years 4.4-11.6 6.4-12.1 0.08-0.30 0.02-0.35 200.2-288.2 16.1-32.2 19.0-36.9 0.07-0.30
32 years 4.4-11.8 6.4-12.2 0.08-0.31 0.02-0.35 201.7-290.0 16.1-31.8 19.1-36.7 0.07-0.30
33 years 4.4-11.9 6.4-12.3 0.08-0.31 0.02-0.35 203.4-291.5 16.1-31.5 19.2-36.5 0.07-0.29
34 years 4.5-12.1 6.4-12.4 0.08-0.31 0.02-0.35 205.2-292.9 16.1-31.2 19.3-36.3 0.07-0.29
35 years 4.5-12.2 6.4-12.6 0.08-0.32 0.02-0.35 207.2-294.1 16.1-30.8 19.4-36.1 0.07-0.28
36 years 4.6-12.4 6.4-12.8 0.08-0.32 0.02-0.35 209.3-295.1 16.1-30.5 19.5-35.9 0.07-0.28
37 years 4.6-12.5 6.4-12.9 0.08-0.33 0.02-0.35 211.5-296.0 16.1-30.2 19.6-35.6 0.07-0.27
38 years 4.7-12.7 6.4-13.1 0.08-0.33 0.02-0.35 213.8-296.9 16.1-29.9 19.7-35.4 0.07-0.27
39 years 4.7-12.8 6.4-13.2 0.08-0.34 0.02-0.35 216.3-297.7 16.1-29.7 19.8-35.2 0.07-0.27
40 years 4.8-13.0 6.5-13.4 0.08-0.34 0.02-0.35 218.9-298.7 16.1-29.4 19.9-35.0 0.07-0.27
41 years 4.8-13.2 6.5-13.5 0.08-0.35 0.02-0.35 221.6-299.7 16.1-29.2 20.0-34.8 0.07-0.27
42 years 4.8-13.4 6.5-13.7 0.08-0.36 0.02-0.35 224.3-300.8 16.2-29.0 20.1-34.6 0.07-0.26
43 years 4.9-13.5 6.6-13.9 0.08-0.36 0.02-0.35 227.0-302.0 16.2-28.8 20.2-34.4 0.07-0.26
44 years 4.9-13.7 6.6-14.0 0.08-0.37 0.02-0.35 229.8-303.5 16.3-28.6 20.3-34.2 0.07-0.26
45 years 4.9-13.9 6.6-14.2 0.08-0.38 0.02-0.35 232.6-305.2 16.3-28.5 20.3-34.0 0.07-0.26
46 years 4.9-14.0 6.7-14.4 0.08-0.38 0.02-0.35 235.3-307.3 16.4-28.4 20.4-33.8 0.07-0.26
47 years 4.9-14.2 6.7-14.5 0.08-0.39 0.02-0.35 238.0-309.7 16.4-28.2 20.4-33.6 0.07-0.26
48 years 5.0-14.3 6.8-14.7 0.08-0.39 0.02-0.35 240.8-312.6 16.5-28.1 20.5-33.3 0.07-0.26
49 years 5.0-14.4 6.8-14.9 0.08-0.40 0.02-0.35 243.5-315.9 16.5-28.0 20.5-33.1 0.07-0.26
50 years 5.0-14.5 6.8-15.0 0.08-0.40 0.02-0.35 246.2-319.7 16.5-27.9 20.6-32.8 0.07-0.26
51 years 5.1-14.6 6.8-15.2 0.08-0.41 0.02-0.35 248.9-323.8 16.5-27.8 20.6-32.5 0.07-0.26
52 years 5.1-14.7 6.9-15.4 0.08-0.41 0.02-0.35 251.5-328.1 16.5-27.6 20.7-32.3 0.07-0.26
53 years 5.1-14.8 6.9-15.5 0.08-0.42 0.02-0.35 254.0-332.4 16.5-27.5 20.8-32.1 0.07-0.26
54 years 5.2-14.9 6.9-15.6 0.08-0.42 0.02-0.35 256.4-336.5 16.5-27.4 21.0-31.9 0.07-0.25
55 years 5.2-15.0 6.9-15.7 0.08-0.43 0.02-0.35 258.6-340.2 16.5-27.3 21.1-31.7 0.07-0.25
56 years 5.3-15.0 6.9-15.8 0.08-0.43 0.02-0.35 260.6-343.6 16.6-27.2 21.2-31.5 0.07-0.25
57 years 5.3-15.1 6.9-15.9 0.08-0.44 0.02-0.35 262.5-346.5 16.6-27.1 21.2-31.3 0.07-0.25
58 years 5.3-15.2 6.9-16.0 0.08-0.44 0.02-0.35 264.3-349.0 16.6-27.1 21.3-31.0 0.07-0.25
59 years 5.4-15.2 6.9-16.0 0.08-0.44 0.02-0.35 266.2-351.1 16.7-27.1 21.3-30.8 0.07-0.25
60 years 5.4-15.3 6.9-16.1 0.08-0.45 0.02-0.35 268.3-353.1 16.8-27.1 21.3-30.6 0.07-0.25
61 years 5.4-15.4 7.0-16.2 0.09-0.45 0.02-0.35 270.8-355.1 16.9-27.2 21.3-30.3 0.07-0.25

62 years 5.5-15.4 7.0-16.2 0.09-0.46 0.02-0.35 273.8-357.3 17.0-27.2 21.2-30.0 0.08-0.25
63 years 5.5-15.5 7.0-16.3 0.09-0.46 0.02-0.35 277.5-359.7 17.1-27.3 21.2-29.8 0.08-0.25
64 years 5.6-15.5 7.1-16.3 0.09-0.46 0.02-0.35 281.9-362.3 17.2-27.4 21.1-29.5 0.08-0.25
65 years 5.6-15.6 7.1-16.3 0.09-0.47 0.02-0.35 286.9-365.2 17.3-27.6 21.1-29.2 0.08-0.25
66 years 5.7-15.6 7.1-16.3 0.09-0.47 0.02-0.35 292.4-368.3 17.4-27.7 21.1-29.0 0.08-0.25
67 years 5.7-15.7 7.2-16.3 0.09-0.47 0.02-0.35 298.1-371.6 17.5-27.8 21.0-28.7 0.09-0.25
68 years 5.8-15.7 7.2-16.3 0.09-0.47 0.02-0.35 303.6-374.8 17.7-27.9 21.0-28.5 0.09-0.25
69 years 5.9-15.7 7.2-16.3 0.09-0.47 0.02-0.35 308.7-377.8 17.8-28.0 21.0-28.4 0.09-0.25
70 years 6.0-15.8 7.3-16.3 0.09-0.48 0.02-0.35 313.1-380.7 18.0-28.1 21.0-28.3 0.09-0.25
71 years 6.1-15.8 7.3-16.3 0.09-0.48 0.02-0.35 316.5-383.2 18.1-28.2 20.9-28.2 0.09-0.25
72 years 6.2-15.8 7.3-16.3 0.09-0.48 0.02-0.35 318.9-385.3 18.3-28.3 20.9-28.0 0.09-0.25
73 years 6.3-15.9 7.3-16.3 0.09-0.48 0.02-0.35 320.1-387.0 18.5-28.4 20.8-27.9 0.10-0.26
74 years 6.4-15.9 7.3-16.3 0.09-0.48 0.02-0.35 320.6-388.3 18.8-28.5 20.8-27.8 0.10-0.26
75 years 6.5-15.9 7.3-16.3 0.09-0.48 0.02-0.35 320.3-389.3 19.1-28.5 20.8-27.7 0.10-0.26
76 years 6.6-15.9 7.3-16.3 0.09-0.48 0.02-0.35 319.6-389.9 19.3-28.6 20.8-27.5 0.10-0.26
77 years 6.7-16.0 7.4-16.3 0.10-0.48 0.02-0.35 319.1-390.2 19.6-28.6 20.9-27.4 0.10-0.26
78 years 6.8-16.0 7.4-16.3 0.10-0.48 0.02-0.35 318.5-390.5 20.0-28.7 20.9-27.2 0.11-0.26
79 years 6.9-16.0 7.5-16.3 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26
80 years 7.0-16.0 7.5-16.3 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26
81 years 7.1-16.0 7.7-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26
82 years 7.2-16.0 7.8-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26
83 years 7.2-16.0 7.9-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26
84 years 7.3-16.0 8.0-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26
85 years 7.3-16.0 8.2-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26
>85 7.4-16.0 8.3-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
Clinical References: 1. Turgeon CT, Magera MJ, Cuthbert CD, et al: Determination of total
homocysteine, methylmalonic acid, and 2-methylcitric acid in dried blood spots by tandem mass
spectrometry. Clin Chem. 2010 Nov;56(11):1686-1695 2. Tortorelli S, Turgeon CT, Lim JS, et al:
Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and other
remethylation disorders with tandem mass spectrometry. J Pediatr. 2010;157(2):271-275 3. Solomon LR:
Disorders of cobalamin (vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and
treatment. Blood Rev. 2007 May;21(3):113-130 4. Baric I, Staufner C, Augoustides-Savvopoulou P,
Chien YH, Dobbelaere D, Grunert SC: Consensus recommendations for the diagnosis, treatment and
follow-up of inherited methylation disorders. J Inherit Metab Dis. 2017;40(1):5-20 5. Sloan JS, Carrillo
N, Adams D, Venditti CP: Disorders of intracellular cobalamin metabolism. In: Adam MP, Ardinger HH,
Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2008. Updated
September 6, 2018. Accessed May 15, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1328/
CMMPS Cobalamin, Methionine, and Methylmalonic Acid Pathways,

606111 Serum
Clinical Information: Homocysteine, methylmalonic acid (MMA), methylcitric acid, methionine,
cysteine, and cystathionine can be used to evaluate patients for inborn errors of methionine, cobalamin,
and propionate metabolism. Homocysteine is an intermediary in the sulfur-amino acid metabolism
pathways, linking the methionine cycle to the folate cycle. Â Inborn errors of metabolism that lead to
homocysteinemia or homocystinuria include cystathionine beta-synthase deficiency (homocystinuria) and
various defects of methionine remethylation. Â Homocystinuria is an autosomal recessive disorder
caused by a deficiency of the enzyme cystathionine beta-synthase. The incidence of homocystinuria is
approximately 1 in 200,000 to 335,000 live births. Classical homocystinuria is characterized by a normal
presentation at birth followed by failure to thrive and developmental delay. Untreated homocystinuria can
lead to ophthalmological problems, developmental delay, seizures, thromboembolic episodes, and skeletal
abnormalities. The biochemical phenotype is characterized by increased plasma concentrations of
methionine and homocysteine along with decreased concentrations of cystine. Â Elevated levels of MMA
result from inherited defects of enzymes involved in MMA metabolism or inherited or acquired
deficiencies of vitamin B12. Â Enzymatic deficiencies of propionyl-CoA carboxylase and
methylmalonyl-CoA mutase are associated with propionic acidemia (PA) and methylmalonic academia
mut(0/-) type (MMAmut), respectively. The clinical phenotype includes vomiting, hypotonia, lethargy,
apnea, hypothermia, and coma. The biochemical phenotype for MMAmut includes elevations of
propionyl carnitine, methylmalonic acid, and methylcitric acid. Patients with PA will have elevations of
propionyl carnitine and methylcitric acid with normal MMA concentrations as the enzymatic defect is
upstream of methylmalonic-CoA mutase. Â Inherited conditions of cobalamin (Cbl) absorption and
transport are caused by variants in several genes encoding Cbl binding factors and transmembrane
transporters and receptors. In addition, inside the cell, Cbl undergoes several steps of modification until it
reaches a divergent point beyond which 2 separate paths lead to the formation of the 2 active components
of this cofactor: a) adenosylcobalamin (AdoCbl),a cofactor for methylmalonyl-CoA mutase; and b)
methylcobalamin (MeCbl), a cofactor for methionine synthase, remethylating homocysteine to
methionine. Â Defects of AdoCbl and MeCbl metabolism after the point where the synthetic pathways
separate lead to isolated deficiencies of methylmalonyl-CoA mutase (elevations of propionyl carnitine,
MMA, and methylcitric acid) or methionine synthase (elevated homocysteine, with low/low normal
methionine) respectively. Defects prior to this point are associated with deficiencies of both enzymes and
lead to elevation of all markers (propionyl carnitine, MMA, methylcitric acid, and homocysteine). Â
Acquired cobalamin (vitamin B12) deficiency can be a result of pernicious anemia, vegan diet,
malabsorption, and decreased intrinsic factor excretion (secondary to gastrectomy) and can be
distinguished from most inherited defects (particularly intracellular deficiencies) with the identification of
decreased levels of vitamin B12. Elderly patients with cobalamin deficiency may present with
megaloblastic anemia, peripheral neuropathy, ataxia, loss of position and vibration senses, memory
impairment, depression, and dementia in the absence of anemia. Other conditions such as renal
insufficiency, hypovolemia, and bacterial overgrowth of the small intestine also contribute to the possible
causes of mild methylmalonic acidemia and aciduria. Additional testing with homocysteine and MMA
determinations may help distinguish between vitamin B12 and folate deficiency states.
Useful For: Screening and monitoring patients suspected of or confirmed with an inherited disorder
of methionine, cobalamin, or propionate metabolism Evaluating individuals with suspected deficiency
of vitamin B12
Interpretation: An interpretive report will be provided. When abnormal results are detected, a
detailed interpretation is given, including an overview of the results and of their significance, a
correlation to available clinical information, elements of differential diagnosis, recommendations for
additional biochemical testing, and in vitro confirmatory studies (complementation studies, molecular
analysis), and a phone number to reach one of the laboratory directors in case the referring physician
has additional questions. Abnormal results are not sufficient to conclusively establish a diagnosis of a
particular disease. To verify a preliminary diagnosis based on the analysis, independent biochemical
(eg, complementation studies) or molecular genetic analyses are required.
Reference Values:
Age Total Methylmalonic 2-Methylcitric Total Methionine Cystathionine

homocysteine acid acid cysteine (nmol/mL) (nmol/mL)
(nmol/mL) (nmol/mL) (nmol/mL) (nmol/mL)
Female Male Female Male
0-11 3.1-8.3 3.2-9.7 0.08-0.32 0.02-0.35 142.8-258.8 14.7-43.1 14.5-42.3 0.07-0.38

months
12-23 3.2-8.3 3.3-9.6 0.08-0.31 0.02-0.35 143.7-258.7 14.7-43.1 14.5-42.2 0.07-0.38

months
24-35 3.2-8.2 3.3-9.6 0.08-0.31 0.02-0.35 144.8-258.6 14.7-43.0 14.5-42.1 0.07-0.38

months
3 years 3.2-8.2 3.3-9.6 0.08-0.31 0.02-0.35 146.0-258.5 14.7-43.0 14.5-42.0 0.07-0.38
4 years 3.3-8.2 3.4-9.5 0.08-0.30 0.02-0.35 148.2-258.4 14.7-42.8 14.5-41.8 0.07-0.38
5 years 3.4-8.1 3.5-9.4 0.08-0.30 0.02-0.35 150.6-258.3 14.8-42.7 14.5-41.6 0.07-0.38
6 years 3.5-8.1 3.6-9.4 0.08-0.29 0.02-0.35 153.2-258.3 14.8-42.5 14.5-41.4 0.07-0.38
7 years 3.5-8.1 3.7-9.4 0.08-0.29 0.02-0.35 155.8-258.4 14.8-42.2 14.5-41.1 0.07-0.38
8 years 3.6-8.2 3.8-9.3 0.08-0.28 0.02-0.35 158.5-258.7 14.9-42.0 14.6-40.9 0.07-0.37
9 years 3.7-8.2 3.9-9.4 0.09-0.28 0.02-0.35 161.0-259.1 14.9-41.7 14.6-40.7 0.07-0.37

10 3.8-8.3 4.1-9.4 0.09-0.28 0.02-0.35 163.5-259.7 15.0-41.4 14.7-40.6 0.07-0.37
years
11 3.9-8.4 4.3-9.4 0.09-0.28 0.02-0.35 165.9-260.5 15.1-41.0 14.8-40.4 0.07-0.37

years
12 3.9-8.6 4.4-9.5 0.09-0.27 0.02-0.35 168.4-261.4 15.1-40.7 14.9-40.3 0.07-0.37

years
13 4.0-8.7 4.6-9.6 0.09-0.27 0.02-0.35 170.9-262.4 15.2-40.3 15.1-40.1 0.07-0.36

years
14 4.1-8.8 4.8-9.7 0.09-0.27 0.02-0.35 173.6-263.6 15.3-39.9 15.3-40.0 0.07-0.36

years
15 4.2-8.9 5.0-9.8 0.09-0.27 0.02-0.35 176.4-264.7 15.4-39.5 15.5-39.9 0.07-0.36

years
16 4.2-9.1 5.2-9.9 0.09-0.27 0.02-0.35 179.3-265.9 15.5-39.1 15.8-39.7 0.07-0.35

years
17 4.3-9.2 5.4-10.0 0.09-0.27 0.02-0.35 182.2-267.1 15.6-38.7 16.1-39.6 0.07-0.35

years
18 4.3-9.3 5.6-10.1 0.08-0.27 0.02-0.35 184.9-268.3 15.7-38.2 16.4-39.4 0.07-0.35
years
19 4.4-9.5 5.7-10.3 0.08-0.26 0.02-0.35 187.4-269.4 15.7-37.8 16.7-39.3 0.07-0.34

years
20 4.4-9.6 5.9-10.5 0.08-0.26 0.02-0.35 189.5-270.5 15.8-37.3 17.0-39.1 0.07-0.34

years
21 4.4-9.8 6.0-10.6 0.08-0.26 0.02-0.35 191.2-271.7 15.9-36.8 17.3-38.9 0.07-0.33

years
22 4.4-9.9 6.1-10.8 0.08-0.27 0.02-0.35 192.5-272.8 15.9-36.3 17.6-38.7 0.07-0.33

years
23 4.4-10.1 6.2-11.0 0.08-0.27 0.02-0.35 193.5-274.1 15.9-35.8 17.9-38.5 0.07-0.33

years
24 4.4-10.3 6.2-11.1 0.08-0.27 0.02-0.35 194.2-275.4 15.9-35.3 18.1-38.3 0.07-0.32

years
25 4.4-10.4 6.3-11.3 0.08-0.28 0.02-0.35 194.8-277.0 15.9-34.8 18.2-38.1 0.07-0.32

years
26 4.4-10.6 6.3-11.4 0.08-0.28 0.02-0.35 195.3-278.6 15.9-34.3 18.4-37.9 0.07-0.32
years
27 4.3-10.8 6.4-11.6 0.08-0.28 0.02-0.35 196.0-280.5 16.0-33.8 18.5-37.7 0.07-0.31

years
28 4.3-11.0 6.4-11.7 0.08-0.29 0.02-0.35 196.7-282.4 16.0-33.4 18.7-37.5 0.07-0.31

years
29 4.3-11.2 6.4-11.8 0.08-0.29 0.02-0.35 197.7-284.3 16.0-33.0 18.8-37.3 0.07-0.31

years
30 4.3-11.4 6.4-11.9 0.08-0.30 0.02-0.35 198.8-286.3 16.1- 32.618.9-37.1 0.07-0.30

years
31 4.4-11.6 6.4-12.1 0.08-0.30 0.02-0.35 200.2-288.2 16.1-32.2 19.0-36.9 0.07-0.30

years
32 4.4-11.8 6.4-12.2 0.08-0.31 0.02-0.35 201.7-290.0 16.1-31.8 19.1-36.7 0.07-0.30

years
33 4.4-11.9 6.4-12.3 0.08-0.31 0.02-0.35 203.4-291.5 16.1-31.5 19.2-36.5 0.07-0.29

years
34 4.5-12.1 6.4-12.4 0.08-0.31 0.02-0.35 205.2-292.9 16.1-31.2 19.3-36.3 0.07-0.29

years
35 4.5-12.2 6.4-12.6 0.08-0.32 0.02-0.35 207.2-294.1 16.1-30.8 19.4-36.1 0.07-0.28

years
36 4.6-12.4 6.4-12.8 0.08-0.32 0.02-0.35 209.3-295.1 16.1-30.5 19.5-35.9 0.07-0.28

years
37 4.6-12.5 6.4-12.9 0.08-0.33 0.02-0.35 211.5-296.0 16.1-30.2 19.6-35.6 0.07-0.27

years
38 4.7-12.7 6.4-13.1 0.08-0.33 0.02-0.35 213.8-296.9 16.1-29.9 19.7-35.4 0.07-0.27

years
39 4.7-12.8 6.4-13.2 0.08-0.34 0.02-0.35 216.3-297.7 16.1-29.7 19.8-35.2 0.07-0.27

years
40 4.8-13.0 6.5-13.4 0.08-0.34 0.02-0.35 218.9-298.7 16.1-29.4 19.9-35.0 0.07-0.27

years
41 4.8-13.2 6.5-13.5 0.08-0.35 0.02-0.35 221.6-299.7 16.1-29.2 20.0-34.8 0.07-0.27

years
42 4.8-13.4 6.5-13.7 0.08-0.36 0.02-0.35 224.3-300.8 16.2-29.0 20.1-34.6 0.07-0.26
years
43 4.9-13.5 6.6-13.9 0.08-0.36 0.02-0.35 227.0-302.0 16.2-28.8 20.2-34.4 0.07-0.26

years
44 4.9-13.7 6.6-14.0 0.08-0.37 0.02-0.35 229.8-303.5 16.3-28.6 20.3-34.2 0.07-0.26

years
45 4.9-13.9 6.6-14.2 0.08-0.38 0.02-0.35 232.6-305.2 16.3-28.5 20.3-34.0 0.07-0.26

years
46 4.9-14.0 6.7-14.4 0.08-0.38 0.02-0.35 235.3-307.3 16.4-28.4 20.4-33.8 0.07-0.26

years
47 4.9-14.2 6.7-14.5 0.08-0.39 0.02-0.35 238.0-309.7 16.4-28.2 20.4-33.6 0.07-0.26

years
48 5.0-14.3 6.8-14.7 0.08-0.39 0.02-0.35 240.8-312.6 16.5-28.1 20.5-33.3 0.07-0.26

years
49 5.0-14.4 6.8-14.9 0.08-0.40 0.02-0.35 243.5-315.9 16.5-28.0 20.5-33.1 0.07-0.26

years
50 5.0-14.5 6.8-15.0 0.08-0.40 0.02-0.35 246.2-319.7 16.5-27.9 20.6-32.8 0.07-0.26
years
51 5.1-14.6 6.8-15.2 0.08-0.41 0.02-0.35 248.9-323.8 16.5-27.8 20.6-32.5 0.07-0.26

years
52 5.1-14.7 6.9-15.4 0.08-0.41 0.02-0.35 251.5-328.1 16.5-27.6 20.7-32.3 0.07-0.26

years
53 5.1-14.8 6.9-15.5 0.08-0.42 0.02-0.35 254.0-332.4 16.5-27.5 20.8-32.1 0.07-0.26

years
54 5.2-14.9 6.9-15.6 0.08-0.42 0.02-0.35 256.4-336.5 16.5-27.4 21.0-31.9 0.07-0.25

years
55 5.2-15.0 6.9-15.7 0.08-0.43 0.02-0.35 258.6-340.2 16.5-27.3 21.1-31.7 0.07-0.25

years
56 5.3-15.0 6.9-15.8 0.08-0.43 0.02-0.35 260.6-343.6 16.6-27.2 21.2-31.5 0.07-0.25

years
57 5.3-15.1 6.9-15.9 0.08-0.44 0.02-0.35 262.5-346.5 16.6-27.1 21.2-31.3 0.07-0.25

years
58 5.3-15.2 6.9-16.0 0.08-0.44 0.02-0.35 264.3-349.0 16.6-27.1 21.3-31.0 0.07-0.25

years
59 5.4-15.2 6.9-16.0 0.08-0.44 0.02-0.35 266.2-351.1 16.7-27.1 21.3-30.8 0.07-0.25

years
60 5.4-15.3 6.9-16.1 0.08-0.45 0.02-0.35 268.3-353.1 16.8-27.1 21.3-30.6 0.07-0.25

years
61 5.4-15.4 7.0-16.2 0.09-0.45 0.02-0.35 270.8-355.1 16.9-27.2 21.3-30.3 0.07-0.25

years
62 5.5-15.4 7.0-16.2 0.09-0.46 0.02-0.35 273.8-357.3 17.0-27.2 21.2-30.0 0.08-0.25

years
63 5.5-15.5 7.0-16.3 0.09-0.46 0.02-0.35 277.5-359.7 17.1-27.3 21.2-29.8 0.08-0.25

years
64 5.6-15.5 7.1-16.3 0.09-0.46 0.02-0.35 281.9-362.3 17.2-27.4 21.1-29.5 0.08-0.25

years
65 5.6-15.6 7.1-16.3 0.09-0.47 0.02-0.35 286.9-365.2 17.3-27.6 21.1-29.2 0.08-0.25

years
66 5.7-15.6 7.1-16.3 0.09-0.47 0.02-0.35 292.4-368.3 17.4-27.7 21.1-29.0 0.08-0.25
years
67 5.7-15.7 7.2-16.3 0.09-0.47 0.02-0.35 298.1-371.6 17.5-27.8 21.0-28.7 0.09-0.25

years
68 5.8-15.7 7.2-16.3 0.09-0.47 0.02-0.35 303.6-374.8 17.7-27.9 21.0-28.5 0.09-0.25

years
69 5.9-15.7 7.2-16.3 0.09-0.47 0.02-0.35 308.7-377.8 17.8-28.0 21.0-28.4 0.09-0.25

years
70 6.0-15.8 7.3-16.3 0.09-0.48 0.02-0.35 313.1-380.7 18.0-28.1 21.0-28.3 0.09-0.25

years
71 6.1-15.8 7.3-16.3 0.09-0.48 0.02-0.35 316.5-383.2 18.1-28.2 20.9-28.2 0.09-0.25

years
72 6.2-15.8 7.3-16.3 0.09-0.48 0.02-0.35 318.9-385.3 18.3-28.3 20.9-28.0 0.09-0.25

years
73 6.3-15.9 7.3-16.3 0.09-0.48 0.02-0.35 320.1-387.0 18.5-28.4 20.8-27.9 0.10-0.26

years
74 6.4-15.9 7.3-16.3 0.09-0.48 0.02-0.35 320.6-388.3 18.8-28.5 20.8-27.8 0.10-0.26
years
75 6.5-15.9 7.3-16.3 0.09-0.48 0.02-0.35 320.3-389.3 19.1-28.5 20.8-27.7 0.10-0.26

years
76 6.6-15.9 7.3-16.3 0.09-0.48 0.02-0.35 319.6-389.9 19.3-28.6 20.8-27.5 0.10-0.26

years
77 6.7-16.0 7.4-16.3 0.10-0.48 0.02-0.35 319.1-390.2 19.6-28.6 20.9-27.4 0.10-0.26

years
78 6.8-16.0 7.4-16.3 0.10-0.48 0.02-0.35 318.5-390.5 20.0-28.7 20.9-27.2 0.11-0.26

years
79 6.9-16.0 7.5-16.3 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
80 7.0-16.0 7.5-16.3 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
81 7.1-16.0 7.7-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
82 7.2-16.0 7.8-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
83 7.2-16.0 7.9-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
84 7.3-16.0 8.0-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
85 7.3-16.0 8.2-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26

years
>85 7.4-16.0 8.3-16.2 0.10-0.48 0.02-0.35 317.9-390.6 20.3-28.7 21.0-27.1 0.11-0.26 An

years interpretive
report will
also be
provided.
Clinical References: 1. Turgeon CT, Magera MJ, Cuthbert CD, et al: Determination of total
homocysteine, methylmalonic acid, and 2-methylcitric acid in dried blood spots by tandem mass
spectrometry. Clin Chem. 2010 Nov;56(11):1686-1695 2. Tortorelli S, Turgeon CT, Lim JS, et al:
Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and
other remethylation disorders with tandem mass spectrometry. J Pediatr. 2010 Aug;157(2):271-275 3.
Solomon LR: Disorders of cobalamin (vitamin B12) metabolism: Emerging concepts in
pathophysiology, diagnosis and treatment. Blood Rev. 2007 May;21(3):113-130 4. Baric I, Staufner C,
Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grunert SC: Consensus recommendations for
the diagnosis, treatment and follow-up of inherited methylation disorders. J Inherit Metab Dis.
2017;40(1):5-20 5. Sloan JS, Carrillo N, Adams D, Venditti CP: Disorders of intracellular cobalamin
metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of
Washington, Seattle; 2008. Updated September 6, 2018. Accessed May 15, 2020. Available at
COUO Cobalt Occupational Exposure, Random, Urine

607762 Clinical Information: Cobalt is rare but widely distributed in the environment. It is an essential
cofactor in vitamin B12. While cobalt is an essential element, cobalt deficiency has not been reported in
humans. Cobalt is used in the manufacture of hard alloys with high melting points and resistance to
oxidation. Cobalt salts are also used in the glass and pigment industry. Previously, cobalt salts were
sometimes used as foam stabilizers in the brewing industry; this practice was banned due to the
cardiovascular diseases it induced. The radioactive isotope of cobalt, (60)Co, is used as a gamma
emitter in experimental biology, cancer therapy, and industrial radiography. Cobalt is not highly toxic,
but large doses will produce adverse clinical manifestations. Acute symptoms are pulmonary edema,
allergy, nausea, vomiting, hemorrhage, and renal failure. Chronic symptoms include pulmonary
syndrome, skin disorders, and thyroid abnormalities. The inhalation of dust during machining of cobalt
alloyed metals can lead to interstitial lung disease. Improperly handled (60)Co can cause radiation
poisoning from exposure to gamma radiation.
Useful For: Screening for occupational exposure

Interpretation: For occupational exposure, the sampling time is at the end of the shift at the end of
the work week. The American Conference of Governmental Industrial Hygienists (ACGIH) Biological
Exposure Index (BEI) for cobalt is a concentration of15.0 mcg/L or above at the end of the work
week.Â
Reference Values:
> or =18 years: The American Conference of Governmental Industrial Hygienists (ACGIH) Biological
Exposure Index for cobalt in urine is an end-of-shift concentration of >14.9 mcg/L at the end of the
work week.
Clinical References: 1. Limit Values for Chemical Substances and Physical Agents and Biological
Exposure Indices. American Conference of Governmental Industrial Hygienists (ACGIH); 2010 2. U.S.
Toxicology profile for cobalt. April 2004. Accessed 11/06/2020. Available at
www.atsdr.cdc.gov/ToxProfiles/tp33.pdf 3. Lison D, Buchet JP, Swennen B, Molders J, Lauwerys R:
Biological monitoring of workers exposed to cobalt metal, salt, oxides, and hard metal dust. Occup
Environ Med. 1994 Jul;51(7):447-450. doi: 10.1136/oem.51.7.447 4. Rifai N, Horwath AR, Wittwer
CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018
COU Cobalt, 24 Hour, Urine

80083 Clinical Information: Cobalt is rare but widely distributed in the environment. It is an essential
cofactor in vitamin B12. While cobalt is an essential element, cobalt deficiency has not been reported in
humans. Cobalt is used in the manufacture of hard alloys with high melting points and resistance to
oxidation. Cobalt salts are also used in the glass and pigment industry. Previously, cobalt salts were
sometimes used as foam stabilizers in the brewing industry; this practice was banned due to the
cardiovascular diseases it induced. The radioactive isotope of cobalt, (60)Co, is used as a gamma
poisoning from exposure to gamma radiation. Urine cobalt concentrations are likely to be increased
above the reference value in patients with metallic joint prosthesis. Prosthetic devices produced by
Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics,
Richards Company, Tricon, and Whiteside typically are made of chromium, cobalt, and molybdenum.
Useful For: Detecting cobalt exposure Monitoring metallic prosthetic implant wear This test is not
useful to assess vitamin B12 activity.
Interpretation: Concentrations of 2.0 mcg/specimen or more indicate excess exposure. There are no
Occupational Safety and Health Administration (OSHA) blood or urine criteria for occupational exposure
to cobalt. Prosthesis wear is known to result in increased circulating concentration of metal ions. In a
patient with a cobalt-based implant, modest increase (2-4 mcg/specimen) in urine cobalt concentration is
likely to be associated with a prosthetic device in good condition. Excessive exposure is indicated when
urine cobalt concentration is above 5 mcg/specimen, consistent with prosthesis wear. Urine concentrations
above 20 mcg/specimen in a patient with a cobalt-based implant suggest significant prosthesis wear.
Increased urine trace element concentrations in the absence of corroborating clinical information do not
independently predict prosthesis wear or failure.
Reference Values:
> or =18 years: 0.2-3.5 mcg/24 hours
Clinical References: 1. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the
actual, potential, and theoretical health effects of cobalt and chromium from industry and surgical
implants. Crit Rev Toxicol. 2008;38:645-674 2. Lhotka C, Szekes T, Stefan I, et al: Four-year study of
cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip
replacements. J Orthop Res. 2003;21:189-195 3. Lison D, De Boeck M, Verougstraete V, Kirsch-Volders
M: Update on the genotoxicity and carcinogenicity of cobalt compounds. Occup Environ Med.
2001;58(10):619-625
COWB Cobalt, Blood

60355 Clinical Information: Cobalt (Co) is a naturally occurring, hard, grey element widely distributed in
the environment. It is used to produce alloys in the manufacturing of aircraft engines, cutting tools, and
some artificial hip and knee joint prosthesis devices. Cobalt salts are also used in the glass and pigment
industry. Previously, cobalt salts were sometimes used as foam stabilizers in the brewing industry; this
practice was banned due to the cardiovascular diseases it induced. One of the radioactive isotopes of
cobalt, (60)Co, is used to sterilize medical equipment, in radiation therapy for cancer patients, and to
irradiate food. Cobalt is an essential cofactor in vitamin B12, which is necessary for neurological
function, brain function, and the formation of blood. For most people, food is the largest source of cobalt
intake. However, more than a million workers are potentially exposed to cobalt and its compounds, with
the greatest exposure in mining processes, cemented tungsten-carbide industry, cobalt powder industry,
and alloy production industry. Cobalt is not highly toxic, but large doses will produce adverse clinical
manifestations. Acute symptoms include pulmonary edema, allergy, nausea, vomiting, hemorrhage, and
renal failure. Chronic exposure to cobalt-containing hard metal (dust or fume) can result in a serious lung
disease called hard metal lung disease, which is a type of pneumoconiosis (lung fibrosis). Furthermore,
inhalation of cobalt particles can cause respiratory sensitization, asthma, shortness of breath, and
decreased pulmonary function. Even though the primary route of occupational exposure to cobalt is the
respiratory tract, skin contact is also important because dermal exposures to hard metal and cobalt salts
can result in significant systemic uptake. Sustained exposures can cause skin sensitization, which may
result in eruptions of contact dermatitis. Per FDA recommendations, orthopedic surgeons should consider
measuring and following serial cobalt concentrations in EDTA anticoagulated whole blood in
symptomatic patients with metal-on-metal hip implants as part of their overall clinical evaluation. Blood
cobalt concentrations are likely to be increased above the reference range in patients with joint prosthesis
containing cobalt. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS,
PCA, Osteonics, Richards Company, Tricon, and Whiteside are typically made of chromium, cobalt, and
molybdenum. This list of products is incomplete, and these products change occasionally; see prosthesis
product information for each device for composition details.
Useful For: Monitoring exposure to cobalt using whole blood specimens Monitoring metallic
prosthetic implant wear This test is not useful for assessment of vitamin B12 activity.
Interpretation: Concentrations of 1.0 ng/mL and above indicate possible environmental or

occupational exposure. Cobalt concentrations associated with toxicity must be interpreted in the context
of the source of exposure. In the context of failed metal-on-metal prosthetics, elevated cobalt in serum
or blood is rarely the initial finding and is often preceded by physical symptoms including reduced
range of motion, swelling, inflammation around the joints, and general discomfort or pain. The
American Conference of Governmental Industrial Hygienists (ACGIH) Biological Exposure Index
(BEI) for cobalt in blood is 1 mcg/L (1 ng/mL), which should be collected at the end of shift at the end
of the work week.
Reference Values:
Clinical References: 1. Tower SS: Arthroprosthetic cobaltism: Neurological and cardiac

manifestations in two patients with metal-on-metal arthroplasty: A case report. J Bone Joint Surg Am.
2010 Dec;92(17):2847-2851 2. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the
actual, potential, and theoretical health effects of cobalt and chromium exposures from industry and
surgical implants. Crit Rev Toxicol. 2008;38:645-674 3. De Smet K, De Hann R, Calistri A, et al: Metal
ion measurement as a diagnostic tool to identify problems with metal-on-metal hip resurfacing. J Bone
Joint Surg Am. 2008;90:202-208 4. Lison D, De Boeck M, Verougstraete V, Kirsch-Volders M: Update
on the genotoxicity and carcinogenicity of cobalt compounds. Occup Environ Med. 2001;58:619-625 5.
US Food and Drug Administration: Information about Soft Tissue Imaging and Metal Ion Testing.
Updated March 15, 2019. Accessed March 2, 2021. Available at:
www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHi
pImplants/ucm331971.htm 6. U.S. Department of Health and Human Services, Agency for Toxic
Substances and Disease Registry. Toxicology profile for cobalt. April 2004. Accessed November 06,
2020. Available at www.atsdr.cdc.gov/ToxProfiles/tp33.pdf 7. Rifai N, Horwath AR, Wittwer CT, eds:
Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018
COS Cobalt, Serum

80084 Clinical Information: Cobalt is rare but widely distributed in the environment, used in the
manufacture of hard alloys with high melting points and resistance to oxidation; cobalt alloys are used
in manufacture of some artificial joint prosthesis devices. Cobalt salts are used in the glass and pigment
industry. Previously, cobalt salts were sometimes used as foam stabilizers in the brewing industry; this
practice was banned due to the cardiovascular diseases it induced. The radioactive isotope of cobalt,
(60)Co, is used as a gamma emitter in experimental biology, cancer therapy, and industrial radiography.
Cobalt is an essential cofactor in vitamin B12 metabolism. Cobalt deficiency has not been reported in
humans. Cobalt is not highly toxic, but large doses will produce adverse clinical manifestations. Acute
symptoms are pulmonary edema, allergy, nausea, vomiting, hemorrhage, and renal failure. Chronic
symptoms include pulmonary syndrome, skin disorders, and thyroid abnormalities. The inhalation of
dust during machining of cobalt alloyed metals can lead to interstitial lung disease. Serum cobalt
concentrations are likely to be increased above the reference range in patients with joint prosthesis
containing cobalt. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS,
PCA, Osteonics, Richards Company, Tricon, and Whiteside are typically made of chromium, cobalt,
and molybdenum. This list of products is incomplete, and these products change occasionally; see
prosthesis product information for each device for composition details.
Useful For: Detecting cobalt toxicity Monitoring metallic prosthetic implant wear This test is not
useful for assessment of vitamin B12 activity.
Interpretation: Concentrations greater than or equal to 1.0 ng/mL indicate possible environmental or
occupational exposure. Cobalt concentrations associated with toxicity must be interpreted in the context
of the source of exposure. If cobalt is ingested, concentrations greater than 5 ng/mL suggest major
exposure and likely toxicity. If cobalt exposure is due to orthopedic implant wear, there are no large case
number reports associating high circulating serum cobalt with toxicity. There are no Occupational Health
and Safety Administration (OSHA) blood or urine criteria for occupational exposure to cobalt. Prosthesis
wear is known to result in increased circulating concentration of metal ions. Modest increase (4-10
ng/mL) in serum cobalt concentration is likely to be associated with a prosthetic device in good condition.
Serum concentrations above 10 ng/mL in a patient with cobalt-based implant suggest significant
prosthesis wear. Increased serum trace element concentrations in the absence of corroborating clinical
information do not independently predict prosthesis wear or failure. However, the FDA recommends
testing cobalt in EDTA anticoagulated whole blood in symptomatic patients with metal-on-metal
implants.
Reference Values:
<1.0 ng/mL
<10.0 ng/mL (Metal-on-metal implant)
The reported unit of measurement for cobalt of ng/mL is equivalent to mcg/L.
Clinical References: 1. Tower SS: Arthroprosthetic cobaltism: neurological and cardiac

manifestations in two patients with metal-on-metal arthroplasty: A case report. J Bone Joint Surg Am.
2010;92:1-5 2. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the actual, potential,
and theoretical health effects of cobalt and chromium exposures from industry and surgical implants. Crit
Rev Toxicol. 2008;38:645-674 3. De Smet K, De Hann R, Calistri A, et al: Metal ion measurement as a
diagnostic tool to identify problems with metal-on-metal hip resurfacing. J Bone Joint Surg Am.
2008;90:202-208 4. Lison D, De Boeck M, Verougstraete V, Kirsch-Volders M: Update on the
genotoxicity and carcinogenicity of cobalt compounds. Occup Environ Med. 2001;58:619-625
COSY Cobalt, Synovial Fluid

606352 Clinical Information: Per FDA recommendations, orthopedic surgeons should consider measuring
and following serial cobalt (Co) concentrations in EDTA anticoagulated whole blood in symptomatic
patients with metal-on-metal hip implants as part of their overall clinical evaluation. However, a recent
publication(1) has shown synovial fluid measurements were superior to whole blood and serum Co
concentrations in predicting local tissue destruction in failed hip arthroplasty constructs. Prosthetic
devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards
Company, Tricon, and Whiteside are typically made of chromium, Co, and molybdenum. This list of
products is incomplete, and these products' compositions change occasionally; see each prostheses'
product information for composition details. Co is a naturally occurring, hard, grey element widely
distributed in the environment. It is used to produce alloys in the manufacturing of aircraft engines,
cutting tools, and some artificial hip and knee joint prosthesis devices. Co is an essential cofactor for
vitamin B12, which is necessary for neurological function, brain function, and the formation of blood. For
most people, food is the largest source of Co intake. The greatest environmental exposure occurs in
mining processes, cemented tungsten-carbide industry, Co powder industry, and alloy production
industry. Co is not highly toxic; however large doses may produce adverse clinical manifestations. Acute
symptoms include pulmonary edema, allergy, nausea, vomiting, hemorrhage, and renal failure. Chronic
exposure to Co-containing hard metal (dust or fume) can result in a serious lung disease called "hard
metal lung disease," which is a type of pneumoconiosis (lung fibrosis). Furthermore, inhalation of Co
particles can cause respiratory sensitization, asthma, shortness of breath, and decreased pulmonary
function. Even though the primary route of occupational exposure to Co is the respiratory tract, skin
contact is also important because dermal exposures to hard metal and cobalt salts can result in significant
systemic uptake. Sustained exposures can cause skin sensitization, which may result in eruptions of
contact dermatitis. In cases of suspected toxicity, blood, serum, or urine concentrations of Co can be
checked. Vitamin B12 should be used to assess nutritional status.
arthroplasty constructs This test is not useful for assessment of nutritional status or potential cobalt
toxicity.
Interpretation: Based on an internal study, synovial fluid cobalt concentrations of 19.8 ng/mL or
above were more likely due to a metal reaction (eg, adverse local tissue reaction [ALTR]/adverse
reaction to metal debris [ARMD]) versus a nonmetal reaction in patients undergoing metal-on-metal
revision (sensitivity of 92.3% and specificity of 96.3%).
Reference Values:
Clinical References: 1. Houdek MT, Taunton MJ, Wyles CC, Jannetto PJ, Lewallen DG, Berry
DJ: Synovial fluid metal ion levels are superior to blood metal ion levels in predicting an adverse local
tissue reaction in failed total hip arthroplasty. J Arthroplasty. 2021 Sep;36(9):3312-3317.e1. doi:
ion levels in metal-on-metal total hip arthroplasty at minimum follow-up of 18 years. J Orthop Res.
2014 Sept;32(9):1234-1240. doi: 10.1002/jor.22652 4. De Pasquale D, Stea S, Squarzoni S, et al:
chromium ions in the bloodstream. Int Orthop. 2014 Mar;38(3):469-475. doi:
10.1007/s00264-013-2137-5
COBRU Cobalt/Creatinine Ratio, Random, Urine

607760 Clinical Information: Cobalt (Co) is rare but widely distributed in the environment. It is an
essential cofactor in vitamin B12. While cobalt is an essential element, cobalt deficiency has not been
reported in humans. Cobalt is used in the manufacture of hard alloys with high melting points and
resistance to oxidation. Cobalt salts are also used in the glass and pigment industry. Previously, cobalt
salts were sometimes used as foam stabilizers in the brewing industry; this practice was banned due to
the cardiovascular diseases it induced. The radioactive isotope of cobalt, (60)Co, is used as a gamma
poisoning from exposure to gamma radiation. Urine cobalt concentrations are likely to be increased
above the reference value in patients with metallic joint prosthesis. Prosthetic devices produced by
Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics,
Richards Company, Tricon, and Whiteside typically are made of chromium, cobalt, and molybdenum.
Useful For: Detecting cobalt exposure in a random urine collection Monitoring metallic prosthetic
implant wear This test is not useful for assessment of vitamin B12 activity.
Interpretation: Concentrations greater or equal to 2.0 mcg/g creatinine indicate excess exposure.
There are no Occupational Safety and Health Administration (OSHA) blood or urine criteria for
occupational exposure to cobalt. Prosthesis wear is known to result in increased circulating
concentration of metal ions. In a patient with a cobalt-based implant, modest increase (2-4 mcg/g
creatinine) in urine cobalt concentration is likely to be associated with a prosthetic device in good
condition. Excessive exposure is indicated when urine cobalt concentration is greater than 5 mcg/g
creatinine, consistent with prosthesis wear. Urine concentrations greater than 20 mcg/g creatinine in a
patient with a cobalt-based implant suggest significant prosthesis wear. Increased urine trace element
concentrations in the absence of corroborating clinical information do not independently predict
prosthesis wear or failure.
Reference Values:
>17 years: <1.7 mcg/g Creatinine
Clinical References: 1. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the
actual, potential, and theoretical health effects of cobalt and chromium from industry and surgical
implants. Crit Rev Toxicol. 2008;38:645-674 2. Lhotka C, Szekes T, Stefan I, et al: Four-year study of
cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip
replacements. J Orthop Res. 2003;21:189-195 3. Lison D, De Boeck M, Verougstraete V, Kirsch-Volders
M: Update on the genotoxicity and carcinogenicity of cobalt compounds. Occup Environ Med.
2001;58(10):619-625 4. Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry
FCOKE Cocaine Analysis - Whole Blood

Cocaine Screen:
Cocaine and Metabolite, UA Ã¢â‚¬â€œ Negative; Cutoff: 25 ng/mL
Cocaine Confirmation: Cocaine

Benzoylecgonine
Confirmation threshold: 10 ng/mL
COKMX Cocaine and Metabolite Confirmation, Chain of Custody,

62720 Meconium
Clinical Information: Cocaine is an alkaloid found in Erythroxylon coca, which grows principally in
the northern South American Andes and to a lesser extent in India, Africa, and Java.(1) Cocaine is a
powerfully addictive stimulant drug. Cocaine abuse has a long history and is rooted into the drug culture
in the United States,(2) and is one of the most common illicit drugs of abuse.(3,4) Cocaine is rapidly
metabolized primarily to benzoylecgonine, which is further metabolized to m-hydroxybenzoylecgonine
(m-HOBE).(1,5) Cocaine is frequently used with other drugs, most commonly ethanol, and the
simultaneous use of both drugs can be determined by the presence of the unique metabolite
cocaethylene.(4) Intrauterine drug exposure to cocaine has been associated with placental abruption,
premature labor, small for gestational age status, microcephaly, and congenital anomalies (eg, cardiac and
genitourinary abnormalities, necrotizing enterocolitis, and central nervous system stroke or
hemorrhage).(6) The disposition of drug in meconium, the first fecal material passed by the neonate, is not
well understood. The proposed mechanism is that the fetus excretes drug into bile and amniotic fluid.
Drug accumulates in meconium either by direct deposition from bile or through swallowing of amniotic
fluid.(7) The first evidence of meconium in the fetal intestine appears at approximately the 10th to 12th
week of gestation, and slowly moves into the colon by the 16th week of gestation.(8) Therefore, the
presence of drugs in meconium has been proposed to be indicative of in utero drug exposure during the
final 4 to 5 months of pregnancy, a longer historical measure than is possible by urinalysis.(7) Chain of
custody is a record of the disposition of a specimen to document each individual that collected, handled,
and performed the analysis. When a specimen is submitted in this manner, analysis will be performed in
such a way that it will withstand regular court scrutiny.
separating the baby from the mother, a complete chain of custody ensures that the test results are
Interpretation: The presence of any of the following: cocaine, benzoylecgonine, cocaethylene, or

m-hydroxybenzoylecgonine, at 20 ng/g or more is indicative of in utero drug exposure up to 5 months
before birth.
Reference Values:
Negative
(LC-MS/MS) result.
Cocaine: 20ng/g
Benzoylecgonine: 20 ng/g
Cocaethylene: 20 ng/g
m-Hydroxybenzoylecgonine: 20ng/g
Clinical References: 1. Isenschmid DS: Cocaine. In: Levine B, ed. Principles of Forensic
Toxicology. 2nd ed. AACC Press; 2003:207-228 2. US Drug Enforcement Administration: Cocaine.
DEA; 2020 Accessed 04/16/2021. Available at
www.dea.gov/sites/default/files/2020-06/Cocaine-2020.pdf 3. National Institute on Drug Abuse:
Cocaine DrugFacts. NIDA; 2021 Accessed 04/16/2021. Available at
www.drugabuse.gov/publications/drugfacts/cocaine 4. Isenschmid DS: Cocaine-effects on human
performance and behavior. Forsensic Sci Rev 2002;14:61 5. Kolbrich EA, Barnes AJ, Gorelick DA,
Susan J Boyd, Edward J Cone, Marilyn A Huestis: Major and minor metabolites of cocaine in human
plasma following controlled subcutaneous cocaine administration. J Anal Toxicol. 2006;30:501-510 6.
Kwong TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National
Academy of Clinical Biochemistry. Clin Chem. 1997;43:235-242 7. Ostrea EM Jr, Brady MJ, Parks
PM, Asensio DC, Naluz A: Drug screening of meconium in infants of drug-dependent mothers; an
alternative to urine testing. J Pediatr. 1989;115:474-477 8. Ahanya SN, Lakshmanan J, Morgan BL,
Ross MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol
Surv. 2005;60:45-56
COKEX Cocaine and Metabolite Confirmation, Chain of Custody,

62719 Random, Urine
Clinical Information: Cocaine is a drug of current health concern because of its proliferation
among recreational drug abusers. Freebase and crack increase the potential for major cocaine toxicity.
Cocaine use is declining across the nation according to the National Institute of Drug Abuse.
Increasingly, laboratory results are disputed or there are medical/legal overtones. Therefore, physicians
are finding an increased need to confirm positive results before informing or confronting the patients.
Chain of custody is a record of the disposition of a specimen to document each individual who
collected, handled, and performed the analysis. When a specimen is submitted in this manner, analysis
will be performed in such a way that it will withstand regular court scrutiny.
Useful For: Detecting and confirming drug abuse involving cocaine Chain of custody is required
individual contributing the specimen by demonstrating that it was under the control of personnel
tampering would be limited. This test is not intended for use in employment-related testing.
Interpretation: Reports will specifically indicate the presence or absence of cocaine and
benzoylecgonine. The presence of cocaine, or its major metabolite, benzoylecgonine, indicates use
within the past 4 days. Cocaine has a 6-hour half-life, so it will be present in urine for 1 day after last
use. Benzoylecgonine has a half-life of 12 hours, so it will be detected in urine up to 72 hours after last
use. There is no correlation between concentration and pharmacologic or toxic effects.
Reference Values:
Negative
Positives are reported with a quantitative GC-MS result.
IMMUNOASSAY SCREEN
<150 ng/mL
COCAINE BY GC-MS
<50 ng/mL
BENZOYLECGONINE BY GC-MS
<50 ng/mL
Clinical References: 1. Baselt RC, Cravey RH: Disposition of Toxic Drugs and Chemicals in Man.
3rd ed. Year Book Medical Publishers; 1989 2. Langman LJ, Bechtel LK, Meier BM, Holstege C:
Clinical toxicology. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018:1328-1333
COKEU Cocaine and Metabolite Confirmation, Random, Urine

9286 Clinical Information: Cocaine is a drug of current health concern because of its proliferation among
recreational drug abusers. Freebase and crack increase the potential for major cocaine toxicity. Cocaine
use is declining across the nation according to the National Institute of Drug Abuse. Increasingly,
laboratory results are disputed or there are medical/legal overtones. Therefore, physicians are finding an
increased need to confirm positive results before informing or confronting the patients.
Useful For: Detecting and confirming drug abuse involving cocaine This test is not intended for
employment-related testing.
Interpretation: Reports will specifically indicate the presence or absence of cocaine and
benzoylecgonine. The presence of cocaine, or its major metabolite, benzoylecgonine, indicates use within
the past 4 days. Cocaine has a 6-hour half-life, so it will be present in urine for 1 day after last use.
Benzoylecgonine has a half-life of 12 hours, so it will be detected in urine up to 4 days after last use.
There is no correlation between concentration and pharmacologic or toxic effects.
Reference Values:
Negative
Positive results are reported with a quantitative GC-MS result.
COCAINE BY GC-MS
<50 ng/mL
BENZOYLECGONINE BY GC-MS
<50 ng/mL
Clinical References: 1. Disposition of Toxic Drugs and Chemicals in Man. Tenth edition. Edited by
RC Baselt. Foster City, CA: Biomedical Publications, 2014 2. Langman LJ, Bechtel L, Holstege CP:
Chapter 35: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER
Ashwood, DE Bruns. WB Saunders Company, 2011, pp 1109-1188
COKEM Cocaine and Metabolites Confirmation, Meconium

84140 Clinical Information: Cocaine is an alkaloid found in Erythroxylon coca, which grows principally in
the northern South American Andes and to a lesser extent in India, Africa, and Java.(1) Cocaine is a
powerfully addictive stimulant drug. Cocaine abuse has a long history and is rooted into the drug culture
in the United States,(2) and is 1 of the most common illicit drugs of abuse.(3,4) Cocaine is rapidly
metabolized primarily to benzoylecgonine, which is further metabolized to m-hydroxybenzoylecgonine
(m-HOBE).(1,5) Cocaine is frequently used with other drugs, most commonly ethanol, and the
simultaneous use of both drugs can be determined by the presence of the unique metabolite
cocaethylene.(4) Intrauterine drug exposure to cocaine has been associated with placental abruption,
premature labor, small for gestational age status, microcephaly, and congenital anomalies (eg, cardiac and
genitourinary abnormalities, necrotizing enterocolitis, and central nervous system stroke or
hemorrhage).(6) The disposition of drug in meconium, the first fecal material passed by the neonate, is not
well understood. The proposed mechanism is that the fetus excretes drug into bile and amniotic fluid.
Drug accumulates in meconium either by direct deposition from bile or through swallowing of amniotic
fluid.(7) The first evidence of meconium in the fetal intestine appears at approximately the 10th to 12th
week of gestation, and slowly moves into the colon by the 16th week of gestation.(8) Therefore, the
final 4 to 5 months of pregnancy, a longer historical measure than is possible by urinalysis.(7)
Useful For: Detection of in utero drug exposure up to 5 months before birth

Interpretation: The presence of any of the following: cocaine, benzoylecgonine, cocaethylene, or
m-hydroxybenzoylecgonine, at 20 ng/g or more is indicative of in utero drug exposure up to 5 months
before birth.
Reference Values:
Negative
(LC-MS/MS) result.
Cocaine: 20 ng/g
Benzoylecgonine: 20 ng/g
Cocaethylene: 20 ng/g
m-Hydroxybenzoylecgonine: 20 ng/g
Clinical References: 1. Isenschmid DS: Cocaine. In: Levine B, ed. Principles of Forensic
Toxicology. 2nd ed. AACC Press; 2003:207-228 2. US Drug Enforcement Administration: Cocaine.
DEA; 2020 Accessed 04/16/2021. Available at
www.dea.gov/sites/default/files/2020-06/Cocaine-2020.pdf 3. National Institute on Drug Abuse:
Cocaine DrugFacts. NIDA; 2021 Accessed 04/16/2021. Available at
www.drugabuse.gov/publications/drugfacts/cocaine 4. Isenschmid DS: Cocaine-effects on human
performance and behavior. Forsensic Sci Rev 2002;14:61 5. Kolbrich EA, Barnes AJ, Gorelick DA,
Boyd SJ, Cone EJ, Huestis MA: Major and minor metabolites of cocaine in human plasma following
controlled subcutaneous cocaine administration. J Anal Toxicol. 2006;30:501-510 6. Kwong TC, Ryan
RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National Academy of
Clinical Biochemistry. Clin Chem. 1997;43:235-242 7. Ostrea EM Jr, Brady MJ, Parks PM, Asensio
DC, Naluz A: Drug screening of meconium in infants of drug-dependent mothers; an alternative to urine
testing. J Pediatr. 1989;115:474-477 8. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium
passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv. 2005;60:45-56
FCDU6 Cocaine and Metabolites, Umbilical Cord Tissue

Units: ng/g
RSCOC Coccidioides Antibody Reflex, Complement Fixation and

35928
Immunodiffusion, Serum
Clinical Information: Coccidioidomycosis (valley fever, San Joaquin Valley fever) is a fungal
infection found in the southwestern US, Central America, and South America. It is acquired by inhalation
of arthroconidia of Coccidioides immitis/posadasii. Usually, it is a mild, self-limiting pulmonary
infection. Less commonly, chronic pneumonia may occur, progressing to fibronodular, cavitary disease. A
rash often develops within a day or 2, followed by erythema nodosum or multiforme and accompanying
arthralgias. About 2 weeks after exposure, symptomatic patients develop fever, cough, malaise, and
anorexia; chest pain is often severe. Coccidioidomycosis may disseminate beyond the lungs to involve
multiple organs, including the meninges. IgG antibody is detected by the complement-fixation tests.
Precipitating antibodies (IgM and IgG) are detected by immunodiffusion. They are rarely found in
cerebrospinal fluid; however, their presence is associated with meningitis. Chronic coccidioidal
pulmonary cavities are often accompanied by IgG and IgM precipitating antibodies. Serologic testing for
coccidioidomycosis should be considered when patients exhibit symptoms of pulmonary or meningeal
infection and have lived or traveled in areas where Coccidioides immitis/possadasii is endemic. Any
history of exposure to the organism or travel cannot be overemphasized when a diagnosis of
coccidioidomycosis is being considered.
Useful For: Detection of antibodies to Coccidioides species

Interpretation: Complement Fixation: Titers of 1:2 or higher may suggest active disease; however,
titers may persist for months after infection has resolved. Increasing complement fixation (CF) titers in
serial specimens are considered diagnostic of active disease. Immunodiffusion: The presence of IgM
antibody may be detectable within 2 weeks after the onset of symptoms; however, antibody may be
detected longer than 6 months after infection. The presence of IgG antibody parallels the CF antibody and
may suggest an active or a recent asymptomatic infection with Coccidioides immitis/posadasii; however,
antibodies may persist after the infection has resolved. An equivocal result (a band of nonidentity) cannot
be interpreted as significant for a specific diagnosis. However, this may be an indication that a patient
should be followed serologically. Over 90% of primary symptomatic cases will be detected by combined
immunodiffusion (ID) and CF testing.
Reference Values:
Only orderable as a reflex. For more information see COXIS / Coccidioides Antibody Screen with Reflex,
Serum.
COMPLEMENT FIXATION:
Negative
IMMUNODIFFUSION:
Negative
Results are reported as positive, negative, or equivocal.
Clinical References: 1. Larone D, Mitchell T, Walsh T: Histoplasma, blastomyces, coccidioides,

and other dimorphic fungi causing systemic mycoses. In: Murray PR, Baron EJ, Pfaller MA, et al, eds.
Manual of Clinical Microbiology. 7th ed. ASM Press; 1999:1260-1261 2. Ramanan P, Wengenack NL,
Theel ES: Laboratory diagnosis for fungal infections. A review of current and future diagnostic assays.
Clin Chest Med. 2017 Sep;38(3):535-554. doi: 10.1016/j.ccm.2017.04.013
COXIS Coccidioides Antibody Screen with Reflex, Serum

62079 Clinical Information: Coccidioidomycosis (valley fever, San Joaquin Valley fever, desert
rheumatism) is a caused by the dimorphic fungus Coccidioides immitis/posadasii, which is found in the
southwestern US, regions in the northwestern US, and in Central and South America. It is acquired by
inhalation of airborne Coccidioides arthroconidia. The majority of infections are subclinical. Among
symptomatic patients, the majority will present acute flulike, pulmonary symptoms approximately 7 to 28
days post exposure. Symptoms may include chest pain, cough, fever, malaise, and lymphadenopathy.(1) A
rash often develops within a couple of days, followed by erythema nodosum or multiforme with
accompanying arthralgia. A pulmonary lesion or nodule may develop months following infection and may
be a source of infection if the patient becomes immunosuppressed in the future. Coccidioidomycosis may
disseminate beyond the lungs to involve multiple organs including the meninges. Individuals at greater
risk for dissemination include African Americans, patients of Filipino descent, pregnant women, and
immunocompromised patients.(2) Serologic testing for coccidioidomycosis should be considered when
patients exhibit symptoms of pulmonary or meningeal infection and have lived or traveled in areas where
Coccidioides immitis/posadasii is endemic. Any history of exposure to the organism or travel cannot be
overemphasized when a diagnosis of coccidioidomycosis is being considered.
Useful For: Detection of antibodies to Coccidioides immitis/posadasii This assay should not be used
for monitoring response to therapy.
Interpretation: Enzyme immunoassay (EIA) results greater than or equal to 0.75 will be reported as
Reactive: Confirmatory testing by complement fixation and immunodiffusion has been ordered. A
reactive result is presumptive evidence that the patient was previously or is currently infected with
Coccidioides immitis/posadasii. EIA results less than 0.75 will be reported as Negative:Â Â Repeat
testing on a new sample in 2 â€“ 3 weeks if clinically indicated. A negative result indicates the absence
of antibodies to Coccidioides immitis/posadasii and is presumptive evidence that the patient has not
been previously exposed to and is not infected with Coccidioides. However, a negative result does not
preclude the diagnosis of coccidioidomycosis as the specimen may have been drawn before antibodies
levels were detectable due to early acute infection or immunosuppression. This test is designed for the
qualitative detection of both IgM- and IgG-class antibodies against antigens from Coccidioides. The
report will not indicate which class of antibody is present.
Reference Values:
Negative
Reference value applies to all ages
Clinical References: 1. Thompson GR: Pulmonary coccidioidomycosis. Semin Respir Crit Care
Med. 2011;32(6):754-763 2. Ruddy BE, Mayer AP, Ko MG, et al: Coccidioidomycosis in African
Americans. Mayo Clin Proc. 2011;86(1):63-69
SCOC Coccidioides Antibody, Complement Fixation and

8295 Immunodiffusion, Serum
Clinical Information: Coccidioidomycosis (valley fever, San Joaquin Valley fever) is a fungal
infection found in the southwestern US, Central America, and South America. It is acquired by
inhalation of arthroconidia of Coccidioides immitis/posadasii. Usually, it is a mild, self-limiting
pulmonary infection. Less commonly, chronic pneumonia may occur, progressing to fibronodular,
cavitary disease. A rash often develops within a day or 2, followed by erythema nodosum or multiforme
and accompanying arthralgias. About 2 weeks after exposure, symptomatic patients develop fever,
cough, malaise, and anorexia; chest pain is often severe. Coccidioidomycosis may disseminate beyond
the lungs to involve multiple organs, including the meninges. IgG antibody is detected by the
complement-fixation tests. Precipitating antibodies (IgM and IgG) are detected by immunodiffusion.
They are rarely found in cerebrospinal fluid; however, their presence is associated with meningitis.
Chronic coccidioidal pulmonary cavities are often accompanied by IgG and IgM precipitating
antibodies. Serologic testing for coccidioidomycosis should be considered when patients exhibit
symptoms of pulmonary or meningeal infection and have lived or traveled in areas where C
immitis/possadasii is endemic. Any history of exposure to the organism or travel cannot be
overemphasized when a diagnosis of coccidioidomycosis is being considered.
Useful For: Diagnosis of coccidioidomycosis using serum specimens

Interpretation: Complement Fixation: Titers of 1:2 or higher may suggest active disease; however,
titers may persist for months after infection has resolved. Increasing complement fixation (CF) titers in
serial specimens are considered diagnostic of active disease. Immunodiffusion: The presence of IgM
antibodies may be detectable within 2 weeks after the onset of symptoms; however, the antibody may
be detected longer than 6 months after infection. The presence of IgG antibodies parallels the CF
antibodies and may suggest an active or a recent asymptomatic infection with Coccidioides
immitis/posadasii; however, antibodies may persist after the infection has resolved. An equivocal result
(a band of nonidentity) cannot be interpreted as significant for a specific diagnosis. However, this may
be an indication that a patient should be followed serologically. Over 90% of primary symptomatic
cases will be detected by combined immunodiffusion and CF testing.
Reference Values:
COMPLEMENT FIXATION
Negative
IMMUNODIFFUSION
Negative

Manual of Clinical Microbiology. 7th ed. ASM Press; 1999:1260-1261 2. Ramanan P, Wengenack NL,
Theel ES: Laboratory diagnosis for fungal infections: a review of current and future diagnostic assays.
Clin Chest Med. 2017 Sep;38(3):535-554. doi: 10.1016/j.ccm.2017.04.013. doi:
10.1016/j.ccm.2017.04.013
CCOC Coccidioides Antibody, Complement Fixation and

81542 Immunodiffusion, Spinal Fluid
Clinical Information: Coccidioidomycosis (Valley fever, San Joaquin Valley fever) is a fungal
infection found in the southwestern United States, Central America, and South America. It is acquired by
inhalation of arthroconidia of Coccidioides immitis/posadasii. Usually, it is a mild, self-limiting
pulmonary infection. Less commonly, chronic pneumonia may occur,Â progressing to fibronodular
cavitary disease. A rash often develops within 1 to 2 days, followed by erythema nodosum or multiforme
and accompanying arthralgias. About 2 weeks after exposure, symptomatic patients develop fever, cough,
malaise, and anorexia; chest pain is often severe. Coccidioidomycosis may disseminate beyond the lungs
to involve multiple organs, including the meninges. Serologic testing for coccidioidomycosis should be
considered when patients exhibit symptoms of meningeal infection and have lived in or traveled to areas
where Coccidioides immitis/posadasii is endemic. Any history of exposure to the organism or travel
cannot be overemphasized when coccidioidomycosis serologic tests are being considered.
Useful For: Diagnosing coccidioidomycosis in spinal fluid

Interpretation: Complement Fixation: IgG antibody is detected by complement fixation (CF) testing.
Any CF titer in cerebrospinal fluid (CSF) should be considered significant. A positive complement
fixation test in un-concentrated CSF is diagnostic of meningitis. Immunodiffusion: IgM and IgG
precipitins are rarely found in CSF. However, when present, they are diagnostic of meningitis (100%
specific). Since the immunodiffusion test is 100% specific, it is helpful in interpreting CF results.
Reference Values:
COMPLEMENT FIXATION
Negative
IMMUNODIFFUSION
Negative

Manual of Clinical Microbiology. 7th ed. ASM Press, 1999:1260-1261 2. Ramanan P, Wengenack NL,
Theel ES: Laboratory diagnosis for fungal infections. A review of current and future diagnostic assays.
Clin Chest Med. 2017 Sep;38(3):535-554. doi: 10.1016/j.ccm.2017.04.013
CIMT Coccidioides immitis/posadasii, Molecular Detection, PCR,

62204 Paraffin, Tissue
Clinical Information: Coccidioidomycosis is caused by the dimorphic fungi, Coccidioides immitis
and Coccidioides posadasii. These organisms are endemic to the southwestern regions of the United
States, northern Mexico, and areas of Central and South America. The illness commonly manifests as a
self-limited upper respiratory tract infection, but can also result in disseminated disease that may be
refractory to treatment.(1) Clinical onset generally occurs 10 to 16 days following inhalation of
coccidioidal spores (arthroconidia).(2) Disease progression may be rapid in previously healthy or
immunosuppressed individuals. At present, the gold standard for the diagnosis of coccidioidomycosis is
culture of the organism from clinical specimens. Culture is highly sensitive and, with the
implementation of DNA probe assays for confirmatory testing of culture isolates, yields excellent
specificity.(3) However, growth in culture may take up to several weeks. This often delays the diagnosis
and treatment of infected individuals. Serological tests including immunodiffusion and complement
fixation are widely used for the detection of antibody against Coccidioides. Serology for Coccidioides
can be limited by delays in antibody development or nonspecificity due to cross-reactions with other
fungi. In addition, immunodiffusion and complement fixation tests are highly labor intensive and are
generally limited to reference laboratories. Molecular methods can identify Coccidioides species
directly from clinical specimens and should be used in conjunction with culture. For specimen types
such as formalin-fixed, paraffin-embedded tissue, culture is not possible, but the molecular test may
provide useful information.
Useful For: Rapid detection of Coccidioides DNA Aiding in the diagnosis of coccidioidomycosis
Interpretation: A positive result indicates presence of Coccidioides DNA. A negative result
indicates absence of detectable Coccidioides DNA. An inhibition result indicates that the detection of
Coccidioides DNA is inhibited in this specimen. A new specimen can be resubmitted under a new order,
if desired.
Reference Values:
Not applicable
Clinical References: 1. Vucicevic D, Blair JE, Binnicker MJ: The utility of Coccidioides
polymerase chain reaction testing in the clinical setting. Mycopathologia, 2010; 170:345-351 2.
Hartmann CA, Aye WT, Blair JE: Treatment considerations in pulmonary coccidioidomycosis. 2016;
10:1079-1091
CIMRP Coccidioides immitis/posadasii, Molecular Detection, PCR,

88804 Varies
Clinical Information: Coccidioidomycosis is caused by the dimorphic fungi, Coccidioides immitis
and Coccidioides posadasii. These organisms are endemic to the southwestern regions of the United
States, northern Mexico, and areas of Central and South America. The illness commonly manifests as a
self-limited upper respiratory tract infection, but can also result in disseminated disease that may be
refractory to treatment.(1) Clinical onset generally occurs 10 to 16 days following inhalation of
coccidioidal spores (arthroconidia).(2) Disease progression may be rapid in previously healthy or
immunosuppressed individuals. At present, the gold standard for the diagnosis of coccidioidomycosis is
culture of the organism from clinical specimens. Culture is highly sensitive and, with the
implementation of DNA probe assays for confirmatory testing of culture isolates, yields excellent
specificity.(3) However, growth in culture may take up to several weeks. This often delays the diagnosis
and treatment of infected individuals. In addition, the propagation of Coccidioides species in the clinical
laboratory is a significant safety hazard to laboratory personnel, serving as an important cause of
laboratory-acquired infections if the organism is not quickly identified and handled appropriately (ie, in
a Biosafety Level 3 facility). Serological tests including immunodiffusion and complement fixation are
widely used for the detection of antibody against Coccidioides. Serology for Coccidioides can be
limited by delays in antibody development or nonspecificity due to cross-reactions with other fungi. In
addition, immunodiffusion and complement fixation tests are highly labor intensive and are generally
limited to reference laboratories. Molecular methods can identify Coccidioides species directly from
clinical specimens, allowing for a more rapid diagnosis. Fungal culture should also be performed since
the isolate may be needed for antifungal susceptibility testing.
Useful For: Rapid detection of Coccidioides DNA, preferred method An aid in diagnosing
coccidioidomycosis
Interpretation: A positive result indicates presence of Coccidioides DNA. A negative result indicates
absence of detectable Coccidioides DNA.
Reference Values:
Not applicable
Clinical References: 1. Chiller TM, Galgiani JN, Stevens DA: Coccidioidomycosis. Infect Dis Clin
North Am 2003;17:41-57 2. Feldman BS, Snyder LS: Primary pulmonary coccidioidomycosis. Semin
Respir Infect 2001;16:231-237 3. Padhye AA, Smith G, Standard PG, et al: Comparative evaluation of
chemiluminescent DNA probe assays and exoantigen tests for rapid identification of Blastomyces
dermatitis and Coccidioides immitis. J Clin Microbiol 1994;32:867-870 4. Inoue T, Nabeshima K,
Kataoka H, Koono M: Feasibility of archival non-buffered formalin-fixed and paraffin-embedded tissues
for PCR amplification: an analysis of resected gastric carcinoma. Pathol Int 1996;46:997-1004 5.
Binnicker MH, Popa AS, Catania J, et al: Meningeal coccidioidomycosis diagnosed by real-time
polymerase chain reaction analysis of cerebrospinal fluid. Mycopathologia 2011;171:285-289 6.
Vucicevic D, Blair JE, Binnicker MJ, et al: The utility of Coccidioides polymerase chain reaction testing
in the clinical setting. Mycopathologia 2010;170:345-351
FCKTF Cockatiel Feathers IgE

Reference Values:
<0.35 kU/L
CBUR Cocklebur, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cocklebur Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
FCAIG Cockroach American (Periplaneta americana) IgE

75561 Clinical Information: This assay is used to detect allergen specific-IgE using the ImmunoCAPÂ®
FEIA method. In vitro allergy testing is the primary testing mode for allergy diagnosis.
Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10 - 0.34 Equivocal/Borderline
1 0.35 - 0.69 Low Positive 2 0.70 - 3.49 Moderate Positive 3 3.50 - 17.49 High Positive 4 17.50 - 49.99
Reference Values:
<0.35 kU/L
COCR Cockroach, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cockroach Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
FCOCN Coconut IgG

Reference Values:
CCNT Coconut, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to coconut Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
COD Codfish, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to codfish Defining the allergen responsible for

Reference Values:
0 Negative
apply to all ages.
Q10 Coenzyme Q10, Reduced and Total, Plasma

87853 Clinical Information: Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial
respiratory chain responsible for oxidative phosphorylation where it functions as an electron carrier and
acts as an antioxidant. It is found in all cell membranes and is carried by lipoproteins in the circulation.
Approximately 60% of CoQ10 is associated with low-density lipoprotein (LDL), 25% with high-density
lipoprotein, and 15% with other lipoproteins. CoQ10 is present in the body in both the reduced and
oxidized forms, with the antioxidant activity of CoQ10 dependent on both its concentration and its
reduction-oxidation (redox) status. CoQ10 deficiencies, which are clinically and genetically diverse, can
occur due to defects in genes involved in the biosynthesis of ubiquinone (primary CoQ10 deficiency) or
due to other causes such as mitochondrial disorders (secondary or CoQ10 deficiency). Five major clinical
phenotypes of CoQ10 deficiency have been described: -Encephalomyopathy (elevated serum creatine
kinase [CK], recurrent myoglobinuria, lactic acidosis) -Cerebellar ataxia and atrophy (neuropathy,
hypogonadism) -Severe multisystemic infant form (nystagmus, optic atrophy, sensorineural hearing loss,
dystonia, rapidly progressing nephropathy) -Nephropathy, steroid resistant nephrotic syndrome leading to
end stage kidney disease -Isolated myopathy (exercise intolerance, fatigue, elevated serum CK) Treatment
with CoQ10 in patients with mitochondrial cytopathies can improve mitochondrial respiration in both
brain and skeletal muscle. CoQ10 has been implicated in other disease processes, including Parkinson
disease, diabetes, and Alzheimer disease, as well as in aging and oxidative stress. CoQ10 may also play a
role in hydroxymethylglutaryl-CoA reductase inhibitor (statin) therapy; changes in CoQ10 may be
relevant to statin-induced myalgia. Additionally, the redox status of CoQ10 may be a useful early marker
for the detection of oxidative LDL modification.
Useful For: Diagnosis of primary coenzyme Q10 (CoQ10) deficiencies in some patients who are not
supplemented with CoQ10 Diagnosis of CoQ10 deficiency in mitochondrial disorders Monitoring CoQ10
status during treatment of various degenerative conditions including Parkinson and Alzheimer disease
This test is not useful for distinguishing primary CoQ10 deficiencies from acquired CoQ10 deficiencies.
available.
Reference Values:
COENZYME Q10 (CoQ10) REDUCED
<18 years: 320-1376 mcg/L
> or =18 years: 415-1480 mcg/L
CoQ10 TOTAL
<18 years: 320-1558 mcg/L
> or =18 years: 433-1532 mcg/L
CoQ10 % REDUCED
<18 years: 93-100%
> or =18 years: 92-98%
Miles MV, Horn PS, Tang PH, et al: Age-related changes in plasma coenzyme Q10 concentrations and
redox state in apparently healthy children and adults. Clin Chim Acta. 2004;34:139-144
Clinical References: 1. Salviati L, Trevisson E, Doimo M, Navas P: Primary coenzyme Q10

deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews [Internet]. University of
Washington, Seattle; 2017. Accessed July 15, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK410087/ 2. Desbats MA, Lunardi G, Doimo M, Trevisson E, Salviati
L: Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. J Inherit Metab Dis.
2015 Jan;38(1):145-56. doi: 10.1007/s10545-014-9749-9 3. Littarru GP, Tiano L: Clinical aspects of
coenzyme Q10: An update. Nutrition. 2010;26:250-254 4. Hargreaves I, Heaton RA, Mantle D: Disorders
of human coenzyme Q10 metabolism: An overview. Int J Mol Sci. 2020;21(18):6695. doi:
10.3390/ijms21186695 5. Banach M, Serban C, Ursoniu S, et al: Statin therapy and plasma coenzyme
Q10 concentrations-A systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res.
2015 Sep;99:329-336. oi: 10.1016/j.phrs.2015.07.008 6. Emmanuele V, Lopez LC, Berardo A, et al.
Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol.
2012;69(8):978-983. doi: 10.1001/archneurol.2012.206
TQ10 Coenzyme Q10, Total, Plasma

63148 Clinical Information: Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial
respiratory chain responsible for oxidative phosphorylation, where it functions as an electron carrier and
acts as an antioxidant. It is found in all cell membranes and is carried by lipoproteins in the circulation.
Approximately 60% of CoQ10 is associated with low-density lipoprotein (LDL), 25% with high-density
lipoprotein, and 15% with other lipoproteins. CoQ10 is present in the body in both the reduced and
oxidized forms, with the antioxidant activity of CoQ10 dependent on both its concentration and
reduction-oxidation (redox) status. CoQ10 deficiencies, which are clinically and genetically diverse, can
occur due to defects in genes involved in the biosynthesis of ubiquinone (primary CoQ10 deficiency) or
due to other causes such as mitochondrial disorders (secondary CoQ10 deficiency). Five major clinical
phenotypes of CoQ10 deficiency have been described: -Encephalomyopathy (elevated serum creatine
kinase [CK], recurrent myoglobinuria, lactic acidosis) -Cerebellar ataxia and atrophy (neuropathy,
hypogonadism) -Severe multisystemic infant form (nystagmus, optic atrophy, sensorineural hearing
loss, dystonia, rapidly progressing nephropathy) -Nephropathy, steroid resistant nephrotic syndrome
leading to end stage kidney disease -Isolated myopathy (exercise intolerance, fatigue, elevated serum
CK) Treatment with CoQ10 in patients with mitochondrial cytopathies can improve mitochondrial
respiration in both brain and skeletal muscle. CoQ10 has been implicated in other disease processes,
including Parkinson disease, diabetes, and Alzheimer disease, as well as in aging and oxidative stress.
CoQ10 may also play a role in hydroxymethylglutaryl-CoA reductase inhibitor (statin) therapy; changes
in CoQ10 may be relevant to statin-induced myalgia. Additionally, the redox status of CoQ10 may be a
useful early marker for the detection of oxidative LDL modification.
Useful For: Diagnosis of primary coenzyme Q10 (CoQ10) deficiencies in some patients who are not
supplemented with CoQ10 Monitoring patients receiving statin therapy Monitoring CoQ10 status
during treatment of various degenerative conditions including Parkinson and Alzheimer disease
Providing accurate quantitation of total CoQ10 when specimens are hemolyzed This test is not useful
for distinguishing primary CoQ10 deficiencies from acquired CoQ10 deficiencies.
available.
Reference Values:
<18 years: 320-1558 mcg/L
> or =18 years: 433-1532 mcg/L
Miles MV, Horn PS, Tang PH, et al: Age-related changes in plasma coenzyme Q10 concentrations and
redox state in apparently healthy children and adults. Clin Chim Acta. 2004;34:139-144
Clinical References: 1. Salviati L, Trevisson E, Doimo M, Navas P: Primary coenzyme Q10

deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al. eds. GeneReviews [Internet]. University of
Washington, Seattle; 2017. Accessed July 15, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK410087/ 2. Desbats MA, Lunardi G, Doimo M, Trevisson E, Salviati
L: Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. J Inherit Metab
Dis. 2015 Jan;38(1):145-156. doi: 10.1007/s10545-014-9749-9 3. Littarru GP, Tiano L: Clinical aspects
of coenzyme Q10: An update. Nutrition. 2010;26:250-254 4. Hargreaves I, Heaton RA, Mantle D:
Disorders of human coenzyme Q10 metabolism: An overview. Int J Mol Sci. 2020;21(18):6695. doi:
10.3390/ijms21186695 5. Banach M, Serban C, Ursoniu S, et al: Statin therapy and plasma coenzyme
Q10 concentrations-A systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res.
2015 Sep;99:329-336. doi: 10.1016/j.phrs.2015.07.008 6. Emmanuele V, Lopez LC, Berardo A, et al.
Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol.
2012;69(8):978-983. doi: 10.1001/archneurol.2012.206
FCOFE Coffee (Coffea spp) IgE

57525 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.1 Ã¢â‚¬â€œ 0.34 Equivocal 1
0.35 Ã¢â‚¬â€œ 0.69 Low Positive 2 0.70 Ã¢â‚¬â€œ 3.4 Moderate Positive 3 3.5 Ã¢â‚¬â€œ 17.4 High
Positive 4 17.5 Ã¢â‚¬â€œ 49.9 Very High Positive 5 50.0 Ã¢â‚¬â€œ 99.9 Very High Positive 6 >=100
Very High Positive
Reference Values:
<0.35 kU/L
ML20C COG Metaphases, 1-19 (Bill Only)

M25C COG Metaphases, 20-25 (Bill Only)

MG25C COG Metaphases, >25 (Bill Only)

CATTR Cold Agglutinin Titer, Serum

614034 Clinical Information: The cold agglutinin titer test is to be used as a tool in the evaluation of
suspected cold agglutinin syndrome. In this syndrome, cold agglutinins, usually IgM with anti-I
specificity, attach to the patient's erythrocytes causing a variety of symptoms. Symptoms may include
chronic anemia due to premature removal of the sensitized erythrocytes from circulation by hemolysis, to
acrocyanosis of the ears, fingers, or toes due to local blood stasis in the skin capillaries.
Useful For: Detection of cold agglutinins in patients with suspected cold agglutinin disease This test is
not recommended to diagnose Mycoplasma pneumoniae infections.
Interpretation: Titers above 64 are considered elevated, but hemolytic anemia resulting from
cold-reactive autoagglutinins rarely occurs unless the titer is 1000 or above. Titers below 1000 may be
obtained when the autoantibody has a different specificity (eg, anti-i) or if the cold agglutinin is of the
less-common low-titer, high-thermal-amplitude type. The test is not a direct measure of clinical
significance and must be used in conjunction with other in vitro and in vivo parameters.
Reference Values:
Titer results:
>64: Elevated
>1000: May be indicative of hemolytic anemia
Clinical References: Cohn CS, Delaney M, Johnson ST, Katz LM, eds: Technical Manual. 20th
ed. AABB; 2020
COLIV Collagen IV Immunostain, Technical Component Only

70408 Clinical Information: Collagen IV stains the basal lamina of capillaries as well as basement
membrane structures in all organs. In the kidney, the antibody stains the glomerular and tubular
basement membranes and mesangial cells and matrix within the glomerulus.
Useful For: A marker of the basal lamina of capillaries and basement membranes in all organs
Clinical References: 1. Abreu-Velez AM, Howard MS: Collagen IV in normal skin and in
pathological processes. N Am J Med Sci. 2012 Jan;4(1):1-8 2. Agarwal P, Ballabh R: Expression of
type IV collagen in different histological grades of oral squamous cell carcinoma: an
immunohistochemical study. J Cancer Res Ther. 2013 Apr-Jun;9(2):272-275 3. Girolamo F, Errede M,
Longo G, et al: Defining the role of NG2-expressing cells in experimental models of multiple sclerosis.
A biofunctional analysis of the neurovascular unit in wild type and NG2 null mice. PLoS One. 2019
Mar 14;14(3):e0213508. doi: 10.1371/journal.pone.0213508
FFTYC Collagen Type II Antibodies

91496 Interpretation: Anti-collagen II antibodies occur in 22% of patients with idiopathic SNHL, 30% of
patients with sudden deafness and 20% of patients with MeniereÃ¢â‚¬â„¢s disease. Anti-collagen II
antibodies also occur in patients with relapsing polychondritis and in rheumatoid arthritis.
Reference Values:
Negative: <20 EU/mL
Borderline/Equivocal: 20-25 EU/mL
Positive: >25 EU/mL
MSCG Collagenofibrotic Glomerulopathy Confirmation, Mass

615298 Spectrometry
Clinical Information: Collagenofibrotic glomerulopathy (CG) also called collagen type III
glomerulopathy, is a rare kidney disease characterized by large amounts of atypical type III collagen
fibrils in the mesangium and subendothelial space of renal glomeruli. Liquid chromatography-tandem
mass spectrometry performed on microdissected glomeruli from patients with CG demonstrates a
unique proteomic profile. The presence of type III collagen, in the appropriate clinical and pathological
context, can be useful to establish a diagnosis of CG.
Useful For: Aiding in the diagnosis of collagenofibrotic glomerulopathy
Interpretation: An interpretation will be provided.
Clinical References: 1. Chen X, Wan H, Xu W, Zhu J: Collagen type III glomerulopathy: Case
report and review of the literature. Clin Nephrol. 2017 Jan;87:39-46. doi: 10.5414/CN108907 2. Dong J,
Wei H, Han M, Guan Y, Wu Y, Li H: Collagen type III glomerulopathy: A case report and review of 20
cases. Exp Ther Med. 2015 Oct;10(4):1445-1449. doi: 10.3892/etm.2015.2695 3. Kurien AA, Larsen CP,
Cossey N: Collagenofibrotic glomerulopathy. Clin Kidney J. 2015 Oct;8(5):543-547. doi:
10.1093/ckj/sfv061 4. Cohen AH: Collagen Type III Glomerulopathies. Adv Chronic Kidney Dis. 2012
Mar;19(2):101-106. doi: 10.1053/j.ackd.2012.02.017 5. Duggal R, Nada R, Rayat CS, Rane SU, Sakhuja
V, Joshi K: Collagenofibrotic glomerulopathy - a review. Clin Kidney J. 2012 Feb;5(1):7-12. doi:
10.1093/ndtplus/sfr144
CRMWS Collapsin Response-Mediator Protein-5-IgG, Western Blot,

83107 Serum
Clinical Information: Autoantibodies specific for neurons and muscle are important serological
markers of neurological autoimmunity. Most are highly predictive of specific neoplasms that are
metastatic when diagnosed, but usually limited in spread to regional lymph nodes and adjacent
structures.(1-4) Collapsin response-mediator protein-5 (CRMP-5) is highly expressed in small-cell lung
carcinomas (SCLC), in neurons throughout the adult central and peripheral nervous systems, and in a
subset of glial cells.(1) In Western blot analyses the native antigen is a 62-kDa protein (recombinant
human CRMP-5 is 68-kDa).(1) CRMP-5-IgG (also known as anti-CV-2)(4,5) is a more common
autoantibody accompaniment of SCLC than antineuronal nuclear antibodies-1 (ANNA-1; anti-Hu) and
sometimes occurs with thymoma. The neurological presentation of CRMP-5 seropositive patients is
usually multifocal, and can affect any level of the neuraxis. Neurological presentations that suggest a
CRMP-5-IgG-related syndrome include subacute chorea or cranial neuropathy (particularly loss of vision,
taste, or smell), dementia, myelopathy and gastrointestinal dysmotility in a patient with risk factors for
lung cancer, or encephalopathy or neuromuscular hyperexcitability in a patient with serological or clinical
evidence of myasthenia gravis.(1) Fourteen percent of patients have thromboembolic phenomena.
Seropositive patients who have thymoma usually present with other myasthenia gravis neurological
manifestations (eg, encephalopathy, disorders of continuous muscle fiber activity).(3) CRMP-5-IgG is
defined in serum or spinal fluid (CSF) by its characteristic immunofluorescence (IF) staining pattern on a
mixed tissue substrate of adult mouse central and peripheral neurons. However, CRMP-5-IgG is not
detectable by standard IF screening if the titer is low (serum <1:240; CSF <1:2) or if coexisting
autoantibodies, either neuron-specific or nonorgan-specific antinuclear and antimitochondrial antibodies,
preclude identification of CRMP-5-IgG with certainty. In these situations, CRMP-5-IgG may be detected
by Western blot analysis.
Useful For: Evaluation of cases of chorea, vision loss, cranial neuropathy and myelopathy
Interpretation: A positive result confirms that a patient's subacute neurological disorder has an
autoimmune basis, and is likely to be associated with a small-cell lung carcinoma (SCLC) or thymoma,
which may be occult.(1,2) A positive result has a predictive value of 90% for neoplasm (77% SCLC, 6%
thymoma).(1) Seropositivity is found in approximately 3% of patients who have SCLC with limited
metastasis without evidence of neurological autoimmunity.(6) Clinical-serological correlations have not
yet been established for children. Western blot analysis is indicated when interfering nonorgan-specific or
coexisting neuron-specific autoantibodies in serum or spinal fluid preclude unambiguous detection of
CRMP-5-IgG by indirect immunofluorescence assay, or when the immunofluorescence assay is negative
in a patient whose neurological presentation suggests a CRMP-5-IgG-related syndrome.
Reference Values:
Negative
Clinical References: 1. Yu Z, Kryzer TJ, Griesmann GE, et al: CRMP-5 neuronal autoantibody:
marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001 February;49(2):146-154 2.
Vernino S, Tuite P, Adler CH, et al: Paraneoplastic chorea associated with CRMP-5 neuronal antibody
and lung carcinoma. Ann Neurol 2002 May;51(5):625-630 3. Vernino S, Lennon VA: Autoantibody
profiles and neurological correlations of thymoma. Clin Cancer Res 2004;10(21):7270-7275 4. Galanis E,
Frytak S, Rowland KM Jr, et al: Neuronal autoantibody titers in the course of small cell lung carcinoma
and platinum associated neuropathy. Cancer Immunol Immunother 1999 May-June;48(2-3):85 5. Klein
CJ: Autoimmune-mediated peripheral neuropathies and autoimmune pain In Handbook of Clinical
Neurology; Autoimmune Neurology. Edited by SJ Pittock, A Vincent.Â Elsevier; 2016 pp 417-446
CRMWC Collapsin Response-Mediator Protein-5-IgG, Western Blot,

21747 Spinal Fluid
Clinical Information: Autoantibodies specific for neurons and muscle are important serological
markers of neurological autoimmunity. Most are highly predictive of specific neoplasms that are
metastatic when diagnosed, but usually limited in spread to regional lymph nodes and adjacent
structures.(1-4) Collapsin response-mediator protein-5 (CRMP-5) is highly expressed in small-cell lung
carcinomas (SCLC), in neurons throughout the adult central and peripheral nervous systems, and in a
subset of glial cells.(1) In Western blot analyses, the native antigen is a 62-kDa protein (recombinant
human CRMP-5 is 68 kDa).(1) CRMP-5-IgG (also known as "anti-CV-2")(4,5) is a more common
autoantibody accompaniment of SCLC than antineuronal nuclear antibodies-1 (ANNA-1; anti-Hu) and
sometimes occurs with thymoma. The neurological presentation of CRMP-5 seropositive patients is
usually multifocal, and can affect any level of the neuraxis. Neurological presentations that suggest a
CRMP-5-IgG-related syndrome include subacute chorea or cranial neuropathy (particularly loss of
vision, taste, or smell), dementia, myelopathy and gastrointestinal dysmotility in a patient with risk
factors for lung cancer, or encephalopathy or neuromuscular hyperexcitability in a patient with
serological or clinical evidence of myasthenia gravis.(1) Fourteen percent of patients have
thromboembolic phenomena. Seropositive patients who have thymoma usually present with other
myasthenia gravis neurological manifestations (eg, encephalopathy, disorders of continuous muscle
fiber activity).(3) CRMP-5-IgG is defined in serum or spinal fluid (CSF) by its characteristic
immunofluorescence (IF) staining pattern on a mixed tissue substrate of adult mouse central and
peripheral neurons. However, CRMP-5-IgG is not detectable by standard IF screening if the titer is low
(serum <1:240; CSF <1:2) or if coexisting autoantibodies, either neuron-specific or nonorgan-specific
antinuclear and antimitochondrial antibodies, preclude identification of CRMP-5-IgG with certainty. In
these situations, CRMP-5-IgG may be detected by Western blot analysis.
Useful For: Evaluation of cases of chorea, vision loss, cranial neuropathy and myelopathy
Interpretation: A positive result confirms that a patient's subacute neurological disorder has an
autoimmune basis and is likely to be associated with a small-cell lung carcinoma (SCLC) or thymoma,
which may be occult.(1,2) A positive result has a predictive value of 90% for neoplasm (77% SCLC,
6% thymoma).(1) Seropositivity is found in approximately 3% of patients who have SCLC with limited
metastasis without evidence of neurological autoimmunity.(6) Clinical-serological correlations have not
yet been established for children.
Reference Values:
Negative
Clinical References: 1. Yu Z, Kryzer TJ, Griesmann GE, et al: CRMP-5 neuronal autoantibody:
marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001 February;49(2):146-154
2. Vernino S, Tuite P, Adler CH, et al: Paraneoplastic chorea associated with CRMP-5 neuronal
antibody and lung carcinoma. Ann Neurol 2002 May;51(5):625-630 3. Vernino S, Lennon VA:
Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res
2004;10(21):7270-7275 4. Galanis E, Frytak S, Rowland KM Jr, et al: Neuronal autoantibody titers in
the course of small cell lung carcinoma and platinum associated neuropathy. Cancer Immunol
Immunother 1999 May-June;48(2-3):85-90 5. Klein CJ: Autoimmune-mediated peripheral neuropathies
and autoimmune pain In Handbook of Clinical Neurology; Autoimmune Neurology. Edited by SJ
Pittock, A Vincent. Elsevier; 2016 pp 417-446
MITOT Combined Mitochondrial Analysis, Mitochondrial Full Genome

65212
and Nuclear Gene Panel, Varies
Clinical Information: The mitochondrion occupies a unique position in eukaryotic biology. It is the
site of energy metabolism, and it is the sole subcellular organelle that is composed of proteins derived
from 2 genomes, mitochondrial and nuclear. A group of hereditary disorders due to variants in either the
mitochondrial genome or nuclear mitochondrial genes have been well characterized. The diagnosis of
mitochondrial disease can be particularly challenging as the presentation can occur at any age, involve
virtually any organ system, and be associated with widely varying severities. Due to the considerable
overlap in the clinical phenotypes of various mitochondrial disorders, it is often difficult to distinguish
these specific inherited disorders without genetic testing. This test utilizes massively parallel sequencing,
also termed next-generation sequencing (NGS), to analyze 176 nuclear-encoded genes implicated in
mitochondrial disease and to determine the exact sequence of the entire 16,569 base-pair mitochondrial
genome. The utility of this test is to assist in the diagnosis of mitochondrial diseases that result from
variants in both nuclear encoded genes and in the mitochondrial genome. Those diseases involving
nuclear genes include disorders of mitochondrial protein synthesis, coenzyme Q10 biosynthesis,
respiratory chain complexes, and mtDNA maintenance (ie, mitochondrial DNA depletion disorders).
Disorders of the mitochondrial genome include those caused by point alterations, such as mitochondrial
encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS), myoclonic epilepsy with ragged red
fibers (MERRF), mitochondrial myopathy (MM), neurogenic muscle weakness, ataxia, and retinitis
pigmentosa (NARP), Leigh syndrome, Leber hereditary optic neuropathy (LHON), and chronic
progressive external ophthalmoplegia (CPEO). In addition to the detection of single base changes with
these disorders, large deletions, such as those associated with Kearns-Sayre or Pearson syndromes, are
also detected. In contrast to variants in nuclear genes, which are present in either 0, 1, or 2 copies,
mitochondrial variants can be present in any fraction of the total organelles, a phenomenon known as
heteroplasmy. Typically, the severity of disease presentation is a function of the degree of heteroplasmy.
Individuals with a higher fraction of altered mitochondria present with more severe disease than those
with lower percentages of altered alleles. The sensitivity for the detection of altered alleles in a
background of wild-type (or normal) mitochondrial sequences by NGS is approximately 10%. See
Targeted Genes Interrogated by Mitochondrial Nuclear Gene Panel in Special Instructions for details
regarding the targeted nuclear genes identified by this test.
Useful For: Diagnosis of mitochondrial disease that results from variants in either nuclear-encoded
genes or the mitochondrial genome A second-tier test for patients in whom previous targeted gene variant
analyses for specific mitochondrial disease-related genes were negative Identification of variants known
to be associated with mitochondrial disease, allowing for predictive testing of at-risk family members
Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or
possible pathogenicity and reported with interpretive comments detailing their potential or known
significance. For mitochondrial DNA (mtDNA) alterations, the degree of heteroplasmy of each single
nucleotide or INDEL (insertion/deletion) variant, defined as the ratio (percentage) of variant sequence
reads to the total number of reads, will also be reported. Large mtDNA deletions will be reported as either
homoplasmic or heteroplasmic, but the degree of heteroplasmy will not be estimated, due to possible
preferential amplification of the smaller deletion product by long-range PCR.
Reference Values:
May;17(5):405-424 2. Munnich A, Rotig A, Cormier-Daire V, Rustin P: Clinical presentation of
respiratory chain deficiency. In: Valle D, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA eds. The
Online Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill; 2019. Accessed September 28,
2020. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225086827 3. Wallace DC,
Lott MT, Brown MD, Kerstann K: Mitochondria and neuro-ophthalmologic diseases. In: Valle D,
Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA et al, eds. The Online Metabolic and Molecular
Basis of Inherited Disease. McGraw-Hill; 2019. Accessed September 28, 2020.
https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225088522 4. Wong LJ:
Molecular genetics of mitochondrial disorders. Dev Disabil Res. Rev 2010 Jun;16(2):154-162
CMIL Common Millet, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to common millet Defining the allergen

Reference Values:
0 Negative

apply to all ages.
REED Common Reed, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to common reed Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
CVID Common Variable Immunodeficiency Confirmation Flow Panel,

87993 Blood
Clinical Information: Common variable immunodeficiency (CVID) is the most prevalent primary
immunodeficiency with a prevalence of CVID of 1:25,000 to 1:50,000.(1) It has a bimodal presentation
with a subset presenting in early childhood and a second set presenting between 15 and 40 years of age or
even later. CVID is characterized by hypogammaglobulinemia usually involving most or all of the
immunoglobulin classes (IgG, IgA, IgM, and IgE), impaired functional antibody responses, and recurrent
sinopulmonary infections.(1) B-cell numbers are usually normal, although a minority of patients
(5%-10%) have very low B-cell counts (<1% of peripheral blood leukocytes). It is reasonable to suspect a
transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) defect in
patients with low to absent IgA, low IgG, and low or normal IgM, along with splenomegaly, autoimmune
cytopenias, autoimmune thyroiditis, and tonsillar hypertrophy. In TACI-deficient patients, there may be
an increased risk for developing neoplasias such as non-Hodgkin lymphoma or other solid tumors. CD19
defects result in absence of B cells expressing CD19.(2) When an alternative B-cell marker such as CD20
is used, however, B cells can be detected in the blood of these patients. Of all patients with CVID, 25% to
30% have increased numbers of CD8 T cells and a reduced CD4/CD8 ratio (<1).(1) A subset (5%-10%)
exhibit noncaseating, sarcoid-like granulomas in different organs and also tend to develop a progressive T
cell deficiency.(1) Patients with variants in the TACI gene (see below) are particularly prone to
developing autoimmune disease, including cytopenias as well as lymphoproliferative disease. The
etiology of CVID is heterogeneous.(3,4) Variants of the gene that encodes TACI, TNFRSF13B (tumor
necrosis factor receptor superfamily, member 13B), probably account for about 10% to 15% of all CVID
cases.(3,5) Patients with variants in the TACI gene are particularly prone to developing autoimmune
disease, including cytopenias, as well as lymphoproliferative disease. The other variants each have been
reported in only a handful of patients. The etiopathogenesis is still undefined in more than 65% to 75% of
CVID patients.(3) A BAFF-R (B-cell activating factor receptor, encoded by the TNFRSF13C gene) defect
should be suspected in patients with low to very low class switched and non-switched memory B cells and
very high numbers of transitional B cells (see IABC / B-Cell Phenotyping Screen for Immunodeficiency
and Immune Competence Assessment, Blood).(6) Class switching is the process that allows B cells,
which possess IgD and IgM on their cell surface as a part of the antigen-binding complex, to produce IgA,
IgE, or IgG antibodies. A TACI defect is suspected in patients with low IgA and low IgG with normal to
low switched B cells, with autoimmune or lymphoproliferative manifestations or both, and normal B cell
responses to mitogens.
Useful For: Screening for common variable immunodeficiency (CVID) Identifying defects in TACI
(transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BAFF-R (B-cell
activating factor receptor) in patients presenting with clinical symptoms and other laboratory features
consistent with CVID Evaluating B cell immune competence by assessing expression of BAFF-R and
TACI proteins Assessing BAFF-R and TACI protein expression and frequency of B cells bearing these
receptors TNFRSF13C (BAFF-R) and TNFRSF13B (TACI) gene variants have been described in a
small subset of patients with humoral immunodeficiencies classified as CVID. The majority of
TNFRSF13B variants preserve TACI protein expression and require genetic testing to identify
disease-causing or potentially disease-causing variants. This test is not useful for general evaluation of
immune competence.
Interpretation: B-cell activating factor receptor (BAFF-R) is normally expressed on over 95% of B
cells, while TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) is
expressed on a smaller subset of B cells (3%-70%) and some activated T cells. Expression on B cells
increases with B-cell activation. The lack of TACI or BAFF-R surface expression on B cells is
suggestive of a potential common variable immunodeficiency (CVID)-associated defect if other features
of CVID are present. The majority of TACI variants (>95%) preserve protein expression but abrogate
protein function, hence the only way to conclusively establish a TACI alteration is to perform
TNFRSF13B genetic testing.
Reference Values:
%CD19+TACI+: >3.4%
%CD19+BAFF-R+: >90.2%
Clinical References: 1. Warnatz K, Denz A, Drager R, et al: Severe deficiency of switched

memory B cells (CD27+ IgM-IgD-) in subgroups of patients with common variable immunodeficiency:
a new approach to classify a heterogeneous disease. Blood. 2002 Mar 1;99(5):1544-1551 2. van Zelm
M, Reisli I, van der Burg M, et al: An antibody-deficiency syndrome due to mutations in the CD19
gene. N Engl J Med. 2006 May 4;354(18):1901-1912 3. Salzer U, Grimbacher B: TACI deficiency - a
complex system out of balance. Curr Opin Immunol. 2021 Aug;71:81-88. doi:10.1016/j.coi.2021.06.004
4. Ramirez NJ, Posadas-Cantera S, Caballero-Oteyza A, Camacho-Ordonez N, Grimbacher B. There is
no gene for CVID - novel monogenetic causes for primary antibody deficiency. Curr Opin Immunol.
2021 Oct;72:176-185. doi:10.1016/j.coi.2021.05.010 5. Salzer U, Chapel HM, Webster AD, et al:
Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in
humans. Nat Genet. 2005 Aug;37(8):820-828 6. Warnatz K, Salzer U, Gutenberger S, et al: Finally
found: human BAFF-R deficiency causes hypogammaglobulinemia. Clin Immunol. 2005;115(Suppl
1):820
CO4D Complement 4d Immunostain, Technical Component Only

70407 Clinical Information: Complement 4d (C4d) is a split product resulting from complement
activation. The deposition of C4d on the walls of peritubular capillaries in kidney allografts or
capillaries in cardiac allografts has been associated with antibody-mediated transplant rejection.
Useful For: Identification of antibody-mediated transplant rejection
Clinical References: 1. Roden AC, Maleszewski JJ, Yi ES, et al. Reproducibility of complement 4d
deposition by immunofluorescence and immunohistochemistry in lung allograft biopsies. J Heart Lung
Transplant. 2014;33(12):1223-1232. doi: 10.1016/j.healun.2014.06.006 2. Miller DV, Roden AC, Gamez
JD, Tazelaar HD: Detection of C4d deposition in cardiac allografts: a comparative study of
immunofluorescence and immunoperoxidase methods. Arch Pathol Lab Med. 2010;134(11):1679-1684.
doi: 10.1043/2009-0511-OAR1.1 3. Troxell ML, Lanciault C: Practical applications in
immunohistochemistry: Evaluation of rejection and infection in organ transplantation. Arch Pathol Lab
Med. 2016;140(9):910-925. doi: 10.5858/arpa.2015-0275-CP
C1Q Complement C1q, Serum

8851 Clinical Information: The first component of complement (C1) is composed of 3 subunits designated
as C1q, C1r, and C1s. C1q recognizes and binds to immunoglobulin complexed to antigen and initiates
the complement cascade. Congenital deficiencies of any of the early complement components (C1, C2,
C4) results in an inability to clear immune complexes. Inherited deficiency of C1 is rare. Like the more
common C2 deficiency, C1 deficiency is associated with increased incidence of immune complex disease
(systemic lupus erythematosus, polymyositis, glomerulonephritis, and Henoch-Schonlein purpura). Low
C1 levels have also been reported in patients with abnormal immunoglobulin levels (Bruton and common
variable hypogammaglobulinemia and severe combined immunodeficiency). This is most likely due to
increased catabolism. The measurement of C1q is an indicator of the amount of C1 present.
Useful For: Assessment of an undetectable total complement (CH50) level Diagnosing congenital C1
(first component of complement) deficiency Diagnosing acquired deficiency of C1 inhibitor
Interpretation: An undetectable C1q in the presence of an absent total complement (CH50) and
normal C2, C3, and C4 suggests a congenital C1 (first component of complement) deficiency. A low C1q
in combination with a low C1 inhibitor and low C4 suggests an acquired C1 inhibitor deficiency.
Reference Values:
12-22 mg/dL
Clinical References: 1. Frank MM: Complement in the pathophysiology of human disease. N Engl J
Med 1987 June 11;316(24):1525-1530 2. Frank MM: Complement deficiencies. Pediatr Clin North Am
2000 December;47(6):1339-1354 3. Frigas E: Angioedema with acquired deficiency of the C1 inhibitor: a
constellation of syndromes. Mayo Clin Proc 1989 October;64(10):1269-1275
C3 Complement C3, Serum

8174 Clinical Information: The complement system is an integral part of the body's immune defenses. The
primary complement pathway consists of recognition (Clq, Clr, Cls), activation (C4, C2, C3), and attack
(C5, C6, C7, C8, C9) mechanisms with respect to their role in antibody-mediated cytolysis. The
complement system can be activated via immune complexes, and the alternative pathway (properdin
pathway), which is activated primarily by foreign bodies such as microorganisms. C3 activation involves
cleavage by C3 convertase into C3a and C3b. When immune complexes are not involved, the alternate
method of complement activation initiates the reactant sequence at C3, bypassing C1, C4, and C2. Severe
recurrent bacterial infections occur in patients with homozygous C3 deficiency and in those patients with
low levels of C3 secondary to the absence of C3b activator. Decreased C3 may be associated with acute
glomerulonephritis, membranoproliferative glomerulonephritis, immune complex disease, active systemic
lupus erythematosus, septic shock, and end-stage liver disease.
Useful For: Assessing disease activity in systemic lupus erythematosus (SLE) Investigating an
undetectable total complement (CH50) level
Interpretation: A decrease in C3 levels to the abnormal range is consistent with disease activation in
systemic lupus erythematosus (SLE).
Reference Values:
75-175 mg/dL
Clinical References: 1. Ross SC, Densen P: Complement deficiency states and infection:
epidemiology, pathogenesis, and consequences of neisserial and other infections in an immune
deficiency. Medicine 1984;63:243-273 2. Frank MM: Complement in the pathophysiology of human
disease. N Engl J Med 1987;316:1525-1530
C4 Complement C4, Serum

8171 Clinical Information: The complement system is an integral part of the immune defenses. It can be
activated via immune complexes (classic pathway) or by bacterial polysaccharides (alternative
pathway). The classic complement pathway consists of recognition, (C1q, C1r, C1s), activation (C2, C3,
C4), and attack (C5, C6, C7, C8, C9) mechanisms with respect to their role in antibody-mediated
cytolysis. C4 is one of the activation proteins of the classic pathway. In the absence of C4, immune
complexes will not be cleared by C3 activation peptides, but bacterial infections can still be defended
via the alternative pathway. C4 may be decreased in systemic lupus erythematosus, early
glomerulonephritis, immune complex disease, cryoglobulinemia, hereditary angioedema, and congenital
C4 deficiency.
Useful For: Investigating an undetectable total complement (CH50) Confirming hereditary

angioedema (with low C1 inhibitor) Assessing disease activity in systemic lupus erythematosus,
proliferative glomerulonephritis, rheumatoid arthritis, and autoimmune hemolytic anemia
Interpretation: C4 levels will be decreased in acquired autoimmune disorders, in active phase of

lupus erythematosus, and in rheumatoid arthritis An undetectable C4 level (with normal C3) suggests a
congenital C4 deficiency Levels will be increased in patients with autoimmune hemolytic anemia
Reference Values:
14-40 mg/dL
Clinical References: 1. Ross SC, Densen P: Complement deficiency states and infection:
epidemiology, pathogenesis, and consequences of neisserial and other infections in an immune
deficiency. Medicine 1984;63:243-273 2. Frank MM: Complement in the pathophysiology of human
disease. N Engl J Med 1987;316:1525-1530 3. Tiffany TO: Fluorometry, nephelometry, and
turbidimetry. In Textbook of Clinical Chemistry. Edited by NW Tietz. Philadelphia, WB Saunders
Company, 1986, pp 79-97
COM Complement, Total, Serum

8167 Clinical Information: Complement (C) proteins are components of the innate immune system.
There are 3 pathways to complement activation: 1) the classical pathway, 2) the alternative (or
properdin) pathway, and 3) the lectin (or mannan-binding lectin) pathway. The classical pathway of the
complement system is composed of a series of proteins that are activated in response to the presence of
immune complexes. A single IgM molecule or two IgG molecules are sufficient to trigger activation of
the recognition complex initiated by C1q. The activation process triggers a cascade that includes an
amplification loop. The amplification loop is mediated by C3, with cleavage of a series of proteins, and
results in three main end products: 1) anaphylatoxins which promote inflammation (C3a, C5a), 2)
opsonization peptides that are chemotactic for neutrophils (C3b) and facilitate phagocytosis, and 3) the
membrane attack complex (MAC), which promotes cell lysis. The absence of early components (C1,
C2, C3, C4) of the complement cascade results in the inability of immune complexes to activate the
cascade. Patients with deficiencies of the early complement proteins are unable to generate the peptides
that are necessary to clear immune complexes and to attract neutrophils or to generate lytic activity.
These patients have increased susceptibility to infections with encapsulated microorganisms. They may
also have symptoms that suggest autoimmune disease; complement deficiency may be an etiologic
factor in the development of autoimmune disease. Patients with deficiencies of the late complement
proteins (C5, C6, C7, C8, and C9) are unable to form the MAC and may have increased susceptibility to
neisserial infections. Undetectable complement levels are found in patients with specific component
deficiencies. Decreased complement levels are found in infectious and autoimmune diseases due to
fixation and consumption of complement.
Useful For: Detection of individuals with an ongoing immune process First-tier screening test for
congenital complement deficiencies
Interpretation: Low levels of total complement (total hemolytic complement) may occur during
infections, disease exacerbation in patients with systemic lupus erythematosus, and in patients with
immune complex diseases such as glomerulonephritis. Undetectable levels suggest the possibility of a
complement component deficiency. Individual complement component assays are useful to identify the
specific deficiency.
Reference Values:
30-75 U/mL
Clinical References: 1. Daha MR: Role of complement in innate immunity and infections. Crit Rev
Immunol. 2010;30(1):47-52. doi: 10.1615/critrevimmunol.v30.i1.30 2. Prohaszka Z, Varga L, Fust G: The
use of â€˜real-timeâ€™ complement analysis to differentiate atypical haemolytic uraemic syndrome from
other forms of thrombotic microangiopathies. Br J Haematol. 2012 Aug;158(3):424-425. doi:
10.1111/j.1365-2141.2012.09168.x 3. Cataland SR, Holers VM, Geyer S, Yang S, Wu HM: Biomarkers
of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP.
Blood. 2014 Jun;123(24):3733-3738. doi: 10.1182/blood-2013-12-547067 4. Frazer-Abel A, Sepiashvili
L, Mbughuni MM, Willrich MA: Overview of laboratory testing and clinical presentations of complement
deficiencies and dysregulation. Adv Clin Chem. 2016;77:1-75. doi: 10.1016/bs.acc.2016.06.001
AHUSP Complement-Mediated Atypical Hemolytic-Uremic Syndrome

64663 (aHUS)/Thrombotic Microangiopathy (TMA) Gene Panel, Varies
Clinical Information: Complement-mediated hemolytic uremic syndrome, also known as atypical
hemolytic uremic syndrome (aHUS), is a well-recognized disease entity characterized by complement
activation in the microvasculature. Abnormalities of the alternate pathway of complement, which may be
inherited (genetic) or acquired, underlie both the sporadic and familial forms of the disease and are
identified in at least two-thirds (approximately 60%) of patients. Unlike many other monogenic disorders
of the immune system, multiple hits may be required for disease manifestation, which may include a
trigger event (transplantation, pregnancy, malignant hypertension, autoimmune disorders, sepsis,
malignancy, etc), and 1 or more contributing genetic variants or haplotypes in the alternate pathway
complement genes. The overall prognosis is poor with most patients developing end-stage kidney disease
or permanent kidney injury within 1 year of diagnosis despite plasma exchange (PLEX/PEX) or plasma
infusion (PI) therapy. Kidney transplantation in most patients is also associated with a poor prognosis
with loss of the allograft. Drugs targeting the complement pathway, notably Eculizumab, have achieved
success in modulating clinical remission and there are a few reports of combined liver-kidney transplants
for these patients. Newer therapies are also likely to emerge over time. Individuals with genetic aHUS
frequently experience relapse even after complete recovery following the presenting episode.
Complement-mediated HUS presents with clinical features that are nearly identical to thrombotic
thrombocytopenic purpura (TTP) and Shiga-toxin HUS (ST-HUS), making laboratory differentiation
essential. TTP is a rare clinical entity but is an important diagnosis as it is associated with very high
mortality (90%) if untreated. Mortality can be reduced by early PLEX. Congenital TTP is due to genetic
defects in the ADAMTS13 gene, while acquired TTP is related to autoantibodies against ADAMTS13,
which reduces function. While TTP was initially characterized by thrombocytopenia, microangiopathic
hemolytic anemia, fluctuating neurological signs, kidney failure and fever, the disease can present with
only some of these features. The thrombotic microangiopathies (TMA) cover both aHUS and TTP and the
clinical distinctions are not always clear-cut. Besides the thrombocytopenia, which is one of the key
features of TMA, there is presence of schistocytes and highly increased levels of lactate dehydrogenase.
Complement-mediated HUS is considered genetic when 2 or more members of the same family are
affected by the disease at least 6 months apart and exposure to a common triggering infectious agent has
been excluded, or when pathogenic variants are identified in 1 or more of the genes known to be
associated with aHUS, irrespective of familial history. A patient may have both autoantibodies to
complement alternate pathway proteins and genetic defects in these genes. It is important to note that
certain genetic defects in these genes, eg, complement C3, may be associated with a more classic
immunodeficiency phenotype with recurrent infections with encapsulated pathogens and connective tissue
diseases with no evidence of aHUS/TMA. Table. Genes included in this panel Gene symbol (alias)
Protein OMIM Incidence Inheritance Phenotype disorder ADAMTS13 A disintegrin and
metalloproteinase with thrombospondin motifs 13 isoform 1 preproprotein 604134 Not available AR
Familial thrombotic thrombocytopenic purpura C3 Complement C3 preproprotein 120700 Approximately
5% of aHUS AD, AR C3 deficiency (AR), susceptibility to aHUS (AD) CD46 (MCP) Membrane cofactor
protein isoform 1 precursor 120920 Approximately 12% of aHUS AD, AR Susceptibility to aHUS 2 CFB
Complement factor B preproprotein 138470 Rare AD Complement factor B deficiency, susceptibility to
aHUS 4 CFD Complement factor D isoform 1 preproprotein 134350 Rare AR Complement factor D
deficiency CFH Complement factor H isoform a precursor 134370 Approximately 30% of aHUS patients
AD, AR Complement factor H deficiency, susceptibility to aHUS 1 CFHR1 Complement factor H-related
protein 1 precursor 134371 Rare AD, AR Susceptibility to aHUS CFHR3 Complement factor H-related
protein 3 isoform 1 precursor 605336 Rare AD, AR Susceptibility to aHUS CFHR5 Complement factor
H-related protein 5 precursor 608593 3% of aHUS AD Nephropathy due to CFHR5 deficiency CFI
Complement factor I isoform 2 preproprotein 217030 4%-10% of aHUS AD, AR Complement factor I
deficiency (AR), susceptibility to aHUS (AD) DGKE Diacylglycerol kinase epsilon 601440 Rare AR
Nephrotic syndrome Type 7, susceptibility to aHUS PLG Plasminogen isoform 1 precursor 173350 Rare
AR Dysplasminogenemia, plasminogen deficiency Type I THBD Thrombomodulin precursor 188040
Approximately 3%-5% of aHUS AD Thrombophilia due to thrombomodulin defect, susceptibility to
aHUS
history suggestive of complement-mediated hemolytic uremic syndrome (HUS)/atypical HUS (aHUS)
or thrombotic microangiopathies (TMA) Establishing a diagnosis and, in some cases, allowing for
appropriate management and surveillance for disease features based on the gene involved Identifying
variants in genes encoding complement alternate pathway components and specific coagulation
pathway genes known to be associated with increased risk for aHUS/TMA allowing for predictive
testing of at-risk family members
Reference Values:
May;17(5):405-424 2. Picard C, Gaspar HB, Al-Herz W, et al: International Union of Immunological
Societies: 2017 Primary Immunodeficiency Disease Committee Report on inborn errors of immunity. J
Clin Immunol. 2018;38:96-128 3. Noris M, Bresin E, Mele C, et al: Genetic atypical hemolytic-uremic
syndrome. In: Adam MP, Ardinger HH, Pagon RA, eds. GeneReviews [Internet]. University of
Washington, Seattle; 2007. Updated June 9, 2016. Accessed July 2018. Available at
www.ncbi.nlm.nih.gov/books/NBK1367/ 4. Kavanagh D, Goodship THJ: Atypical hemolytic uremic
syndrome, genetic basis and clinical manifestations. Hematology. (ASH); 2011:15-20 5. George JN,
Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371:1654-1666 6. Go RS,
Winters JL, Leung N, et al: Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the
Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA)
Disease-Oriented Group. Mayo Clin Proceedings. 2016;91(9):1189-1211
CBC Complete Blood Cell Count (CBC) with Differential, Blood

9109 Clinical Information: RBCs, WBCs, and platelets are produced in the bone marrow and released into
the peripheral blood. The primary function of the RBC is to deliver oxygen to tissues. WBCs are key
components of the immune system. Platelets play a vital role in blood clotting. Mean corpuscular volume
(MCV) is a measure of the size of the average RBC. Anemias are characterized as microcytic (MCV
<80), macrocytic (MCV >100), or normocytic. The red cell distribution width (RDW) is a measure of the
degree of variation in RBC size (anisocytosis). RDW may be helpful in distinguishing between some
anemias. For example, iron deficiency anemia is characterized by a high RDW, while thalassemia is
characterized by a low RDW. These counts are used as clinical guides in the diagnosis or monitoring of
many diseases.
Useful For: Screening tool to confirm a hematologic disorder, to establish or rule out a diagnosis, to
detect an unsuspected hematologic disorder, or to monitor effects of radiation or chemotherapy
Interpretation: Results outside of normal value ranges may reflect a primary disorder of the
cell-producing organs or an underlying disease. Results should be interpreted in conjunction with the
patient's clinical picture and appropriate additional testing performed.
Reference Values:
RED BLOOD CELL COUNT (RBC)
Males:
0-14 days: 4.10-5.55 x 10(12)/L
15 days-4 weeks: 3.16-4.63 x 10(12)/L
5 weeks-7 weeks: 3.02-4.22 x 10(12)/L
8 weeks-5 months: 3.43-4.80 x 10(12)/L
6 months-23 months: 4.03-5.07 x 10(12)/L
24 months-35 months: 3.89-4.97 x 10(12)/L
3-5 years: 4.00-5.10 x 10(12)/L
6-10 years: 4.10-5.20 x 10(12)/L
11-14 years: 4.20-5.30 x 10(12)/L
15-17 years: 4.30-5.70 x 10(12)/L
Adults: 4.35-5.65 x 10(12)/L
Females:
0-14 days: 4.12-5.74 x 10(12)/L
15 days-4 weeks: 3.32-4.80 x 10(12)/L
5 weeks-7 weeks: 2.93-3.87 x 10(12)/L
8 weeks-5 months: 3.45-4.75 x 10(12)/L
6 months-23 months: 3.97-5.01 x 10(12)/L
24 months-35 months: 3.84-4.92 x 10(12)/L
3-5 years: 4.00-5.10 x 10(12)/L
6-10 years: 4.10-5.20 x 10(12)/L
11-14 years: 4.10-5.10 x 10(12)/L
15-17 years: 3.80-5.00 x 10(12)/L
Adults: 3.92-5.13 x 10(12)/L
HEMOGLOBIN
Males:
0-14 days: 13.9-19.1 g/dL
15 days-4 weeks: 10.0-15.3 g/dL
5 weeks-7 weeks: 8.9-12.7 g/dL
8 weeks-5 months: 9.6-12.4 g/dL
6 months-23 months: 10.1-12.5 g/dL
3-5 years: 11.4-14.3 g/dL
6-8 years: 11.5-14.3 g/dL
9-10 years: 11.8-14.7 g/dL
11-14 years: 12.4-15.7 g/dL
15-17 years: 13.3-16.9 g/dL
Adults: 13.2-16.6 g/dL
Females:
0-14 days: 13.4-20.0 g/dL
15 days-4 weeks: 10.8-14.6 g/dL
5 weeks-7 weeks: 9.2-11.4 g/dL
8 weeks-5 months: 9.9-12.4 g/dL
3-5 years: 11.4-14.3 g/dL
6-8 years: 11.5-14.3 g/dL
9-10 years: 11.8-14.7 g/dL
11-17 years: 11.9-14.8 g/dL
Adults: 11.6-15.0 g/dL
HEMATOCRIT
Males:
0-14 days: 39.8-53.6%
15 days-4 weeks: 30.5-45.0%
5 weeks-7 weeks: 26.8-37.5%
8 weeks-5 months: 28.6-37.2%
6 months-23 months: 30.8-37.8%
24 months-35 months: 31.0-37.7%
3-7 years: 34-42%
8-11 years: 35-43%
12-15 years: 38-47%
16-17 years: 40-50%
Adults: 38.3-48.6%
Females:
0-14 days: 39.6-57.2%
15 days-4 weeks: 32.0-44.5%
5 weeks-7 weeks: 27.7-35.1%
8 weeks-5 months: 29.5-37.1%
24 months-35 months: 31.2-37.8%
3-7 years: 34-42%
8-17 years: 35-43%
Adults: 35.5-44.9%
MEAN CORPUSCULAR VOLUME (MCV)

Males:
0-14 days: 91.3-103.1 fL
15 days-4 weeks: 89.4-99.7 fL
5 weeks-7 weeks: 84.3-94.2 fL
8 weeks-5 months: 74.1-87.5 fL
6 months-23 months: 69.5-81.7 fL
3-5 years: 77.2-89.5 fL
6-11 years: 77.8-91.1 fL
12-14 years: 79.9-93.0 fL
15-17 years: 82.5-98.0 fL
Adults: 78.2-97.9 fL
Females:
0-14 days: 92.7-106.4 fL
15 days-4 weeks: 90.1-103.0 fL
5 weeks-7 weeks: 83.4-96.4 fL
8 weeks-5 months: 74.8-88.3 fL
3-5 years: 77.2-89.5 fL
6-11 years: 77.8-91.1 fL
12-14 years: 79.9-93.0 fL
15-17 years: 82.5-98.0 fL
Adults: 78.2-97.9 3 fL
RED CELL DISTRIBUTION WIDTH (RDW)

Males:
0-14 days: 14.8-17.0%
15 days-4 weeks: 14.3-16.8%
5 weeks-7 weeks: 13.8-16.1%
8 weeks-5 months: 12.4-15.3%
24 months-35 months: 12.5-14.9%
3-5 years: 11.3-13.4%
6-17 years: 11.4-13.5%
Adults: 11.8-14.5%
Females:
0-14 days: 14.6-17.3%
15 days-4 weeks: 14.4-16.2%
5 weeks-7 weeks: 13.6-15.8%
8 weeks-5 months: 12.2-14.3%
24 months-35 months: 12.4-14.9%
3-5 years: 11.3-13.4%
6-17 years: 11.4-13.5%
Adults: 12.2-16.1%
WHITE BLOOD CELL COUNT (WBC)

Males:
0-14 days: 8.0-15.4 x 10(9)/L
15 days-4 weeks: 7.8-15.9 x 10(9)/L
5 weeks-7 weeks: 8.1-15.0 x 10(9)/L
8 weeks-5 months: 6.5-13.3 x 10(9)/L
6 months-23 months: 6.0-13.5 x 10(9)/L
24 months-35 months: 5.1-13.4 x 10(9)/L
3-5 years: 4.4-12.9 x 10(9)/L
6-17 years: 3.8-10.4 x 10(9)/L
Adults: 3.4-9.6 x 10(9)/L
Females:
0-14 days: 8.2-14.6 x 10(9)/L
15 days-4 weeks: 8.4-14.4 x 10(9)/L
5 weeks-7 weeks: 7.1-14.7 x 10(9)/L
8 weeks-5 months: 6.0-13.3 x 10(9)/L
6 months-23 months: 6.5-13.0 x 10(9)/L
24 months-35 months: 4.9-13.2 x 10(9)/L
3-5 years: 4.4-12.9 x 10(9)/L
6-17 years: 3.8-10.4 x 10(9)/L
Adults: 3.4-9.6 x 10(9)/L
PLATELETS
Males:
0-14 days: 218-419 x 10(9)/L
15 days-4 weeks: 248-586 x 10(9)/L
5 weeks-7 weeks: 229-562 x 10(9)/L
8 weeks-5 months: 244-529 x 10(9)/L
6 months-23 months: 206-445 x 10(9)/L
24 months-35 months: 202-403 x 10(9)/L
3-5 years: 187-445 x 10(9)/L
6-9 years: 187-400 x 10(9)/L
10-13 years: 177-381 x 10(9)/L
14-17 years: 139-320 x 10(9)/L
Adults: 135-317 x 10(9)/L
Females:
0-14 days: 144-449 x 10(9)/L
15 days-4 weeks: 279-571 x 10(9)/L
5 weeks-7 weeks: 331-597 x 10(9)/L
8 weeks-5 months: 247-580 x 10(9)/L
6 months-23 months: 214-459 x 10(9)/L
24 months-35 months: 189-394 x 10(9)/L
3-5 years: 187-445 x 10(9)/L
6-9 years: 187-400 x 10(9)/L
10-13 years: 177-381 x 10(9)/L
14-17 years: 158-362 x 10(9)/L
Adults: 157-371 x 10(9)/L
NEUTROPHILS
Males:
0-14 days: 1.60-6.06 x 10(9)/L
15 days-4 weeks: 1.18-5.45 x 10(9)/L
5 weeks-7 weeks: 0.83-4.23 x 10(9)/L
8 weeks-5 months: 0.97-5.45 x 10(9)/L
6 months-23 months: 1.19-7.21 x 10(9)/L
24 months-35 months: 1.54-7.92 x 10(9)/L
3-5 years: 1.60-7.80 x 10(9)/L
6-16 years: 1.40-6.10 x 10(9)/L
17 years: 1.80-7.20 x 10(9)/L
Adults: 1.56-6.45 x 10(9)/L
Females:
0-14 days: 1.73-6.75 x 10(9)/L
15 days-4 weeks: 1.23-4.80 x 10(9)/L
5 weeks-7 weeks: 1.00-4.68 x 10(9)/L
8 weeks-5 months: 1.04-7.20 x 10(9)/L
6 months-23 months: 1.27-7.18 x 10(9)/L
24 months-35 months: 1.60-8.29 x 10(9)/L
3-5 years: 1.60-7.80 x 10(9)/L
6-14 years: 1.50-6.50 x 10(9)/L
15-17 years: 2.00-7.40 x 10(9)/L
Adults: 1.56-6.45 x 10(9)/L
LYMPHOCYTES
Males:
0-14 days: 2.07-7.53 x 10(9)/L
15 days-4 weeks: 2.11-8.38 x 10(9)/L
5 weeks-7 weeks: 2.47-7.95 x 10(9)/L
8 weeks-5 months: 2.45-8.89 x 10(9)/L
6 months-23 months: 1.56-7.83 x 10(9)/L
24 months-35 months: 1.13-5.52 x 10(9)/L
3-5 years: 1.60-5.30 x 10(9)/L
6-11 years: 1.40-3.90 x 10(9)/L
12-17 years: 1.00-3.20 x 10(9)/L
Adults: 0.95-3.07 x 10(9)/L
Females:
0-14 days: 1.75-8.00 x 10(9)/L
15 days-4 weeks: 2.42-8.20 x 10(9)/L
5 weeks-7 weeks: 2.29-9.14 x 10(9)/L
8 weeks-5 months: 2.14-8.99 x 10(9)/L
6 months-23 months: 1.52-8.09 x 10(9)/L
24 months-35 months: 1.25-5.77 x 10(9)/L
3-5 years: 1.60-5.30 x 10(9)/L
6-11 years: 1.40-3.90 x 10(9)/L
12-17 years: 1.00-3.20 x 10(9)/L
Adults: 0.95-3.07 x 10(9)/L
MONOCYTES
Males:
0-14 days: 0.52-1.77 x 10(9)/L
15 days-4 weeks: 0.28-1.38 x 10(9)/L
5 weeks-7 weeks: 0.28-1.05 x 10(9)/L
8 weeks-5 months: 0.28-1.07 x 10(9)/L
6 months-23 months: 0.25-1.15 x 10(9)/L
24 months-35 months: 0.19-0.94 x 10(9)/L
3-5 years: 0.30-0.90 x 10(9)/L
6-17 years: 0.20-0.80 x 10(9)/L
Adults: 0.26-0.81 x 10(9)/L
Females:
0-14 days: 0.57-1.72 x 10(9)/L
15 days-4 weeks: 0.42-1.21 x 10(9)/L
5 weeks-7 weeks: 0.28-1.21 x 10(9)/L
8 weeks-5 months: 0.24-1.17 x 10(9)/L
6 months-23 months: 0.26-1.08 x 10(9)/L
24 months-35 months: 0.24-0.92 x 10(9)/L
3-5 years: 0.30-0.90 x 10(9)/L
6-17 years: 0.20-0.80 x 10(9)/L
Adults: 0.26-0.81 x 10(9)/L
EOSINOPHILS
Males:
0-14 days: 0.12-0.66 x 10(9)/L
15 days-4 weeks: 0.08-0.80 x 10(9)/L
5 weeks-7 weeks: 0.05-0.57 x 10(9)/L
8 weeks-5 months: 0.03-0.61 x 10(9)/L
6 months-23 months: 0.02-0.82 x 10(9)/L
24 months-35 months: 0.03-0.53 x 10(9)/L
3-11 years: 0.00-0.50 x 10(9)/L
12-17 years: 0.10-0.20 x 10(9)/L
Adults: 0.03-0.48 x 10(9)/L
Females:
0-14 days: 0.09-0.64 x 10(9)/L
15 days-4 weeks: 0.06-0.75 x 10(9)/L
5 weeks-7 weeks: 0.04-0.63 x 10(9)/L
8 weeks-5 months: 0.02-0.74 x 10(9)/L
6 months-23 months: 0.02-0.58 x 10(9)/L
24 months-35 months: 0.03-0.46 x 10(9)/L
3-11 years: 0.00-0.50 x 10(9)/L
12-17 years: 0.10-0.20 x 10(9)/L
Adults: 0.03-0.48 x 10(9)/L
BASOPHILS
Males:
0-14 days: 0.02-0.11 x 10(9)/L
15 days-7 weeks: 0.01-0.07 x 10(9)/L
8 weeks-35 months: 0.01-0.06 x 10(9)/L
3-17 years: 0.00-0.10 x 10(9)/L
Adults: 0.01-0.08 x 10(9)/L
Females:
0-14 days: 0.02-0.07 x 10(9)/L
15 days-4 weeks: 0.01-0.06 x 10(9)/L
5 weeks-7 weeks: 0.01-0.05 x 10(9)/L
8 weeks-5 months: 0.01-0.07 x 10(9)/L
6 months-35 months: 0.01-0.06 x 10(9)/L
3-17 years: 0.00-0.10 x 10(9)/L
Adults: 0.01-0.08 x 10(9)/L
Clinical References: 1. Adel K, Raizman J, Chen Y, et al: Complex biological profile of

hematologic markers across pediatric, adult, and geriatric ages: establishment of robust pediatric and
adult reference intervals on the basis of the Canadian Health Measures Survey. Clin Chem 2015;61:8 2.
CLSI. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved
Guideline, Third Edition. CLSI document EP28-A3c. Wayne, PA, Clinical and Laboratory Standards
Institute, 2008 3. Soldin J, Brugnara C, Wong EC: Pediatric Reference Intervals. Fifth Edition. AACC
Press. Washington, DC, 2005. ISBN 1-594250-32-4
CCMGP Comprehensive Cardiomyopathy Multi-Gene Panel, Blood

63164 Clinical Information: The cardiomyopathies are a group of disorders characterized by disease of
the heart muscle. Cardiomyopathy can be caused by inherited, genetic factors or by nongenetic
(acquired) causes such as infection or trauma. When the presence or severity of the cardiomyopathy
observed in a patient cannot be explained by acquired causes, genetic testing for the inherited forms of
cardiomyopathy may be considered. Overall, the cardiomyopathies are some of the most common
genetic disorders. The inherited forms of cardiomyopathy include hypertrophic cardiomyopathy (HCM),
dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC or AC), and
left ventricular noncompaction (LVNC). The hereditary form of HCM is characterized by left
ventricular hypertrophy in the absence of other causes, such as structural abnormalities, systemic
hypertension, or physiologic hypertrophy due to rigorous athletic training (athlete's heart). The
incidence of HCM in the general population is approximately 1 in 500, and the hereditary form is most
often caused by variants in genes encoding the components of the cardiac sarcomere. The clinical
presentation of HCM can be variable, even within the same family. HCM can be asymptomatic in some
individuals but can also cause life-threatening arrhythmias that increase the risk of sudden cardiac
death. DCM is established by the presence of left ventricular enlargement and systolic dysfunction.
DCM may present with heart failure with symptoms of congestion, arrhythmias or conduction system
disease, or thromboembolic disease (stroke). The incidence of DCM is likely higher than originally
reported due to subclinical phenotypes and underdiagnosis, with recent estimates suggesting that DCM
affects approximately 1 in every 250 people. After exclusion of nongenetic causes such as ischemic
injury, DCM is traditionally referred to as "idiopathic" dilated cardiomyopathy. Approximately 20% to
50% of individuals with idiopathic DCM may have an identifiable genetic cause for their disease.
Families with 2 or more affected individuals are diagnosed with familial dilated cardiomyopathy.
Arrhythmogenic right ventricular dysplasia (ARVD or AC) is characterized by breakdown of the
myocardium and replacement of the muscle tissue with fibrofatty tissue, resulting in an increased risk of
arrhythmia and sudden death. Age of onset and severity are variable, but symptoms typically develop in
adulthood. The incidence of ARVC is approximately 1 in 1000 to 1 in 2500. LVNC is characterized by
left ventricular hypertrophy and prominent trabeculations of the ventricular wall, giving a spongy
appearance to the muscle wall. It is thought to be caused by the arrest of normal myocardial
morphogenesis. Clinical presentation is highly variable, ranging from no symptoms to congestive heart
failure and life-threatening arrhythmias. An increased risk of thromboembolic events is also present
with LVNC. Approximately 67% of LVNC is considered familial. Restrictive cardiomyopathy (RCM)
is the rarest form of cardiomyopathy and is associated with abnormally rigid ventricular walls. Systolic
function can be normal or near normal, but diastolic dysfunction is present. There are several
nongenetic causes of RCM, but this condition can be familial as well, with the TNNI3 gene accounting
for the majority of inherited cases. The age at presentation for familial RCM ranges from childhood to
adulthood, and there is an increased risk of sudden death associated with this condition. Noonan
syndrome (NS) is an autosomal dominant disorder of variable expressivity characterized by short
stature, congenital heart defects, and characteristic facial dysmorphology. HCM is present in
approximately 20% to 30% of individuals affected with NS. There are a number of disorders with
significant phenotypic overlap with NS, including Costello syndrome, cardiofaciocutaneous (CFC)
syndrome, and multiple lentigines syndrome (formerly called LEOPARD syndrome). NS and related
disorders (also called the RASopathies) are caused by variants in genes involved in the RAS-MAPK
signaling pathway. In some cases, variants in these genes may cause cardiomyopathy in the absence of
other syndromic features. Cardiomyopathy may also be caused by an underlying systemic disease such
as a mitochondrial disorder, a muscular dystrophy, or a metabolic storage disorder. In these cases,
cardiomyopathy may be the first feature to come to attention clinically. The hereditary forms of
cardiomyopathy are most frequently associated with an autosomal dominant form of inheritance;
however, X-linked and autosomal recessive forms of disease are also present. In some cases, compound
heterozygous or homozygous variants may be present in genes typically associated with autosomal
dominant inheritance, often leading to a more severe phenotype. Digenic variants (2 different
heterozygous variants at separate genetic loci) in autosomal dominant genes have also been reported to
occur in patients with severe disease (particularly HCM and ARVC). The inherited cardiomyopathies
display both allelic and locus heterogeneity, whereby a single gene may cause different forms of
cardiomyopathy (allelic heterogeneity) and variants in different genes can cause the same form of
cardiomyopathy (locus heterogeneity).This comprehensive cardiomyopathy panel includes sequence
analysis of 55 genes and may be considered for individuals with HCM, DCM, ARVC, or LVNC, whom
have had uninformative test results from a more targeted, disease-specific test. This test may also be
helpful when the clinical diagnosis is not clear, or when there is more than 1 form of cardiomyopathy in
the family history. It is important to note that the number of variants of uncertain significance detected
by this panel may be higher than for the disease-specific panels, making clinical correlation more
difficult. Genes included in this gene panel Gene Protein Inheritance Disease association ABCC9
ATP-binding cassette, subfamily C, member 9 AD DCM, Cantu syndrome ACTC1 Actin, alpha, cardiac
muscle AD CHD, DCM, HCM, LVNC ACTN2 Actinin, alpha-2 AD DCM, HCM ANKRD1 Ankyrin
repeat domain-containing protein 1 AD HCM, DCM BRAF V-RAF murine sarcoma viral oncogene
homolog B1 AD Noonan/CFC/Costello syndrome CAV3 Caveolin 3 AD, AR HCM, LQTS, LGMD,
Tateyama-type distal myopathy, rippling muscle disease CBL CAS-BR-M murine ecotropic retroviral
transforming sequence homolog AD Noonan syndrome-like disorder CRYAB Crystallin, alpha-B AD,
AR DCM, myofibrillar myopathy CSRP3 Cysteine-and glycine-rich protein 3 AD HCM, DCM DES
Desmin AD, AR DCM, ARVC, myofibrillar myopathy, RCM with AV block, neurogenic
scapuloperoneal syndrome Kaeser type, LGMD DSC2 Desmocollin AD, AR ARVC, ARVC + skin and
hair findings DSG2 Desmoglein AD ARVC DSP Desmoplakin AD, AR ARVC, DCM, Carvajal
syndrome DTNA Dystrobrevin, alpha AD LVNC, CHD GLA Galactosidase, alpha X-linked Fabry
disease HRAS V-HA-RAS Harvey rat sarcoma viral oncogene homolog AD Costello syndrome JUP
Junction plakoglobin AD, AR ARVC, Naxos disease KRAS V-KI-RAS2 Kirsten rat sarcoma viral
oncogene homolog AD Noonan/CFC/Costello syndrome LAMA4 Laminin, alpha-4 AD DCM LAMP2
Lysosome-associated member protein 2 X-linked Danon disease LDB3 LIM domain-binding 3 AD
DCM, LVNC, myofibrillar myopathy LMNA Lamin A/C AD, AR DCM, EMD, LGMD, congenital
muscular dystrophy (see OMIM for full listing) MAP2K1 Mitogen-activated protein kinase kinase 1
AD Noonan/CFC MAP2K2 Mitogen-activated protein kinase kinase 2 AD Noonan/CFC MYBPC3
Myosin-binding protein-C, cardiac AD HCM, DCM MYH6 Myosin, heavy chain 6, cardiac muscle,
alpha HCM, DCM MYH7 Myosin, heavy chain 7, cardiac muscle, beta AD HCM, DCM, LVNC,
myopathy MYL2 Myosin, light cahin 2, regulatory, cardiac, slow AD HCM MYL3 Myosin, light chain
3, alkali, ventricular, skeletal, slow AD, AR HCM MYLK2 Myosin light chain kinase 2 AD HCM
MYOZ2 Myozenin 2 AD HCM MYPN Myopalladin AD HCM, DCM NEXN Nexilin AD HCM, DCM
NRAS Neuroblastoma RAS viral oncogene homolog AD Noonan syndrome PKP2 Plakophilin 2 AD
ARVC PLN Phospholamban AD HCM, DCM PRKAG2 Protein kinase, AMP-activated, noncatalytic,
gamma2 AD HCM, Wolff-Parkinson-White syndrome PTPN11 Proetin-tyrosine phosphatase,
nonreceptor-type, 11 AD Noonan/CFC/multiple lentigines syndrome RAF1 V-RAF-1 murine leukemia
viral oncogene homolog 1 AD Noonan/multiple lentigines syndrome RBM20 RNA-binding motif
protein 20 AD DCM RYR2 Ryanodine receptor 2 AD ARVC, CPVT, LQTS SCN5A Sodium channel,
voltage gated, type V, alpha subunit AD Brugada syndrome, DCM, Heart block, LQTS, SSS, SIDS
SGCD Sarcoglycan, delta AD, AR DCM, LGMD SHOC2 Suppressor of clear, C. elegans, homolog of
AD Noonan syndrome-like with loose anagen hair SOS1 Son of sevenless, dropsophil, homolog 1 AD
Noonan syndrome TAZ Tafazzin X-linked Barth syndrome, LVNC, DCM TCAP Titin-cap (telethonin)
AD, AR HCM, DCM, LGMD TMEM43 Transmembrane protein 43 AD ARVC, EMD TNNC1
Troponin C, slow AD HCM, DCM TNNI3 Troponin I, cardiac AD, AR DCM, HCM, RCM TNNT2
Troponin T2, cardiac AD HCM, DCM, RCM, LVNC TPM1 Tropomyosin 1 AD HCM, DCM, LVNC
TTN Titin AD, AR HCM, DCM, ARVC, myopathy TTR Transthyretin AD Transthyretin-related
amyloidosis VCL Vinculin AD HCM, DCM Abbreviations: Hypertrophic cardiomyopathy (HCM),
dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left
ventricular noncompaction cardiomyopathy (LVNC), restrictive cardiomyopathy (RCM), limb-girdle
muscular dystrophy (LGMD), Emory muscular dystrophy (EMD), congenital heart defect (CHD),
sudden infant death syndrome (SIDS), long QT syndrome (LQTS), sick sinus syndrome (SSS),
autosomal dominant (AD), autosomal recessive (AR)
history suggestive of hereditary cardiomyopathy Establishing a diagnosis of a hereditary
cardiomyopathy and, in some cases, allowing for appropriate management and surveillance for disease
features based on the gene involved Identifying a pathogenic variant within a gene known to be
associated with disease that allows for predictive testing of at-risk family members
Reference Values:
May;17(5):405-424 2. Hershberger RE, Morales A: Dilated cardiomyopathy overview. In: Adam MP,
Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2007.
Updated July 29, 2021. Accessed September 21, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK1309/ 3. Cirino AL, Ho C: Hypertrophic cardiomyopathy overview.
In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington,
Seattle; 2008. Updated July 8, 2021. Accessed September 21, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK1768/ 4. McNally E, MacLeod H, Dellefave-Castillo L:
Arrhythmogenic right ventricular dysplasia/cardiomyopathy. In: Adam MP, Ardinger HH, Pagon RA, et
al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2005. Updated May 25, 2017.
Accessed June 2018. Available at www.ncbi.nlm.nih.gov/books/NBK1131/ 5. Allanson JE, Roberts
AE: Noonan syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet].
University of Washington, Seattle; 2001. Updated August 8, 2019. Accessed September 21, 2021.
Available at www.ncbi.nlm.nih.gov/books/NBK1124/ 6. Ichida F: Left ventricular noncompaction. Circ
J. 2009;73(1):19-26 7. Callis TE, Jensen BC, Weck KE, Willis MS: Evolving molecular diagnostics for
familial cardiomyopathies: at the heart of it all. Expert Rev Mol Diagn. 2010 April:10;3:329-351 8.
Ackerman MJ, Priori SG, Willems S, et al: HRS/EHRA expert consensus statement on the state of
genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8:1308-1339 9.
Hoedemaekers YM, Caliskan K, Michels M, et al: The importance of genetic counseling, DNA
diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ
Cardiovasc Genet. 2010;3:232-239
_G109 Comprehensive CDG Panel (Bill Only)

FCDSU Comprehensive Drug Screen, Umbilical Cord Tissue

Reporting limit(s) determined each analysis.
None Detected ng/g
EPPAN Comprehensive Epilepsy With or Without Encephalopathy Gene

616550 Panel, Varies
Clinical Information: Epilepsy is a chronic neurological disorder characterized by recurrent and
unprovoked seizures. Epilepsy is common, impacting just over 1% of the population. The underlying
cause of epilepsy is multifactorial, with both genetic and nongenetic etiologies. Inherited forms of
epilepsy may present with varying seizure types, age of onset, comorbidities and underlying molecular
causes, including channelopathies, metabolic conditions, and disorders associated with structural brain
anomalies. Different hereditary epilepsies may follow autosomal dominant, autosomal recessive, or
X-linked patterns of inheritance, or may occur as a result of a de novo pathogenic variant; therefore,
identification of a specific molecular cause is essential to assess recurrence risk and impact to at risk
family members. Clinical diagnoses can be challenging as pathogenic variants in different genes may be
associated with strikingly similar clinical presentations. Comprehensive diagnostic genetic testing is
useful to determine the molecular etiology which in turn can assist in establishing long-term prognosis
and identifying appropriate therapeutic and management strategies.
Useful For: Establishing a diagnosis of an epilepsy or seizure disorder associated with known causal
genes Identifying disease-causing variants within genes known to be associated with inherited epilepsy or
seizure disorders, allowing for predictive testing of at-risk family members Impacting patient treatment
and management through the identification of a specific underlying etiology for epilepsy (eg, directing
appropriate use of antiepileptic drugs and other treatment modalities)
significance. Reference values for CSTB repeat expansion assay Normal: <5 dodecamer repeats Repeat
Size of Uncertain Significance: 5-29 dodecamer repeats Full Penetrance Expansion: >29 dodecamer
repeats
Reference Values:
May;17(5):405-42. 2. Martinez L, Lai Y, Holder J, et al: Genetics in epilepsy. Neurol Clin. 2021 Aug;
39(3):743-777 3. Helbig I, Ellis C: Personalized medicine in genetic epilepsies-possibilities, challenges,
and new frontiers. Neuropharmacology. 2020 Aug 1;172:107970
CMAMA Comprehensive Metabolic Panel, Serum

113631 Clinical Information: The comprehensive metabolic panel measures 14 analytes and calculates an
anion gap. It is used to assess kidney or liver status, electrolyte and acid/base balance, and blood
glucose This comprehensive metabolic panel can also provide information about a patient's response to
medications that would impact kidney or liver function.
Useful For: Routine health monitoring Patient monitoring while hospitalized for information
regarding metabolism, including the current kidney status, electrolyte and acid/base balance, and blood
glucose
Interpretation: Comprehensive metabolic panel results are usually evaluated in conjunction with
each other for patterns of results. The pattern of abnormal results can help identify the possible
conditions or diseases present. Many conditions will cause abnormal results including kidney failure,
breathing problems, and diabetes-related complications.
Reference Values:
SODIUM
> or =1 year: 135-145 mmol/L
POTASSIUM
> or =1 year: 3.6-5.2 mmol/L
CHLORIDE
1-17 years: 102-112 mmol/L
BICARBONATE
Males:
Females:
ANION GAP
> or =7 years: 7-15
BLOOD UREA NITROGEN (BUN)

Males:
Females:
CREATININE
Males:
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-14 years: 0.35-0.86 mg/dL
> or =15 years: 0.74-1.35 mg/dL
Females:
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-15 years: 0.35-0.86 mg/dL
> or =16 years: 0.59-1.04 mg/dL
ESTIMATED GLOMERULAR FILTRATION RATE (eGFR)

>60 mL/min/BSA
Estimated GFR calculated using the 2009 CKD_EPI creatinine equation
CALCIUM
<1 year: 8.7-11.0 mg/dL
1-17 years: 9.3-10.6 mg/dL
18-59 years: 8.6-10.0 mg/dL
60-90 years: 8.8-10.2 mg/dL
>90 years: 8.2-9.6 mg/dL
GLUCOSE
> or =1 year: 70-140 mg/dL
TOTAL PROTEIN
> or =1 year: 6.3-7.9 g/dL
ALBUMIN
> or =12 months: 3.5-5.0 g/dL
ASPARTATE AMINOTRANSFERASE (AST)

Males:
1-13 years: 8-60 U/L
> or =14 years: 8-48 U/L
Females:
1-13 years: 8-50 U/L
> or =14 years: 8-43 U/L
ALKALINE PHOSPHATASE (ALP)

Males:
4 years: 149-369 U/L
5 years: 179-416 U/L
6 years: 179-417 U/L
7 years: 172-405 U/L
8 years: 169-401 U/L
9 years: 175-411 U/L
10 years: 191-435 U/L
11 years: 185-507 U/L
12 years: 185-562 U/L
13 years: 182-587 U/L
14 years: 166-571 U/L
15 years: 138-511 U/L
16 years: 102-417 U/L
17 years: 69-311 U/L
18 years: 52-222 U/L
> or =19 years: 45-115 U/L
Females:
4 years: 169-372 U/L
5 years: 162-355 U/L
6 years: 169-370 U/L
7 years: 183-402 U/L
8 years: 199-440 U/L
9 years: 212-468 U/L
10 years: 215-476 U/L
11 years: 178-526 U/L
12 years: 133-485 U/L
13 years: 120-449 U/L
14 years: 153-362 U/L
15 years: 75-274 U/L
16 years: 61-264 U/L
17-23 years: 52-144 U/L
24-45 years: 37-98 U/L
46-50 years: 39-100 U/L
51-55 years: 41-108 U/L
56-60 years: 46-118 U/L
61-65 years: 50-130 U/L
> or =66 years: 55-142 U/L
Reference values have not been established for patients that are <4 years of age.
ALANINE AMINOTRANSFERASE (ALT)

Males:
> or =1 year: 7-55 U/L
Females:
> or =1 year: 7-45 U/L
TOTAL BILIRUBIN
0-6 days: Refer to http://bilitool.org/ for information on age-specific (postnatal hour of life) serum
bilirubin values.
7-14 days: <15.0 mg/dL
>18 years: < or =1.2 mg/dL
Clinical References: AACC: Lab Tests Online: Access 03/22/2017. Available from
https://labtestsonline.org/understanding/analytes/cmp
TBT Concentration, Mycobacteria (Bill Only)

FFCAH Congenital Adrenal Hyperplasia (CAH) Pediatric Profile 6,

75305 Comprehensive Screen
Interpretation:
Reference Values:
Androstenedione
Units: ng/dL
Age Range
Premature (26-28w) Day 4 63 - 935
Premature (31-35w) Day 4 50 - 449
Full Term (1-7 days) 279
Levels decrease rapidly to after one week.
1 - 11m 37
Androstenedione gradually decreases during the first six months to prepubertal levels.
Prepubertal Children 17
Adult Males 44 - 186
Adult Females 28 - 230
Females Postmenopausal
Cortisol
Units: ug/dL
Age Range
Premature (26-28w) Day 4 1.0 - 11
Premature (31-35w) Day 4 2.5 - 9.1
Full Term Day 3 1.7 - 14
Full Term Day 7 2.0 - 11
31d - 11m 2.8 - 23
12m - 15y (8:00 AM) 3 .0 - 21
Adults
8:00 AM 8.0 - 19
4:00 PM 4.0 - 11
Deoxycorticosterone (DOC)
Units: ng/dL
Age Range
Premature (26 - 28w) Day 4 20 - 105
Premature (34 - 36w) Day 4 28 - 78
Newborn: Levels are markedly elevated at birth and decrease rapidly during the first week to the range of 7 - 49 as
found in older infants.
1 - 11m 7 - 49
Prepubertal Children 2 - 34
Pubertal Children and Adults 8:00 AM 2 - 19
Dehydroepiandrosterone (DHEA)
Units: ng/dL
Age Range
Premature (26 - 31w) 82 - 1484
Premature (32 - 35w) 56 - 1853
Full Term (2 - 7d) 41 - 1292
8d - 5m
6 - 12m
1-5y
6-7y
8 - 10 y
11 - 12 y
13 - 14 y
15 - 16 y 39 - 481
17 - 19 y 40 - 491
20 - 49 y 31 - 701
> or = 50 y 21 - 402
11-Desoxycortisol
Units: ng/dL
Age Range
Premature (26-28w) Day 4 110 - 1376
Premature (31-35w) Day 4 48 - 579
Newborn Day 3 13 - 147
1 - 11m 156
Prepubertal 8:00 AM 20 - 155
Pubertal Children and Adults 8:00 AM 12 - 158
17-OH Pregnenolone
Units: ng/dL
Age Range
Premature (26-28w) Day 4 375 - 3559
Premature (31-35w) Day 4 64 - 2380
3 Days 10 - 829
1 - 5m 36 - 763
6 - 11m 42 - 540
12 - 23m 14 - 207
24m - 5y 10 - 103
6 - 9y 10 - 186
Pubertal 44 - 235
Adults 53 - 357
Progesterone
Units: ng/dL
Males
Age Range
1 - 16y 15
Adults 11
Females
Age Range
1-10y 26
11y 255
12y 856
13y 693
14y 1204
15y 1076
16y
Adult
Cycle Days Range
1-6 17
7 - 12 135
13 - 15 1563
16 - 28 2555
Post Menopausal
Note: Luteal progesterone peaked from 350 to 3750 ng/dL on days ranging from 17 to 23.
17-Alpha-Hydroxyprogesterone 17-OHP
Units: ng/dL
Age Range
Premature (26-28w) Day 4 124 - 841
Premature (31-35w) Day 4 26 - 568
Full-Term Day 3
Males: Levels increase after the first week to peak values ranging from 40 - 200 between 30 and 60 days. Values then
decline to a prepubertal value of one year.
Prepubertal
Adult Males 27 - 199
Females
1 - 11m 13 - 106
Prepubertal
Adult Females
Follicular 15-70
Luteal 35-290
Testosterone, Total
Units: ng/dL
Age Range
Males
Premature (26-28w) Day 4 59 - 125
Premature (31-35w) Day 4 37 - 198
Newborns 75 - 400
1 - 7m: Levels decrease rapidly the first week to 20 - 50, then increase to 60 - 400 between 20 - 60 days. Levels then
decline to prepubertal range levels of 10 by seven months.
Females
Premature (26 - 28w) Day 4 5 - 16
Premature (31 - 35w) Day 4 5 - 22
Newborns 20 - 64
1 - 7m: Levels decrease during the first month to less than 10 and remain there until puberty.
Prepubertal Males and Females 10
Adult Males >18 years 264 - 916
Adult Females
Premenopausal 10 - 55
Postmenopausal 7 - 40
Males
Tanner Stage Age (years) Male

1 10
2 9.8 - 14.5 18 - 150
3 10.7 - 15.4 100 - 320
4 11.8 - 16.2 200 - 620
5 12.8 - 17.3 350 - 970
Females
Tanner Stage Age (years) Female
1 10
2 9.2 - 13.7 7 - 28
3 10.0 - 14.4 15 - 35
4 10.7 - 15.6 13 - 32
5 11.8 - 18.6 20 - 38
CAH21 Congenital Adrenal Hyperplasia (CAH) Profile for

87815 21-Hydroxylase Deficiency, Serum
Clinical Information: The cause of congenital adrenal hyperplasia (CAH) is an inherited genetic
defect that results in decreased formation of 1 of the many enzymes that are involved in the production of
cortisol. The enzyme defect results in reduced glucocorticoids and mineralocorticoids, and elevated
17-hydroxyprogesterone (OHPG) and androgens. The resulting hormone imbalances can lead to
life-threatening, salt-wasting crises in the newborn period and incorrect gender assignment of virilized
females. Adult-onset CAH may result in hirsutism or infertility in females. The adrenal glands, ovaries,
testes, and placenta produce OHPG. It is hydroxylated at the 11 and 21 positions to produce cortisol.
Deficiency of either 11- or 21-hydroxylase results in decreased cortisol synthesis, and the feedback
inhibition of adrenocorticotropic hormone (ACTH) secretion is lost. Consequently, increased pituitary
release of ACTH increases production of OHPG. In contrast, if 17-alpha-hydroxylase (which allows
formation of OHPG from progesterone) or 3-beta-ol-dehydrogenase (which allows formation of
17-hydroxyprogesterone formation from 17-hydroxypregnenolone) are deficient, OHPG levels are low
with possible increase in progesterone or pregnenolone, respectively. Most (90%) cases of CAH are due
to mutations in the 21-hydroxylase gene (CYP21A2). CAH due to 21-hydroxylase deficiency is diagnosed
by confirming elevations of OHPG and androstenedione with decreased cortisol. By contrast, in 2 less
common forms of CAH, due to 17-hydroxylase or 11-hydroxylase deficiency, OHPG and
androstenedione levels are not significantly elevated and measurement of progesterone (PGSN /
Progesterone, Serum) and deoxycorticosterone (DCRN / 11-Deoxycorticosterone, Serum), respectively,
are necessary for diagnosis. OHPG is bound to both transcortin and albumin, and total OHPG is measured
in this assay. OHPG is converted to pregnanetriol, which is conjugated and excreted in the urine. In all
instances, more specific tests than pregnanetriol measurement are available to diagnose disorders of
steroid metabolism. The CAH profile allows the simultaneous determination of OHPG, androstenedione,
and cortisol. These steroids can also be ordered individually (OHPG / 17-Hydroxyprogesterone, Serum;
ANST / Androstenedione, Serum; CINP / Cortisol, Serum, LC-MS/MS).
Useful For: Preferred screening test for congenital adrenal hyperplasia (CAH) that is caused by
21-hydroxylase deficiency Part of a battery of tests to evaluate females with hirsutism or infertility,
which can result from adult-onset CAH
requires the measurement of several steroids. Patients with CAH due to 21-hydroxylase gene
(CYP21A2) mutations usually have very high levels of androstenedione, often 5- to 10-fold elevations.
17-Hydroxyprogesterone (OHPG) levels are usually even higher, while cortisol levels are low or
undetectable. All 3 analytes should be tested. In the much less common CYP11A mutation,
androstenedione levels are elevated to a similar extent as in CYP21A2 mutation, and cortisol is also
low, but OHPG is only mildly, if at all, elevated. Also less common is 3 beta-hydroxysteroid
dehydrogenase type 2 (3 beta HSD-2) deficiency, characterized by low cortisol and substantial
elevations in dehydroepiandrosterone sulfate (DHEA-S) and 17-alpha-hydroxypregnenolone, while
androstenedione is either low, normal, or rarely, very mildly elevated (as a consequence of peripheral
tissue androstenedione production by 3 beta HSD-1). In the very rare steroidogenic acute regulatory
protein deficiency, all steroid hormone levels are low and cholesterol is elevated. In the also very rare
17-alpha-hydroxylase deficiency, androstenedione, all other androgen-precursors
(17-alpha-hydroxypregnenolone, OHPG, DHEA-S), androgens (testosterone, estrone, estradiol), and
cortisol are low, while production of mineral corticoid and its precursors, in particular progesterone,
11-deoxycorticosterone, corticosterone, and 18-hydroxycorticosterone, are increased. The goal of CAH
treatment is normalization of cortisol levels and, ideally, also of sex-steroid levels. OHPG is measured
to guide treatment, but this test correlates only modestly with androgen levels. Therefore,
androstenedione and testosterone should also be measured and used to guide treatment modifications.
Normal prepubertal levels may be difficult to achieve, but if testosterone levels are within the reference
range, androstenedione levels up to 100 ng/dL are usually regarded as acceptable.
Reference Values:
Stage II 9.8-14.5 31-65
Stage III 10.7-15.4 50-100
Stage IV 11.8-16.2 48-140
Stage V 12.8-17.3 65-210 Females*
Stage II 9.2-13.7 42-100
Stage III 10.0-14.4 80-190
Stage IV 10.7-15.6 77-225
Stage V 11.8-18.6 80-240 *Source: Androstenedione. In Pediatric
Reference Ranges. Fourth Edition. Edited by SJ
Soldin, C Brugnara, EC Wong. Washington, DC,
AACC Press, 2003, pp 32-34 ADULTS Males: 40-150
ng/dL Females: 30-200 ng/dL
17-HYDROXYPROGESTERONE Children Preterm
infants: Preterm infants may exceed 630 ng/dL,
however, it is uncommon to see levels reach 1,000
ng/dL. Term infants 0-28 days: Levels fall from
newborn ( to prepubertal gradually within 6 months.
Prepubertal males: Prepubertal females: Adults
Males: Females Follicular: Luteal: Postmenopausal:
Note: For pregnancy reference ranges, see: Soldin OP,
Guo T, Weiderpass E, et al: Steroid hormone levels in
pregnancy and 1 year postpartum using isotope
dilution tandem mass spectrometry. Fertil Steril 2005
Sept;84(3):701-710

hyperplasia. Eur J Pediatr 1980;133(3):259-267 2. Sciarra F, Tosti-Croce C, Toscano V:
Androgen-secreting adrenal tumors. Minerva Endocrinol 1995;20(1):63-68 3. Collett-Solberg PF:
Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part I. Clin Pediatr
2001;40(1):1-16 4. Speiser PW, Azziz R, Baskin LS, et al: Congenital adrenal hyperplasia due to steroid
21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab
2010;95(9):4133-4160; Available at: jcem.endojournals.org
CAH2T Congenital Adrenal Hyperplasia Newborn Screen, Blood Spot

42202 Clinical Information: Congenital adrenal hyperplasia (CAH) is a group of disorders caused by
inherited defects in steroid biosynthesis, most commonly, 21-hydroxylase deficiency (approximately 90%
of cases) and 11-beta hydroxylase deficiency (approximately 5% of cases). The overall incidence of CAH
due to 21-hydroxylase deficiency is approximately 1 in 15,000 live births. Individuals with CAH may
present with life-threatening salt-wasting crises in the newborn period and incorrect gender assignment of
virilized females, which occurs due to in utero exposure to reduced glucocorticoids and
mineralocorticoids and elevated 17-hydroxyprogesterone (17-OHP) and androgens. Hormone replacement
therapy, when initiated early, results in a significant reduction in morbidity and mortality. Therefore,
newborn screening for CAH is desirable and has been implemented in all 50 states. Immunoassays are
typically used to quantify 17-OHP as a marker for CAH in the newborn screen setting. However, these
immunoassays are hampered by cross-reactivity of the antibodies with other steroids, yielding a high rate
of false-positive results. Tandem mass spectrometry (MS/MS) allows for the simultaneous specific
determination of 17-OHP and other steroids, such as androstenedione, cortisol, 11-deoxycortisol, and
21-deoxycortisol. Application of this technology to the determination of steroids in newborn blood spots
significantly enhances the correct identification of patients with CAH and reduces the number of
false-positive screening results when implemented as a second-tier analysis performed prior to reporting
of initial newborn screen results.
Useful For: Second-tier testing of newborns with abnormal screening result for congenital adrenal
hyperplasia
Interpretation: Findings of a 17-hydroxyprogesterone (17-OHP) value greater than 15.0 ng/mL and a
high (17-OHP + androstenedione)/cortisol ratio (> or =1) are supportive of the initial abnormal newborn
screening result. Findings of an 11-deoxycortisol value greater than 15.0 ng/mL or 21-deoxycortisol
greater than 4.0 ng/mL with elevated 17-OHP further support the abnormal newborn screening result and
increase the diagnostic specificity. Clinical and laboratory follow-up is strongly recommended.
Reference Values:
17-HYDROXYPROGESTERONE
<15.1 ng/mL
ANDROSTENEDIONE
<3.1 ng/mL
CORTISOL
Not applicable
11-DEOXYCORTISOL
<15.1 ng/mL
21-DEOXYCORTISOL
<4.1 ng/mL
(17 OHP + ANDROSTENEDIONE)/CORTISOL RATIO

<1.1
Note: Abnormal (17 OHP + Androstenedione)/Cortisol Ratio: > or =1.1 is only applicable when 17-OHP
is elevated
11-DEOXYCORTISOL/CORTISOL RATIO
Not applicable
Clinical References: 1. Antal Z, Zhou P: Congenital adrenal hyperplasia: diagnosis, evaluation

and management. Pediatr Rev. 2009 Jul;30(7):e49-57 2. Minutti CZ, Lacey JM, Magera MJ, et al:
Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn
screening for congenital adrenal hyperplasia. J Clin Endo Met. 2004;89:3687-3693 3. Turcu AF,
Auchus RJ: The next 150 years of congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2015
Sep;153:63-714 4. Witchel SF, Azziz R: Congenital adrenal hyperplasia. Pediatri Adolesc Gynecol.
2011;24:116-126
CDGGP Congenital Disorders of Glycosylation Gene Panel, Varies

608010 Clinical Information: Congenital disorders of glycosylation (CDG), formerly known as
carbohydrate-deficient glycoprotein syndrome, are a group of disorders affecting several steps of the
pathway involved in the glycosylation of proteins. CDG are classified into 5 groups. CDG types I and II
will have abnormal biochemical findings detected by serum transferrin and serum total N-glycan
analyses (see CDG / Carbohydrate Deficient Transferrin for Congenital Disorders of Glycosylation,
Serum). In the other 3 groups these analyses will be normal. CDG type I disorders are characterized by
defects in the assembly or transfer of the dolichol-linked glycan, while CDG type II includes defects of
the glycan moiety processing. The third group includes disorders of glycosylphosphatidyl inositol (GPI)
anchor protein glycosylation. If clinically suspected, a flow cytometry analysis could facilitate the
diagnostic workup. The fourth group involves disorders of O-mannosylation, a process that takes place
predominantly in the muscle and brain tissues. The fifth group involves deglycosylation defects (eg,
NAGLY1-CDG). The urine oligosaccharide profile by matrix-assisted laser desorption/ionization
time-of-flight/time-of-flight mass spectrometer (MALDI-TOF/TOF-MS) may be abnormal and facilitate
the diagnostic workup. CDG typically present as multisystemic disorders with a broad range of clinical
features including developmental delay, hypotonia, abnormal magnetic resonance imaging findings,
skin manifestations, and coagulopathy. There is considerable variation in the severity of this group of
diseases, ranging from hydrops fetalis to a mild presentation in adults. Almost all types of CDG are
autosomal recessive in inheritance, but some are X-linked. The broad clinical spectrum and genetic
heterogeneity of CDG make a comprehensive panel a helpful tool in establishing a diagnosis for
patients with suggestive clinical features.
Useful For: Establishing a molecular diagnosis for patients with congenital disorders of
glycosylation Identifying variants within genes known to be associated with congenital disorders of
glycosylation, allowing for predictive testing of at-risk family members
significance.
Reference Values:
May;17(5):405-424 2. Freeze HH, Chong JX, Bamshad MJ, et al: Solving glycosylation disorders:
fundamental approaches reveal complicated pathways. Am J Hum Genet. 2014;94(2):161-175 3.
Krasnewich D: Human glycosylation disorders. Cancer Biomark. 2014;14(1):3-16
CDGN Congenital Disorders of N-Glycosylation, Serum

65485 Clinical Information: Congenital disorders of glycosylation (CDG) are a group of over 100 inherited
metabolic disorders largely affecting N- and O-glycosylation of proteins. Almost 50 inborn errors of
metabolism are attributed to congenital defects in N-glycosylation, which takes place primarily in the
cytoplasm and in the membranes of the endoplasmic reticulum. O-glycosylation defects are commonly
tissue specific and present differently than classic N-linked defects. CDG are currently classified into 2
main groups. Type I CDG is characterized by defects in the assembly or transfer of the dolichol-linked
glycan (sugar chain), while type II involves processing defects of the glycan. Depending on the specific
defect, an N-glycosylation disorder can be either a type I or type II CDG. N-linked CDG are
phenotypically diverse, commonly presenting as clinical syndromes with multisystemic involvement and
a broad clinical spectrum. There is considerable variation in the severity of this group of diseases ranging
from a mild presentation in adults to severe multi-organ dysfunction causing infantile lethality.
Intellectual disability is common, although in some subtypes, phosphomannose isomerase (MPI)-CDG
(CDG-Ib) in particular, intellect is preserved. CDG should be considered in all patients with multisystem
disease and in those with neurologic abnormalities including developmental delay and seizures, brain
abnormalities such as cerebellar atrophy or hypoplasia as well as unexplained liver dysfunction.
Additional common symptoms that may be present include abnormal subcutaneous fat distribution,
gastrointestinal issues such as vomiting, chronic diarrhea, and protein-losing enteropathy, eye
abnormalities including retinal degeneration and strabismus, and cardiomyopathy. Matrix-assisted laser
desorption/ionization time-of-flight (MALDI TOF) analysis of released N-linked oligosaccharides, as is
performed in this assay, is a global assessment of N-linked glycosylation. This complements the also
performed transferrin and apolipoprotein CIII isoform analysis (see CDG / Carbohydrate Deficient
Transferrin for Congenital Disorders of Glycosylation, Serum) by providing additional information on
specific structural oligosaccharide abnormalities that can guide molecular testing.
Useful For: Screening for N-linked congenital disorders of glycosylation Providing information on
specific structural oligosaccharide abnormalities to potentially direct further genetic testing
Interpretation: The results of the transferrin and apolipoprotein CIII isoform analysis are followed up
with matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) analysis of released
N-linked oligosaccharides to assess N-linked glycosylation. Reports of abnormal results will include
recommendations for additional biochemical and molecular genetic studies to identify more precisely the
specific congenital disorder of glycosylation. Treatment options, the name and telephone number of
contacts who may provide studies, and a telephone number for one of the laboratory directors (if the
referring physician has additional questions) will be provided.
Reference Values:
Interpretative comment only.
Clinical References: 1. Sparks SE, Krasnewich DM: Congenital disorders of N-linked glycosylation
and multiple pathway overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews
[Internet]. University of Washington, Seattle; 2005. Updated January 12, 2017. Accessed July 20, 2021.
Available at: www.ncbi.nlm.nih.gov/books/NBK1332/ 2. Chang IJ, He M, Lam CT: Congenital disorders
of glycosylation. Ann Transl Med. 2018 Dec;6(24):477. doi: 10.21037/atm.2018.10.45 3. Francisco R,
Marques-da-Silva D, Brasil S, et al: The challenge of CDG diagnosis. Mol Genet Metab. 2019
Jan;126(1):1-5. doi: 10.1016/j.ymgme.2018.11.003 4. Freeze HH, Chong JX, Bamshad MJ, Ng BG:
Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet.
2014 Feb 6;94(2):161-175. doi: 10.1016/j.ajhg.2013.10.024 5. Scott K, Gadomski T, Kozicz, Morava E:
Congenital disorders of glycosylation: new defects and still counting. J Inherit Metab Dis. 2014
Jul;37(4):609-617. doi: 10.1007/s10545-014-9720-9
NGCDA Congenital Dyserythropoietic Anemia Panel, Next-Generation

Clinical Information: Next-generation sequencing is a methodology that can interrogate large
regions of genomic DNA in a single assay. The presence and pattern of gene variants can provide
critical diagnostic, prognostic, and therapeutic information for managing physicians. This panel aids in
the diagnosis and genetic counseling of individuals with clinical or familial features of congenital
dyserythropoietic anemia (CDA). CDA is a disorder of ineffective erythropoiesis clinically subdivided
into subtypes with various phenotypic findings that segregate into different gene associations.(1-4)
These disorders have distinctive cytopathologic findings consisting of nuclear abnormalities in bone
marrow erythroid precursors. Types I and II CDA are inherited in an autosomal recessive pattern
whereas types III and IV are autosomal dominant.
Useful For: Confirmation of the diagnosis or carrier variant status of genes associated with
congenital dyserythropoietic anemia Identifying variants within genes associated with phenotypic
severity, allowing for predictive testing and further genetic counseling
published American College of Medical Genetics recommendations as a guideline.(5) Variants are
classified based on known, predicted, or possible pathogenicity and reported with interpretive comments
detailing their potential or known significance. Multiple in silico evaluation tools may be used to assist
in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is
highly dependent upon the data available for a given gene, and predictions made by these tools may
change over time. Results from in silico evaluation tools should be interpreted with caution and
Reference Values:
Clinical References: 1. Orkin SH, Nathan DG, Ginsburg D, et al, eds. Nathan and Oski's
Hematology of Infancy and Childhood.Â 7th ed. Saunders Elsevier; 2009:360-364 2. Iolascon A,
Heimpel H, Wahlin A, Tamary H: Congenital dyserythropoietic anemias: molecular insights and
diagnostic approach. Blood. 2013 Sep 26;122(13):2162-2166 3. Arnaud L, Saison C, Helias V, et al. A
dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital
dyserythropoietic anemia. Am J Hum Genet. 2010 Nov 12;87(5):721-727 4. Iolascon A, Andolfo I,
Barcellini W, et al: Recommendations for splenectomy in hereditary hemolytic anemias. Haematologica
2017 May 26. PMID: 28550188. doi: 10.3324/haematol.2016.161166 5. Richards S, Aziz N, Bale S, et
al: Standards and guidelines for the interpretation of sequence variants: a joint consensus
recommendation of the American College of Medical Genetics and Genomics and the Association for
Molecular Pathology. Genet Med 2015 May;17(5):405-424
FIBNG Congenital Fibrinogen Disorders, FGA, FGB, and FGG Genes,

64867 Next-Generation Sequencing, Varies
Clinical Information: Fibrinogen forms the insoluble fibrin matrix that is a major component of the
blood clots critical for stopping blood loss. Fibrinogen is made up of 6 polypeptide chains, 1 pair each
of alpha, beta, and gamma chains (encoded by the FGA, FGB, and FGG genes respectively), that are
held together by 29 disulfide bonds.(2) The alpha, beta, and gamma fibrinogen subunits polymerize to
form an insoluble fibrin matrix that is a major component of the blood clots critical for stopping blood
loss. Fibrinogen also has a role in the early stages of wound repair. Fibrinogen disorders are classified
as either: afibrinogenemia or hypofibrinogenemia, a quantitative defect of low or absent fibrinogen
plasma antigen levels, or dysfibrinogenemia or hypodysfibrinogenemia, a qualitative defect in function
and activity with normal or reduced antigen levels. Congenital afibrinogenemia and hypofibrinogenemia
are inherited in an autosomal recessive manner. Congenital dysfibrinogenemia is, in most cases,
inherited in an autosomal dominant manner, but cases of recessive inheritance have also been reported.
Afibrinogenemia: Afibrinogenemia is characterized by the complete absence of fibrinogen in
circulation. Although all individuals with afibrinogenemia have unmeasurable functional fibrinogen, the
severity of bleeding is highly variable, even among those with the same genetic alterations.(3)
Abnormal bleeding may occur in the neonatal period as umbilical cord bleeding. Bleeding may occur in
skin, the oral cavity, gastrointestinal tract, genitourinary tract, or central nervous system. Intracranial
hemorrhage is a major cause of death in affected individuals, who are also at risk for joint bleeds and
spontaneous splenic rupture. Venous and arterial thromboembolic complications and poor wound
healing may also occur. Affected women have increased risk for menometrorrhagia and recurrent
pregnancy loss. The prevalence of afibrinogenemia is estimated to be 1 in 1 million.
Hypofibrinogenemia: Most individuals with hypofibrinogenemia (characterized by fibrinogen levels
less than 1.5 g/L) are asymptomatic.(3) Thromboembolism may occur spontaneously or with fibrinogen
substitution therapy. Affected individuals may experience abnormal bleeding after trauma or if they
have a second hemostatic abnormality. Recurrent pregnancy loss and postpartum hemorrhage are
reported in affected women. There is typically good correlation between fibrinogen levels and clinical
severity, with levels less than 0.5 g/L associated with major bleeding.(4) Specific alterations associated
with hypofibrinogenemia are strongly correlated with hepatic storage disease.(3) Acquired
hypofibrinogenemia has been reported in individuals with hepatic failure or decompensation cirrhosis.
Hypofibrinogenemia is also commonly associated with acute disseminated intravascular coagulation.
Less common acquired causes include administration of L-asparaginase and valproic acid or other drugs
that impair hepatic synthesis. These causes of acquired hypofibrinogenemia should be excluded prior to
genetic testing for a fibrinogen disorder. Dysfibrinogenemia and Hypodysfibrinogenemia: About half of
individuals with dysfibrinogenemia and hypodysfibrinogenemia are asymptomatic. However, genetic
carriers have a high risk of major bleeding and/or thromboembolic complications.(5) Patients bleed
most after trauma, surgery, or postpartum. Some women have spontaneous abortions. Specific
alterations associated with dysfibrinogenemia are strongly associated with thromboembolic pulmonary
hypertension and amyloidosis. Causes of acquired (nongenetic) dysfibrinogenemia or defects in
fibrinogen that should be excluded prior to genetic testing include cirrhosis, acute or chronic hepatitis,
metastatic hepatoma, renal carcinoma, and biliary obstruction. Individuals treated with isotretinoin
therapy have also been reported to develop acquired dysfibrinogenemia. Fibrinogen antibodies and
inhibitors have been reported in systemic lupus erythematosus, ulcerative colitis, and multiple myeloma.
These causes of acquired dysfibrinogenemia and hypodysfibrinogenemia should be considered and
excluded prior to genetic testing for a fibrinogen disorder.
Useful For: Genetic confirmation of congenital disorders of fibrinogen with the identification of an
alteration in FGA, FGB, or FGG that is known or suspected to cause disease Testing for close family
members of an individual with a diagnosis of afibrinogenemia/hypofibrinogenemia or
dysfibrinogenemia/hypodysfibrinogenemia This test is not intended for prenatal diagnosis
Interpretation: An interpretive report will be provided. Evaluation and categorization of variants is

performed using the most recent published American College of Medical Genetics and Genomics
(ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible
Consultations with the Mayo Clinic Special Coagulation Clinic, Molecular Hematopathology Laboratory,
or Thrombophilia Center are available for DNA diagnosis cases. This may be especially helpful in
complex cases or in situations where the diagnosis is atypical or uncertain.
Reference Values:
Clinical References: 1. Verhovsek M, Moffat KA, Hayward CPM: Laboratory testing for fibrinogen
abnormalities. Am J Hematol. 2008 Dec;83(12):928-931 2. Weisel JW, Litvinov R: Mechanisms of fibrin
polymerization and clinical implications. Blood. 2013 Mar 7;121(10):1712-1719 3. de Moerloose P,
Casini A, Neerman-Arbez M: Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013
Sep;39(6):585-595 4. de Moerloose P, Schved JF, Nugent D: Rare coagulation disorders: fibrinogen,
factor VII and factor XIII. Haemophilia. 2016 Jul;22(Suppl 5):61-65 5. Casini A, Blondon M, Lebreton A,
et al: Natural history of patients with congenital dysfibrinogenemia. Blood. 2015 Jan 15;125(3):553-561
6. Casini A, Neerman-Arbez M, Ariens RA, de Moerloose P: Dysfibrinogenemia: from molecular
anomalies to clinical manifestations and management. J Thromb Haemost. 2015 Jun;13(6):909-919 7.
Peyvandi F: Epidemiology and treatment of congenital fibrinogen deficiency. Thromb Res. 2012
Dec;130(Suppl 2):S7-11
CILDF Congenital Infantile Leukemia, Diagnostic FISH, Varies

609597 Clinical Information: While pediatric leukemia is the most common malignancy affecting
children, acute leukemia occurring prior to the age of 18 months (infant leukemia) or occurring within
the first 3 months of life (congenital leukemia) are relatively rare in occurrence. The incidence of
congenital and infant acute leukemia cases (through 12 months of age) is estimated at only 30 to 40
cases/million/year, with the majority comprising infant cases. Nearly all cases of congenital and infant
acute leukemia represent either acute myeloid leukemia (AML) or B-cell acute lymphoblastic
leukemia/lymphoma (B-ALL/LBL) with only very rare cases of T-cell acute lymphoblastic
leukemia/lymphoma (T-ALL/LBL) identified in this age group. Characteristic genetic abnormalities
have been identified in both the congenital acute leukemia and infant acute leukemia setting, each with
uniquely associated clinical-pathologic correlations. Rare but important patients with KAT6A/CREBBP
translocations and congenital acute leukemia have been described with spontaneously remitting AML
despite the lack of therapeutic intervention. In addition, transient abnormal myelopoiesis associated with
Down syndrome is another common manifestation encountered in the neonatal setting that can be
associated with the development of frank acute leukemia. In contrast, nearly 80% of infant acute
leukemia cases are associated with MLL(KMT2A) translocation events with varying percentages of
translocation partners based on an AML versus B-ALL/LBL presentation. Due to the underlying genetic
heterogeneity associated with both congenital and infant leukemia and the important prognostic,
diagnostic and occasional therapeutic targets identified, appropriate genetic characterization of this
uncommon acute leukemia presentation is critical. These thorough fluorescence in situ hybridization
(FISH) panels have been developed by Mayo Clinic Laboratories to interrogate the more common AML
and B-ALL abnormalities associated with both congenital and infant acute leukemias. These FISH
probes have been validated both in bone marrow/blood (this test) and in paraffin (CILPF / Congenital
Infantile Leukemia, FISH, Tissue), since a significant minority of these patientâ€™s present clinically
with isolated extramedullary (tissue) manifestations (ie, myeloid sarcoma).
classic rearrangements seen in congenital and infant patients with acute leukemia using
laboratory-designed probe sets An adjunct to conventional chromosome studies in congenital and infant
patients with acute leukemia
Reference Values:
Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. IARC Press; 2017 2. Tomizawa D: Recent
progress in the treatment of infant acute lymphoblastic leukemia. Pediatr Int. 2015 Oct;57(5):811-819.
doi: 10.1111/ped.12758 3. Inaba H, Zhou Y, Abla O, et al: Heterogeneous cytogenetic subgroups and
outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood.
2015 Sep 24;126(13):1575-1584. doi: 10.1182/blood-2015-02-629204 4. Coenen EA, Zwaan CM,
Reinhardt D, et al: Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and
biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study
group. Blood. 2013 Oct 10;122(15):2704-2713. doi: 10.1182/blood-2013-02-485524
CILPF Congenital Infantile Leukemia, FISH, Tissue
614180 Clinical Information: While pediatric leukemia is the most common malignancy affecting children,
acute leukemia occuring prior to the age of 18 months (infant leukemia) or occuring within the first 3
months of life (congenital leukemia) are relatively rare in occurrence. The incidence of congenital and
infant acute leukemia cases (through 12 months of age) is estimated at only 30 to 40 cases/million/year,
with the majority comprising infant cases. Nearly all cases of congenital and infant acute leukemia
represent either acute myeloid leukemia (AML) or B-cell acute lymphocytic leukemia/lymphoblastic
lymphoma (B-ALL/LBL) with only very rare cases of T-cell-ALL/LBL identified in this age group.
Characteristic genetic abnormalities have been identified in both the congenital acute leukemia and infant
acute leukemia setting, each with uniquely associated clinical-pathologic correlations. Rare but important
patients with KAT6A/CREBBP translocations and congenital acute leukemia have been described with
spontaneously remitting AML despite the lack of therapeutic intervention. In addition, transient abnormal
myelopoiesis associated with Down syndrome is another common manifestation encountered in the
neonatal setting that can be associated with the development of frank acute leukemia. In contrast, nearly
80% of infant acute leukemia cases are associated with MLL(KMT2A) translocation events with varying
percentages of translocation partners based on an AML versus B-ALL/LBL presentation. Due to the
underlying genetic heterogeneity associated with both congenital and infant leukemia and the important
prognostic, diagnostic, and occasional therapeutic targets identified, appropriate genetic characterization
of this uncommon acute leukemia presentation is critical. These thorough fluorescence in situ
hybridization (FISH) panels have been developed by Mayo Clinic Laboratories to interrogate the more
common AML and B-ALL abnormalities associated with both congenital and infant acute leukemias.
These FISH probes have been validated both in bone marrow/blood CILDF / Congenital Infantile
Leukemia, Diagnostic FISH, Varies and in paraffin CILPF / Congenital Infantile Leukemia, FISH,
Tissuesince a significant minority of these patientâ€™s present clinically with isolated extramedullary
(tissue) manifestations (ie, myeloid sarcoma).
classic rearrangements seen in infant patients with leukemia using tissue specimens
the normal reference range for any given probe. A positive result is not diagnostic for congenital or
infantile leukemia but may provide relevant prognostic information. The absence of an abnormal clone
does not rule out the presence of neoplastic disorder.
Reference Values:
Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. IARC Press; 2017 2. Tomizawa D: Recent
progress in the treatment of infant acute lymphoblastic leukemia. Pediatr Int. 2015;57(5):811-819. doi:
10.1111/ped.12758 3. Inaba H, Zhou Y, Abla O, et al: Heterogeneous cytogenetic subgroups and
2015;126(13):1575-1584. doi: 10.1182/blood-2015-02-629204 4. Coenen EA, Zwaan CM, Reinhardt D,
et al: Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a
collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood.
2013;122(15):2704-2713. doi: 10.1182/blood-2013-02-485524
CILMF Congenital Infantile Leukemia, Specified FISH, Varies

614239 Clinical Information: While pediatric leukemia is the most common malignancy affecting children,
acute leukemia occurring prior to the age of 18 months (infant leukemia) or occurring within the first 3
months of life (congenital leukemia) are relatively rare in occurrence. The incidence of congenital and
infant acute leukemia cases (through 12 months of age) is estimated at only 30 to 40 cases/million/year,
with the majority comprising infant cases. Nearly all cases of congenital and infant acute leukemia
represent either acute myeloid leukemia (AML) or B-cell acute lymphoblastic leukemia/lymphoma
(B-ALL/LBL) with only very rare cases of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL)
identified in this age group. Characteristic genetic abnormalities have been identified in both the
congenital acute leukemia and infant acute leukemia setting, each with uniquely associated
clinical-pathologic correlations. Rare but important patients with KAT6A/CREBBP translocations and
congenital acute leukemia have been described with spontaneously remitting AML despite the lack of
therapeutic intervention. In addition, transient abnormal myelopoiesis associated with Down syndrome is
another common manifestation encountered in the neonatal setting that can be associated with the
development of frank acute leukemia. In contrast, nearly 80% of infant acute leukemia cases are
associated with MLL(KMT2A) translocation events with varying percentages of translocation partners
based on an AML versus B-ALL/LBL presentation. Due to the underlying genetic heterogeneity
associated with both congenital and infant leukemia and the important prognostic, diagnostic and
occasional therapeutic targets identified, appropriate genetic characterization of this uncommon acute
leukemia presentation is critical. These thorough fluorescence in situ hybridization (FISH) panels have
been developed by Mayo Clinic LaboratoriesÂ to interrogate the more common AML and B-ALL
abnormalities associated with both congenital and infant acute leukemias. These FISH probes have been
validated both in bone marrow/blood (CILDF / Congenital Infantile Leukemia, Diagnostic FISH, Varies)
and in paraffin (CILPF / Congenital Infantile Leukemia, FISH, Tissue), since a significant minority of
these patientâ€™s present clinically with isolated extramedullary (tissue) manifestations (ie, myeloid
sarcoma).
classic rearrangements seen in infant patients with leukemia using client specified probe sets An adjunct
to conventional chromosome studies in infant patients with leukemia.
Reference Values:
Tumours of Haematopoietic and Lymphoid Tissues. IARC Press; 2017 2. Tomizawa D: Recent progress
in the treatment of infant acute lymphoblastic leukemia. Pediatr Int. 2015;57(5):811-819. doi:
10.1111/ped.12758 3. Inaba H, Zhou Y, Abla O, et al: Heterogeneous cytogenetic subgroups and
2015;126(13):1575-84. doi: 10.1182/blood-2015-02-629204 4. Coenen EA, Zwaan CM, Reinhardt D, et
al: Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a
collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood.
2013;122(15):2704-13. doi: 10.1182/blood-2013-02-485524
CLADP Congenital Lactic Acidosis Panel, Varies

608019 Clinical Information: Congenital lactic acidosis (CLA) is a rare, but serious, condition that
presents in newborns with extreme elevations of lactic acid and is caused by a variety of biochemical
disorders, resulting in impaired mitochondrial activity. Elevated lactate in multiple specimen types such
as blood and cerebrospinal fluid (CSF) are typically observed. However, additional symptoms are
extremely variable, as any high-energy organ or tissue may be impaired, resulting in a need for
multisystem screening that may involve biopsies and biochemical analysis. CLA can be caused by
pathogenic variants in genes encoding enzymes involved in gluconeogenesis, pyruvate oxidation, the
Krebs cycle, and mitochondrial function. A comprehensive gene panel with mitochondrial genome
analysis is an essential tool to establish a diagnosis for patients with congenital lactic acidosis. As
biomarker testing and multisystem organ assessments are not specific and can yield complex results,
genetic testing is required to distinguish among the spectrum of conditions that can cause CLA. This
panel analyzes a combination of nuclear genes for single-gene biochemical disorders known to cause
CLA, as well as analysis of the mitochondrial genome.
Useful For: Follow up for abnormal biochemical results suggestive of congenital lactic acidosis
Establishing a molecular diagnosis for patients with congenital lactic acidosis Identifying variants
within genes known to be associated with congenital lactic acidosis, allowing for predictive testing of
significance.
Reference Values:
May;17(5):405-424 2. Bravo-Alonso I, Navarrette R, Vega AI, et al: Genes and variants underlying
human congenital lactic acidosis-from genetics to personalized treatment. J Clin Med. 2019;8(11):1811
SCNGP Congenital Neutropenia, Primary Immunodeficiency Disorder

65669 Panel (18 genes), Next-Generation Sequencing, Varies
Clinical Information: Severe congenital neutropenia is a primary immunodeficiency disorder that is
characterized by severe and recurrent bacterial infections, such as otitis media, bronchitis, pneumonia,
osteomyelitis, and cellulitis, typically with the absence of pus at the infected site. Susceptibility to fungal
infections may also be observed. Neutropenia may be an isolated finding or may be part of a syndrome.
This panel includes genes associated with neutropenia as a major presenting feature; other panels may be
more appropriate when neutropenia is identified but not as the main finding. Pathogenic variants in
ELANE, which encodes neutrophil elastase, can result in severe congenital neutropenia type 1 (SCN1) or
cyclic neutropenia. SCN1 often presents immediately with omphalitis, while diarrhea, pneumonia, and
deep abscesses affecting the liver, lungs, or subcutaneous tissues are noted within the first year. Patients
are at risk for development of myelodysplastic syndrome or acute myelogenous leukemia, presumably due
to acquired mutations in CSF3R (which may also be identified in the presence of congenital neutropenia
due to variants in genes other than ELANE, see below). Biallelic mutations in CSF3R have also been
recently reported to be associated with severe congenital neutropenia. Cyclic neutropenia typically
presents in the first year of life with 3-week-long oscillations in cell counts along with intervals of fever,
oral ulcerations, and ulcerations; between intervals, patients are generally healthy. Unlike SCN1, cyclic
neutropenia is not associated with risk of malignancy. Both SCN1 and cyclic neutropenia are inherited in
an autosomal dominant pattern from an affected parent, although de novo variants have been identified.
Studies have demonstrated pathogenic variants in ELANE in nearly 100% of cases with well-documented
classical cyclic neutropenia, while in some cases with atypical presentations (ie, oscillations that are not 3
weeks) a variant in ELANE is not identified. ELANE variants are identified in 38% to 80% of cases of
congenital neutropenia, depending on the criteria used to identify patients. Although there is some
overlap, generally, variants at the active site of neutrophil elastase result in cyclic neutropenia, while
variants that prevent normal folding or packaging of the enzyme cause congenital neutropenia. In addition
to variants in ELANE, severe congenital neutropenia, where the predominant finding is neutropenia, can
be inherited as a result of pathogenic variants in other genes. Dominant variants in GFI1 (encoding growth
factor independent 1) result in severe congenital neutropenia type 2 (SCN2). Pathogenic variants in
G6PC3 (encoding glucose-6-phosphate 3), which are inherited in an autosomal recessive manner, can
result in a phenotypic spectrum from isolated/nonsyndromic severe congenital neutropenia to classic
G6PC3 deficiency (severe neutropenia along with cardiovascular and urogenital abnormalities) to severe
G6PC3 deficiency (also known as Dursun syndrome, which includes features of classic G6PC3 deficiency
along with severe lymphopenia, primary pulmonary hypertension, thymic hypoplasia, among other
features). Kostmann disease or severe congenital neutropenia type 3 (SCN3) is due to recessive
inheritance of pathogenic variants in HAX1 (which encodes HCLS1-associated protein X-1) and may
result in seizures and developmental delay in addition to neutropenia. Along with neutropenia, variants in
VPS45 inherited in an autosomal recessive manner (also known as severe congenital neutropenia type 5
[SNC5]) are associated with neutrophil dysfunction, bone marrow fibrosis, and nephromegaly due to renal
extramedullary hematopoiesis. While loss-of-function variants in WAS, which is located on the X
chromosome, cause Wiskott-Aldrich syndrome (characterized by thrombocytopenia, eczema, and
recurrent infections), gain-of-function variants affecting the autoinhibitory structure of the protein, have
been associated with congenital neutropenia, along with variable lymphopenia, decreased lymphocyte
proliferation, and impaired phagocyte activity. Pathogenic variants in WIPF1 can present with similar
findings to Wiskott-Aldrich syndrome. Severe neutropenia may also be present as part of a multisystem
disorder. Barth syndrome, due to pathogenic variants in TAZ, which is located on the X-chromosome, is
characterized by neutropenia, cardio- and skeletal myopathy, growth delay, and distinctive facial features.
Biallelic variants in C16orf57 manifest as poikiloderma with neutropenia; the neutropenia may be
cyclical. In Cohen syndrome, an autosomal recessive disorder due to variants in COH1 (also known as
VPS13B), neutropenia is accompanied by hypotonia, developmental delays, microcephaly, failure to
thrive in infancy, truncal obesity in adolescent years, ophthalmologic findings, joint hypermobility, a
cheerful disposition, and characteristic facial features. Glycogen storage disease type I (GSDI), caused by
biallelic pathogenic variants in either G6PC or SLC37A4, when untreated can result in chronic
neutropenia and impaired neutrophil and monocyte function, as well as the characteristic findings that
include accumulation of glycogen and fat in the liver and kidneys. Pathogenic variants in
LAMTOR2/MAPBPIP have been shown to result in neutropenia, decreased cytotoxic activity of CD8+ T
cells, short stature, and hypopigmented skin. Persistent or intermittent neutropenia is often a presenting
feature of Shwachman-Diamond syndrome (SDS), which is also characterized by exocrine pancreatic
dysfunction (with malabsorption, malnutrition, and growth failure), bone abnormalities, and hematologic
abnormalities (single- or multilineage cytopenias along with predisposition to myelodysplastic syndrome
and acute myelogenous leukemia). SDS is an autosomal recessive disorder due to pathogenic variants in
SBDS. Warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome is
characterized by neutropenia in addition to hypogammaglobulinemia, and susceptibility to human
papillomavirus. It is due to autosomal dominant pathogenic variants in CXCR4. Although most forms of
Hermansky-Pudlak syndrome do not include significant neutropenia, type 2 caused by variants in AP3B1
can be associated with persistent neutropenia and increased infections in addition to the typical findings of
tyrosinase-positive oculocutaneous albinism, platelet storage pool deficiency, pulmonary fibrosis, and
granulomatous colitis. Few patients with RAC2 pathogenic variants have been identified, but neutrophil
dysfunction appears to be a feature, though CD11b expression and specific granule release appear to be
preserved. Both individuals with dominant and individuals with recessive inheritance have been
identified, with and without additional associated phenotypic findings. GATA-binding protein (GATA2)
deficiency demonstrates a wide spectrum of clinical presentations, including neutropenia. Most variants
appear to arise de novo (spontaneously) and are then transmitted in an autosomal dominant manner. If the
clinical phenotype strongly suggests GATA2 deficiency, this gene is available as a stand-alone test (see
GATA2 / GATA-Binding Protein 2 [GATA2], Full Gene, Next-Generation Sequencing, Varies). This
panel does not evaluate for somatic (acquired) ASXL1 variants associated with GATA2 deficiency. Genes
included in this test Gene (alias) Protein OMIM Incidence Inheritance Phenotype disorder AP3B1 AP-3
complex subunit beta-1 isoform 1 603401 Rare AR Hermansky-Pudlak syndrome 2 CSF3R Granulocyte
colony-stimulating factor receptor isoform a precursor 138971 AR, acquired Severe congenital
neutropenia CXCR4 C-X-C chemokine receptor type 4 isoform b 162643 AD Myelokathexis, isolated,
WHIM syndrome (AD) ELANE Neutrophil elastase preproprotein 130130 2:1,000,000-3:1,000,000
(SCN); 1:1,000,000 (cyclic neutropenia) AD Severe congenital neutropenia (SCN), cyclic neutropenia
G6PC3 Glucose-6-phosphatase 3 611045 AR Dursun syndrome, severe congenital neutropenia (SCN) 4
GATA2 Endothelial transcription factor GATA-2 isoform 1 137295 AD Immunodeficiency 21, Emberger
syndrome, susceptibility to acute myeloid leukemia and myelodysplastic syndrome GFI1 Zinc finger
protein Gfi-1 600871 AD Severe congenital neutropenia (SCN) 2(AD), nonimmune chronic idiopathic
neutropenia of adults HAX1 HCLS1-associated protein X-1 isoform a 605998 AR Severe congenital
neutropenia (SCN) 3 LAMTOR2 (MAPBPIP) Ragulator complex protein LAMTOR2 isoform 1 610389
AR Immunodeficiency due to defect in MAPBP-interacting protein RAC2 ras-Related C3 botulinum
toxin substrate 2 602049 AD/AR Neutrophil functional defects SBDS Ribosome maturation protein
SBDS 607444 AR Shwachman-Diamond syndrome, susceptibility to aplastic anemia SLC37A4
Ddipeptidyl peptidase 1 isoform a preproprotein 602671 AR Glycogen storage disease Ib and 1c TAZ
Tafazzin isoform 1 300394 XL Barth syndrome USB1 (C16ORF57) U6 snRNA phosphodiesterase
isoform 1 613276 Rare AR Poikiloderma with neutropeniaÂ Â VPS13B (COH1) Vacuolar protein
sorting-associated protein 13B isoform 5 607817 AR Cohen syndrome VPS45 Vacuolar protein
sorting-associated protein 45 isoform 1 610035 AR Severe congenital neutropenia (SCN) 5 WAS
(Gain-of-function mutations) Wiskott-Aldrich syndrome protein 300392 XL (gain of function)
Neutropenia, severe congenital, X-linked, thrombocytopenia, X-linked WIPF1 WAS/WASL-interacting
protein family member 1 602357 In progress Wiskott-Aldrich syndrome 2 AD=autosomal dominant
AR=autosomal recessive XL=X-linked
history suggestive of congenital neutropenia, cyclic neutropenia, or other primary immunodeficiency
disorder (PIDD) presenting with significant neutropenia Establishing a diagnosis and, in some cases,
allowing for appropriate management and surveillance for disease features based on the gene involved
Identifying variants within genes known to be associated with PIDD characterized by significant
neutropenia allowing for predictive testing of at-risk family members
Interpretation: Evaluation and categorization of variants is performed using the most recent published
American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants
are classified based on known, predicted, or possible pathogenicity and reported with interpretive
comments detailing their potential or known significance. Multiple in silico evaluation tools may be used
to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation
tools is highly dependent upon the data available for a given gene, and predictions made by these tools
may change over time. Results from in silico evaluation tools should be interpreted with caution and
Reference Values:
Clinical References: 1. Picard C, Gaspar HB, Al-Herz W, et al: International Union of

Immunological Societies: 2017 Primary Immunodeficiency Disease Committee report on inborn errors of
immunity, J Clin Immunol. 2018;38:96-128. doi: 10.1007/s10875-017-0464-9 2. Donadieu J, Fenneteau
O, Beaupain B, Mahlaoui N, Bellanne Chantelot C: Congenital neutropenia: diagnosis, molecular bases
and patient management. Orphanet J Rare Dis. 2011;6:26. doi: 10.1186/1750-1172-6-26 3. Boxer LA,
Stein S, Buckley D, et al: Strong evidence for autosomal dominant inheritance of severe congenital
neutropenia associated with ELA2 mutations. J Pediatr. 2006;148:633-636 4. Beel K, Bandenberghe P:
G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or
myelodysplasia. Haematologica. 2009;94(10):1449-1452 5. Klein C: Genetic defects in severe congenital
neutropenia: emerging insights into life and death of human neutrophil granulocytes. Ann Rev Immunol.
2011;29:399-413 6. Albert MH, Notarangelo LD, Ochs HD: Clinical spectrum, pathophysiology and
treatment of the Wiskott-Aldrich syndrome. Cur Opin Hematol. 2011;18(1):42-48 7. Concolino D,
Roversi G, Muzzi GL, et al: Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with
mutations in the C16orf57 gene: delineation of the phenotype. Am J Med Genet.
2010;152A(10):2588-2594 8. Bohn G, Allroth A, Brandea G, et al: A novel human primary
immunodeficiency syndrome caused by deficiency of endosomal adaptor protein p14. Nature Med.
2007;13(1):38-45 9. Triot A, Jarvinen PM, Arostegui JI, et al: Inherited biallelic CSF3R mutations in
severe congenital neutropenia. Blood. 2014;123:3811-3817 10. Bousifiha AA, et al: A phenotypic
approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin
Immunol. 2013;Aug;33(6):1078-1087
CTDC Connective Tissue Diseases Cascade, Serum

83631 Clinical Information: The following diseases are often referred to as connective tissue diseases
(CTD): rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis including CREST
syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia),
Sjogren syndrome, mixed connective tissue disease, and idiopathic inflammatory myopathies. CTD (also
known as systemic rheumatic diseases) are characterized by immune-mediated inflammation that involves
the joints, skin, and visceral organs. These diseases are also accompanied by antibodies to a host of
nuclear and cytoplasmic autoantigens. The diagnosis of any CTD is based on clinical signs and symptoms
and characteristic radiographic, histopathologic, and serologic findings. Certain CTD are characterized by
autoantibodies that are highly specific for individual diseases as outlined in the Table. CTD often present
clinically with signs and symptoms that are nonspecific, including constitutional signs such as fever,
weight loss, fatigue, and arthralgias. Table. Autoantibodies and Clinical Associations with Specific
Connective Tissue Diseases Cyclic citrullinated peptide antibodies Rheumatoid arthritis Double-Stranded
DNA (dsDNA) Systemic lupus erythematosus (SLE) Smith (Sm) SLE Ribosome P SLE SS-B/La Sjogren
syndrome (SjS) SS-A/Ro (Ro52 or Ro60) SjS, SLE, systemic sclerosis (SSc), antisynthetase syndrome
RNP 68 and A (RNP) Mixed connective tissue disease Topoisomerase 1 (topo-1, Scl-70) SSc Histidyl
tRNA synthetase (JO1) Idiopathic inflammatory myositis (commonly anti-synthetase syndrome)
Centromere B SSc (most commonly the limited cutaneous forms: LcSSc) In this testing cascade, serum is
tested initially for the presence of antinuclear antibodies (ANA) and for cyclic citrullinated peptide (CCP)
antibodies. The presence of CCP antibodies indicates a strong likelihood of rheumatoid arthritis (RA).(1)
However, additional testing for rheumatoid factor, which is not included in the cascade, is important for
optimal diagnosis as per the 2010 American College of Rheumatology/European League Against
Rheumatism RA classification criteria.(2) The presence of ANA supports the possibility of a CTD, and
the level of ANA is used to identify sera for second-order testing for antibodies to dsDNA and the other
autoantigens. The decision threshold for performing second-order tests is based on empirical data derived
from testing patients with varying levels of ANA and is chosen to minimize testing in situations in which
positive results for dsDNA and other antibodies is very unlikely.(3) However, a negative ANA enzyme
immunoassay result does not rule out a diagnosis of CTD as has been reported in a number of studies.
Therefore, in patients with a strong clinical suspicion of CTD, testing for ANA by indirect
immunofluorescence assay may be warranted.(4,5)
Useful For: Evaluation of patients with signs and symptoms compatible with connective tissue
diseases Initial evaluation of patients in clinical situations in which the prevalence of disease is low (6)
This test is not recommended for: -Testing in clinical situations in which there is a high prevalence of
connective tissue diseases (eg, rheumatology specialty practice) -Follow-up evaluation of patients with
known connective tissue diseases
Interpretation: Interpretive comments are provided. See individual test IDs for additional
information. Differential testing for Ro52 and Ro60 antibodies in SS-A/Ro positive patients may be
useful in the diagnosis of specific CTD clinical subset, disease stratification, and prognosis. Consider
testing for Ro52 and Ro60 antibodies (ROPAN / Ro52 and Ro60 Antibodies, IgG, Serum) if the patient
is positive for SS-A/Ro.
Reference Values:
ANTINUCLEAR ANTIBODIES (ANA)
< or =1.0 U (negative)
1.1-2.9 U (weakly positive)
3.0-5.9 U (positive)
> or =6.0 U (strongly positive)
CYCLIC CITRULLINATED PEPTIDE ANTIBODIES, IgG

<20.0 U (negative)
20.0-39.9 U (weak positive)
> or =60.0 U (strong positive)
Clinical References: 1. Tomar R, Homburger H: Assessment of immunoglobulins and antibodies.

In: Rich R, Fleisher T, Shearer W, et al, eds. Clinical Immunology: Principles and Practice. 2nd ed.
Mosby-Year Book Inc; 2001:120.1-120.14 2. Aletaha D, Neogi T, Silman AJ, et al: 2010 Rheumatoid
arthritis classification criteria: an American College of Rheumatology/European League Against
Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-2581 3. Deng X, Peters B,
Ettore MW, et al: Utility of antinuclear antibody screening by various methods in a clinical laboratory
patient cohort. J Appl Lab Med. 2016 Jul 1;1(1):36-46 4. Pisetky DS, Spencer DM, Lipsky PE, Rovin
BH: Assay variation in the detection of antinuclear antibodies in the sera of patients with established
SLE. Ann Rheum Dis. 2018 Jun;77(6):911-913 5. Claessens J, Belmondo T, De Langhe E, et al: Solid
phase assays versus automated indirect immunofluorescence for detection of antinuclear antibodies.
Autoimmun Rev. 2018 Jun;17(6):533-540 6. van Boekel MAM, Vossenaar ER, van den Hoogen FHJ,
van Venrooij WJ: Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic
value. Arthritis Res. 2002;4(2):87-93 7. Kavanaugh A, Tomar R, Reveille J, Solomon DH, Homburger
HA: Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to
nuclear antigens. Arch Pathol Lab Med. 2000 Jan;124(1):71-81
COSPC Consult, Outside Slide (Bill Only)

CRHPC Consult, w/Comp Rvw of His (Bill Only)

CSPPC Consult, w/Slide Prep (Bill Only)

CUPPC Consult, w/USS Prof (Bill Only)

CSMEU Controlled Substance Monitoring Enhanced Profile with Reflex,

615907 21 Drug Classes, High Resolution Mass Spectrometry and
Immunoassay Screen, Random, Urine
Clinical Information: This test uses screening techniques that involves immunologic testing and
high-resolution accurate mass spectrometry screening for drugs by class. All positive immunoassay
screening results are confirmed by gas chromatography-mass spectrometry (GC-MS) or liquid
chromatography-tandem mass spectrometry (LC-MS/MS), and quantitated, before a positive result is
reported. The following drugs/drug classes are tested by immunoassay and confirmed by GC-MS:
-Barbiturates -Cocaine -Tetrahydrocannabinol Ethyl glucuronide is also screened using an immunoassay
and confirmation of ethyl glucuronide/ethyl sulfate is performed using LC-MS/MS. The targeted opioid,
benzodiazepine, and stimulant screen portions are performed using liquid chromatography-tandem mass
spectrometry, high-resolution accurate mass (HRAM) and are completed for all opioids, benzodiazepines,
and stimulants. Opioids are a large class of medications commonly used to relieve acute and chronic pain
or help manage opioid abuse and dependence. Medications that fall into this class include buprenorphine,
codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone,
tapentadol, tramadol, and others. Opioids work by binding to the opioid receptors that are found in the
brain, spinal cord, gastrointestinal tract, and other organs. Common side effects include drowsiness,
confusion, nausea, constipation, and, in severe cases, respiratory depression depending on the dose. These
medications can also produce physical and psychological dependence and have a high risk for abuse and
diversion, which is one of the main reasons many professional practice guidelines recommend compliance
testing in patients prescribed these medications. Â Opioids are readily absorbed from the gastrointestinal
tract, nasal mucosa, lungs, and after subcutaneous or intermuscular injection. Opioids are primarily
excreted from the kidney in both free and conjugated forms. This assay doesn't hydrolyze the urine
sample and looks for both parent drugs and metabolites (including glucuronide forms). The detection
window for most opioids in urine is approximately 1 to 3 days with longer detection times for some
compounds (ie, methadone). Â Benzodiazepines represent a large family of medications used to treat a
wide range of disorders from anxiety to seizures and are also used in pain management. With a high risk
for abuse and diversion, professional practice guidelines recommend compliance monitoring for these
medications using urine drug tests. However, traditional benzodiazepine immunoassays suffer from a lack
of cross-reactivity with all the benzodiazepines, so many compliant patients taking clonazepam
(Klonopin) or lorazepam (Ativan) may screen negative by immunoassay but are positive when
confirmatory testing is done. The new targeted benzodiazepine screening test provides a more sensitive
and specific test to check for compliance to all the commonly prescribed benzodiazepines and looks for
both parent and metabolites in the urine. Â Stimulants are sympathomimetic amines that stimulate the
central nervous system activity and, in part, suppress the appetite. Amphetamine and methamphetamine
are also prescription drugs used in the treatment of narcolepsy and attention-deficit
disorder/attention-deficit hyperactivity disorder (ADHD). Methylphenidate is another stimulant used to
treat ADHD. Phentermine is indicated for the management of obesity. All of the other amphetamines (eg,
methylenedioxymethamphetamine: MDMA) are Drug Enforcement Administration scheduled Class I
compounds. Due to their stimulant effects, the drugs are commonly sold illicitly and abused.
amphetamine psychosis. Ethyl glucuronide is a direct metabolite of ethanol that is formed by enzymatic
conjugation of ethanol with glucuronic acid. Alcohol in urine is normally detected for only a few hours,
whereas ethyl glucuronide can be detected in the urine for 1 to 5 days. This procedure uses immunoassay
reagents that are designed to produce a negative result when no drugs are present in a natural (eg,
unadulterated) specimen of urine; the assay is designed to have a high true-negative rate. Like all
immunoassays, it can have a false-positive rate due to cross-reactivity with natural chemicals and drugs
other than those they were designed to detect. The immunoassay also has a false-negative rate to the
antibody's ability to cross-react with different drugs in the class being screened for. Â This test is
intended to be used in a setting where the test results can be used to make a definitive diagnosis
tetrahydrocannabinol, and alcohol This test is not intended for use in employment-related testing.
including estimated detection times, see Specific Drug Groups.
Reference Values:
ADULTERANT SURVEY:
Oxidants: 200 mg/L
Nitrites: 500 mg/L

Negative

Not Detected
Codeine: 25 ng/mL
Morphine: 25 ng/mL
Oxycodone: 25 ng/mL
Fentanyl: 2 ng/mL
Naloxone: 25 ng/mL
Methadone: 25 ng/mL
EDDP: 25 ng/mL
Tramadol: 25 ng/mL

Not Detected
Â
Clobazam: 10 ng/mL
Diazepam: 10 ng/mL
Lorazepam: 10 ng/mL
Midazolam: 10 ng/mL
Oxazepam: 10 ng/mL
Prazepam: 10 ng/mL
Temazepam: 10 ng/mL
Triazolam: 10 ng/mL
Zolpidem: 10 ng/mL
Â
Not Detected
Â
ETHYL GLUCURONIDE SCREEN:

Negative

Ethyl Glucuronide: 500 ng/mL
Clin Lab Med. 2012;32(32):379-390 7. Jannetto PJ, Bratanow NC, Clark WA, et al: Executive
clinical laboratory tests to monitor drug therapy in pain management patients. J Appl Lab Med.
2018;2(4):489-526 8. McMillin GA, Marin SJ, Johnson-Davis KL, Lawlor BG, Strathmann FG: A
hybrid approach to urine drug testing using high-resolution mass spectrometry and select
immunoassays. Am J Clin Pathol. 2015;143(2):234-240 9. Cone EJ, Caplan YH, Black DL, Robert T,
Moser F: Urine drug testing of chronic pain patients: licit and illicit drug patterns. J Anal Toxicol.
2008;32(8):530-543
CSMHU Controlled Substance Monitoring Hybrid Drug Profile, 20 Drug

615293 Classes, High-Resolution Mass Spectrometry and
Immunoassay Screen, Random, Urine
Clinical Information: This test uses the simple screening technique that involves immunologic
testing for drugs by class. All positive immunoassay screening results can be confirmed by gas
chromatography-mass spectrometry (GC-MS) and quantitated if applicable. The targeted opioid,
benzodiazepine, and stimulant screen portions are performed by liquid chromatography-tandem mass
spectrometry, high-resolution accurate mass (LC-MS/MS HRAM) and are completed for all opioids,
benzodiazepines, and stimulants. Opioids are a large class of medications commonly used to relieve
acute and chronic pain or help manage opioid abuse and dependence. Medications that fall into this
class include buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine,
oxycodone, oxymorphone, tapentadol, tramadol, and others. Opioids work by binding to the opioid
receptors that are found in the brain, spinal cord, gastrointestinal tract, and other organs. Common side
effects include drowsiness, confusion, nausea, constipation, and, in severe cases, respiratory depression
depending on the dose. These medications can also produce physical and psychological dependence and
have a high risk for abuse and diversion, which is one of the main reasons many professional practice
guidelines recommend compliance testing in patients prescribed these medications. Opioids are readily
absorbed from the gastrointestinal tract, nasal mucosa, lungs, and after subcutaneous or intermuscular
injection. Opioids are primarily excreted from the kidney in both free and conjugated forms. This assay
doesn't hydrolyze the urine sample and looks for both parent drugs and metabolites (including
glucuronide forms). The detection window for most opioids in urine is approximately 1 to 3 days with
longer detection times for some compounds (eg, methadone). Benzodiazepines represent a large family
of medications used to treat a wide range of disorders from anxiety to seizures and are also used in pain
management. With a high risk for abuse and diversion, professional practice guidelines recommend
compliance monitoring for these medications using urine drug tests. However, traditional
benzodiazepine immunoassays suffer from a lack of cross-reactivity with all the benzodiazepines, so
many compliant patients taking clonazepam (Klonopin) or lorazepam (Ativan) may screen negative by
immunoassay but are positive when confirmatory testing is done. The new targeted benzodiazepine
screening test provides a more sensitive and specific test to check for compliance to all the commonly
prescribed benzodiazepines and looks for both parent and metabolites in the urine. Stimulants are
sympathomimetic amines that stimulate the central nervous system activity and, in part, suppress the
appetite. Amphetamine and methamphetamine are also prescription drugs used in the treatment of
narcolepsy and attention-deficit disorder/attention-deficit hyperactivity disorder (ADHD).
drugs are commonly sold illicitly and abused. Physiological symptoms associated with very high
amounts of ingested amphetamine or methamphetamine include elevated blood pressure, dilated pupils,
hyperthermia, convulsions, and acute amphetamine psychosis. This test is intended to be used in a
setting where the test results can be used to make a definitive diagnosis.
and tetrahydrocannabinol This test is not intended for use in employment-related testing.
Interpretation: For information about drug testing, including estimated detection times, see Specific
Drug Groups.
Reference Values:
ADULTERANT SURVEY:
Oxidants: 200 mg/L
Nitrites: 500 mg/L
LIMITED DRUG PANEL:

Negative
This report is intended for use in clinical monitoring or management of patients. It is not intended for use
in employment-related testing.

Not Detected
Codeine: 25 ng/mL
Morphine: 25 ng/mL
6-Monoacetylmorphine: 25 ng/mL
Oxycodone: 25 ng/mL
Fentanyl: 2 ng/mL
Naloxone: 25 ng/mL
Methadone: 25 ng/mL
2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP): 25 ng/mL
Tramadol: 25 ng/mL

Not Detected
Alpha-hydroxyalprazolam glucuronide: 50 ng/mL
Clobazam: 10 ng/mL
N-desmethylclobazam: 200 ng/mL
Diazepam: 10 ng/mL
Lorazepam: 10 ng/mL
Lorazepam glucuronide: 50 ng/mL
Midazolam: 10 ng/mL
Oxazepam: 10 ng/mL
Oxazepam glucuronide: 50 ng/mL
Prazepam: 10 ng/mL
Temazepam: 10 ng/mL
Temazepam glucuronide: 50 ng/mL
Triazolam: 10 ng/mL
Zolpidem: 10 ng/mL

Not Detected
3,4-Methylenedioxymethamphetamine (MDMA): 100 ng/mL
3,4-Methylenedioxy-N-ethylamphetamine (MDEA): 100 ng/mL
3,4-Methylenedioxyamphetamine (MDA): 100 ng/mL
Clinical References: 1. Physicians' Desk Reference: 60th ed. Medical Economics Company; 2006 2.
Bruntman LL Lazo JS, Parker KL, eds: Goodman and Gilman's: The Pharmacological Basis of
Therapeutics. 11th ed. McGraw-Hill Book Company; 2006 3. Langman LJ, Bechtel L, Meier BM,
Holstege CP: Clinical toxicology In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 4. Gutstein HB, Akil H: Opioid
analgesics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's: The Pharmacological Basis
of Therapeutics. 11th ed. McGraw-Hill Companies; 2006:chap 21 5. Chronic Pain in America:
Roadblocks to Relief, survey conducted for the American Pain Society, The American Academy of the
Pain Medicine and Janssen Pharmaceutical; 1999 6. Magnani B, Kwong T: Urine drug testing for pain
management. Clin Lab Med. 2012 Sep;32(3):379-390 7. Jannetto PJ, Bratanow NC, Clark WA, et al:
Executive summary: American Association of Clinical Chemistry Laboratory Medicine Practice
Guideline-using clinical laboratory tests to monitor drug therapy in pain management patients. J Appl Lab
Med. 2018 Jan 1;2(4):489-526 8. McMillin GA, Marin SJ, Johnson-Davis KL, Lawlor BG, Strathmann
FG: A hybrid approach to urine drug testing using high-resolution mass spectrometry and select
immunoassays. Am J Clin Pathol. 2015 Feb;143(2):234-240 9. Cone EJ, Caplan YH, Black DL, Robert T,
Moser F: Urine drug testing of chronic pain patients: licit and illicit drug patterns. J Anal Toxicol. 2008
Oct;32(8):530-543
CSMPU Controlled Substance Monitoring Panel, Random, Urine

610271 Clinical Information: This test uses the simple screening technique that involves immunologic
testing for drugs by class. All positive immunoassay screening results are confirmed by gas
chromatography-mass spectrometry (GC-MS) and quantitated, before a positive result is reported. This
assay was designed to test for and confirm by GC-MS the following: -Barbiturates -Cocaine
-Tetrahydrocannabinol The targeted opioid, benzodiazepine, and stimulant screen portions are performed
by liquid chromatography-tandem mass spectrometry, high-resolution accurate mass (LC-MS/MS
HRAM) and are completed for all opioids, benzodiazepines, and stimulants. Opioids are a large class of
medications commonly used to relieve acute and chronic pain or help manage opioid abuse and
dependence. Medications that fall into this class include: buprenorphine, codeine, fentanyl, hydrocodone,
hydromorphone, methadone, morphine, oxycodone, oxymorphone, tapentadol, tramadol, and others.
Opioids work by binding to the opioid receptors that are found in the brain, spinal cord, gastrointestinal
tract, and other organs. Common side effects include drowsiness, confusion, nausea, constipation, and, in
severe cases, respiratory depression depending on the dose. These medications can also produce physical
and psychological dependence and have a high risk for abuse and diversion, which is one of the main
reasons many professional practice guidelines recommend compliance testing in patients prescribed these
medications. Opioids are readily absorbed from the gastrointestinal tract, nasal mucosa, lungs, and after
subcutaneous or intermuscular injection. Opioids are primarily excreted from the kidney in both free and
conjugated forms. This assay doesn't hydrolyze the urine sample and looks for both parent drugs and
metabolites (including glucuronide forms). The detection window for most opioids in urine is
approximately 1 to 3 days with longer detection times for some compounds (ie, methadone).
Benzodiazepines represent a large family of medications used to treat a wide range of disorders from
anxiety to seizures and are also used in pain management. With a high risk for abuse and diversion,
professional practice guidelines recommend compliance monitoring for these medications using urine
drug tests. However, traditional benzodiazepine immunoassays suffer from a lack of cross-reactivity with
all the benzodiazepines, so many compliant patients taking clonazepam (Klonopin) or lorazepam (Ativan)
may screen negative by immunoassay but are positive when confirmatory testing is done. The new
targeted benzodiazepine screening test provides a more sensitive and specific test to check for compliance
to all the commonly prescribed benzodiazepines and looks for both parent and metabolites in the urine.
Stimulants are sympathomimetic amines that stimulate the central nervous system activity and, in part,
suppress the appetite. Amphetamine and methamphetamine are also prescription drugs used in the
treatment of narcolepsy and attention-deficit disorder/attention-deficit hyperactivity disorder (ADHD).
drugs are commonly sold illicitly and abused. Physiological symptoms associated with very high amounts
of ingested amphetamine or methamphetamine include elevated blood pressure, dilated pupils,
hyperthermia, convulsions, and acute amphetamine psychosis. This test is intended to be used in a setting
where the test results can be used to make a definitive diagnosis.
Useful For: Detecting drug use involving stimulants, barbiturates, benzodiazepines, cocaine, opioids,
and tetrahydrocannabinol This test is not intended for use in employment-related testing.
including estimated detection times, see Specific Drug Groups at
Reference Values:
ADULTERANT SURVEY:
Oxidants: 200 mg/L
Nitrites: 500 mg/L

Negative

Not Detected
Codeine: 25 ng/mL
Morphine: 25 ng/mL
Oxycodone: 25 ng/mL
Fentanyl: 2 ng/mL
Naloxone: 25 ng/mL
Methadone: 25 ng/mL
EDDP: 25 ng/mL
Tramadol: 25 ng/mL

Not Detected
Clobazam: 10 ng/mL
Diazepam: 10 ng/mL
Lorazepam: 10 ng/mL
Midazolam: 10 ng/mL
Oxazepam: 10 ng/mL
Prazepam: 10 ng/mL
Temazepam: 10 ng/mL
Triazolam: 10 ng/mL
Zolpidem: 10 ng/mL

Not Detected
Phencyclidine (PCP):: 20 ng/mL
Clin Lab Med. 2012;32(32):379-390 7. Jannetto PJ, Bratanow NC, Clark WA, et al: Executive
clinical laboratory tests to monitor drug therapy in pain management patients. J Appl Lab Med.
2018;2(4):489-526 8. McMillin GA, Marin SJ, Johnson-Davis KL, Lawlor BG, Strathmann FG: A
hybrid approach to urine drug testing using high-resolution mass spectrometry and select
immunoassays. Am J Clin Pathol. 2015;143(2):234-240 9. Cone EJ, Caplan YH, Black DL, Robert T,
Moser F: Urine drug testing of chronic pain patients: licit and illicit drug patterns. J Anal Toxicol.
2008;32(8):530-543
CSMTU Controlled Substance Monitoring Targeted Profile, 17 Drug

615292 Classes, Mass Spectrometry, Random, Urine
Clinical Information: The targeted opioid, benzodiazepine, and stimulant screen portions are
performed by liquid chromatography-tandem mass spectrometry, high-resolution accurate mass
(LC-MS/MS HRAM) and are completed for all opioids, benzodiazepines, and stimulants. Opioids are a
large class of medications commonly used to relieve acute and chronic pain or help manage opioid
abuse and dependence. Medications that fall into this class include buprenorphine, codeine, fentanyl,
hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tapentadol, tramadol,
and others. Opioids work by binding to the opioid receptors that are found in the brain, spinal cord,
gastrointestinal tract, and other organs. Common side effects include drowsiness, confusion, nausea,
constipation, and, in severe cases, respiratory depression depending on the dose. These medications can
also produce physical and psychological dependence and have a high risk for abuse and diversion,
which is one of the main reasons many professional practice guidelines recommend compliance testing
in patients prescribed these medications. Opioids are readily absorbed from the gastrointestinal tract,
nasal mucosa, lungs, and after subcutaneous or intermuscular injection. Opioids are primarily excreted
from the kidney in both free and conjugated forms. This assay doesn't hydrolyze the urine sample and
looks for both parent drugs and metabolites (including glucuronide forms). The detection window for
most opioids in urine is approximately 1 to 3 days with longer detection times for some compounds (eg,
methadone). Benzodiazepines represent a large family of medications used to treat a wide range of
disorders from anxiety to seizures and are also used in pain management. With a high risk for abuse and
diversion, professional practice guidelines recommend compliance monitoring for these medications
using urine drug tests. However, traditional benzodiazepine immunoassays suffer from a lack of
cross-reactivity with all the benzodiazepines, so many compliant patients taking clonazepam (Klonopin)
or lorazepam (Ativan) may screen negative by immunoassay but are positive when confirmatory testing
is done. The new targeted benzodiazepine screening test provides a more sensitive and specific test to
check for compliance to all the commonly prescribed benzodiazepines and looks for both parent and
metabolites in the urine. Stimulants are sympathomimetic amines that stimulate the central nervous
system activity and, in part, suppress the appetite. Amphetamine and methamphetamine are also
prescription drugs used in the treatment of narcolepsy and attention-deficit disorder/attention-deficit
hyperactivity disorder (ADHD). Methylphenidate is another stimulant used to treat ADHD.
Phentermine is indicated for the management of obesity. All of the other amphetamines (eg,
methylenedioxymethamphetamine: MDMA) are Drug Enforcement Administration (DEA) scheduled
Class I compounds. Due to their stimulant effects, the drugs are commonly sold illicitly and abused.
amphetamine psychosis. This test is intended to be used in a setting where the test results can be used to
make a definitive diagnosis.
Useful For: Detecting drug use involving stimulants, benzodiazepines, and opioids This test is not
intended for use in employment-related testing.
Interpretation: For information about drug testing, including estimated detection times, see Specific
Drug Groups.
Reference Values:
ADULTERANT SURVEY:
Oxidants: 200 mg/L
Nitrites: 500 mg/L

Not Detected
Codeine: 25 ng/mL
Morphine: 25 ng/mL
6-Monoacetylmorphine: 25 ng/mL
Oxycodone: 25 ng/mL
Fentanyl: 2 ng/mL
Naloxone: 25 ng/mL
Methadone: 25 ng/mL
2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP): 25 ng/mL
Tramadol: 25 ng/mL

Not Detected
Alpha-hydroxyalprazolam glucuronide: 50 ng/mL
Clobazam: 10 ng/mL
N-desmethylclobazam: 200 ng/mL
Diazepam: 10 ng/mL
Lorazepam: 10 ng/mL
Lorazepam glucuronide: 50 ng/mL
Midazolam: 10 ng/mL
Oxazepam: 10 ng/mL
Oxazepam glucuronide: 50 ng/mL
Prazepam: 10 ng/mL
Temazepam: 10 ng/mL
Temazepam glucuronide: 50 ng/mL
Triazolam: 10 ng/mL
Zolpidem: 10 ng/mL

Not Detected
3,4-Methylenedioxymethamphetamine (MDMA): 100 ng/mL
3,4-Methylenedioxy-N-ethylamphetamine (MDEA): 100 ng/mL
3,4-Methylenedioxyamphetamine (MDA): 100 ng/mL
Clinical References: 1. Physicians' Desk Reference: 60th ed. Medical Economics Company; 2006
2. Bruntman LL Lazo JS, Parker KL, eds: Goodman and Gilman's: The Pharmacological Basis of
Therapeutics. 11th ed. McGraw-Hill Book Company; 2006 3. Langman LJ, Bechtel L, Meier BM,
Holstege CP: Clinical toxicology In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical
Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:832-887 4. Gutstein HB, Akil H: Opioid
analgesics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's: The Pharmacological
Basis of Therapeutics. 11th ed. McGraw-Hill Companies; 2006:chap 21 5. Chronic Pain in America:
Roadblocks to Relief, survey conducted for the American Pain Society, The American Academy of the
Pain Medicine and Janssen Pharmaceutical; 1999 6. Magnani B, Kwong T: Urine drug testing for pain
management. Clin Lab Med. 2012 Sep;32(3):379-390 7. Jannetto PJ, Bratanow NC, Clark WA, et al:
Guideline-using clinical laboratory tests to monitor drug therapy in pain management patients. J Appl
Lab Med. 2018 Jan 1;2(4):489-526 8. McMillin GA, Marin SJ, Johnson-Davis KL, Lawlor BG,
Strathmann FG: A hybrid approach to urine drug testing using high-resolution mass spectrometry and
select immunoassays. Am J Clin Pathol. 2015 Feb;143(2):234-240 9. Cone EJ, Caplan YH, Black DL,
Robert T, Moser F: Urine drug testing of chronic pain patients: licit and illicit drug patterns. J Anal
Toxicol. 2008 Oct;32(8):530-543
CPAVP Copeptin proAVP, Plasma

603599 Clinical Information: Arginine vasopressin (AVP) and copeptin (also known as copeptin proAVP or
copeptin AVP) are derived from the same precursor peptide. Copeptin has been proposed as a more
stable, potentially superior, surrogate marker of AVP in the assessment of water balance disorders. Unlike
AVP, copeptin is stable in plasma. Both copeptin and AVP are responsive to osmotic stimuli and increase
in response to water deprivation. In healthy subjects, water deprivation causes the plasma osmolality to
rise above approximately 280-290 mOsmol/kg, leading to the release of AVP and copeptin into the
circulation. Copeptin increases gradually with fasting and water deprivation and declines rapidly after
intake of water and/or food. Diabetes insipidus (DI) is characterized by the inability to appropriately
concentrate urine in response to volume and osmolar stimuli. The main causes for DI are decreased AVP
production (central DI) or decreased renal response to AVP (nephrogenic DI). The determination of the
underlying disease pathology in patients with polyuria and altered plasma osmolality is often difficult.
Polyuria can be related to insufficient AVP (central DI), reduced sensitivity to AVP (nephrogenic DI), or
excessive water intake. Measurement of plasma copeptin concentration has been shown to be useful in the
investigation of these AVP-related disorders. Additionally, utilization of copeptin has been proposed in
the assessment of syndrome of inappropriate antidiuretic (SIADH). Copeptin is also a marker of acute
hemodynamic stress and has been reported to aid in the prognosis or diagnosis of several cardiac disorders
such as acute coronary syndrome, stable coronary artery disease, congestive heart failure, and acute
ischemic stroke. Some studies have demonstrated that copeptin may improve prediction of mortality and
heart disease outcome when combined with natriuretic peptides such as B-type natriuretic peptide (BNP)
and N-terminal pro b-type natriuretic peptide (NT-proBNP).
Useful For: The investigation of the differential diagnosis of patients with water balance disorders,
including diabetes insipidus, in conjunction with osmolality and hydration status May aid in the
evaluation of cardiovascular disease in conjunction with other cardiac markers
Interpretation: While secreted in equimolar concentrations in conjunction with arginine vasopressin

(AVP), measured plasma concentrations of copeptin do not correlate strongly with AVP concentrations
due to in vivo and in vitro differences in stability. Copeptin is a more stable surrogate biomarker of AVP
release. The clinical utility of copeptin of differentiating polyuria and water balance disorders has been
demonstrated in a number of studies, when used in conjunction with osmolality and hydration status. In a
prospective clinical study, an algorithm was established based on patients with polyuria-polydipsia
syndrome (n=55). A nonwater-deprived baseline copeptin concentration of 21.4 pmol/L or greater was
found to be consistent with the presence of nephrogenic diabetes insipidus (DI). In a described
algorithm(1), patients with a copeptin concentrations of under 21.4 pmol/L and a copeptin cut-off of 4.9
pmol/L after fluid deprivation, was used to distinguish between complete or partial DI (<4.9 pmol/L) and
primary polydipsia (> or =4.9 pmol/L). Central DI may also be differentiated from nephrogenic DI by
measuring copeptin during a stimulus for AVP release such as a water deprivation test. Copeptin
concentrations obtained in the process of a water deprivation test can be difficult to interpret because of
variation in water deprivation protocols. Patients with psychogenic polydipsia will either have a normal
response to water deprivation or, in long-standing cases, show a pattern suggestive of mild nephrogenic
DI. Expert consultation is recommended in these circumstances. Although the water-deprivation test is
considered the reference standard for the evaluation of DI, measurement of saline stimulated copeptin was
shown to be more accurate than the water-deprivation test.(2) In this indirect water deprivation test with a
cutoff of 4.9 pmol/L or less indicated central DI while a concentration greater than 4.9 pmol/L indicated
primary polydipsia. An elevated plasma copeptin AVP concentration in a hyponatremic patient may be
indicative of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). However copeptin
determination alone is not typically sufficient to distinguish SIADH from other hyponatremic
disorders.(3) Elevations of plasma copeptin in patients with symptoms of heart failure may be prognostic
of short- and long-term mortality. In patients with heart failure (HF) following a myocardial infarction
(MI), elevations in copeptin are associated with severity of HF and poorer prognosis.(4) In a cohort of
patients with class III or IV HF, copeptin concentrations of 40 pmol/L or greater significantly increased
the risk of death or need for cardiac transplantation. The combination of elevated copeptin and
hyponatremia was an even stronger predictor of heart failure, independent of B-type natriuretic peptide
(BNP) and cardiac troponin (cTn) concentrations.(5)
Reference Values:
Non-water deprived, non-fasting adults: <13.1 pmol/L
Water deprived, fasting adults: <15.2 pmol/L
Non-water deprived, non-fasting pediatric patients: <14.5 pmol/L
Note:
1. The reference interval for non-water deprived healthy adults is from Keller T, Tzikas S, Zeller T, et
al: Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol. 2010 May
11;55(19):2096-2106. doi: 10.1016/j.jacc.2010.01.029
2. The reference interval for fasting and water deprived adults (at least 8 hours of fasting and water
deprivation) was determined from an in-house Mayo study.
3. The reference interval for non-water deprived healthy pediatric individuals is from Du JM, Sang G,
Jiang CM, He XJ, Han Y: Relationship between plasma copeptin levels and complications of
community-acquired pneumonia in preschool children. Peptides. 2013 Jul;45:61-65. doi:
10.1016/j.peptides.2013.04.015
Clinical References: 1. Timper K, Fenske W, Kuhn F, et al: Diagnostic accuracy of copeptin in

the differential diagnosis of the polyuria-polydipsia syndrome: A prospective multicenter study. J Clin
Endocrinol Metab. 2015 Jun;100(6):2268-2274. doi: 10.1210/jc.2014-4507 2. Fenske W, Refardt J,
Chifu I, et al: A copeptin-based approach in the diagnosis of diabetes insipidus. N Engl J Med. 2018
Aug 2;379(5):428-439. doi: 10.1056/NEJMoa1803760 3. Fenske W, Stork S, Blechschmidt A, Maier
GK, Morgenthaler NG, Allolio B: Copeptin in the differential diagnosis of hyponatremia. J Clin
Endocrinol Metab. 2009 Jan;94(1):123-129. doi: 10.1210/jc.2008-1426 4. Neuhold S, Huelsmann M,
Strunk G, et al: Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type
natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the
disease. J Am Coll Cardiol. 2008 Jul 22;52(4):266-272. doi: 10.1016/j.jacc.2008.03.050 5. Miller WL,
Grill DE, Struck J, Jaffe ASP: Association of hyponatremia and elevated copeptin with death and need
for transplantation in ambulatory patients with chronic heart failure. Am J Cardiol. 2013 Mar
15;111(6):880-885. doi: 10.1016/j.amjcard.2012.11.053 6. Morgenthaler NG, Struck J, Alonso C,
Bergmann A: Assay for the measurement of copeptin, a stable peptide derived from the precursor of
vasopressin. Clin Chem. 2006 Jan;52(1):112-119. doi: 10.1373/clinchem.2005.060038 7. Mueller C,
Mockel M, Giannitsis E, et al: Use of copeptin for rapid rule-out of acute myocardial infarction. Eur
Heart J Acute Cardiovasc Care. 2018 Sep;7(6):570-576. doi: 10.1177/2048872617710791 8. Maisel A,
Mueller C, Neath SX, et al: Copeptin helps in the early detection of patients with acute myocardial
infarction: primary results of the CHOPIN trial (copeptin helps in the early detection of patients with
acute myocardial infarction). J Am Coll Cardiol. 2013 Jul 9;62:150-160. doi:
10.1016/j.jacc.2013.04.011 9. Keller T, Tzikas S, Zeller T, et al: Copeptin improves early diagnosis of
acute myocardial infarction. J Am Coll Cardiol. 2010 May 11;55(19):2096-2106. doi:
10.1016/j.jacc.2010.01.029 10. Du JM, Sang G, Jiang CM, He XJ, Han Y: Relationship between plasma
copeptin levels and complications of community-acquired pneumonia in preschool children. Peptides.
2013 Jul;45:61-65. doi: 10.1016/j.peptides.2013.04.015
CUU
Current
8590 as of July 20, 2022 12:05 pm CDT 800-533-1710 or 507-266-5700 or mayocliniclabs.com Page 751
Copper, 24 Hour, Urine
Clinical Information: The biliary system is the major pathway of copper excretion. Biliary excretion
of copper requires an adenosine triphosphate (ATP)-dependent transporter protein. Variants in the gene
for the transporter protein cause hepatolenticular degeneration (Wilson disease). Ceruloplasmin, the
primary copper-carrying protein in the blood, is also reduced in Wilson disease. Urine copper excretion is
increased in Wilson disease due to a decreased serum binding of copper to ceruloplasmin or due to allelic
variances in cellular metal ion transporters. Hypercupricuria (increased urinary copper) is also found in
hemochromatosis, biliary cirrhosis, thyrotoxicosis, various infections, and a variety of other acute,
chronic, and malignant diseases (including leukemia). Urine copper concentrations are also elevated in
patients taking contraceptives or estrogens and during pregnancy. Low urine copper levels are seen in
malnutrition, hypoproteinemias, malabsorption, and nephrotic syndrome. Increased zinc consumption
interferes with normal copper absorption from the gastrointestinal tract causing hypocupremia.
Useful For: Investigation of Wilson disease and obstructive liver disease using a 24-hour urine
specimen
Interpretation: Humans normally excrete less than 60 mcg/day of copper in the urine. Urinary copper
excretion greater than 60 mcg/day may be seen in: -Wilson disease -Obstructive biliary disease (eg,
primary biliary cirrhosis, primary sclerosing cholangitis) -Nephrotic syndrome (due to leakage through the
kidney) -Chelation therapy -Estrogen therapy -Mega dosing of zinc-containing vitamins Because
ceruloplasmin is an acute phase reactant, urine copper is elevated during acute inflammation. During the
recovery phase, urine copper is usually below normal, reflecting the expected physiologic response to
replace the copper that was depleted during inflammation.
Reference Values:
Clinical References: 1. Zorbas YG, Kakuris KK, Deogenov VA, et al: Copper homeostasis during
hypokinesia in healthy subjects with higher and lower copper consumption. Tr Elem Electro.
2008;25:169-178 2. Lech T, Sadlik JK: Contribution to the data on copper concentration in blood and
urine in patients with Wilson's disease and in normal subjects. Biol Trace Elem Res. 2007
July;118(1):16-20 3. Rifai N, Horwath AR, Wittwer CT, eds: Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed. Elsevier; 2018
CUT Copper, Liver Tissue

8687 Clinical Information: Homeostatic regulation of copper metabolism is very complex. The liver is the
key organ to facilitate copper storage and incorporation of copper into the transport protein ceruloplasmin.
Intestinal absorption and biliary excretion also play major roles in the regulation of copper homeostasis.
Abnormal copper metabolism is associated with liver disease. Elevated serum copper concentrations are
seen in portal cirrhosis, biliary tract disease, and hepatitis, probably because excess copper that would
normally be excreted in the bile is retained in circulation. In primary biliary cirrhosis, ceruloplasmin is
high, resulting in high serum copper. Lesser elevations of hepatic copper are found in chronic copper
poisoning, obstructive jaundice, and certain cases of hepatic cirrhosis. Reduced serum copper
concentration is typical of Wilson disease (hepatolenticular degeneration). Wilson disease is characterized
by liver disease, neurologic abnormalities, and psychiatric disturbances. Kayser-Fleischer rings are
normally present and urinary copper excretion is increased, while serum copper and ceruloplasmin are
low.
Useful For: Diagnosing Wilson disease and primary biliary cirrhosis using liver tissue specimens
Interpretation: The constellation of symptoms associated with Wilson disease (WD), which includes
Kayser-Fleischer rings, behavior changes, and liver disease, is commonly associated with liver copper
concentration above 250 mcg/g dry weight. VERY HIGH >1000 mcg/g dry weight: This finding is
strongly suggestive of Wilson disease. HIGH 250-1000 mcg/g dry weight: This finding is suggestive of
possible Wilson disease. MODERATELY HIGH 50-250 mcg/g dry weight: Excessive copper at this level
can be associated with cholestatic liver disease, such as primary biliary cirrhosis, primary sclerosing
cholangitis, autoimmune hepatitis, and familial cholestatic syndrome. Heterozygous carriers for Wilson
disease occasionally have modestly elevated values, but rarely higher than 125 mcg/g of dry weight. In
general, the liver copper content is higher than 250 mcg/g dried tissue in patients with Wilson disease. If
any of the above findings are without supporting histology and other biochemical test results,
contamination during collection, handling, or processing should be considered. Genetic testing for Wilson
disease (WDZ / Wilson Disease, Full Gene Analysis, Varies) is available at Mayo Clinic Laboratories,
call 800-533-1710 if you need additional assistance. In patients with elevated levels of copper without
supporting histology and other biochemical test results, contamination during collection, handling, or
processing should be considered.
Reference Values:
<50 mcg/g dry weight
Clinical References: 1. Korman J, Volenberg I, Balko J, et al: Screening for Wilson disease in
acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008
Oct;48(4):1167-1174 2. Roberts EA, Schlisky ML: Diagnosis and Treatment of Wilson Disease:
AASLD Practice Guidelines. Hepatology. 2008;47:2089-2111 3. de Bie P, Muller P, Wijmenga C,
Klomp LW: Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with
molecular defects and disease phenotypes. J Med Genet. 2007 November;44(11):673-688 4. Merle U,
Schaefer M, Ferenci P, Stremmel W: Clinical presentation, diagnosis and long-term outcome of
Wilson's disease: a cohort study. Gut. 2007;56:115-120 5. Rifai N, Horwath AR, Wittwer CT, eds. Tietz
FCOPP Copper, RBCs

Units: mcg/dL
NMS Labs derived data for 2.5th-97.5th percentile range is 59-91 mcg/dL (n=1999).
The RBC sample used for analysis was measured by weight and multiplied by the density of human
RBC (1.10 g/mL) to obtain mcg/dL units.
CUS1 Copper, Serum

616155 Clinical Information: Copper (Cu) is an important trace element that is associated with a number
of metalloproteins. Cu in biological material is complexed with proteins, peptides, and other organic
ligands. Up to 90% of Cu exported from the liver into peripheral blood is protein bound to
ceruloplasmin, transcuprein, or metallothionein. A smaller amount of Cu in plasma (<10%) is bound to
albumin by specific peptide sequences, and this Cu is in equilibrium with plasma amino acids. The
ceruloplasmin molecule contains 6 to 8 atoms of Cu per molecule with 6 atoms of Cu involved in the
protein's ferroxidase and free radical scavenging activities. The other 1 to 2 atoms of Cu are termed
"labile" and may allow ceruloplasmin to act as a Cu transporter, with a pool of Cu being exchanged
between albumin, transcuprein, and the labile sites of ceruloplasmin. Low serum copper, most often due
to excess iron or zinc ingestion and infrequently due to dietary copper deficit, results in severe
derangement in growth and impaired erythropoiesis. Low serum copper is also observed in
hepatolenticular degeneration (Wilson disease) due to a decrease in the synthesis of ceruloplasmin and
allelic variances in cellular metal ion transporters. In Wilson disease, the albumin-bound copper may
actually be increased, but ceruloplasmin-bound copper is low, resulting in low serum copper. However,
during the acute phase of Wilson disease (fulminant hepatic failure), ceruloplasmin and copper levels
may be normal; in this circumstance, hepatic inflammation causes increased release of ceruloplasmin. It
is useful to relate the degree of liver inflammation to the ceruloplasmin and copper-see discussion on
hypercupremia below. Significant hepatic inflammation with normal ceruloplasmin and copper suggest
acute Wilson disease. Other disorders associated with decreased serum copper concentrations include
malnutrition, hypoproteinemia, malabsorption, nephrotic syndrome, Menkes disease, copper toxicity,
and megadosing of zinc-containing vitamins (zinc interferes with normal copper absorption from the
gastrointestinal [GI] tract). Hypercupremia is found in primary biliary cholangitis (formerly primary
biliary cirrhosis), primary sclerosing cholangitis, hemochromatosis, malignant diseases (including
leukemia), thyrotoxicosis, and various infections. Serum copper concentrations are also elevated in
patients taking contraceptives or estrogens and during pregnancy. Since the GI tract effectively excludes
excess copper, it is the GI tract that is most affected by copper ingestion. Increased serum concentration
does not, by itself, indicate copper toxicity.
Useful For: Diagnosis of: -Wilson disease -Primary biliary cholangitis -Primary sclerosing cholangitis
Interpretation: Serum copper below the normal range is associated with Wilson disease, as well as a
variety of other clinical situations (see Clinical Information). Excess use of denture cream containing zinc
can cause hypocupremia. Serum concentrations above the normal range are seen in primary biliary
cirrhosis and primary sclerosing cholangitis, as well as a variety of other clinical situations (see Clinical
Information).
Reference Values:
0-2 months: 40-140 mcg/dL
13 months-10 years: 80-180 mcg/dL
11-17 years: 75-145 mcg/dL
Males:
> or =18 years: 73-129 mcg/dL
Females:
> or =18 years: 77-206 mcg/dL
Clinical References: 1. McCullough AJ, Fleming CR, Thistle JL, et al: Diagnosis of Wilson's
disease presenting as fulminant hepatic failure. Gastroenterology. 1983;84:161-167 2. Wiesner RH,
LaRusso NF, Ludwig J, Dickson ER: Comparison of the clinicopathologic features of primary sclerosing
cholangitis and primary biliary cirrhosis. Gastroenterology. 1985;88:108-114 3. Spain RI, Leist TP, De
Sousa EA: When metals compete: a case of copper-deficiency myeloneuropathy and anemia. Nat Clin
Pract Neurol. 2009 Feb;5(2):106-111 4. Kale SG, Holmes CS, Goldstein DS, et al: Neonatal Diagnosis
and Treatment of Menkes Disease. N Engl J Med. 2008 Feb 7;358(6):605-614 5. Nations SP, Boyer PJ,
Love LA, et al: Denture cream: An unusual source of excess zinc, leading to hypocupremia and
neurologic disease. Neurology. 2008;71;639-643 6. Strathmann FG, Blum LM: Toxic elements. In: Rifai
N, Chiu RWK, Young I, Burnham CAD, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 7th ed. Elsevier; 2023:chap 44
CURCU Copper/Creatinine Ratio, Random, Urine

615257 Clinical Information: The biliary system is the major pathway of copper excretion. Biliary excretion
of copper requires an adenosine triphosphate (ATP)-dependent transporter protein. Variants in the gene
for the transporter protein cause hepatolenticular degeneration (Wilson disease). Ceruloplasmin, the
primary copper-carrying protein in the blood, is also reduced in Wilson disease. Urine copper excretion is
increased in Wilson disease due to a decreased serum binding of copper to ceruloplasmin or due to allelic
variances in cellular metal ion transporters. Hypercupriuria (increased urinary copper) is also found in
hemochromatosis, biliary cirrhosis, thyrotoxicosis, various infections, and a variety of other acute,
chronic, and malignant diseases (including leukemia). Urine copper concentrations are also elevated in
patients taking contraceptives or estrogens and during pregnancy. Low urine copper levels are seen in
malnutrition, hypoproteinemia, malabsorption, and nephrotic syndrome. Increased zinc consumption
interferes with normal copper absorption from the gastrointestinal tract causing hypocupremia.
Useful For: Investigation of Wilson disease and obstructive liver disease using a random urine
specimen
Interpretation: Humans normally excrete less than 60 mcg/24 hour in the urine. Urinary copper
excretion greater than 60 mcg/24 hour may be seen in: -Wilson disease -Obstructive biliary disease (eg,
primary biliary cirrhosis, primary sclerosing cholangitis) -Nephrotic syndrome (due to leakage through the
kidney) -Chelation therapy -Estrogen therapy -Mega dosing of zinc-containing vitamins Because
Reference Values:
COPPER/CREATITINE:
Males:
> or =18 years: 9-43 mcg/g creatinine
Females:
CREATITINE:
Clinical References: 1. Zorbas YG, Kakuris KK, Deogenov VA, Yerullis KB: Copper
homeostasis during hypokinesia in healthy subjects with higher and lower copper consumption. Tr Elem
Electro. 2008;25:169-178 2. Lech T, Sadlik JK: Contribution to the data on copper concentration in
blood and urine in patients with Wilson's disease and in normal subjects. Biol Trace Elem Res. 2007
Jul;118(1):16-20 3. Czlonkowska A, Litwin T, Dusek P, et al: Wilson disease. Nat Rev Dis Primers.
2018 Sep 6;4(1):21. doi: 10.1038/s41572-018-0018-3 4. Rifai N, Horwath AR, Wittwer CT, eds: Tietz
CURC Copper/Creatinine Ratio, Urine

615258 Clinical Information: The biliary system is the major pathway of copper excretion. Biliary
excretion of copper requires an adenosine triphosphate (ATP)-dependent transporter protein. Variants in
the gene for the transporter protein cause hepatolenticular degeneration (Wilson disease).
Ceruloplasmin, the primary copper-carrying protein in the blood, is also reduced in Wilson disease.
Urine copper excretion is increased in Wilson disease due to a decreased serum binding of copper to
ceruloplasmin or due to allelic variances in cellular metal ion transporters. Hypercupriuria (increased
urinary copper) is also found in hemochromatosis, biliary cirrhosis, thyrotoxicosis, various infections,
and a variety of other acute, chronic, and malignant diseases (including leukemia). Urine copper
concentrations are also elevated in patients taking contraceptives or estrogens and during pregnancy.
Low urine copper levels are seen in malnutrition, hypoproteinemia, malabsorption, and nephrotic
syndrome. Increased zinc consumption interferes with normal copper absorption from the
gastrointestinal tract causing hypocupremia.
Useful For: Measurement of copper concentration of a part of the investigation of Wilson disease
and obstructive liver disease using a random urine specimen
Interpretation: Humans normally excrete less than 60 mcg/24 hour in the urine. Urinary copper
excretion greater than 60 mcg/24 hour may be seen in: -Wilson disease -Obstructive biliary disease (eg,
primary biliary cirrhosis, primary sclerosing cholangitis) -Nephrotic syndrome (due to leakage through
the kidney) -Chelation therapy -Estrogen therapy -Mega dosing of zinc-containing vitamins Because
Reference Values:
Only orderable as part of a profile. For more information see CURCU / Copper/Creatinine Ratio,
Random, Urine.
Not applicable
Clinical References: 1. Zorbas YG, Kakuris KK, Deogenov VA, Yerullis KB: Copper homeostasis
during hypokinesia in healthy subjects with higher and lower copper consumption. Tr Elem Electro.
2008;25:169-178 2. Lech T, Sadlik JK: Contribution to the data on copper concentration in blood and
urine in patients with Wilson's disease and in normal subjects. Biol Trace Elem Res. 2007
Jul;118(1):16-20 3. Czlonkowska A, Litwin T, Dusek P, et al: Wilson disease. Nat Rev Dis Primers. 2018
Sep 6;4(1):21. doi: 10.1038/s41572-018-0018-3 4. Rifai N, Horwath AR, Wittwer CT, eds: Tietz
CORI Coriander, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to coriander Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
FCORG Corn IgG
Reference Values:
FCOR4 Corn IgG4

Reference Values:
Reference ranges have not been established for food-specific IgG4 tests. The clinical utility of
food-specific IgG4 tests has not been clearly established. These tests can be used in special clinical
situations to select foods for evaluation by diet elimination and challenge in patients who have
food-related complaints, and to evaluate food allergic patients prior to food challenges. The presence of
food-specific IgG4 has been studied in response to various oral food immunotherapy treatments but
cutoffs have not been established.
CRNP Corn Pollen, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to corn pollen

Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
CORN Corn-Food, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to corn-food Defining the allergen responsible for
episode -To confirm sensitization prior to beginning immunotherapy

Reference Values:
0 Negative

apply to all ages.
CORTC Corticosterone, Serum
88221 Clinical Information: Corticosterone is a steroid hormone and a precursor molecule for
aldosterone. It is produced from deoxycorticosterone, further converted to 18-hydroxy corticosterone
and, finally, to aldosterone in the mineralocorticoid pathway. The adrenal glands, ovaries, testes, and
placenta produce steroid hormones, which can be subdivided into 3 major groups: mineral corticoids,
glucocorticoids, and sex steroids. Synthesis proceeds from cholesterol along 3 parallel pathways,
corresponding to these 3 major groups of steroids, through successive side-chain cleavage and
hydroxylation reactions. At various levels of each pathway, intermediate products can move into the
respective adjacent pathways via additional, enzymatically catalyzed reactions (see Steroid Pathways in
Special Instructions). Corticosterone is the first intermediate in the corticoid pathway with significant
mineral corticoid activity. Its synthesis from 11-deoxycorticosterone is catalyzed by 11
beta-hydroxylase 2 (CYP11B2) or by 11 beta-hydroxylase 1 (CYP11B1). Corticosterone is in turn
converted to 18-hydroxycorticosterone and finally to aldosterone, the most active mineral corticoid.
Both of these reactions are catalyzed by CYP11B2, which, unlike its sister enzyme CYP11B1, also
possesses 18-hydroxylase and 18-methyloxidase (also known as aldosterone synthase) activity. The
major diagnostic utility of measurements of steroid synthesis intermediates lies in the diagnosis of
disorders of steroid synthesis, in particular congenital adrenal hyperplasia (CAH). All types of CAH are
associated with cortisol deficiency with the exception of CYP11B2 deficiency and isolated impairments
of the 17-lyase activity of CYP17A1 (this enzyme also has 17 alpha-hydroxylase activity). In cases of
severe illness or trauma, CAH predisposes patients to poor recovery or death. Patients with the most
common form of CAH (21-hydroxylase deficiency, >90% of cases), with the third most common form
of CAH (3-beta-steroid dehydrogenase deficiency, <3% of cases) and those with the extremely rare
StAR (steroidogenic acute regulatory protein) or 20,22 desmolase deficiencies might also suffer mineral
corticoid deficiency, as the enzyme blocks in these disorders are proximal to potent mineral corticoids.
These patients might suffer salt-wasting crises in infancy. By contrast, patients with the second most
common form of CAH, 11-hydroxylase deficiency (<5% of cases) are normotensive or hypertensive, as
the block affects either CYP11B1 or CYP11B2, but rarely both, thus ensuring that at least
corticosterone is still produced. In addition, patients with all forms of CAH might suffer the effects of
substrate accumulation proximal to the enzyme block. In the 3 most common forms of CAH, the
accumulating precursors spill over into the sex steroid pathway, resulting in virilization of females or, in
milder cases, hirsutism, polycystic ovarian syndrome or infertility, as well as in possible premature
adrenarche and pubarche in both genders. Measurement of the various precursors of mature mineral
corticoid and glucocorticoids, in concert with the determination of sex steroid concentrations, allows
diagnosis of CAH and its precise type, and serves as an aid in monitoring steroid replacement therapy
and other therapeutic interventions. Measurement of corticosterone is used as an adjunct to
11-deoxycorticosterone and 11-deoxycortisol (also known as compound S) measurement in the
diagnosis of: -CYP11B1 deficiency (associated with cortisol deficiency) -The less common CYP11B2
deficiency (no cortisol deficiency) -The rare glucocorticoid responsive hyperaldosteronism (where
expression of the gene CYP11B2 is driven by the CYP11B1 promoter, thus making it responsive to
adrenocorticotrophic hormone: ACTH rather than renin) -Isolated loss of function of the 18-hydroxylase
or 18-methyloxidase activity of CYP11B2 For other forms of CAH, the following tests might be
relevant: -21-Hydroxylase deficiency: Â - OHPG / 17-Hydroxyprogesterone, Serum Â - ANST /
Androstenedione, Serum Â - 21DOC / 21-Deoxycortisol, Serum -3-Beta-steroid dehydrogenase
deficiency: Â - 17PRN / Pregnenolone and 17-Hydroxypregnenolone -17-Hydroxylase deficiency or
17-lyase deficiency (CYP17A1 has both activities): Â - 17PRN / Pregnenolone and
17-Hydroxypregnenolone Â - PGSN / Progesterone, Serum Â - OHPG / 17-Hydroxyprogesterone,
Serum - DHEA_ / Dehydroepiandrosterone (DHEA), Serum - ANST / Androstenedione, Serum Cortisol
should be measured in all cases of suspected CAH. When evaluating for suspected 11-hydroxylase
deficiency, this test should be used in conjunction with measurements of 11-deoxycortisol,
11-corticosteone, 18-hydroxycorticosterone, cortisol, renin, and aldosterone. When evaluating
congenital adrenal hyperplasia newborn screen-positive children, this test should be used in conjunction
with 11-deoxycortisol and 11-deoxycorticosteorone measurements as an adjunct to
17-hydroxyprogesterone, aldosterone and cortisol measurements.
Useful For: Diagnosis of suspected 11-hydroxylase deficiency, including the differential diagnosis of
11 beta-hydroxylase 1 (CYP11B1) versus 11 beta-hydroxylase 2 (CYP11B2) deficiency, and the
diagnosis of glucocorticoid-responsive hyperaldosteronism Evaluating congenital adrenal hyperplasia
newborn screen-positive children, when elevations of 17-hydroxyprogesterone are only moderate,
thereby suggesting possible 11-hydroxylase deficiency
Interpretation: In 11 beta-hydroxylase 1 (CYP11B1) deficiency, serum concentrations of cortisol will

be low (usually <7 microgram/dL for a morning draw). 11-Deoxycortisol and 11-deoxycorticosterone are
elevated, usually to at least 2 to 3 times (more typically 20 to 300 times) the upper limit of the normal
reference range on a morning blood draw. Elevations in 11-deoxycortisol are usually relatively greater
than those of 11-deoxycorticosterone because of the presence of intact 11 beta-hydroxylase 2 (CYP11B2).
For this reason, serum concentrations of all potent mineral corticoids (corticosterone,
18-hydroxycorticosterone, and aldosterone) are typically increased above the normal reference range.
Plasma renin activity is correspondingly low or completely suppressed. Caution needs to be exercised in
interpreting the mineral corticoid results in infants younger than 7 days; mineral corticoid levels are often
substantially elevated in healthy newborns in the first few hours of life and only decline to near-adult
levels by week 1. Mild cases of CYP11B1 deficiency might require adrenocorticotrophic hormone
(ACTH)1-24 stimulation testing for definitive diagnosis. In affected individuals, the observed serum
11-deoxycortisol concentration 60 minutes after intravenous or intramuscular administration of 250
microgram of ACTH1-24 will usually exceed 20 ng/mL, or at least a 4-fold rise. Such increments are
rarely, if ever, observed in unaffected individuals. The corresponding cortisol response will be blunted
(<18 ng/mL peak). In CYP11B2 deficiency, serum cortisol concentrations are usually normal, including a
normal response to ACTH1-24. 11-Deoxycorticosterone will be elevated, often more profoundly than in
CYP11B1 deficiency, while 11-deoxycortisol may or may not be significantly elevated. Serum
corticosterone concentrations can be low, normal, or slightly elevated, while serum
18-hydroxycorticosterone and aldosterone concentrations will be low in the majority of cases. However, if
the underlying genetic defect has selectively affected 18-hydroxylase activity, corticosterone
concentrations will be substantially elevated. Conversely, if the deficit affects aldosterone synthase
function primarily, 18-hydroxycorticosterone concentrations will be very high. Expression of the
CYP11B2 gene is normally regulated by renin and not ACTH. In glucocorticoid-responsive
hyperaldosteronism, the ACTH-responsive promoter of CYP11B1 exerts aberrant control over CYP11B2
gene expression. Consequently, corticosterone, 18-hydroxycorticosterone, and aldosterone are
significantly elevated in these patients and their levels follow a diurnal pattern, governed by the rhythm of
ACTH secretion. In addition, the high levels of CYP11B2 lead to 18-hydroxylation of 11-deoxycortisol
(an event that is ordinarily rare, as CYP11B1, which has much greater activity in 11-deoxycortisol
conversion than CYP11B2, lacks 18-hydroxylation activity). Consequently, significant levels of
18-hydroxycortisol, which normally is only present in trace amounts, might be detected in these patients.
Ultimate diagnostic confirmation comes from showing directly responsiveness of mineral corticoid
production to ACTH1-24 injection. Normally, this has little, if any, effect on corticosterone,
18-hydroxycorticosterone, and aldosterone levels. This testing may then be further supplemented by
showing that mineral corticoid levels fall after administration of dexamethasone. Sex steroid levels are
moderately to significantly elevated in CYP11B1 deficiency and much less, or minimally, pronounced, in
CYP11B2 deficiency. Sex steroid levels in glucocorticoid-responsive hyperaldosteronism are usually
normal. Most untreated patients with 21-hydroxylase deficiency have serum 17-hydroxyprogesterone
concentrations well in excess of 1,000 ng/dL. For the few patients with levels in the range of greater than
630 ng/dL (upper limit of reference range for newborns) to 2,000 or 3,000 ng/dL, it might be prudent to
consider 11-hydroxylase deficiency as an alternative diagnosis. This is particularly true if serum
androstenedione concentrations are also only mildly to modestly elevated, and if the phenotype is not salt
wasting but either simple virilizing (female) or normal (female or male). 11-Hydroxylase deficiency, in
particular if it affects CYP11B1, can be associated with modest elevations in serum
17-hydroxyprogesterone concentrations. In these cases, testing for CYP11B1 deficiency and CYB11B2
deficiency should be considered and interpreted as described above. Alternatively, measurement of
21-deoxycortisol might be useful in these cases. This minor pathway metabolite accumulates in CYP21A2
deficiency, as it requires 21-hydroxylation to be converted to cortisol, but is usually not elevated in
CYP11B1 deficiency, since its synthesis requires 11-hydroxylation of 17-hydroxyprogesterone.
Reference Values:
< or =18 years: 18-1,970 ng/dL
>18 years: 53-1,560 ng/dL

hyperplasia. Eur J Pediatr 1980;133(3):259-267 2. Therrell BL: Newborn screening for congenital adrenal
hyperplasia. Endocrinol Metab Clin North Am 2001;30(1):15-30 3. Collett-Solberg PF: Congenital
adrenal hyperplasia: From genetics and biochemistry to clinical practice, part I. Clin Pediatr 2001;40:1-16
4. Forest MG: Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to
21-hydroxylase deficiency. Hum Reprod Update 2004;10:469-485 5. Tonetto-Fernandes V,
Lemos-Marini SH, Kuperman H, et al: Serum 21-deoxycortisol,17-hydroxyprogesterone, and
11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and hormonal correlations and
identification of patients with 11 beta-hydroxylase deficiency among a large group with alleged
21-hydroxylase deficiency. J Clin Endocrinol Metab 2006;91:2179-2184
CORTO Cortisol, Free and Total, Serum

65484 Clinical Information: Cortisol, the main glucocorticoid (representing 75%-95% of the plasma
corticoids), plays a critical role in glucose metabolism and in the body's response to stress. Both
hypercortisolism (Cushing disease) and hypocortisolism (Addison disease) can cause disease. Cortisol is
also used to treat skin disease, allergic disorders, respiratory system disease, inflammatory disorders,
and nephrotic syndrome. Cortisol levels are regulated by adrenocorticotropic hormone (ACTH), which
is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). CRH is released
in a cyclic fashion by the hypothalamus, resulting in diurnal peaks (6 a.m.-8 a.m.) and troughs (11 p.m.)
in plasma ACTH and cortisol levels. The majority of cortisol circulates bound to corticosteroid-binding
globulin (CBG) and albumin. Normally, less than 5% of circulating cortisol is free (unbound). Only free
cortisol can access the enzyme transporters in liver, kidney, and other tissues that mediate metabolic and
excretory clearance. Historically, measurements of free cortisol have been achieved from indirect means
using a ratio known as the free cortisol index. This measurement takes into account the amount of total
cortisol and CBG to give a percentage and, ultimately, absolute value of free cortisol. These methods do
not take into account the possibility variations in albumin levels. These calculations also rely on CBG,
which can be lowered in critically ill patients despite normal adrenal function. Equilibrium dialysis best
serves to separate free from bound cortisol without disrupting the bound fraction. Pathological
hypercortisolism due to endogenous or exogenous glucocorticoids is termed Cushing syndrome. Signs
and symptoms of pathological hypercortisolism may include central obesity, hypertension,
hyperglycemia, hirsutism, muscle weakness, and osteoporosis. However, these symptoms and signs are
not specific for pathological hypercortisolism. The majority of individuals with some or all of the
symptoms and signs will not suffer from Cushing syndrome. When Cushing syndrome is present, the
most common cause is iatrogenic, due to repeated or prolonged administration of, mostly, synthetic
corticosteroids. Spontaneous Cushing syndrome is less common and results from either primary adrenal
disease (adenoma, carcinoma, or nodular hyperplasia) or an excess of ACTH (from a pituitary tumor or
an ectopic source). ACTH-dependent Cushing syndrome due to a pituitary corticotroph adenoma is the
most frequently diagnosed subtype, most commonly seen in women in the third through fifth decades of
life. The onset is insidious and usually occurs 2 to 5 years before a clinical diagnosis is made.
Hypocortisolism most commonly presents with nonspecific lassitude, weakness, hypotension, and
weight loss. Depending on the cause, hyperpigmentation may be present. More advanced cases and
patients submitted to physical stress (ie, infection, spontaneous or surgical trauma) also may present
with abdominal pain, hyponatremia, hyperkalemia, hypoglycemia, and in extreme cases, cardiovascular
shock and renal failure. The more common causes of hypocortisolism are: Primary adrenal
insufficiency: -Addison disease -Congenital adrenal hyperplasia, defects in enzymes involved in cortisol
synthesis Secondary adrenal insufficiency: -Prior, prolonged corticosteroid therapy -Pituitary
insufficiency -Hypothalamic insufficiency See Steroid Pathways in Special Instructions.
Useful For: Assessment of cortisol status in cases where there is known or a suspected abnormality
in cortisol-binding proteins or albumin Assessment of adrenal function in the critically ill or stressed
patient, thus preventing unnecessary use of glucocorticoid therapy Second-order testing when cortisol
measurement by immunoassay (eg, CORT / Cortisol, Serum) gives results that are not consistent with
clinical symptoms, or if patients are known to, or suspected of, taking exogenous synthetic steroids An
adjunct in the differential diagnosis of primary and secondary adrenal insufficiency An adjunct in the
differential diagnosis of Cushing syndrome
Interpretation: Cortisol is converted to cortisone in human kidneys and cortisone is less active
toward the mineralocorticoid receptor. The conversion of cortisol to cortisone in the kidney is mediated
by 11- beta-hydroxysteroid dehydrogenase isoform-2. Also, cortisol renal clearance will be reduced
when there is a deficiency in the cytochrome P450 3A5 (CYP3A5) enzyme as well as a deficiency in
P-glycoprotein. Cortisol-binding globulin (CBG) has a low capacity and high affinity for cortisol,
whereas albumin has a high capacity and low affinity for binding cortisol. Variations in CBG and serum
albumin due to renal or liver disease may have a major impact on free cortisol. Based on the study by
Bancos(1), normal ranges of free cortisol found in patients without adrenal insufficiency were: -Free
cortisol at baseline: median 0.400 mcg/dL (interquartile range: IQR 2.5-97.5% - 0.110-1.425 mcg/dL)
-Free cortisol at 30 minutes: median 1.355 mcg/dL (IQR 2.5-97.5% - 0.885-2.440 mcg/dL) -Free
cortisol at 60 minutes: median 1.720 mcg/dL (IQR 2.5-97.5% - 1.230-2.930 mcg/dL) Based on the
study by Bancos,(1) the following cutoffs were calculated for exclusion of adrenal insufficiency: -Free
cortisol at baseline*: greater than 0.271 mcg/dL (>271 ng/dL, area under the curve: AUC 0.81) -Free
cortisol at 30 minutes: greater than 0.873 mcg/dL (>873 ng/dL, AUC 0.99) -Free cortisol at 60 minutes:
greater than 1.190 mcg/dL (>1,190 ng/dL, AUC 0.99) (*please note that baseline free cortisol should
not be used to exclude adrenal insufficiency given low performance) The use of free cortisol in the
management of glucocorticoid levels in the stressed patient due to major surgery or trauma requires
further studies to establish clinical dosing levels and efficacy. Cortisol pediatric reference ranges are
generally the same as adults as confirmed by peer-reviewed literature.(2) In primary adrenal
insufficiency, adrenocorticotropic hormone (ACTH) levels are increased and cortisol levels are
decreased; in secondary adrenal insufficiency both ACTH and cortisol levels are decreased. When
symptoms of glucocorticoid deficiency are present and the 8 a.m. plasma cortisol value is less than 10
mcg/dL (or the 24-hour urinary free cortisol value is <50 mcg/24 hours), further studies are needed to
establish the diagnosis. The 3 most frequently used tests are the ACTH (cosyntropin) stimulation test,
the metyrapone test, and insulin-induced hypoglycemia test. First, the basal plasma ACTH
concentration should be measured and the short cosyntropin stimulation test performed. Symptoms or
signs of Cushing syndrome in a patient with low serum and urine cortisol levels suggest possible
exogenous synthetic steroid effects.
Reference Values:
FREE CORTISOL
6-10:30 a.m. Collection: 0.121-1.065 mcg/dL
TOTAL CORTISOL
5-25 mcg/dL (a.m.)
2-14 mcg/dL (p.m.)
Pediatric reference ranges are the same as adults, as confirmed by peer-reviewed literature.
Petersen KE: ACTH in normal children and children with pituitary and adrenal diseases. I. Measurement
in plasma by radioimmunoassay-basal values. Acta Paediatr Scand 1981;70:341-345
Clinical References: 1. Bancos I, Erickson D, Bryant S, et al: Performance of free versus total
cortisol following cosyntropin stimulation testing in an outpatient setting. Endocr Pract. 2015
Dec;21(12):1353-1363 doi: 10.4158/EP15820 2. Petersen KE: ACTH in normal children and children
with pituitary and adrenal diseases. I. Measurement in plasma by radioimmunoassay-basal values. Acta
Paediatr Scand. 1981;70:341-345. doi: 10.1111/j.1651-2227.1981.tb16561.x.Â 3. Hamrahian AH, Oseni
TS, Arafah BM: Measurements of serum free cortisol in critically ill patients. N Engl J Med.
2004;350;16:1629-1638. doi: 10.1111/j.1651-2227.1981.tb16561.x. 4. Ho JT, Al-Musalhi H, Chapman
MJ, et al: Septic shock and sepsis: a comparison of total and free plasma cortisol levels. J Clin Endocrinol
Metab. 2006;91:105-114. doi: 10.1210/jc.2005-0265.Â 5. le Roux CW, Chapman GA, Kong WM, Dhillo
WS, Jones J, Alaghband-Zadeh J: Free cortisol index is better than serum total cortisol in determining
hypothalamic-pituitary-adrenal status in patients undergoing surgery. J Clin Endocrinol Metab.
2003;88:2045-2048. doi: 10.1210/jc.2002-021532. 6. Huang W, Kalhorn TF, Baillie M, Shen DD,
Thummel KE: Determination of free and total cortisol in plasma and urine by liquid
chromatography-tandem mass spectrometry. Ther Drug Monit. 2007;29(2):215-224. doi:
10.1097/FTD.0b013e31803d14c0.Â
CORTU
Current 8546
Cortisol, Free, 24 Hour, Urine
Clinical Information: Cortisol is a steroid hormone synthesized from cholesterol by a multienzyme
cascade in the adrenal glands. It is the main glucocorticoid in humans and acts as a gene transcription
factor influencing a multitude of cellular responses in virtually all tissues. Cortisol plays a critical role
in glucose metabolism, maintenance of vascular tone, immune response regulation, and in the body's
response to stress. Its production is under hypothalamic-pituitary feedback control. Only a small
percentage of circulating cortisol is biologically active (free), with the majority of cortisol inactive
(protein bound). As plasma cortisol values increase, free cortisol (ie, unconjugated cortisol or
hydrocortisone) increases and is filtered through the glomerulus. Urinary free cortisol (UFC) in the
urine correlates well with the concentration of plasma free cortisol. UFC represents excretion of the
circulating, biologically active, free cortisol that is responsible for the signs and symptoms of
hypercortisolism. UFC is a sensitive test for the various types of adrenocortical dysfunction, particularly
hypercortisolism (Cushing syndrome). A measurement of 24-hour UFC excretion, by liquid
chromatography-tandem mass spectrometry (LC-MS/MS), is the preferred screening test for Cushing
syndrome. LC-MS/MS methodology eliminates analytical interferences including carbamazepine
(Tegretol) and synthetic corticosteroids, which can affect immunoassay-based cortisol results.
Useful For: Preferred screening test for Cushing syndrome Diagnosis of pseudo-hyperaldosteronism
due to excessive licorice consumption Test may not be useful in the evaluation of adrenal insufficiency
Interpretation: Most patients with Cushing syndrome have increased 24-hour urinary excretion of
cortisol. Further studies, including suppression or stimulation tests, measurement of serum
corticotrophin concentrations, and imaging are usually necessary to confirm the diagnosis and
determine the etiology. Values in the normal range may occur in patients with mild Cushing syndrome
or with periodic hormonogenesis. In these cases, continuing follow-up and repeat testing are necessary
to confirm the diagnosis. Patients with Cushing syndrome due to intake of synthetic glucocorticoids
should have suppressed cortisol. In these circumstances a synthetic glucocorticoid screen might be
ordered (SGSU / Synthetic Glucocorticoid Screen, Urine). Suppressed cortisol values may also be
observed in primary adrenal insufficiency and hypopituitarism. However, many normal individuals may
also exhibit a very low 24-hour urinary cortisol excretion with considerable overlap with the values
observed in pathological hypocorticalism. Therefore, without other tests, 24-hour urinary cortisol
measurements cannot be relied upon for the diagnosis of hypocorticalism.
Reference Values:
3-8 years: 1.4-20 mcg/24 hours
> or =18 years: 3.5-45 mcg/24 hours
Use the factor below to convert from mcg/24 hours to nmol/24 hours:
Conversion factor
Cortisol: mcg/24 hours x 2.76=nmol/24 hours (molecular weight=362.5)
Clinical References: 1. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing's
syndrome. Endocrinol Metab Clin North Am 2001;30:729-747 2. Boscaro M, Barzon L, Fallo F, Sonino
N: Cushing's syndrome. Lancet 2001;357:783-791 3. Taylor RL, Machacek D, Singh RJ: Validation of
a high-throughput liquid chromatography-tandem mass spectrometry method for urinary cortisol and
cortisone. Clin Chem 2002;48:1511-1519 4. Eisenhofer G, Grebe S, Cheung N-K V: Chapter 63
Monoamine-Producing Tumors. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics.
Sixth edition. Edited by N Rafai, AR Horvath, CT Wittwer. Elsevier, 2018. pp 1421 5. Luo A, El
Gierari ETM, Nally LM, et al: Clinical utility of an ultrasensitive urinary free cortisol assay by tandem
mass spectrometry. Steroids. 2019 Jun;146:65-69. doi: 10.1016/j.steroids.2019.03.014
CRANR Cortisol, Free, Random, Urine
609741 Clinical Information: Cortisol is a steroid hormone synthesized from cholesterol by a multienzyme
factor influencing a multitude of cellular responses in virtually all tissues. Cortisol plays a critical role in
glucose metabolism, maintenance of vascular tone, immune response regulation, and in the body's
hydrocortisone) increases and is filtered through the glomerulus. Urinary free cortisol (UFC) correlates
well with the concentration of plasma free cortisol. UFC represents excretion of the circulating,
biologically active, free cortisol that is responsible for the signs and symptoms of hypercortisolism. UFC
is a sensitive test for the various types of adrenocortical dysfunction, particularly hypercortisolism
(Cushing syndrome). A measurement of 24-hour UFC excretion by liquid chromatography-tandem mass
spectrometry (LC-MS/MS) is the preferred screening test for Cushing syndrome. LC-MS/MS
methodology eliminates analytical interferences including carbamazepine (Tegretol) and synthetic
corticosteroids, which can affect immunoassay-based cortisol results.
Useful For: Investigating suspected hypercortisolism when a 24-hour collection is prohibitive (ie,
pediatric patients)
cortisol. Further studies, including suppression or stimulation tests, measurement of serum corticotropin
(adrenocorticotropic hormone) concentrations, and imaging are usually necessary to confirm the diagnosis
and determine the etiology. Values in the normal range may occur in patients with mild Cushing
syndrome or with periodic hormonogenesis. In these cases, continuing follow-up and repeat testing are
necessary to confirm the diagnosis. Patients with Cushing syndrome due to intake of synthetic
glucocorticoids should have suppressed cortisol. In these circumstances a synthetic glucocorticoid screen
might be ordered (SGSU / Synthetic Glucocorticoid Screen, Random, Urine). Suppressed cortisol values
may also be observed in primary adrenal insufficiency and hypopituitarism. The optimal specimen type
for evaluation of primary adrenal insufficiency and hypopituitarism is serum (CORT / Cortisol, Serum).
Reference Values:
Males
0-2 years: 3.0-120 mcg/g creatinine
> or =18 years: 1.0-119 mcg/g creatinine
Females
Use the conversion factors below to convert each analyte from mcg/g creatinine to nmol/mol creatinine.
Conversion factor
Cortisol: mcg/g creatinine x 312=nmol/mol creatinine
Cortisol molecular weight=362.5

Creatinine molecular weight=113.12
Clinical References: 1. Taylor RL, Machacek DA, Singh RJ: Validation of a high-throughput liquid
chromatography-tandem mass spectrometry method for urinary cortisol and cortisone. Clin Chem.
2002;48:1511-1519 2. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing's syndrome.
Endocrinol Metab Clin North Am. 2001;30:729-747 3. Boscaro M, Barzon L, Fallo F, Sonino N:
Cushing's syndrome. Lancet 2001;357:783-791 4. Suzuki S, Minamidate T, Shiga A, et al. Steroid
metabolites for diagnosing and predicting clinicopathological features in cortisol-producing adrenocortical
carcinoma. BMC Endocr Disord. 2020;20(1):173. doi: 10.1186/s12902-020-00652-y
CORTF Cortisol, Free, Serum

hypercortisolism (Cushing disease) and hypocortisolism (Addison disease) can cause disease. Cortisol is
also used to treat skin disease, allergic disorders, respiratory system disease, inflammatory disorders,
and nephrotic syndrome. Cortisol levels are regulated by adrenocorticotropic hormone (ACTH), which
is synthesized by the pituitary in response to corticotropin releasing hormone (CRH). CRH is released in
a cyclic fashion by the hypothalamus, resulting in diurnal peaks (6 a.m.-8 a.m.) and troughs (11 p.m.) in
plasma ACTH and cortisol levels. The majority of cortisol circulates bound to corticosteroid-binding
globulin (CBG) and albumin. Normally, less than 5% of circulating cortisol is free (unbound). Only free
cortisol can access the enzyme transporters in liver, kidney, and other tissues that mediate metabolic and
excretory clearance. Historically, measurements of free cortisol have been achieved from indirect means
using a ratio known as the free cortisol index. This measurement takes into account the amount of total
cortisol and CBG to give a percentage and ultimately absolute value of free cortisol. These methods do
not take into account the possible variations in albumin levels. These calculations also rely on CBG,
which can be lowered in critically ill patients despite normal adrenal function. Equilibrium dialysis best
serves to separate free from bound cortisol without disrupting the bound fraction.
Useful For: Assessment of cortisol status in cases where there is known or a suspected abnormality
in cortisol-binding proteins or albumin Assessment of adrenal function in the critically ill or stressed
patient, thus preventing unnecessary use of glucocorticoid therapy
Interpretation: Cortisol is converted to cortisone in human kidneys and cortisone is less active
toward the mineralocorticoid receptor. The conversion of cortisol to cortisone in the kidney is mediated
by 11-beta-hydroxysteroid dehydrogenase isoform-2. Also, cortisol renal clearance will be reduced
when there is a deficiency in the cytochrome P450 3A5 (CYP3A5) enzyme as well as a deficiency in
P-glycoprotein. Cortisol binding globulin (CBG) has a low capacity and high affinity for cortisol,
whereas albumin has a high capacity and low affinity for binding cortisol. Variations in CBG and serum
albumin due to renal or liver disease may have a major impact on free cortisol. Based on the study by
Bancos,(1) normal ranges of free cortisol found in patients without adrenal insufficiency were: -Free
cortisol at baseline: median 0.400 mcg/dL (interquartile range: IQR 2.5-97.5% - 0.110-1.425 mcg/dL)
-Free cortisol at 30 minutes: median 1.355 mcg/dL (IQR 2.5-97.5% - 0.885-2.440 mcg/dL) -Free
cortisol at 60 minutes: median 1.720 mcg/dL (IQR 2.5-97.5% - 1.230-2.930 mcg/dL) Based on the
study by Bancos,(1) the following cutoffs were calculated for exclusion of adrenal insufficiency: -Free
cortisol at baseline*: greater than 0.271 mcg/dL (>271 ng/dL, area under the curve: AUC 0.81) -Free
cortisol at 30 minutes: greater than 0.873 mcg/dL (>873 ng/dL, AUC 0.99) -Free cortisol at 60 minutes:
greater than 1.190 mcg/dL (>1190 ng/dL, AUC 0.99) *baseline free cortisol should not be used to
exclude adrenal insufficiency given low performance The use of free cortisol in the management of
glucocorticoid levels in the stressed patient due to major surgery or trauma requires further studies to
establish clinical dosing levels and efficacy.
Reference Values:
6-10:30 a.m. Collection: 0.121-1.065 mcg/dL
Clinical References: 1. Bancos I, Erickson D, Bryant S, et al: Performance of free versus total
cortisol following cosyntropin stimulation testing in an outpatient setting. Endocr Pract. 2015
Dec;21(12):1353-1363. doi: 10.4158/EP15820 2. Hamrahian AH, Oseni TS, Arafah BM: Measurements
of serum free cortisol in critically ill patients. N Engl J Med. 2004;350;16:1629-1638 3. Ho JT,
Al-Musalhi H, Chapman MJ, et al: Septic shock and sepsis: a comparison of total and free plasma
cortisol levels. J Clin Endocrinol Metab. 2006;91:105-114 4. le Roux CW, Chapman GA, Kong WM,
Dhillo WS, Jones J, Alaghband-Zadeh Jl: Free cortisol index is better than serum total cortisol in
determining hypothalamic-pituitary-adrenal status in patients undergoing surgery. J Clin Endocrinol
Metab. 2003;88:2045-2048 5. Huang W, Kalhorn TF, Baillie M, Shen DD, Thummel KE:
Determination of free and total cortisol in plasma and urine by liquid chromatography-tandem mass
spectrometry. Ther Drug Monit. 2007;29(2):215-224
CIVC Cortisol, Inferior Vena Cava, Serum

CLAV Cortisol, Left Adrenal Vein, Serum

CINP Cortisol, Mass Spectrometry, Serum

hypercortisolism and hypocortisolism can cause disease. Cortisol levels are regulated by
adrenocorticotropic hormone (ACTH), which is synthesized by the pituitary in response to corticotropin
releasing hormone (CRH). CRH is released in a cyclic fashion by the hypothalamus, resulting in diurnal
peaks (6-8 a.m.) and troughs (11 p.m.) in plasma ACTH and cortisol levels. The majority of cortisol
circulates bound to corticosteroid-binding globulin and albumin. Normally, less than 5% of circulating
cortisol is free (unbound). Free cortisol is the physiologically active form and is filterable by the renal
glomerulus. Pathological hypercortisolism due to endogenous or exogenous glucocorticoids is termed
Cushing syndrome. Signs and symptoms of pathological hypercortisolism may include central obesity,
hypertension, hyperglycemia, hirsutism, muscle weakness, and osteoporosis. However, these symptoms
and signs are not specific for pathological hypercortisolism. The majority of individuals with some or all
of the symptoms and signs will not suffer from Cushing syndrome. When Cushing syndrome is present,
the most common cause is iatrogenic, due to repeated or prolonged administration of, mostly, synthetic
corticosteroids. Spontaneous Cushing syndrome is less common and results from either primary adrenal
disease (adenoma, carcinoma, or nodular hyperplasia) or an excess of ACTH (from a pituitary tumor or an
ectopic source). ACTH-dependent Cushing syndrome due to a pituitary corticotroph adenoma is the most
frequently diagnosed subtype; most commonly seen in women in the third through fifth decades of life.
The onset is insidious and usually occurs 2 to 5 years before a clinical diagnosis is made. Hypocortisolism
most commonly presents with nonspecific lassitude, weakness, hypotension, and weight loss. Depending
on the cause, hyperpigmentation may be present. More advanced cases and patients submitted to physical
stress (ie, infection, spontaneous or surgical trauma) also may present with abdominal pain, hyponatremia,
hyperkalemia, hypoglycemia, and in extreme cases, cardiovascular shock and renal failure. The more
common causes of hypocortisolism are: Primary adrenal insufficiency: -Addison disease -Congenital
adrenal hyperplasia, defects in enzymes involved in cortisol synthesis Secondary adrenal insufficiency:
-Prior, prolonged corticosteroid therapy -Pituitary insufficiency -Hypothalamic insufficiency See Steroid
Pathways in Special Instructions.
Useful For: Second-order testing when cortisol measurement by immunoassay (eg, CORT / Cortisol,
Serum) gives results that are not consistent with clinical symptoms, or if patients are known to, or
suspected of, taking exogenous synthetic steroids. For confirming the presence of synthetic steroids, order
SGSS / Synthetic Glucocorticoid Screen, Serum. An adjunct in the differential diagnosis of primary and
secondary adrenal insufficiency An adjunct in the differential diagnosis of Cushing syndrome This test is
not recommended for evaluating response to metyrapone; DOC / 11-Deoxycortisol, Serum is more
reliable.
Interpretation: In primary adrenal insufficiency, adrenocorticotropic hormone (ACTH) levels are

increased, and cortisol levels are decreased; in secondary adrenal insufficiency both ACTH and cortisol
levels are decreased. When symptoms of glucocorticoid deficiency are present and the 8 a.m. plasma
cortisol value is <10 mcg/dL (or the 24-hour urinary free cortisol value is <50 mcg/24 hours), further
studies are needed to establish the diagnosis. The 3 most frequently used tests are the ACTH (cosyntropin)
stimulation test, the metyrapone test, and insulin-induced hypoglycemia test. First, the basal plasma
ACTH concentration should be measured, and the short cosyntropin stimulation test performed. Cushing
syndrome is characterized by increased serum cortisol levels. However, the 24-hour urinary free cortisol
excretion is the preferred screening test for Cushing syndrome, specifically CORTU / Cortisol, Free, 24
Hour, Urine that utilizes liquid chromatography-tandem mass spectrometry. A normal result makes the
diagnosis unlikely. Symptoms or signs of Cushing syndrome in a patient with low serum and urine
cortisol levels suggest possible exogenous synthetic steroid effects.
Reference Values:
5-25 mcg/dL (a.m.)
2-14 mcg/dL (p.m.)
Pediatric reference ranges are the same as adults, as confirmed by peer-reviewed literature.
Petersen KE: ACTH in normal children and children with pituitary and adrenal diseases. I.
Measurement in plasma by radioimmunoassay-basal values. Acta Paediatr Scand. 1981;70:341-345
Clinical References: 1. Lin CL, Wu TJ, Machacek DA, Jiang NS, Kao PC: Urinary free cortisol
and cortisone determined by high-performance liquid chromatography in the diagnosis of Cushing's
syndrome. J Clin Endocrinol Metab. 1997;82:151-155. doi: 10.1210/jcem.82.1.3687.Â 2. Findling JW,
Raff H: Diagnosis and differential diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am.
2001;30(3):729-747. doi: 10.1016/s0889-8529(05)70209-7. 3. Buchman Al: Side effects of
corticosteroid therapy. J Clin Gastroenterol. 2001;33(4):289-297. doi:
10.1097/00004836-200110000-00006. 4. Dodds HM, Taylor PJ, Cannell GR, Pond SM: A
high-performance liquid chromatography-electrospray-tandem mass spectrometry analysis of cortisol
and metabolites in placental perfusate. Anal Biochem. 1997;247:342-347. doi: 10.1006/abio.1997.2074.
CRAV Cortisol, Right Adrenal Vein, Serum

SALCT Cortisol, Saliva

84225 Clinical Information: Cortisol levels are regulated by adrenocorticotropic hormone (ACTH),
which is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). Cushing
syndrome results from overproduction of glucocorticoids because of either primary adrenal disease
(adenoma, carcinoma, or nodular hyperplasia) or an excess of ACTH (from a pituitary tumor or an
ectopic source). ACTH-dependent Cushing syndrome due to a pituitary corticotroph adenoma is the
most frequently diagnosed subtype; most commonly seen in women in the third through fifth decades of
life. CRH is released in a cyclic fashion by the hypothalamus, resulting in diurnal peaks (elevated in the
morning) and nadirs (low in the evening) for plasma ACTH and cortisol levels. The diurnal variation is
lost in patients with Cushing syndrome and these patients have elevated levels of evening plasma
cortisol. The measurement of late-night salivary cortisol is an effective and convenient screening test for
Cushing syndrome.(1) In a recent study from the National Institute of Health, nighttime salivary cortisol
measurement was superior to plasma and urine free cortisol assessments in detecting patients with mild
Cushing syndrome.(2) The sensitivity of nighttime salivary cortisol measurements remained superior to
all other measures. The distinction between Cushing syndrome and pseudo-Cushing states is most
difficult in the setting of mild-to-moderate hypercortisolism. Subtle increases in salivary cortisol
collected at midnight (cortisol of nadir) appear to be one of the earliest abnormalities in Cushing
syndrome.
Useful For: Screening for Cushing syndrome Diagnosis of Cushing syndrome in patients presenting
with symptoms or signs suggestive of the disease
Interpretation: Cushing syndrome is characterized by increased salivary cortisol levels, and

late-night saliva cortisol measurements may be the optimum test for the diagnosis of Cushing syndrome.
It is standard practice to confirm elevated results at least once. This can be done by repeat late-night
salivary cortisol measurements, midnight blood sampling for cortisol (CORT / Cortisol, Serum),
24-hour urinary free cortisol collection (CORTU / Cortisol, Free, 24 Hour, Urine), or overnight
dexamethasone suppression testing. Upon confirmation of the diagnosis, the cause of hypercortisolism,
adrenal versus pituitary versus ectopic adrenocorticotropic hormone production, needs to be established.
This is typically a complex undertaking, requiring dynamic testing of the pituitary adrenal axis and
imaging procedures. Referral to specialized centers or in-depth consultation with experts is strongly
recommended.
Reference Values:
7 a.m.-9 a.m.: 100-750 ng/dL
3 p.m.-5 p.m.: <401 ng/dL
11 p.m.-midnight: <100 ng/dL
Clinical References: 1. Raff H, Raff JL, Findling JW: Late-night salivary cortisol as a screening test
for Cushing's syndrome. J Clin Endocrinol Metab 1998;83:2681-2686 2. Papanicolaou DA, Mullen N,
Kyrou I, Nieman LK: Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome. J
Clin Endocrinol Metab 2002;87:4515-4521
CORT Cortisol, Serum

corticoids) plays a central role in glucose metabolism and in the body's response to stress. Cortisol levels
are regulated by adrenocorticotropic hormone (ACTH), which is synthesized by the pituitary gland in
response to corticotropin-releasing hormone (CRH). CRH is released in a cyclic fashion by the
hypothalamus, resulting in diurnal peaks (6 a.m.-8 a.m.) and troughs (11 p.m.) in plasma ACTH and
cortisol levels. The majority of cortisol circulates bound to cortisol-binding globulin (CBG-transcortin)
and albumin. Normally, less than 5% of circulating cortisol is free (unbound). The free cortisol is the
physiologically active form and is filterable by the renal glomerulus. Although hypercortisolism is
uncommon, the signs and symptoms are common (eg, obesity, high blood pressure, increased blood
glucose concentration). The most common cause of increased plasma cortisol levels in women is a high
circulating concentration of estrogen (eg, estrogen therapy, pregnancy) resulting in increased
concentration of cortisol-binding globulin. Spontaneous Cushing syndrome results from overproduction
of glucocorticoids as a result of either primary adrenal disease (adenoma, carcinoma, or nodular
hyperplasia) or an excess of ACTH (from a pituitary tumor or an ectopic source). ACTH-dependent
Cushing syndrome due to a pituitary corticotroph adenoma is the most frequently diagnosed subtype;
most commonly seen in women in the third through fifth decades of life. The onset is insidious and
usually occurs 2 to 5 years before a clinical diagnosis is made. Causes of hypocortisolism are: -Addison
disease-primary adrenal insufficiency -Secondary adrenal insufficiency: --Pituitary insufficiency
--Hypothalamic insufficiency -Congenital adrenal hyperplasia-defects in enzymes involved in cortisol
synthesis
Useful For: Discrimination between primary and secondary adrenal insufficiency Differential
diagnosis of Cushing syndrome This test is not recommended for evaluating response to metyrapone.
Interpretation: In primary adrenal insufficiency, adrenocorticotropic hormone (ACTH) levels are

increased, and cortisol levels are decreased; in secondary adrenal insufficiency, both ACTH and cortisol
levels are decreased. When symptoms of glucocorticoid deficiency are present and the 8 a.m. plasma
cortisol value is less than 10 mcg/dL (or the 24-hour urinary free cortisol value is <50 mcg/24 hours),
further studies are needed to establish the diagnosis. First, the basal plasma ACTH concentration should
be measured, followed by the short cosyntropin stimulation test. For the cosyntropin (ACTH)-stimulation
test, serum cortisol is measured before and at various time intervals after an ACTH injection. The criteria
for a normal response are:-An increase in serum cortisol to a peak value of at least 15 mcg/dL
post-cosyntropin-Usually also associated with an increase in serum cortisol of at least 7 mcg/dL above the
baseline (if baseline cortisol is >15 mcg/dL this criterion does not apply)-Basal serum cortisol greater than
5 mcg/dL (criterion applies when blood drawn before 9 a.m.) False normal responses may be present in
patients on oral estrogen therapy or in patients with mild secondary adrenal insufficiency. Â Other
frequently used tests are the metyrapone and insulin-induced hypoglycemia test. Consult the Endocrine
Testing Center at 800-533-1710 for testing information and interpretation of test results. Cushing
syndrome is characterized by increased serum cortisol levels. However, the 24-hour urinary free cortisol
excretion is the preferred screening test for Cushing syndrome, specifically CORTU / Cortisol, Free, 24
Hour, Urine, which utilizes liquid chromatography/tandem mass spectrometry (LC-MS/MS). A normal
result makes the diagnosis unlikely. When cortisol measurement by immunoassay gives results that are
not consistent with clinical symptoms, or if patients are known to, or suspected of, taking exogenous
synthetic steroids, consider testing by LC-MS/MS; see CINP / Cortisol, Mass Spectrometry, Serum. For
confirming the presence of synthetic steroids, order SGSS / Synthetic Glucocorticoid Screen, Serum.
Reference Values:
a.m.: 7-25 mcg/dL
p.m.: 2-14 mcg/dL
syndrome. Endocrinol Metab Clin North Am. 2001;30(3):729-747 2. Buchman AL: Side effects of
corticosteroid therapy. J Clin Gastroenterol. 2001;33(4):289-294 3. Rifai N, Horvath AR, Wittwer CT.
eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018 4.
Javorsky B, Carroll T, Algeciras-Schimnich A, Singh R, Colon-Franco J, Findling J: SAT-390 new
cortisol threshold for diagnosis of adrenal insufficiency after cosyntropin stimulation testing using the
Elecsys cortisol II, access cortisol, and LC-MS/MS assays. J Endocr Soc. 2019;3(Suppl 1):SAT-390.
doi: 10.1210/js.2019-SAT-390
COCOU Cortisol/Cortisone, Free, 24 Hour, Urine

factor influencing a multitude of cellular responses in virtually all tissues. Cortisol plays a critical role
in glucose metabolism, maintenance of vascular tone, immune response regulation, and in the body's
hydrocortisone) increases and is filtered through the glomerulus. Urinary free cortisol (UFC) correlates
well with the concentration of plasma free cortisol. UFC represents excretion of the circulating,
biologically active, free cortisol that is responsible for the signs and symptoms of hypercortisolism.
UFC is a sensitive test for the various types of adrenocortical dysfunction, particularly hypercortisolism
(Cushing syndrome). A measurement of 24-hour UFC excretion, by liquid chromatography-tandem
mass spectrometry (LC-MS/MS), is the preferred screening test for Cushing syndrome. LC-MS/MS
methodology eliminates analytical interferences including carbamazepine (Tegretol) and synthetic
corticosteroids, which can affect immunoassay-based cortisol results. Cortisone, a downstream
metabolite of cortisol, provides an additional variable to assist in the diagnosis of various adrenal
disorders, including abnormalities of 11-beta-hydroxy steroid dehydrogenase (11-beta HSD), the
enzyme that converts cortisol to cortisone. Deficiency of 11-beta HSD results in a state of
mineralocorticoid excess because cortisol (but not cortisone) acts as a mineralocorticoid receptor
agonist. Licorice (active component glycyrrhetinic acid) inhibits 11-beta HSD and excess consumption
can result in similar changes.
Useful For: Screening test for Cushing syndrome (hypercortisolism) Assisting in diagnosing
acquired or inherited abnormalities of 11-beta-hydroxy steroid dehydrogenase (cortisol to cortisone
ratio) Diagnosis of pseudo-hyperaldosteronism due to excessive licorice consumption This test has
limited usefulness in the evaluation of adrenal insufficiency.
cortisol and/or cortisone. Further studies, including suppression or stimulation tests, measurement of
serum corticotropin (adrenocorticotropic hormone) concentrations, and imaging are usually necessary to
confirm the diagnosis and determine the etiology. Values in the normal range may occur in patients with
mild Cushing syndrome or with periodic hormonogenesis. In these cases, continuing follow-up and
repeat testing are necessary to confirm the diagnosis. Patients with Cushing syndrome due to intake of
synthetic glucocorticoids should have both suppressed cortisol and cortisone. In these circumstances a
synthetic glucocorticoid screen might be ordered (call 800-533-1710). Suppressed cortisol and cortisone
values may also be observed in primary adrenal insufficiency and hypopituitarism. However, random
urine specimens are not useful for evaluation of hypocorticalism. Further, many normal individuals also
may exhibit a very low 24-hour urinary cortisol excretion with considerable overlap with the values
observed in pathological hypocorticalism. Therefore, without other tests, 24-hour urinary cortisol
measurements cannot be relied upon for the diagnosis of hypocorticalism. Patients with 11-beta HSD
deficiency may have cortisone to cortisol ratios <1, whereas a ratio of 2:1 to 3:1 is seen in normal
patients. Excessive licorice consumption and use of carbenoxolone, a synthetic derivative of
glycyrrhizinic acid used to treat gastroesophageal reflux disease, also may suppress the ratio to <1.
Reference Values:
CORTISOL
> or =18 years: 3.5-45 mcg/24 hours
CORTISONE
Use the factors below to convert each analyte from mcg/24 hours to nmol/24 hours:
Conversion factors
Cortisol: mcg/24 hours x 2.76=nmol/24 hours (molecular weight=362.5)
Cortisone: mcg/24 hours x 2.78=nmol/24 hours (molecular weight=360)
syndrome. Endocrinol Metab Clin North Am 2001;30:729-747 2. Boscaro M, Barzon L, Fallo F, Sonino
N: Cushing's syndrome. Lancet 2001;357:783-791 3. Taylor RL, Machacek D, Singh RJ: Validation of a
high-throughput liquid chromatography-tandem mass spectrometry method for urinary cortisol and
cortisone. Clin Chem 2002;48:1511-1519
CCFR Cortisol/Cortisone, Free, Random, Urine

factor influencing a multitude of cellular responses in virtually all tissues. It plays a critical role in glucose
metabolism, maintenance of vascular tone, immune response regulation, and in the body's response to
stress. Its production is under hypothalamic-pituitary feedback control. Only a small percentage of
circulating cortisol is biologically active (free), with the majority of cortisol inactive (protein bound). As
plasma cortisol values increase, free cortisol (ie, unconjugated cortisol or hydrocortisone) increases and is
filtered through the glomerulus. Urinary free cortisol (UFC) correlates well with the concentration of
plasma free cortisol. UFC represents excretion of the circulating, biologically active, free cortisol that is
responsible for the signs and symptoms of hypercortisolism. UFC is a sensitive test for the various types
of adrenocortical dysfunction, particularly hypercortisolism (Cushing syndrome). A measurement of
24-hour UFC excretion by liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the
preferred screening test for Cushing syndrome. LC-MS/MS methodology eliminates analytical
interferences including carbamazepine (Tegretol) and synthetic corticosteroids, which can affect
immunoassay-based cortisol results. Cortisone, a downstream metabolite of cortisol, provides an
additional variable to assist in the diagnosis of various adrenal disorders, including abnormalities of
11-beta-hydroxy steroid dehydrogenase (11-beta HSD), the enzyme that converts cortisol to cortisone.
Deficiency of 11-beta HSD results in a state of mineralocorticoid excess because cortisol (but not
cortisone) acts as a mineralocorticoid receptor agonist. Licorice (active component glycyrrhetinic acid)
inhibits 11-beta HSD and excess consumption can result in similar changes.
Useful For: Investigating suspected Cushing syndrome (hypercortisolism), when a 24-hour

collection is prohibitive (ie, pediatric patients). Assisting in diagnosing acquired or inherited
abnormalities of 11-beta-hydroxy steroid dehydrogenase (cortisol to cortisone ratio) Diagnosis of
pseudohyperaldosteronism due to excessive licorice consumption This test has limited usefulness in the
evaluation of adrenal insufficiency. This test is not useful for evaluation of hypocorticalism.
Interpretation: Most patients with Cushing syndrome have increased urinary excretion of cortisol
and/or cortisone. Further studies, including suppression or stimulation tests, measurement of serum
corticotrophin concentrations, and imaging are usually necessary to confirm the diagnosis and
determine the etiology. Values in the normal range may occur in patients with mild Cushing syndrome
or with periodic hormonogenesis. In these cases, continuing follow-up and repeat testing are necessary
to confirm the diagnosis. Patients with Cushing syndrome due to intake of synthetic glucocorticoids
should have both suppressed cortisol and cortisone. In these circumstances a synthetic glucocorticoid
screen might be ordered (SGSU / Synthetic Glucocorticoid Screen, Random, Urine). Suppressed
cortisol and cortisone values may also be observed in primary adrenal insufficiency and
hypopituitarism. However, random urine specimens are not useful for evaluation of hypocorticalism.
Patients with 11-beta HSD deficiency may have cortisone to cortisol ratios less than 1, whereas a ratio
of 2 or 3:1 is seen in normal patients. Excessive licorice consumption and use of carbenoxolone, a
synthetic derivative of glycyrrhizinic acid used to treat gastroesophageal reflux disease, also may
suppress the ratio to less than 1.
Reference Values:
CORTISOL
Males
Females
CORTISONE
0-2 years: 25-477 mcg/g creatinine
Use the conversion factors below to convert each analyte from mcg/g creatinine to nmol/mol
creatinine:
Conversion factors
Cortisol: mcg/g creatinine x 312=nmol/mol creatinine
Cortisone: mcg/g creatinine x 314=nmol/mol creatinine
Cortisol molecular weight=362.5

Cortisone molecular weight=360.4
Creatinine molecular weight=113.12
Clinical References: 1. Taylor RL, Machacek D, Singh RJ: Validation of a high-throughput liquid
chromatography-tandem mass spectrometry method for urinary cortisol and cortisone. Clin Chem.
2002;48:1511-1519 2. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing's syndrome.
Endocrinol Metab Clin North Am. 2001;30:729-747 3. Boscaro M, Barzon L, Fallo F, Sonino N:
Cushing's syndrome. Lancet. 2001;357:783-791 4. Suzuki S, Minamidate T, Shiga A, et al. Steroid
metabolites for diagnosing and predicting clinicopathological features in cortisol-producing adrenocortical
carcinoma. BMC Endocr Disord. 2020;20(1):173. doi: 10.1186/s12902-020-00652-y
CDIP Corynebacterium diphtheriae Culture, Varies

89860 Clinical Information: Corynebacterium diphtheriae is the etiological agent of diphtheria and occurs
in 2 forms, respiratory and cutaneous diphtheria. Respiratory diphtheria may be further classified into
pharyngeal, tonsillar, laryngeal, and the less common anterior nasal diphtheria. Due to vaccination
programs in the United States, diphtheria is now a rarely reported disease. Corynebacterium diphtheriae is
primarily spread by droplets from coughing or sneezing. The incubation period averages 2 to 5 days. The
illness is characterized by fever, malaise, and sore throat with a distinguishing thick pseudomembrane
present over the involved mucosa. A swab from beneath the pseudomembrane is the preferred specimen
for culture. The organisms multiplying at the infection site produce a toxin, diphtheria toxin, which may
result in systemic complications affecting the heart, nervous system, etc. In patients with a clinical
diagnosis of possible diphtheria, appropriate specimens should be collected for culture; patients should be
placed in appropriate isolation and consideration given to administration of empiric antitoxin (available in
the United States through the Centers for Disease Control and Prevention) and antibiotics; respiratory and
airway support may be required.
Useful For: Confirmation of the clinical diagnosis of diphtheria

Interpretation: A positive result supports a diagnosis of diphtheria. The pathogenesis of the associated
disease relates to production phage-encoded diphtheria toxin. Since isolates of Corynebacterium
diphtheriae may or may not harbor genes to produce the toxin, they should be further tested for diphtheria
toxin production. When isolated, other potentially toxin-producing organisms (eg, Corynebacterium
ulcerans, Corynebacterium pseudotuberculosis) will also be reported. A negative result is evidence against
a diagnosis of diphtheria but does not definitively rule out this disease since culture may be negative
because of prior antimicrobial therapy or organism present below the limit of detection of the assay.
Reference Values:
No growth of Corynebacterium diphtheriae
Clinical References: Procop GW, Hall GS, Janda WM, Koneman EW, Schreckenberger PC, Woods
GL: Color Atlas and Textbook of Diagnostic Microbiology. 7th ed. In: Wolters Kluwer Health;
2017:890-896
COTT Cotton Fiber, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cotton fiber


Reference Values:
0 Negative

apply to all ages.
CSED Cottonseed, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to cottonseed Defining the allergen responsible
Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CTWD Cottonwood, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cottonwood Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
COW Cow Epithelium, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cow epithelium Defining the allergen

Reference Values:
0 Negative

apply to all ages.
COX2
Current
70633 as of July 20, 2022 12:05 pm CDT 800-533-1710 or 507-266-5700 or mayocliniclabs.com Page 775
COX-2 Immunostain, Technical Component Only
Clinical Information: Cyclooxygenase 2 (COX-2) is an inducible enzyme involved in production of
prostaglandins in inflammatory processes. It is involved in the response of cells to growth factors, tumor
promoters, and cytokines that induce its expression. There is increased evidence that expression of COX-2
plays a role in development and progression of malignant epithelial tumors. Eighty five to 90% of colon
cancers show over-expression of COX-2. COX-2 positivity has been correlated with a poor response to
treatment and shorter overall survival.
Useful For: Identifying normal and neoplastic cells expressing cyclooxygenase-2 (COX-2)
Clinical References: 1. Deng L, Liang H, Han Y: Cyclooxygenase-2 and beta-catenin as potential

diagnostic and prognostic markers in endometrial cancer. Front Oncol. 2020;10:582704 2. Salem AM,
Elfeky MA, Nawar N, Alattar AZ, Atef Elekiabi O, Elaidy MM: Prognostic value of combined; Cox-2,
cyclin D1 and P21 expression in colorectal cancer (CRC) patients: An immunohistochemical study. Open
J Pathol.2018;8(3):106-121 3. Sano Y, Kogashiwa Y, Araki R, et al: Correlation of inflammatory
markers, survival, and COX2 expression in oral cancer and implications for prognosis. Otolaryngol Head
Neck Surg. 2018 Apr;158(4):667-676
CBBRP Coxiella burnetii (Q fever), Molecular Detection, PCR, Blood

62248 Clinical Information: Coxiella burnetii, the causative agent of Q fever, is a small obligate
intracellular bacterium that is distributed ubiquitously in the environment. The agent is acquired through
aerosol exposure and generally causes mild respiratory disease. A small number of these acute cases will
advance to a chronic condition, which typically manifests as endocarditis. If left untreated, cases of Q
fever endocarditis are fatal. Current diagnostic methods of Q fever endocarditis include serologic studies
and histopathologic examination of excised cardiac tissue. These current methods are subjective and
nonspecific, limiting usefulness in patient diagnostics. Evaluation of infected tissue, blood, or serum using
PCR has been shown to be an effective tool for diagnosing C burnetii infection. Mayo Clinic Laboratories
has developed a real-time PCR test that permits rapid identification of C burnetii. The assay targets a
unique sequence of the shikimate dehydrogenase gene (aroE) present in C burnetii.
Useful For: Aiding in the diagnosis of Coxiella burnetii infection (eg, Q fever)
Interpretation: A positive result indicates the presence of Coxiella burnetii DNA. A negative result
indicates the absence of detectable C burnetii DNA, but does not negate the presence of the organism and
may occur due to inhibition of PCR, sequence variability underlying primers or probes, or the presence of
C burnetii DNA in quantities less than the limit of detection of the assay.
Reference Values:
Not applicable
Clinical References: 1. Frangoulidis D, Meyer H, Kahlhofer C, Splettstoesser WD: 'Real-time'

PCR-based detection of Coxiella burnetii using conventional techniques. FEMS Immunol Med Microbiol
2012;64:134-136 2. Marrie TJ, Raoult D: Coxiella burnetii (Q fever). In Mandell, Douglas, and Bennett's
Principles and Practice of Infectious Diseases. Edited by GL Mandell, JE Bennett, R Dolin. Seventh
edition. Philadelphia, Churchill Livingstone/Elsevier, 2010, pp 2511-2519 3. Maurin M, Raoult D: Q
fever. Clin Microbiol Rev 1999;12:518-533 4. Fenollar F, Fournier PE, Raoult D: Molecular detection of
Coxiella burnetii in the sera of patients with Q fever endocarditis or vascular infection. J Clin Microbiol
2004;42:4919-4924 5. Fournier PE, Raoult D: Comparison of PCR and serology assays for early
diagnosis of acute Q fever. J Clin Microbiol 2003;41:5094-5098 6. Tande A, Cunningham S, Raoult D, et
al: Coxiella burnetii prosthetic joint infection-case report and assay for detection. J Clin Microbiol
2013;51:66-69 7. CDC Releases First National Guidelines on Managing Q Fever. JAMA
2013;309(18):1887 8. Anderson A, Bijlmer H, Fournier PE, et al: Diagnosis and management of Q
fever-United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR
Recomm Rep 2013;62(RR-03):1-30
CBSRP Coxiella burnetii (Q Fever), Molecular Detection, PCR, Serum

62194 Clinical Information: Coxiella burnetii, the causative agent of Q fever, is a small obligately
intracellular bacterium, which is associated with animals. It is acquired through aerosol exposure and
generally causes mild respiratory disease. A small number of acute cases advance to a chronic infection,
which typically manifests as endocarditis. Left untreated, Q fever endocarditis may be fatal. Serologic
and histopathologic studies may be nonspecific and subjective, respectively, limiting usefulness for
patient diagnosis. Evaluation of infected tissue, blood, or serum using PCR may be a useful tool for
diagnosing some cases of Coxiella burnetii infection. Mayo Clinic Laboratories has developed a
real-time PCR test that rapidly detects Coxiella burnetii DNA in clinical specimens by targeting a
sequence of the shikimate dehydrogenase gene (aroE) unique to Coxiella burnetii.
Useful For: Aiding in the diagnosis of Coxiella burnetii infection (ie, Q fever) using serum
specimens
indicates the absence of detectable C burnetii DNA, but does not negate the presence of the organism
presence of C burnetii DNA in quantities less than the limit of detection of the assay.
Reference Values:
Not applicable

PCR-based detection of Coxiella burnetii using conventional techniques. FEMS Immunol Med
Microbiol 2012;64:134-136 2. Marrie TJ, Raoult D: Coxiella burnetii (Q fever). In Mandell, Douglas,
and Bennett's Principles and Practice of Infectious Diseases. Edited by GL Mandell, JE Bennett, R
Dolin. Seventh edition. Philadelphia, PA. Churchill Livingstone/Elsevier, 2010, pp 2511-2519 3.
Maurin M, Raoult D: Q fever. Clin Microbiol Rev 1999;12:518-533 4. Fenollar F, Fournier PE, Raoult
D: Molecular detection of Coxiella burnetii in the sera of patients with Q fever endocarditis or vascular
infection. J Clin Microbiol 2004;42:4919-4924 5. Fournier PE, Raoult D: Comparison of PCR and
serology assays for early diagnosis of acute Q fever. J Clin Microbiol 2003;41:5094-5098 6. Tande A,
Cunningham S, Raoult D, et al: Coxiella burnetii prosthetic joint infection-case report and assay for
detection. J Clin Microbiol 2013;51:66-69 7. CDC Releases First National Guidelines on Managing Q
Fever. JAMA 2013;309(18):1887 8. Anderson A, Bijlmer H, Fournier PE, et al: Diagnosis and
management of Q fever-United States, 2013: recommendations from CDC and the Q Fever Working
Group. MMWR Recomm Rep 2013;62(RR-03):1-30
CBRP Coxiella burnetii (Q fever), Molecular Detection, PCR, Varies

62193 Clinical Information: Coxiella burnetii, the causative agent of Q fever, is a small obligate
intracellular bacterium, which is associated with animals. It is acquired through aerosol exposure and
generally causes mild respiratory disease. A small number of acute cases advance to a chronic infection,
which typically manifests as endocarditis. Left untreated, Q fever endocarditis may be fatal. Serologic
and histopathologic studies may be nonspecific and subjective, respectively, limiting usefulness for
patient diagnosis. Evaluation of infected tissue, blood, or serum using PCR may be a useful tool for
diagnosing some cases of C burnetii infection. Mayo Clinic Laboratories has developed a real-time PCR
test that rapidly detects C burnetii DNA in clinical specimens by targeting a sequence of the shikimate
dehydrogenase gene (aroE) unique to C burnetii.
Useful For: Aiding in the diagnosis of Coxiella burnetii infection (eg, Q fever) using tissue
specimens
indicates the absence of detectable C burnetii DNA, but does not negate the presence of the organism and
may occur due to inhibition of PCR, sequence variability underlying primers or probes, or the presence of
C burnetii DNA in quantities less than the limit of detection of the assay.
Reference Values:
Not applicable

PCR-based detection of Coxiella burnetii using conventional techniques. FEMS Immunol Med Microbiol
2012;64:134-136 2. Marrie TJ, Raoult D: Coxiella burnetii (Q fever). In Mandell, Douglas, and Bennett's
Principles and Practice of Infectious Diseases. Edited by GL Mandell, JE Bennett, R Dolin. Seventh
edition. Philadelphia, Churchill Livingstone/Elsevier, 2010, pp 2511-2519 3. Maurin M, Raoult D: Q
fever. Clin Microbiol Rev 1999;12:518-533 4. Fenollar F, Fournier PE, Raoult D: Molecular detection of
Coxiella burnetii in the sera of patients with Q fever endocarditis or vascular infection. J Clin Microbiol
2004;42:4919-4924 5. Fournier PE, Raoult D: Comparison of PCR and serology assays for early
diagnosis of acute Q fever. J Clin Microbiol 2003;41:5094-5098 6. Tande A, Cunningham S, Raoult D, et
al: Coxiella burnetii prosthetic joint infection-case report and assay for detection. J Clin Microbiol
2013;51:66-69 7. CDC Releases First National Guidelines on Managing Q Fever. JAMA
2013;309(18):1887 8. Anderson A, Bijlmer H, Fournier PE, et al: Diagnosis and management of Q
fever-United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR
Recomm Rep 2013;62(RR-03):1-30
FCRAB Crab IgG

Reference Values:
CRAB Crab, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to crab Defining the allergen responsible for eliciting
signs and symptoms Identifying allergens: -Responsible for allergic disease and/or anaphylactic episode
-To confirm sensitization prior to beginning immunotherapy

Reference Values:
0 Negative

apply to all ages.
CRANB Cranberry, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to cranberry Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CRAY Crayfish, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to crayfish Defining the allergen responsible for
specificity.

Reference Values:

0 Negative

apply to all ages.
2017:1057-1070
CRDPP Creatine Disorders Panel, Plasma
606130 Clinical Information: Disorders of creatine synthesis (guanidinoacetate methyltransferase: GAMT,
L-arginine:glycine amidinotransferases: AGAT, and creatine transporter deficiency: CTD) are
collectively described as creatine deficiency syndromes (CDS). GAMT and AGAT deficiencies are
inherited in an autosomal recessive manner, while CTD is X-linked. All 3 disorders result in a depletion
of cerebral creatine and typically present with global developmental delays, intellectual disability, and
severe speech delay. Affected patients may have abnormal magnetic resonance imaging findings and
exhibit cerebral creatine deficiency in brain magnetic resonance spectroscopy. Patients with GAMT and
male patients with CTD develop seizures, behavioral problems, and autistic features and may have
abnormal movements. Female carriers for CTD can be asymptomatic or exhibit features similar to
affected male patients such as intellectual disability, behavioral problems, and seizures. Diagnosis of
creatine synthesis disorders relies on measurement of guanidinoacetate (GAA), creatine (Cr), and
creatinine (Crn) in serum and urine. The profiles are specific for each clinical entity. In serum, patients
with GAMT deficiency typically exhibit very elevated GAA, low Cr, and normal to low Crn. Patients
with AGAT deficiency typically exhibit low to normal GAA, low Cr, and normal to low Crn. In
comparison, patients with CTD typically have normal serum levels of GAA, Cr and Crn, and
measurement of these analytes in urine is required for diagnosis in male patients (characteristic findings
are elevated Cr, normal to low Crn, and an elevated Cr:Crn ratio in urine). The only reliable method for
diagnosis of CTD in female patients is molecular analysis of the SLC6A8 gene. The diagnosis of
GAMT and AGAT can be confirmed by molecular analysis of GAMT and GATM. Treatment with oral
supplementation of creatine monohydrate is available and effective for the AGAT and GAMT
deficiencies. Patients with GAMT deficiency may also be treated with supplemental ornithine and
dietary arginine restriction. Early treatment has been reported to prevent disease manifestations in
affected but presymptomatic newborn siblings of individuals with GAMT or AGAT deficiencies.
Useful For: Evaluation of patients with a clinical suspicion of arginine:glycine amidinotransferase

deficiency and guanidinoacetate methyltransferase deficiency. This test is not useful for the diagnosis of
creatine transporter deficiency.
Interpretation: Reports include concentrations of guanidinoacetate, creatine, and creatinine, and the
calculated analyte ratios. When no significant abnormalities are detected, a simple descriptive
interpretation is provided. When abnormal results are detected, a detailed interpretation is given. This
interpretation includes an overview of the results and their significance, a correlation to available
clinical information, elements of differential diagnosis, and recommendations for additional
biochemical testing.
Reference Values:
Creatine Disorders Panel Reference Values (creatine, creatinine, and guanidinoacetate results reported as nmol/mL)
Creatine 38.6-96.8 39.0-97.0 38.2-96.5 38.6-96.5 37.7-96.0 38.2-96.0
Creatinine 27.6-35.9 27.6-35.2 27.6-36.5 27.6-35.5 27.6-37.1 27.6-36.0
Guanidinoacetate 0.7-2.0 0.7-2.1 0.7-2.0 0.7-2.1 0.7-2.0 0.7-2.1
Creatine/ creatinine < or =3.07 < or =3.60 < or =3.02 < or =3.54 < or =2.96 < or =3.48
Guanidinoacetate/ creatine < or =0.040 < or =0.040 < or =0.042 < or =0.040 < or =0.043 < or =0.042
Guanidinoacetate/ creatinine < or =0.051 < or =0.081 < or =0.051 < or =0.080 < or =0.051 < or =0.079
Creatine 37.1-95.5 37.7-95.3 36.0-94.4 36.8-94.1 34.6-93.2 35.6-92.7

Creatinine 27.6-37.9 27.7-36.9 27.6-39.3 27.7-38.2 27.6-40.9 27.8-39.9
Creatine 33.0-91.7 34.3-91.0 31.2-90.0 32.7-89.2 29.2-88.1 31.0-87.3
Creatinine 27.6-42.8 28.0-41.9 27.7-44.9 28.3-44.3 27.8-47.0 28.8-47.1
Creatine 27.2-85.9 29.3-85.2 25.2-83.7 27.4-83.1 23.4-81.3 25.7-80.9
Creatinine 28.0-49.3 29.5-50.1 28.2-51.5 30.6-53.6 28.4-53.6 32.0-57.2
Creatine 21.7-78.7 23.9-78.6 20.3-76.2 22.3-76.2 19.0-73.6 20.8-73.8
Creatinine 28.7-55.7 33.8-61.0 29.1-57.7 35.9-64.8 29.5-59.5 38.1-68.5
Creatine 18.1-71.1 19.5-71.2 17.4-68.7 18.4-68.6 16.9-66.5 17.4-65.9
Creatinine 29.9-61.3 40.4-71.9 30.4-62.9 42.4-75.0 30.9-64.4 44.2-77.6
Creatine 16.7-64.4 16.6-63.3 16.6-62.7 15.8-60.7 16.5-61.1 15.2-58.3
Creatinine 31.3-65.8 45.6-80.0 31.8-67.0 46.7-82.0 32.2-68.2 47.4-83.9
Creatine 16.6-59.8 14.7-56.0 16.6-58.8 14.2-54.0 16.7-57.9 13.7-52.2
Creatinine 32.5-69.2 47.9-85.6 Â 32.8-70.2 48.2-87.2 Â 33.1-71.1 48.4-88.8

Creatine 16.7-57.2 13.3-50.6 16.7-56.5 12.9-49.3 16.7-56.0 12.5-48.1
Creatinine 33.3-71.9 48.6-90.2 33.6-72.8 48.7-91.5 33.7-73.6 48.9-92.7
Creatine 16.7-55.5 12.1-47.1 16.6-55.1 11.8-46.3 16.5-54.7 11.5-45.4
Creatinine 33.9-74.4 49.0-93.7 34.1-75.2 49.1-94.5 34.2-76.0 49.2-95.3
Creatine 16.4-54.2 11.3-44.7 16.4-53.8 11.1-43.9 16.3-53.4 11.0-43.2
Creatinine 34.4-76.8 49.3-96.0 34.6-77.5 49.3-96.7 34.7-78.2 49.4-97.4
Creatine 16.3-53.0 10.9-42.5 16.4-52.7 10.8-41.7 16.4-52.3 10.7-41.0
Creatinine 34.9-78.8 49.4-98.0 35.1-79.4 49.5-98.6 35.3-79.9 49.5-99.2
Creatine 16.5-52.0 10.7-40.2 16.7-51.6 10.6-39.5 16.9-51.3 10.6-38.9

Creatinine 35.4-80.3 49.5-99.8 35.6-80.7 49.5-100.3 35.8-81.0 49.6-100.8
Creatine 17.1-51.1 10.6-38.2 17.3-50.9 10.7-37.7 17.5-50.8 10.7-37.2
Creatinine 35.9-81.4 49.6-101.3 36.0-81.6 49.6-101.7 36.1-81.9 49.7-102.1
Creatine 17.7-50.8 10.8-36.7 17.8-50.8 10.9-36.3 17.8-50.9 11.0-36.0
Creatinine 36.2-82.1 49.7-102.5 36.3-82.4 49.8-102.8 36.4-82.6 49.8-103.1
Creatine 17.7-51.0 11.1-35.6 17.6-51.2 11.2-35.3 17.4-51.4 11.3-35.1
Creatinine 36.4-82.8 49.9-103.4 36.5-83.0 49.9-103.6 36.5-83.2 49.9-103.9
Creatine 17.2-51.7 11.5-34.8 17.1-51.9 11.6-34.6 17.0-52.1 11.7-34.4
Creatinine 36.6-83.4 49.9-104.1 36.6-83.5 49.9-104.2 36.7-83.7 49.9-104.4

Creatine 17.0-52.2 11.9-34.3 17.1-52.3 12.0-34.3 17.3-52.4 12.2-34.3
Creatinine 36.8-83.9 49.8-104.6 36.8-84.0 49.8-104.8 36.9-84.2 49.8-104.9
Creatine 17.6-52.5 12.4-34.3 18.1-52.6 12.5-34.4 18.6-52.7 12.6-34.4
Creatinine 37.0-84.4 49.8-105.0 37.1-84.5 49.8-105.2 37.2-84.7 49.8-105.3
Creatine 19.2-52.9 12.7-34.4 19.9-53.1 12.8-34.3 20.5-53.3 12.8-34.2
Creatinine 37.3-84.9 49.8-105.4 37.4-85.1 49.8-105.5 37.6-85.2 49.8-105.6
Creatine 21.0-53.6 12.8-34.1 21.5-53.9 12.7-34.0 21.9-54.2 12.6-33.9
Creatinine 37.8-85.4 49.9-105.7 38.0-85.5 49.9-105.9 38.3-85.7 49.9-106.0
Creatine 22.2-54.6 12.4-33.7 22.3-55.0 12.3-33.6 22.5-55.5 12.2-33.4
Creatinine 38.7-85.8 50.0-106.1 39.1-85.9 50.0-106.3 39.6-86.1 50.1-106.4
Creatine 22.6-55.9 12.3-33.1 22.7-56.3 12.3-32.8 22.9-56.7 12.5-32.4
Creatinine 40.2-86.2 50.2-106.6 40.7-86.3 50.3-106.7 41.3-86.5 50.4-106.9
69 Years 70 Years > or = 71 Years
Creatine 23.2-57.0 12.8-32.0 23.6-57.2 13.1-31.4 24.1-57.3 13.6-30.8
Creatinine 41.9-86.6 50.5-107.1 42.4-86.8 50.7-107.4 42.8-86.9 50.8-107.6
Clinical References: 1. Clark JF, Cecil KM: Diagnostic methods and recommendations for the
cerebral creatine deficiency syndromes. Pediatr Res; 2015 Mar;77(3):398-405 2.
Mercimek-Mahmutoglu S, Salomons GS: Creatine deficiency syndromes. In: Pagon RA, Adam MP,
Ardinger HH, et al. eds. GeneReviews [Internet]. University of Washington, Seattle; Jan 15 2009.
Updated 2015 Dec 10. Accessed 2019 Dec 4. Available at www.ncbi.nlm.nih.gov/books/NBK3794/ 3.
Stockler S, Schultz PW, Salomons GS: Cerebral creatine deficiency syndromes: clinical aspects,
treatment, and pathophysiology. Subcell Biochem. 2007;46:149-166 4. Longo N, Ardon O, Vanzo R, et
al: Disorders of creatine transport and metabolism. Am J Med Genet. 2011;157:72-78 doi:
10.1002/ajmg.c.30292
CRDPU Creatine Disorders Panel, Random, Urine
88697 Clinical Information: Disorders of creatine synthesis, deficiency of arginine:glycine
amidinotransferases (AGAT), guanidinoacetate methyltransferase (GAMT) deficiency, and creatine
transporter (SLC6A8) deficiency, are collectively described as creatine deficiency syndromes (CDS).
AGAT and GAMT deficiencies are inherited in an autosomal recessive manner, while the creatine
transporter defect is X-linked. All 3 disorders result in a depletion of cerebral creatine and typically
present with global developmental delays, intellectual disability, and severe speech delay. Commonly,
patients with CDS develop seizures. Patients with GAMT and the creatine transporter deficiency exhibit
behavioral problems and features of autism. Female carriers for the creatine transporter deficiency can
have intellectual disabilities and behavioral problems, and some develop seizures. Diagnosis is possible
by measuring guanidinoacetate (GAA), creatine (Cr), and creatinine (Crn) in plasma and urine. The
profiles are specific for each clinical entity. Patients with GAMT deficiency typically exhibit normal to
low Cr, very elevated GAA, and low Crn. Patients with AGAT deficiency typically exhibit normal to
low Cr, low GAA, and normal to low Crn. In comparison, elevated Cr, normal GAA, normal to low
Crn, and an elevated Cr:Crn ratio characterize patients with creatine transporter defect. Treatment with
oral supplementation of creatine monohydrate is available and effective for the AGAT and GAMT
deficiencies. Early treatment has been reported to prevent disease manifestations in affected but
presymptomatic newborn siblings of individuals with GAMT or AGAT deficiencies. Creatine
supplementation has not been shown to improve outcomes in male patients with the creatine transporter
defect. However, symptomatic female carriers of creatine transporter deficiency have been reported to
benefit from creatine supplementation.
Useful For: Evaluation of patients with a clinical suspicion of inborn errors of creatine metabolism
including arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase
deficiency, and creatine transporter (SLC6A8) defect
Interpretation: Reports include concentrations of guanidinoacetate, creatine, and creatinine, as well

as a calculated creatine:creatinine ratio. When no significant abnormalities are detected, a simple
descriptive interpretation is provided. When abnormal results are detected, a detailed interpretation is
given. This interpretation includes an overview of the results and their significance, a correlation to
available clinical information, elements of differential diagnosis, and recommendations for additional
biochemical testing.
Reference Values:
Age Creatinine (nmol/mL) Guanidinoacetate (nmol/mL) Creatine (nmol/mL) Creatine/ creatinine
< or =31 days 430-5,240 9-210 12-2,930 0.02-0.93
32 days-23 months 313-9,040 16-860 18-10,490 0.02-2.49
2-4 years 1,140-12,820 90-1,260 200-9,210 0.04-1.75
5-18 years 1,190-25,270 40-1,190 60-9,530 0.01-0.96
>18 years (male) 3,854-23,340 30-710 7-470 0.00-0.04 Females
Age Creatinine (nmol/mL) Guanidinoacetate (nmol/mL) Creatine (nmol/mL) Creatine/ creatinine
< or =31 days 430-5,240 9-210 12-2,930 0.02-0.93
32 days-23 months 313-9,040 16-860 18-10,490 0.02-2.49
2-4 years 1,140-12,820 90-1,260 200-9,210 0.04-1.75
5-18 years 1,190-25,270 40-1,190 60-9,530 0.01-0.96
>18 years 1,540-18,050 30-760 5-2810 0.00-0.46
cerebral creatine deficiency syndromes. Pediatr Res. 2015 Mar;77(3):398-405. doi:
10.1038/pr.2014.203 2. Mercimek-Mahmutoglu S, Salomons GS: Creatine deficiency syndromes. In:
Seattle; 2009. Updated February 10, 2022. Accessed June 3, 2022. Available at
www.ncbi.nlm.nih.gov/books/NBK3794/ 3. Stockler S, Schultz PW, Salomons GS: Cerebral creatine
deficiency syndromes: Clinical aspects, treatment and pathophysiology. Subcell Biochem.
2007;46:149-166. doi: 10.1007/978-1-4020-6486-9_8 4. Longo N, Ardon O, Vanzo R, et al: Disorders
of creatine transport and metabolism. Am J Med Genet C Semin Med Genet. 2011 Feb
15;157C(1):72-78. doi: 10.1002/ajmg.c.30292
CRDPS Creatine Disorders Panel, Serum

606131 Clinical Information: Disorders of creatine synthesis (guanidinoacetate methyltransferase: GAMT,
L-arginine:glycine amidinotransferases: AGAT, and creatine transporter deficiency: CTD) are collectively
described as creatine deficiency syndromes (CDS). GAMT and AGAT deficiencies are inherited in an
autosomal recessive manner, while CTD is X-linked. All 3 disorders result in a depletion of cerebral
creatine and typically present with global developmental delays, intellectual disability, and severe speech
delay. Affected patients may have abnormal magnetic resonance imaging findings and exhibit cerebral
creatine deficiency in brain magnetic resonance spectroscopy. Patients with GAMT and male patients
with CTD develop seizures, behavioral problems, and autistic features and may have abnormal
movements. Female carriers for CTD can be asymptomatic or exhibit features similar to affected male
patients such as intellectual disability, behavioral problems, and seizures. Diagnosis of creatine synthesis
disorders relies on measurement of guanidinoacetate (GAA), creatine (Cr), and creatinine (Crn) in serum
and urine. The profiles are specific for each clinical entity. In serum, patients with GAMT deficiency
typically exhibit very elevated GAA, low Cr, and normal to low Crn. Patients with AGAT deficiency
typically exhibit low to normal GAA, low Cr, and normal to low Crn. In comparison, patients with CTD
typically have normal serum levels of GAA, Cr and Crn, and measurement of these analytes in urine is
required for diagnosis in male patients (characteristic findings are elevated Cr, normal to low Crn, and an
elevated Cr:Crn ratio in urine). The only reliable method for diagnosis of CTD in female patients is
molecular analysis of the SLC6A8 gene. The diagnosis of GAMT and AGAT can be confirmed by
molecular analysis of GAMT and GATM. Treatment with oral supplementation of creatine monohydrate
is available and effective for the AGAT and GAMT deficiencies. Patients with GAMT deficiency may
also be treated with supplemental ornithine and dietary arginine restriction. Early treatment has been
reported to prevent disease manifestations in affected but presymptomatic newborn siblings of individuals
with GAMT or AGAT deficiencies.
Useful For: Evaluation of patients with a clinical suspicion of arginine:glycine amidinotransferase

deficiency and guanidinoacetate methyltransferase deficiency. This test is not useful for the diagnosis of
creatine transporter deficiency.
Interpretation: Reports include concentrations of guanidinoacetate, creatine, and creatinine, and the
calculated analyte ratios. When no significant abnormalities are detected, a simple descriptive
interpretation is provided. When abnormal results are detected, a detailed interpretation is given. This
interpretation includes an overview of the results and their significance, a correlation to available clinical
information, elements of differential diagnosis, and recommendations for additional biochemical testing.
Reference Values:
Creatine Disorders Panel Reference Values (creatine, creatinine, and guanidinoacetate results reported as nmol/mL)
Creatine 38.6-96.8 39.0-97.0 38.2-96.5 38.6-96.5 37.7-96.0 38.2-96.0
Creatinine 27.6-35.9 27.6-35.2 27.6-36.5 27.6-35.5 27.6-37.1 27.6-36.0
Creatine 37.1-95.5 37.7-95.3 36.0-94.4 36.8-94.1 34.6-93.2 35.6-92.7
Creatinine 27.6-37.9 27.7-36.9 27.6-39.3 27.7-38.2 27.6-40.9 27.8-39.9

Creatine 33.0-91.7 34.3-91.0 31.2-90.0 32.7-89.2 29.2-88.1 31.0-87.3
Creatinine 27.6-42.8 28.0-41.9 27.7-44.9 28.3-44.3 27.8-47.0 28.8-47.1
Creatine 27.2-85.9 29.3-85.2 25.2-83.7 27.4-83.1 23.4-81.3 25.7-80.9
Creatinine 28.0-49.3 29.5-50.1 28.2-51.5 30.6-53.6 28.4-53.6 32.0-57.2
Creatine 21.7-78.7 23.9-78.6 20.3-76.2 22.3-76.2 19.0-73.6 20.8-73.8
Creatinine 28.7-55.7 33.8-61.0 29.1-57.7 35.9-64.8 29.5-59.5 38.1-68.5
Creatine 18.1-71.1 19.5-71.2 17.4-68.7 18.4-68.6 16.9-66.5 17.4-65.9
Creatinine 29.9-61.3 40.4-71.9 30.4-62.9 42.4-75.0 30.9-64.4 44.2-77.6
Creatine 16.7-64.4 16.6-63.3 16.6-62.7 15.8-60.7 16.5-61.1 15.2-58.3
Creatinine 31.3-65.8 45.6-80.0 31.8-67.0 46.7-82.0 32.2-68.2 47.4-83.9
Creatine 16.6-59.8 14.7-56.0 16.6-58.8 14.2-54.0 16.7-57.9 13.7-52.2
Creatinine 32.5-69.2 47.9-85.6 Â 32.8-70.2 48.2-87.2 Â 33.1-71.1 48.4-88.8
Creatine 16.7-57.2 13.3-50.6 16.7-56.5 12.9-49.3 16.7-56.0 12.5-48.1
Creatinine 33.3-71.9 48.6-90.2 33.6-72.8 48.7-91.5 33.7-73.6 48.9-92.7
Creatine 16.7-55.5 12.1-47.1 16.6-55.1 11.8-46.3 16.5-54.7 11.5-45.4
Creatinine 33.9-74.4 49.0-93.7 34.1-75.2 49.1-94.5 34.2-76.0 49.2-95.3
Creatine 16.4-54.2 11.3-44.7 16.4-53.8 11.1-43.9 16.3-53.4 11.0-43.2
Creatinine 34.4-76.8 49.3-96.0 34.6-77.5 49.3-96.7 34.7-78.2 49.4-97.4
Creatine 16.3-53.0 10.9-42.5 16.4-52.7 10.8-41.7 16.4-52.3 10.7-41.0
Creatinine 34.9-78.8 49.4-98.0 35.1-79.4 49.5-98.6 35.3-79.9 49.5-99.2

Creatine 16.5-52.0 10.7-40.2 16.7-51.6 10.6-39.5 16.9-51.3 10.6-38.9
Creatinine 35.4-80.3 49.5-99.8 35.6-80.7 49.5-100.3 35.8-81.0 49.6-100.8
Creatine 17.1-51.1 10.6-38.2 17.3-50.9 10.7-37.7 17.5-50.8 10.7-37.2
Creatinine 35.9-81.4 49.6-101.3 36.0-81.6 49.6-101.7 36.1-81.9 49.7-102.1
Creatine 17.7-50.8 10.8-36.7 17.8-50.8 10.9-36.3 17.8-50.9 11.0-36.0
Creatinine 36.2-82.1 49.7-102.5 36.3-82.4 49.8-102.8 36.4-82.6 49.8-103.1
Creatine 17.7-51.0 11.1-35.6 17.6-51.2 11.2-35.3 17.4-51.4 11.3-35.1
Creatinine 36.4-82.8 49.9-103.4 36.5-83.0 49.9-103.6 36.5-83.2 49.9-103.9
Creatine 17.2-51.7 11.5-34.8 17.1-51.9 11.6-34.6 17.0-52.1 11.7-34.4

Creatinine 36.6-83.4 49.9-104.1 36.6-83.5 49.9-104.2 36.7-83.7 49.9-104.4
Creatine 17.0-52.2 11.9-34.3 17.1-52.3 12.0-34.3 17.3-52.4 12.2-34.3
Creatinine 36.8-83.9 49.8-104.6 36.8-84.0 49.8-104.8 36.9-84.2 49.8-104.9
Creatine 17.6-52.5 12.4-34.3 18.1-52.6 12.5-34.4 18.6-52.7 12.6-34.4
Creatinine 37.0-84.4 49.8-105.0 37.1-84.5 49.8-105.2 37.2-84.7 49.8-105.3
Creatine 19.2-52.9 12.7-34.4 19.9-53.1 12.8-34.3 20.5-53.3 12.8-34.2
Creatinine 37.3-84.9 49.8-105.4 37.4-85.1 49.8-105.5 37.6-85.2 49.8-105.6
Creatine 21.0-53.6 12.8-34.1 21.5-53.9 12.7-34.0 21.9-54.2 12.6-33.9
Creatinine 37.8-85.4 49.9-105.7 38.0-85.5 49.9-105.9 38.3-85.7 49.9-106.0

Creatine 22.2-54.6 12.4-33.7 22.3-55.0 12.3-33.6 22.5-55.5 12.2-33.4
Creatinine 38.7-85.8 50.0-106.1 39.1-85.9 50.0-106.3 39.6-86.1 50.1-106.4
Creatine 22.6-55.9 12.3-33.1 22.7-56.3 12.3-32.8 22.9-56.7 12.5-32.4
Creatinine 40.2-86.2 50.2-106.6 40.7-86.3 50.3-106.7 41.3-86.5 50.4-106.9
69 Years 70 Years > or = 71 Years
Creatine 23.2-57.0 12.8-32.0 23.6-57.2 13.1-31.4 24.1-57.3 13.6-30.8
Creatinine 41.9-86.6 50.5-107.1 42.4-86.8 50.7-107.4 42.8-86.9 50.8-107.6
cerebral creatine deficiency syndromes. Pediatr Res; 2015 Mar;77(3):398-405 2. Mercimek-Mahmutoglu
S, Salomons GS: Creatine deficiency syndromes. In: Adam MP, Ardinger HH, Pagon RA, et al. eds.
GeneReviews [Internet]. University of Washington, Seattle; 2009. Updated December 10, 2015. Accessed
December 4, 2019. Available at www.ncbi.nlm.nih.gov/books/NBK3794/ 3. Stockler S, Schultz PW,
Salomons GS: Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology.
Subcell Biochem. 2007;46:149-166 4. Longo N, Ardon O, Vanzo R, et al: Disorders of creatine transport
and metabolism. Am J Med Genet. 2011;157:72-78. doi: 10.1002/ajmg.c.30292
CK Creatine Kinase (CK), Serum

8336 Clinical Information: Creatine kinase (CK) is an enzyme that catalyzes the reversible
phosphorylation of creatine (Cr) by adenosine triphosphate (ATP). Physiologically, when muscle
contracts, ATP is converted to adenosine diphosphate (ADP), and CK catalyzes the rephosphorylation of
ADP to ATP using creatine phosphate as the phosphorylation reservoir. The CK enzyme is a dimer
composed of subunits derived from either muscle (M) or brain (B). Three isoenzymes have been
identified: striated muscle (MM), heart tissue (MB), and brain (BB). Normal serum CK is predominantly
the CK-MM isoenzyme. CK activity is greatest in striated muscle (MM isoenzyme ), heart tissue (MB
isoenzyme ), and brain (BB isoenzyme ). Serum CK concentrations are reflective of muscle mass causing
males to have higher concentrations than females. CK may be measured to evaluate myopathy and to
monitor patients with rhabdomyolysis for acute kidney injury.
Useful For: Diagnosing and monitoring myopathies or other trauma, toxin, or drug-induced muscle
injury
Interpretation: Serum creatine kinase (CK) activity may increase in patients with acute
cerebrovascular disease or neurosurgical intervention and with cerebral ischemia as well as in nearly all
patients when injury, inflammation, or necrosis of skeletal or heart muscle occurs, including: -All types of
muscular dystrophy particularly in progressive muscular dystrophy (particularly Duchenne sex-linked
muscular dystrophy). -Viral myositis, polymyositis, and similar muscle diseases -Malignant hyperthermia,
an inherited life-threatening condition characterized by high fever and brought on by administration of
inhalation anesthesia -Muscle trauma, which causes CK elevations within 12 hours of onset, peaking
within 1 to 3 days, and declining 3 to 5 days after cessation of muscle injury ---Serum CK activities
exceeding 200 times the upper reference limit may be found in acute rhabdomyolysis, putting the patient
at great risk for developing acute renal failure. -When given at pharmacologic doses, some drugs
including statins, fibrates, antiretrovirals, and angiotensin II receptor antagonists -Endocrine myopathy,
for which hpothyroidism is a common cause, about 60% of hypothyroid subjects show an average
elevation of CK activity 5-fold greater than the upper reference limit -Normal childbirth causes a 6-fold
elevation in maternal serum For detection of myocardial infarction, changes in serum CK and its heart
tissue (MB) isoenzyme have been largely replaced by the more cardiac-specific nonenzymatic markers,
cardiac troponin I or T.
Reference Values:
Males
< or =3 months: not established
>3 months: 39-308 U/L
Females
>3 months: 26-192 U/L
Reference values have not been established for patients that are less than 3 months of age.
Note: Strenuous exercise or intramuscular injections may cause transient elevation of creatine kinase
(CK).
Clinical References: 1. Tietz Clinical Guide to Laboratory Tests. Fourth edition. Edited by Wu
AHB. St. Louis, Saunders Elsevier, 2006;306-307 2. Huerta-Alardin AL, Varon J, Marik PE:
Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care 2005
Apr;9(2):158-169 3. Morandi L, Angelini C, Prelle A, et al: High plasma creatine kinase: review of the
literature and proposal for a diagnostic algorithm. Neurol Sci 2006 Nov:27(5):303-311
CKELR Creatine Kinase Isoenzyme Reflex, Serum
35063 Clinical Information: Creatine kinase (CK) activity is found in the cytoplasm of several human
tissues; major sources of CK include skeletal muscle, myocardium, and the brain. Cytoplasmic CK
isoenzymes are dimers of the subunits M and B (MM, MB, or BB). Brain tissue contains predominantly
CK-BB (CK1). Skeletal muscle contains almost exclusively CK-MM (CK3). The myocardium contains
approximately 30% of CK-MB (CK2), which has been called the "heart-specific" isoenzyme. CK-MB is
increased in acute myocardial infarction (AMI); however, CK-MB has been replaced by troponin as the
preferred biomarker for the diagnosis of AMI. Mitochondrial CK, located at the outer surface of the
inner mitochondrial membrane, has been suggested to catalyze the rate-limiting step of energy transfer
from mitochondrial adenosine triphosphate (ATP) with the formation of creatine phosphatase (CP). The
CP molecule, which is smaller in size than ATP, diffuses to target organelles in the cytoplasm where its
energy is transferred to ATP by cytoplasmic CK. CK activity results in nonaerobic production of ATP
in muscle tissues during work. Macro CK refers to at least 2 forms of CK. Macro CK type I is an
antibody-bound form of cytoplasmic CK. It migrates between CK-MM and CK-MB. Macro CK type II
(mitochondrial CK) migrates slightly cathodic of CK-MM. Detection of macro forms of CK is the
primary reason for electrophoresis of CK activity.
Useful For: Detecting the macro forms of creatine kinase (CK) Identifying the source of a CK
elevation
Interpretation: Creatine kinase (CK)-MB appears in serum 4 to 6 hours after the onset of pain in a
myocardial infarction, peaks at 18 to 24 hours, and may persist for 72 hours. CK-MB may also be
elevated in cases of carbon monoxide poisoning, pulmonary embolism, hypothyroidism, crush injuries,
and muscular dystrophy. Extreme elevations of CK-MB can be associated with skeletal muscle cell
turnover as in polymyositis, and to a lesser degree in rhabdomyolysis, as seen in strenuous exercise,
particularly in the conditioned athlete. CK-BB can be elevated in patients with head injury, in neonates,
and in some cancers such as prostate cancer and small cell carcinoma of the lung. It can also be elevated
in other malignancies; however, the clinical usefulness of CK-BB as a tumor marker needs further
investigation. The presence of macro CK can explain an elevation of total CK. It does not rise and fall
as rapidly as CK-MM and CK-MB in muscle injury. Macro CK type II (mitochondrial CK) is rarely
observed. It is only seen in acutely ill patients with malignancies and other severe illnesses with a
high-associated mortality, such as liver disease and hypoxic injury.
Reference Values:
CREATINE KINASE, TOTAL
Males
>3 months: 39-308 U/L
Females
>3 months: 26-192 U/L
Reference values have not been established for patients that are less than 3 months of age.
Note: Strenuous exercise or intramuscular injections may cause transient elevation of creatine kinase
(CK).
CREATINE KINASE ISOENZYMES

MM: 100%
MB: 0%
BB: 0%
Clinical References: 1. Apple FS, Quist HE, Doyle PJ, et al: Plasma 99th percentile reference
limits for cardiac troponin and creatine kinase MB mass for use with European Society of
Cardiology/American College of Cardiology consensus recommendations. Clin Chem 2003
Aug;49(8):1331-1336 2. Danese E, Montagnana M: An historical approach to the diagnostic biomarkers
of acute coronary syndrome. Ann Transl Med 2016;4(10):194 doi:10.21037/atm.2016.05.19
CRCL Creatinine Clearance, Serum and 24-Hour Urine
615813 Clinical Information: Estimated glomerular filtration rate using serum creatinine alone: Estimated
glomerular filtration rate (eGFR) is calculated using the 2009 CKD Epidemiology Collaboration
(CKD-EPI) equation: eGFR(CKD-EPI) =141 x min(Scr/k, 1)alpha x max(Scr/k,1)-1.209 x 0.993 age x
1.018 (if patient is female) x 1.159 (if patient is black) -where age is in years -k is 0.7 for females and 0.9
for males -alpha is -0.329 for females and -0.411 for males -min indicates the minimum of Scr/k or 1
-max indicates the maximum of Scr/k or 1 Use of an estimating or prediction equation to estimate GFR
from serum creatinine should be employed for people with chronic kidney disease (CKD) and those with
risk factors for CKD (diabetes, hypertension, cardiovascular disease, and family history of kidney
disease). Reasons given for routine reporting of eGFR with every serum creatinine in adult (18 and over)
patients include: -GFR and creatinine clearance are poorly inferred from serum creatinine alone. GFR and
creatinine clearance are inversely and nonlinearly related to serum creatinine. The effects of age, sex, and,
to a lesser extent, race, on creatinine production further cloud interpretation. -Creatinine is commonly
measured in routine clinical practice. Albuminuria (>30 mg/24 hour or urine albumin to creatinine ratio
>30 mg/g) may be a more sensitive marker of early renal disease, especially among patients with diabetic
nephropathy. However, there is poor adherence to guidelines that suggest annual urinary albumin testing
of patients with known diabetes. Therefore, if a depressed eGFR is calculated from a serum creatinine
measurement, it may help providers recognize early CKD and pursue appropriate follow-up testing and
therapeutic intervention. -Monitoring of kidney function (by GFR or creatinine clearance) is essential
once albuminuria is discovered. Estimated GFR is a more practical means to closely follow changes in
GFR over time, when compared to direct measurement using methods such as iothalamate clearance. -The
CKD-EPI equation does not require weight or height variables. From a serum creatinine measurement, it
generates a GFR result normalized to a standard body surface area (1.73 m[2]) using sex, age, and race.
Unlike the Cockcroft-Gault equation, height and weight, which are often not available in the laboratory
information system, are not required. The CKD-EPI equation does require race (African American or
non-African American), which also may not be readily available. For this reason, eGFR values for both
African Americans and non-African Americans are reported. The difference between the 2 estimates is
typically about 20%. The patient or provider can decide which result is appropriate for a given patient.
The Kidney Disease: Improving Global Outcomes CKD work group clinical practice guidelines,(1) as
further defined by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative
commentary,(2) provide the following recommendations for reporting and interpretation of serum
creatinine and eGFR: 1.4.3: Evaluation of GFR -1.4.3.1: We recommend using serum creatinine and a
GFR estimating equation for initial assessment. -1.4.3.2: We suggest using additional tests (such as
cystatin C or a clearance measurement) for confirmatory testing in specific circumstances when eGFR
based on serum creatinine is less accurate. (2B) -1.4.3.3: We recommend that clinicians: --Use a GFR
estimating equation to derive GFR from serum creatinine (eGFRcreat) rather than relying on the serum
creatinine concentration alone. --Understand clinical settings in which eGFR creat is less accurate.
-1.4.3.4: We recommend that clinical laboratories should: --Measure serum creatinine using a specific
assay with calibration traceable to the international standard reference materials and minimal bias
compared to isotope-dilution mass spectrometry (IDMS) reference methodology. --Report eGFRcreat in
addition to the serum creatinine concentration in adults and specify the equation used whenever reporting
eGFRcreat. --Report eGFRcreat in adults using the 2009 CKD-EPI creatinine equation. An alternative
creatinine-based GFR estimating equation is acceptable if it has been shown to improve accuracy of GFR
estimates compared to the 2009 CKD-EPI creatinine equation. When reporting serum creatinine: -We
recommend that serum creatinine concentration be reported and rounded to the nearest whole number
when expressed as standard international units (mmol/L) and rounded to the nearest 100th of a whole
number when expressed as conventional units (mg/dL). When reporting eGFRcreat: -We recommend that
eGFRcreat should be reported and rounded to the nearest whole number and relative to a body surface
area of 1.73 m(2) in adults using the units mL/min/1.73 m(2). -We recommend eGFRcreat levels less than
60 mL/min/1.73 m(2) should be reported as "decreased". 1.4.3.8: We suggest measuring GFR using an
exogenous filtration marker under circumstances where more accurate ascertainment of GFR will impact
treatment decisions Creatinine Clearance: Creatinine is derived from the metabolism of creatine from
skeletal muscle and dietary meat intake and is released into the circulation at a relatively constant rate.
Thus, the serum creatinine concentration is usually stable. Creatinine is freely filtered by glomeruli and
not reabsorbed or metabolized by renal tubules. Therefore, creatinine clearance can be used to assess
GFR. However, approximately 15% of excreted urine creatinine is derived from proximal tubular
secretion. Because of the tubular secretion of creatinine, creatinine clearance typically overestimates true
GFR by 10% to 15%. Creatinine clearance is usually determined from measurement of creatinine in a
24-hour urine specimen and from a serum specimen obtained during the same collection period. However,
shorter time periods can be used. A key consideration is accurate timing and collection of the urine
sample. Creatinine clearance normalized to body surface area is calculated by the equation: 2.54 cm=1
inch 1 kg=2.2 pounds (lbs) Patient surface area (SA)=wt (kg)(0.425) X ht (cm)(0.725) X 0.007184 Urine
conc (mg/dL) x 24 hr urine volume (mL) Uncorr creat clear= 1440 minutes mL/min Serum creat (mg/dL)
Urine conc (mg/dL) x 24 hr urine volume (mL) X 1.73 m(2) Patient SA Corr creat clear= 1440 minutes
mL/min/1.73m(2) Serum creat (mg/dL)
Useful For: Estimation of glomerular filtration rate

Interpretation: Decreased creatinine clearance indicates decreased glomerular filtration rate (GFR).
This can be due to conditions such as progressive renal disease or result from adverse effects on renal
hemodynamics that are often reversible, including drug effects or decreases ineffective renal perfusion
(eg, volume depletion, heart failure). Increased creatinine clearance is often referred to as hyperfiltration
and is most commonly seen during pregnancy or in patients with early diabetes mellitus, before diabetic
nephropathy has occurred. It may also occur with large dietary protein intake. A major limitation of
creatinine clearance is that its accuracy worsens in relation to the amount of tubular creatinine secretion.
Often as GFR declines, the contribution of urine creatinine from tubular secretion increases, further
increasing the discrepancy between true GFR and measured creatinine clearance. Estimated GFR:
According to the Kidney Disease: Improving Global Outcomes (KDIGO) CKD work group, chronic
kidney disease (CKD) is defined as the abnormalities of kidney structure of function, present for more
than 3 months, with implications for health.(1,2) CKD should be classified by cause, GFR category, and
albuminuria category.(1,2) KDIGO guidelines provide the following GFR categories(1,2): Stage Terms
GFR mL/min/1.73 m(2) G1* Normal or high 90 G2* Mildly decreased 60 to 89 G3a Mildly to
moderately decreased 45 to 59 G3b Moderately to severely decreased 30-44 G4 Severely decreased
15-29 G5 Kidney failure <15 *In the absence of evidence of kidney damage, neither G1 nor G2 fulfill
criteria for CKD. Urinary albumin excretion can also be used to further subdivide CKD stages.
Reference Values:
CREATININE CLEARANCE
Males:
0-18 years: Reference values have not been established
19-75 years: 77-160 mL/min/body surface area (BSA)
> or =76 years: Reference values have not been established
Females:
0-17 years: Reference values have not been established
18-29 years: 78-161 mL/min/BSA
> or =73 years: Reference values have not been established
CREATININE, URINE:
Reported in units of mg/dL
CREATININE, SERUM
Males:
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-14 years: 0.35-0.86 mg/dL
> or =15 years: 0.74-1.35 mg/dL
Females:
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-15 years: 0.35-0.86 mg/dL
> or =16 years: 0.59-1.04 mg/dL
Estimated glomerular filtration rate (eGFR)

> or =60 mL/min/BSA
eGFR calculated using the 2009 CKD_EPI creatinine equation
Note: eGFR results will not be calculated for patients younger than 18 years.
Clinical References: 1. Inker LA, Astor BC, Fox CH, et al: KDOQI US commentary on the 2012
KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014
May;63(5):713-35. doi: 10.1053/j.ajkd.2014.01.416 2. National Kidney Foundation. KDOQI Clinical
Practice Guideline for Diabetes and CKD: 2012 Update. Am J Kidney Dis. 2012 Nov;60(5):850-86. doi:
10.1053/j.ajkd.2012.07.005. Erratum in: Am J Kidney Dis. 2013 Jun;61(6):1049 3. Inker LA, Perrone
RD: Assessment of kidney function. In: Sterns RH, Forman JP, eds. UpToDate. Wolters Kluwer; 2021.
Updated October 04, 2021. Accessed March 16, 2022. Available at
www.uptodate.com/contents/assessment-of-kidney-function 4. Kasiske BL, Keane WF: Laboratory
assessment of renal disease: clearance, urinalysis, and renal biopsy. In: Brenner BM, ed. The Kidney. 6th
ed. WB Saunders Company; 2000:1129-1170 5. Delaney MP, Lamb EJ: Kidney disease. In: Rifai N,
Elsevier; 2018:1256-1323
CRTS1 Creatinine with Estimated Glomerular Filtration Rate (eGFR),

48216 Serum
Clinical Information: In muscle metabolism, creatinine is synthesized endogenously from creatine
and creatine phosphate. Creatinine is removed from plasma by glomerular filtration into the urine without
being reabsorbed by the tubules to any significant extent. Renal tubular secretion also contributes a small
quantity of creatinine to the urine. As a result, creatinine clearance often overestimates the true glomerular
filtration rate (GFR) by 10% to more than 20%. Determinations of creatinine and renal clearance of
creatinine are of value in the assessment of kidney function. Serum or blood creatinine levels in renal
disease generally do not increase until renal function is substantially impaired. Estimated GFR (eGFR) is
calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation:
eGFR (CKD-EPI) = 141 x min(Scr/k, 1)alpha x max(Scr/k,1)-1.209 x 0.993age x 1.018 (if patient is
female) x 1.159 (if patient is black/African American) -where age is in years -k is 0.7 for females and 0.9
for males -alpha is -0.329 for females and -0.411 for males -min indicates the minimum of Scr/k or 1
-max indicates the maximum of Scr/k or 1. Use of an estimating or prediction equation to estimate GFR
from serum creatinine should be employed for people with CKD and those with risk factors for CKD
(diabetes, hypertension, cardiovascular disease, and family history of kidney disease). Reasons given for
routine reporting of eGFR with every serum creatinine in adult (18 and over) patients include: -GFR and
creatinine clearance are poorly inferred from serum creatinine alone. GFR and creatinine clearance are
inversely and nonlinearly related to serum creatinine. The effects of age, sex, and, to a lesser extent, race,
on creatinine production further cloud interpretation. -Creatinine is commonly measured in routine
clinical practice. Albuminuria (>30 mg/24 hour or urine albumin to creatinine ratio >30 mg/g) may be a
more sensitive marker of early renal disease, especially among patients with diabetic nephropathy.
However, there is poor adherence to guidelines that suggest annual urinary albumin testing of patients
with known diabetes. Therefore, if a depressed eGFR is calculated from a serum creatinine measurement,
it may help providers recognize early CKD and pursue appropriate follow-up testing and therapeutic
intervention. -Monitoring of kidney function (by GFR or creatinine clearance) is essential once
albuminuria is discovered. Estimated GFR is a more practical means to closely follow changes in GFR
over time, when compared to direct measurement using methods such as iothalamate clearance. -The
CKD-EPI equation does not require weight or height variables. From a serum creatinine measurement, it
generates a GFR result normalized to a standard body surface area (1.73 m[2]) using sex, age, and race.
Unlike the Cockcroft-Gault equation, height and weight, which are often not available in the laboratory
information system, are not required. The CKD-EPI equation does require race (African American or
non-African American), which also may not be readily available. For this reason, eGFR values for both
African Americans and non-African Americans are reported. The difference between the 2 estimates is
typically about 20%. The patient or provider can decide which result is appropriate for a given patient.
The Kidney Disease: Improving Global Outcomes (KDIGO) CKD work group clinical practice
guideline,(2) as further defined by the National Kidney Foundation-Kidney Disease Outcomes Quality
Initiative (NKF-KDOQI) commentary,(3) provide the following recommendations for reporting and
interpretation of serum creatinine and eGFR: 1.4.3: Evaluation of GFR -1.4.3.1: We recommend using
serum creatinine and a GFR estimating equation for initial assessment. (1A) 1.4.3.2: We suggest using
additional tests (such as cystatin C or a clearance measurement) for confirmatory testing in specific
circumstances when eGFR based on serum creatinine is less accurate. (2B) 1.4.3.3: We recommend that
clinicians (1B): -Use a GFR estimating equation to derive GFR from serum creatinine (eGFRcreat) rather
than relying on the serum creatinine concentration alone. -Understand clinical settings in which
eGFRcreat is less accurate. 1.4.3.4: We recommend that clinical laboratories should (1B): -Measure serum
creatinine using a specific assay with calibration traceable to the international standard reference materials
and minimal bias compared to isotope-dilution mass spectrometry (IDMS) reference methodology.
-Report eGFRcreat in addition to the serum creatinine concentration in adults and specify the equation
used whenever reporting eGFRcreat. -Report eGFRcreat in adults using the 2009 CKD-EPI creatinine
equation. An alternative creatinine-based GFR estimating equation is acceptable if it has been shown to
improve accuracy of GFR estimates compared to the 2009 CKD-EPI creatinine equation. When reporting
serum creatinine: -We recommend that serum creatinine concentration be reported and rounded to the
nearest whole number when expressed as standard international units (mmol/l) and rounded to the nearest
100th of a whole number when expressed as conventional units (mg/dl). When reporting eGFRcreat: -We
recommend that eGFRcreat should be reported and rounded to the nearest whole number and relative to a
body surface area of 1.73 m2 in adults using the units ml/min/1.73 m2. - We recommend eGFRcreat
levels less than 60 ml/min/1.73 m2 should be reported as "decreased". 1.4.3.8: We suggest measuring
GFR using an exogenous filtration marker under circumstances where more accurate ascertainment of
GFR will impact treatment decisions (2B)
Useful For: Diagnosing and monitoring treatment of acute and chronic renal diseases Adjusting
dosage of renally excreted medications Monitoring renal transplant recipients Estimating glomerular
filtration rate for people with chronic kidney disease (CKD) and those with risk factors for CKD
(diabetes, hypertension, cardiovascular disease, and family history of kidney disease)
Interpretation: Because serum creatinine is inversely correlated with glomerular filtration rate
(GFR), when renal function is near normal, absolute changes in serum creatinine reflect larger changes
than do similar absolute changes when renal function is poor. For example, an increase in serum
creatinine from 1 to 2 mg/dL may indicate a decrease in GFR of 50 mL/min (from 100 to 50 mL/min),
whereas an increase in serum creatinine level from 4 to 5 mg/dL may indicate a decrease of only 5
mL/min (from 25 to 20 mL/min). Because of the imprecision of serum creatinine as an assessment of
GFR, there may be clinical situations where a more accurate GFR assessment must be performed,
iothalamate or inulin clearance are superior to serum creatinine and eGFR. Several factors may
influence serum creatinine independent of changes in GFR. For instance, creatinine generation is
dependent upon muscle mass. Thus, young, muscular males may have significantly higher serum
creatinine levels than elderly females, despite having similar GFRs. Also, because some renal clearance
of creatinine is due to tubular secretion, drugs that inhibit this secretory component (eg, cimetidine and
trimethoprim) may cause small increases in serum creatinine without an actual decrease in GFR.
According to the Kidney Disease: Improving Global Outcomes (KDIGO) CKD work group , chronic
kidney disease (CKD) is defined as the abnormalities of kidney structure or function, present for more
than 3 months, with implications for health.(3) CKD should be classified by cause, GFR category, and
albuminuria category.(3) KDIGO guidelines provide the following GFR categories(2,3): Stage Terms
GFR mL/min/1.73 m(4) G1* Normal or high 90 G2* Mildly decreased 60 to 89 G3a Mildly to
moderately decreased 45 to 59 G3b Moderately to severely decreased 30-44 G4 Severely decreased
15-29 G5 Kidney failure <15 *In the absence of evidence of kidney damage, neither G1 nor G2 fulfill
criteria for CKD.
Reference Values:
CREATININE
Males(1)
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-14 years: 0.35-0.86 mg/dL
> or =15 years: 0.74-1.35 mg/dL
Females(1)
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-15 years: 0.35-0.86 mg/dL
> or =16 years: 0.59-1.04 mg/dL
ESTIMATED Glomerular Filtration Rate (eGFR)

> or =60 mL/min/BSA
Note: eGFR results will not be calculated for patients <18 years old.
Clinical References: 1. Kulasingam V, Jung BP, Blaustig IM, et al: Pediatric reference intervals for
28 chemistries and immunoassays on the Roche cobas 6000 analyzer--a CALIPER pilot study. Clin
Biochem. 2010;43:1045-1050 2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work
Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney
disease. Kidney Int Suppl. 2013;3:1-150 3. KDOQI US Commentary on the 2012 KDIGO Clinical
Practice Guideline for the Evaluation and Management of CKD. Am J Kidney Dis. 2014;63:713-735 4.
Saenger AK, Lockwood C, Snozek CL, et al: Catecholamine interference in enzymatic creatinine assays.
Clin Chem. 2009;55(9):1732-1736 5. Rifai N, Horvath AR, Wittwer CT, eds: Tietz Fundamentals of
Clinical Chemistry and Molecular Diagnostics. 8th ed. Elsevier, 2018
CTU Creatinine, 24 Hour, Urine

610601 Clinical Information: Creatinine is formed from the metabolism of creatine and phosphocreatine,
both of which are principally found in muscle. Thus the amount of creatinine produced is, in large part,
dependent upon the individual's muscle mass and tends not to fluctuate much from day-to-day. Creatinine
is not protein bound and is freely filtered by glomeruli. All of the filtered creatinine is excreted in the
urine. Renal tubular secretion of creatinine also contributes to a small proportion of excreted creatinine.
Although most excreted creatinine is derived from an individual's muscle, dietary protein intake,
particularly of cooked meat, can contribute to urinary creatinine levels. The renal clearance of creatinine
provides an estimate of glomerular filtration rate.
Useful For: Calculation of creatinine clearance, a measure of renal function, when used in conjunction
with serum creatinine
Interpretation: Twenty-four-hour urinary creatinine determinations are principally used for the
calculation of creatinine clearance. Decreased creatinine clearance indicates decreased glomerular
filtration rate. This can be due to conditions such as progressive renal disease or result from adverse
effects on renal hemodynamics, which are often reversible, including certain drug usage or from decreases
in effective renal perfusion (eg, volume depletion or heart failure). Increased creatinine clearance is often
referred to as "hyperfiltration" and is most commonly seen during pregnancy or in patients with diabetes
mellitus before diabetic nephropathy has occurred. It also may occur with large dietary protein intake.
Reference Values:
Reference values mg per 24 hours:
Males > or =18 years: 930-2955 mg/24 hours
Females > or =18 years: 603-1783 mg/24 hours
2018:1256-1323 2. Lamb EJ, Jones GRD: Kidney function tests. In: Rifai N, Horvath AR, Wittwer CT,
eds: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:chap32 3.
Kasiske BL, Keane WF: Laboratory assessment of renal disease: clearance, urinalysis, and renal biopsy.
In: Brenner BM, ed. The kidney. 6th ed. WB Saunders; 2000:1129-1170
CRT24 Creatinine, 24 Hour, Urine

both of which are principally found in muscle. Thus, the amount of creatinine produced is in large part
dependent upon the individual's muscle mass and tends not to fluctuate much from day-to-day.
Creatinine is not protein-bound and is freely filtered by glomeruli. All of the filtered creatinine is
excreted in the urine. Renal tubular secretion of creatinine also contributes to a small proportion of
excreted creatinine. Although most excreted creatinine is derived from an individual's muscle, dietary
protein intake, particularly of cooked meat, can contribute to urinary creatinine levels. The renal
clearance of creatinine provides an estimate of glomerular filtration rate.
Useful For: Urinary creatinine, in conjunction with serum creatinine, is used to calculate the
creatinine clearance, a measure of renal function Normalizing urinary analytes to account for the
variation in urinary concentration
Interpretation: Decreased creatinine clearance indicates decreased glomerular filtration rate. This
can be due to conditions such as progressive renal disease, or result from adverse effect on renal
hemodynamics that are often reversible including certain drugs or from decreases in effective renal
perfusion (eg, volume depletion or heart failure). Increased creatinine clearance is often referred to as
"hyperfiltration" and is most commonly seen during pregnancy or in patients with diabetes mellitus,
before diabetic nephropathy has occurred. It also may occur with large dietary protein intake.
Reference Values:
-NMH24 / N-Methylhistamine, 24 Hour, Urine
-RB24 / Retinol-Binding Protein, 24 Hour, Urine
-A124 / Alpha-1-Microglobulin, 24 Hour, Urine
Normal values mg per 24 hours:

Males: 930-2955 mg/24 hours
Females: 603-1783 mg/24 hours
2018:1256-1323 2. Meeusen J, Rule A, Voskoboev, N, Baumann N, Lieske J: Performance of cystatin
C- and creatinine-based estimated glomerular filtration rate equations depends on patient characteristics.
Clin Chem. 2015 Oct;61(10):1265-1272. doi: 10.1373/clinchem.2015.243030 3. Newman DJ, Price CP:
Renal function and nitrogen metabolites. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical
Chemistry. 3rd ed. WB Saunders Company; 1999:1204-1270 4. Kasiske BL, Keane WF: Laboratory
assessment of renal disease: clearance, urinalysis, and renal biopsy. In: Brenner BM, ed. The Kidney.
6th ed. WB Saunders Company; 2000:1129-1170
CRBF Creatinine, Body Fluid

606601 Clinical Information: Byproducts of nitrogen metabolism are present in high concentration in urine
compared to blood and serve as a surrogate marker for the identification of urine leakage into a body
compartment. Concentrations of creatinine or urea nitrogen that exceed the concentration found in a
concurrent sample of blood are suggestive of the presence of urine.(1) Peritoneal, abdominal, pelvic
drain fluid: Trauma as well as abdominal or pelvic surgery can lead to bladder perforation or formation
of urinary fistula with excessive accumulation of peritoneal fluid or increased surgical drain output
caused by intraperitoneal urinary leakage.(1,2) Pleural fluid: Urinoma describes the accumulation of
urine in the perirenal and retroperitoneal spaces caused by genitourinary tract injury due to trauma or
blockage of the urinary tract due to stones, strictures, tumors, benign prostate hypertrophy, etc.(3)
Rarely, this fluid can translocate to the pleural cavity causing pleural effusion via movement of urine
through the diaphragm or via lymphatic communication between retroperitoneal and pleural spaces
caused by increased pressure due to urinoma. Urinothorax is the term used to describe an accumulation
of urine in the pleural space. Patients often develop symptoms of dyspnea, chest pain, abdominal pain,
and reduced diuresis.(4) The condition is reversed when treatment is directed to correct the primary
cause (trauma in 75% and obstruction in 24% of cases). The pleural fluid to serum creatinine ratio is
above 1 in 97.9% of cases (n=48; median ratio=2.9, range=0.95-16). Peritoneal dialysis fluid: Peritoneal
dialysis (PD) is a type of ambulatory dialysis in which hyperosmotic fluid is infused into the patient's
peritoneal cavity, with the peritoneum employed as the dialysis membrane promoting the diffusion of
small molecules and free water from circulation.(5) The peritoneal equilibration test estimates the rate
of small solute transport across the peritoneal membrane and the ultrafiltration capacity. Several
analytes may be measured in order to perform this test. Creatinine is measured in PD fluid as well as in
plasma or serum in samples taken 2 and/or 4 hours after the dialysate is instilled. The dialysate fluid to
serum or plasma creatinine ratio is calculated with larger ratios (approaching 1.0) observed in patients
exhibiting faster transport rates.
Useful For: Identifying the presence of urine as a cause for accumulation of fluid in a body
compartment Measuring the ultrafiltration capacity of the peritoneal membrane in patients receiving
peritoneal dialysis
Interpretation: Peritoneal, pleural, and drain fluid concentrations should be compared to serum or
plasma. Fluid to serum ratios above 1.0 suggest the specimen may be contaminated with urine.(1-4)
Peritoneal dialysate fluid to serum creatinine ratios can be calculated from timed collections to determine
peritoneal membrane transport rates.(5) All other fluids: results should be interpreted in conjunction with
serum creatinine and other clinical findings.
Reference Values:
Clinical References: 1. Manahan KJ, Fanning J: Peritoneal fluid urea nitrogen and creatinine
reference values. Obstet Gynecol. 1999;93:780-782 2. Wong MH, Lim SK, Ng KL, Ng KP: Pseudo-acute
kidney injury with recurrent ascites due to intraperitoneal urine leakage. Intern Med J. 2012;42:848-849 3.
Austin A, Jogani SN, Brasher PB, et al: The urinothorax: A comprehensive review with case series. Am J
Med Sci. 2017;354(1):44â€“53 4. Toubes ME, Lama A, Ferreiro L, et al: Urinothorax: a systematic
review. J Thorac Dis. 2017;9(5):1209-1218 5. Block DR, Florkowski CM: Body fluids. In: Rafai N,
Horvath AR, Wittwer CT. eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed.
Elsevier;2018chap 43
RCTUR Creatinine, Random, Urine

both of which are principally found in muscle. Thus, the amount of creatinine produced is, in large part,
is not protein bound and is freely filtered by glomeruli. All of the filtered creatinine is excreted in the
provides an estimate of glomerular filtration rate. Since creatinine, for the most part, in the urine only
comes from filtration, the concentration of creatinine reflects overall urinary concentration. Therefore,
creatinine can be used to normalize other analytes in a random urine specimen.
Useful For: Calculation of creatinine clearance, a measure of renal function, when used in conjunction
with serum creatinine Normalization of urinary analytes by creatinine concentration to account for the
variation in urinary concentrations between subjects
can be due to conditions such as progressive renal disease, or result from adverse effects on renal
hemodynamics, which are often reversible including certain drugs or from decreases in effective renal
"hyperfiltration" and is most commonly seen during pregnancy or in patients with diabetes mellitus
Reference Values:
CT, eds. Textbook of Clinical Chemistry. 6th ed. Elsevier; 2018:1256-1323 2. Lamb EJ, Jones GRD:
Kidney function tests. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry
and Molecular Diagnostics. 6th ed. Elsevier; 2018:479-517 3. Kasiske BL, Keane WF: Laboratory
assessment of renal disease: clearance, urinalysis, and renal biopsy. In: Brenner BM, ed. The Kidney.
6th ed. WB Saunders Company; 2000:1129-1170
CRETR Creatinine, Random, Urine

dependent upon the individual's muscle mass and tends not to fluctuate much from day-to-day.
Creatinine is not protein-bound and is freely filtered by glomeruli. All of the filtered creatinine is
excreted in the urine. Renal tubular secretion of creatinine also contributes to a small proportion of
excreted creatinine. Although most excreted creatinine is derived from an individual's muscle, dietary
protein intake, particularly of cooked meat, can contribute to urinary creatinine levels. The renal
clearance of creatinine provides an estimate of glomerular filtration rate. Since creatinine for the most
part in the urine only comes from filtration, the concentration of creatinine reflects overall urinary
concentration. Therefore, creatinine can be used to normalize other analytes in a random urine
specimen.
Useful For: Normalization of urinary analytes to account for the variation in urinary concentrations
between individuals when using random urine collections
can be due to conditions such as progressive renal disease, or result from adverse effect on renal
Reference Values:
Only orderable as part of a profile. For more information see orderable test ID.

Reference values have not been established for patients who are younger than 18 years of age.
2018:1256-1323 2. Meeusen JW, Rule AD, Voskoboev N, Baumann NA, Lieske JC: Performance of
cystatin C- and creatinine-based estimated glomerular filtration rate equations depends on patient
characteristics. Clin Chem. 2015 Oct;61(10):1265-1272. doi: 10.1373/clinchem.2015.243030 3.
Newman DJ, Price CP: Renal function and nitrogen metabolites. In: Burtis CA, Ashwood ER, eds. Tietz
Textbook of Clinical Chemistry. 3rd ed. WB Saunders Company; 1999:1204-1270 4. Kasiske BL,
Keane WF: Laboratory assessment of renal disease: clearance, urinalysis, and renal biopsy. In: Brenner
BM, ed. The Kidney. 6th ed. WB Saunders Company; 2000:1129-1170
CRE2 Creatinine, Urine

is not protein-bound and is freely filtered by glomeruli. All of the filtered creatinine is excreted in the
provides an estimate of glomerular filtration rate (GFR). Since creatinine, for the most part, in the urine
only comes from filtration, the concentration of creatinine reflects overall urinary concentration.
Therefore, creatinine can be used to normalize other analytes in a random urine specimen.
Useful For: Normalization of urinary analytes to account for the variation in urinary concentrations
between individuals when using random urine collections
Interpretation: Decreased creatinine clearance indicates decreased glomerular filtration rate. This can
be due to conditions such as progressive renal disease, or result from adverse effect on renal
Reference Values:
ALBR / Albumin, Random, Urine
RALB / Albumin, Random, Urine.
Not applicable
Clinical References: 1. Meeusen J, Rule A, Voskoboev N, Baumann N, Lieske J: Performance of

cystatin C-creatinine-based estimated glomerular filtration rate equations depends on patient
characteristics. Clin Chem. 2015 Oct;61(10):1265-1272. doi:10.1373/clinchem.2015.243030 2. Newman
DJ, Price CP: Renal function and nitrogen metabolites. In: Burtis CA, Ashwood ER, eds. Tietz Textbook
of Clinical Chemistry. 3rd ed. WB Saunders Company; 1999:1204-1270 3. Kasiske BL, Keane WF:
Laboratory assessment of renal disease: clearance, urinalysis, and renal biopsy. In: Brenner BM, ed. The
Kidney. 6th ed. WB Saunders Company; 2000:1129-1170
CRGSP Cryoglobulin and Cryofibrinogen Panel, Serum and Plasma

83659 Clinical Information: Cryoglobulins are immunoglobulins that precipitate when cooled and dissolve
when heated. Because these proteins precipitate when cooled, patients may experience symptoms when
exposed to the cold. Cryoglobulins may be associated with a variety of diseases including plasma cell
disorders, autoimmune diseases, and infections. Cryoglobulins may also cause erroneous results with
some automated hematology instruments. Cryoglobulins may be classified as follows: Type I, Type II,
and Type III. Type I is composed of a monoclonal immunoglobulin: IgG or IgM, or rarely IgA or free
monoclonal light chains. Type II cryoglobulins consist of a monoclonal component and a polyclonal
component. Finally, type III cryoglobulins are composed of only polyclonal immunoglobulins. The
majority of patients with cryoglobulins are asymptomatic. The type or quantity of cryoglobulin does not
reliably predict whether or which symptoms will be present. The concentration of cryoglobulins tends to
vary by type with the majority of cases: of type III, being less than 1 mg/mL; of type II, greater than 1
mg/mL; and of type I, greater than 5 mg/mL. Even though the type I cryoglobulin concentrations tend to
be the highest, they are the least likely to cause symptoms. The thermal amplitude (temperature at which
the cryoglobulin precipitates) is a better predictor of symptoms than quantity or type. Symptoms of
cryoglobulinemia include purpura, Raynaud phenomenon, cyanosis, skin ulceration, gangrene, kidney
failure, peripheral neuropathy, fever, and malaise. Type I cryoglobulinemia is associated with monoclonal
gammopathy of undetermined significance, macroglobulinemia, or multiple myeloma. Type II
cryoglobulinemia is associated with autoimmune disorders such as vasculitis, glomerulonephritis,
systemic lupus erythematosus, rheumatoid arthritis, and Sjogren syndrome. It may be seen in infections
such as hepatitis, infectious mononucleosis, cytomegalovirus, and toxoplasmosis. Type II
cryoglobulinemia may also be essential, ie, occurring in the absence of underlying disease. Type III
cryoglobulinemia usually demonstrates trace levels of cryoprecipitate, may take up to 7 days to appear,
and is associated with the same disease spectrum as Type II cryoglobulinemia. A cryoprecipitate that is
seen in plasma but not in serum is caused by cryofibrinogen. Cryofibrinogens are extremely rare and can
be associated with vasculitis. Patients with cryofibrinogenemia often present asymptomatically, but this
disorder can also be secondary to numerous conditions that include, but are not limited to, malignancies,
infection, inflammation, or thrombotic disorders. Of those with symptoms, primary or essential
cryofibrinogenemia can present with systemic manifestations or with a more specific clinical picture that
typically includes cold intolerance and thrombotic/hemorrhagic manifestations, such as purpura, necrosis,
ulcers and gangrene. Due to the rarity of clinically significant cryofibrinogenemia, testing for
cryoglobulins is usually sufficient for investigation of cryoproteins.
Useful For: Evaluating patients with vasculitis, glomerulonephritis, and lymphoproliferative diseases
Evaluating patients with macroglobulinemia or myeloma in whom symptoms occur with cold exposure
This test is not useful for general screening of a population without a clinical suspicion of
cryoglobulinemia.
Interpretation: An interpretive report will be provided

Reference Values:
CRYOGLOBULIN
Negative (positives reported as percent or trace amount)
If positive after 1 or 7 days, immunotyping of the cryoprecipitate is performed at an additional charge.
CRYOFIBRINOGEN
Negative
Quantitation and immunotyping will not be performed on positive cryofibrinogen.
Clinical References: 1. Kyle RA, Lust JA: Immunoglobulins and laboratory recognition of
monoclonal proteins. Section III. Myeloma and related disorders. In: Wiernik PH, Canellos GP, Dutcher
JP, Kyle RA, eds. Neoplastic Diseases of the Blood. 3rd ed. Churchill Livingstone; 1996:453-475 2.
Desbois AC, Cacoub P, Saadoun D: Cryoglobulinemia: An update in 2019. Joint Bone Spine. 2019
Nov;86(6):707-713. doi: 10.1016/j.jbspin.2019.01.016
CRY_S Cryoglobulin, Serum

80988 Clinical Information: Cryoglobulins are immunoglobulins that precipitate when cooled and
dissolve when heated. Because these proteins precipitate when cooled, patients may experience
symptoms when exposed to the cold. Cryoglobulins may be associated with a variety of diseases
including plasma cell disorders, autoimmune diseases, and infections. Cryoglobulins may also cause
erroneous results with some automated hematology instruments. Cryoglobulins may be classified as
follows: Type I, Type II, and Type III. Type I is composed of a monoclonal immunoglobulin: IgG or
IgM, or rarely IgA or free monoclonal light chains. Type II cryoglobulins consist of a monoclonal
component and a polyclonal component. Finally, type III cryoglobulins are composed of only
polyclonal immunoglobulins. The majority of patients with cryoglobulins are asymptomatic. The type
or quantity of cryoglobulin does not reliably predict whether or which symptoms will be present. The
concentration of cryoglobulins tends to vary by type with the majority of cases: of type III, being less
than 1 mg/mL; of type II, greater than 1 mg/mL; and of type I, greater than 5 mg/mL. Even though the
type I cryoglobulin concentrations tend to be the highest, they are the least likely to cause symptoms.
The thermal amplitude (temperature at which the cryoglobulin precipitates) is a better predictor of
symptoms than quantity or type. Symptoms of cryoglobulinemia include purpura, Raynaud
phenomenon, cyanosis, skin ulceration, gangrene, kidney failure, peripheral neuropathy, fever, and
malaise. Type I cryoglobulinemia is associated with monoclonal gammopathy of undetermined
significance, macroglobulinemia, or multiple myeloma. Type II cryoglobulinemia is associated with
autoimmune disorders such as vasculitis, glomerulonephritis, systemic lupus erythematosus, rheumatoid
arthritis, and Sjogren syndrome. It may be seen in infections such as hepatitis, infectious
mononucleosis, cytomegalovirus, and toxoplasmosis. Type II cryoglobulinemia may also be essential,
ie, occurring in the absence of underlying disease. Type III cryoglobulinemia usually demonstrates trace
levels of cryoprecipitate, may take up to 7 days to appear, and is associated with the same disease
spectrum as Type II cryoglobulinemia.
Useful For: Evaluating cryoglobulins in patients with vasculitis, glomerulonephritis, and

lymphoproliferative diseases Evaluating cryoglobulins in patients with macroglobulinemia or myeloma in
whom symptoms occur with cold exposure This test is not useful for general screening of a population
without a clinical suspicion of cryoglobulinemia.
Interpretation: An interpretive report will be provided

Reference Values:
Negative (positives reported as percent or trace amount)
If positive after 1 or 7 days, immunotyping of the cryoprecipitate is performed at an additional charge.
Clinical References: 1. Kyle RA, Lust JA: Immunoglobulins and laboratory recognition of
monoclonal proteins. Section III. Myeloma and related disorders. In: Wiernik PH, Canellos GP, Dutcher
JP, Kyle RA, eds. Neoplastic Diseases of the Blood. 3rd ed. Churchill Livingstone; 1996:453-475 2.
Desbois AC, Cacoub P, Saadoun D: Cryoglobulinemia: An update in 2019. Joint Bone Spine. 2019
Nov;86(6):707-713. doi: 10.1016/j.jbspin.2019.01.016
SLFA Cryptococcus Antigen Screen with Titer, Serum

62075 Clinical Information: Cryptococcosis is an invasive fungal infection caused by Cryptococcus
neoformans or Cryptococcus gattii. C neoformans has been isolated from several sites in nature,
particularly weathered pigeon droppings. C gatti was previously associated with tropical and subtropical
regions only; however, more recently this organism has also been found to be endemic in British
Columbia and among the Pacific Northwest United States and is associated with several different trees
species. Infection is usually acquired via the pulmonary route. Patients are often unaware of any exposure
history. Approximately half of the patients with symptomatic disease have a predisposing
immunosuppressive condition such as AIDS, steroid therapy, lymphoma, or sarcoidosis. Symptoms may
include fever, headache, dizziness, ataxia, somnolence, and cough. While the majority of C neoformans
infections occur in immunocompromised patient populations, C gattii is has a higher predilection for
infection of healthy individuals.(1,2) In addition to the lungs, cryptococcal infections frequently involve
the central nervous system (CNS), particularly in patients infected with HIV. Mortality among patients
with CNS cryptococcosis may approach 25% despite antibiotic therapy. Untreated CNS cryptococcosis is
invariably fatal. Disseminated disease may affect any organ system and usually occurs in
immunosuppressed individuals.
Useful For: Aiding in the diagnosis of cryptococcosis This test should not be used as a test of cure or
to guide treatment decisions. This test should not be used as a screening procedure for the general
populations.
Interpretation: The presence of cryptococcal antigen in any body fluid (serum or cerebrospinal fluid)
is indicative of cryptococcosis. Specimens that are positive by the lateral flow assay screen are
automatically repeated with the same method utilizing dilutions in order to generate a titer value.
Disseminated infection is usually accompanied by a positive serum test. Higher Cryptococcus antigen
titers appear to correlate with more severe infections. Declining titers may indicate regression of infection.
However, monitoring titers to cryptococcal antigen should not be used as a test of cure or to guide
treatment decisions, as low level titers may persist for extended periods of time following appropriate
therapy and the resolution of infection.(3)
Reference Values:
Negative
Clinical References: 1. Speed B, Dunt D: Clinical and host differences between infections with
the two varieties of Cryptococcus neoformans. Clin Infect Dis. 1995;21(1):28-34 2. Chen S, Sorrell T,
Nimmo G, et al: Epidemiology and host- and variety-dependent characteristics of infection due to
Cryptococcus neoformans in Australia and New Zealand. Australasian Cyrptococcoal Study Group.
Clin Infect Dis. 2000;31(2):499-505 3. Perfect JR, Dismukes WE, Dromer F, et al: Clinical practice
guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society
of America. 2009;50:291-322 4. Warren NG, Hazen KC: Candida, Cryptococcus, and other yeasts of
medical importance. In: Murray PR, ed. Manual of Clinical Microbiology. 7th ed. ASM Press; 1999:
1184-1199 5. Lu H, Zhou Y, Yin Y, et al: Cryptococcal antigen test revisited: significance for
cryptococcal meningitis therapy monitoring in a tertiary Chinese hospital. J Clin Microbiol. 2005
June;43(6):2989-2990 6. Perfect JR: Cryptococcosis (Cryptococcus neoformans and Cryptococcus
gattii). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice
of Infectious Diseases. 9th ed. Elsevier; 2020:3146-3161
CLFA Cryptococcus Antigen Screen with Titer, Spinal Fluid

neoformans or Cryptococcus gattii. Cryptococcus neoformans has been isolated from several sites in
nature, particularly weathered pigeon droppings. C gattii was previously associated with tropical and
subtropical regions only, however, more recently this organism has also been found to be endemic in
British Columbia and among the Pacific Northwest United States and is associated with several
different trees species. Infection is usually acquired via the pulmonary route. Patients are often unaware
of any exposure history. Approximately half of the patients with symptomatic disease have a
predisposing immunosuppressive condition such as AIDS, steroid therapy, lymphoma, or sarcoidosis.
Symptoms may include fever, headache, dizziness, ataxia, somnolence, and cough. While the majority
of C neoformans infections occur in immunocompromised patient populations, C gattii has a higher
predilection for infection of healthy individuals.(1,2) In addition to the lungs, cryptococcal infections
frequently involve the central nervous system (CNS), particularly in patients infected with HIV.
Mortality among patients with CNS cryptococcosis may approach 25% despite antibiotic therapy.
Untreated CNS cryptococcosis is invariably fatal. Disseminated disease may affect any organ system
and usually occurs in immunosuppressed individuals. Note: According to the College of American
Pathologists (CAP, IMM.41840), cerebrospinal fluid (CSF) samples submitted for initial diagnosis,
which test positive by the lateral flow assay, should also be submitted for routine fungal culture. Fungal
cultures are not required for CSF samples that are submitted to monitor Cryptococcus antigen titers
during treatment.
Useful For: Aiding in the diagnosis of cryptococcosis This test should not be performed as a
screening procedure for the general population. This test should not be used as a test of cure or to guide
treatment decisions.
Interpretation: The presence of cryptococcal antigen in any body fluid (serum or cerebrospinal
fluid: CSF) is indicative of cryptococcosis. Specimens that are positive by the lateral flow assay (LFA)
screen are automatically repeated by the same method utilizing dilutions in order to generate a titer
value. CSF specimens submitted for initial diagnosis, which test positive by LFA, should also be
submitted for routine fungal culture. Culture can aid to differentiate between the 2 common
Cryptococcus species causing disease (Cryptococcus neoformans and Cryptococcus gattii) and can be
used for antifungal susceptibility testing, if necessary. CSF specimens submitted to monitor antigen
levels during treatment do not need to be cultured. Disseminated infection is usually accompanied by a
positive serum test. Higher Cryptococcus antigen titers appear to correlate with more severe infections.
Declining titers may indicate regression of infection. However, monitoring titers to cryptococcal antigen
should not be used as a test of cure or to guide treatment decisions, as low level titers may persist for
extended periods of time following appropriate therapy and the resolution of infection.(3)
Reference Values:
Negative
Clinical References: 1. Speed B, Dunt D: Clinical and host differences between infections with the
two varieties of Cryptococcus neoformans. Clin Infect Dis. 1995;21(1):28-34 2. Chen S, Sorrell T,
Cryptococcus neoformans in Australia and New Zealand. Australasian Cyrptococcoal Study Group. Clin
Infect Dis. 2000;31(2):499-505 3. Perfect JR, Dismukes WE, Dromer F, et al: Clinical practice guidelines
for the management of cryptococcal disease: 2010 update by the infectious diseases society of America.
Clin Infect Dis. 2010;50:291-322 4. Warren NG, Hazen KC: Candida, Cryptococcus, and other yeasts of
medical importance. In: Murray PR, ed. Manual of Clinical Microbiology. 7th ed. ASM Press: 1999:
1184-1199 5. Lu H, Zhou Y, Yin Y, et al: Cryptococcal antigen test revisited: significance for
cryptococcal meningitis therapy monitoring in a tertiary Chinese hospital. J Clin Microbiol. 2005
June;43(6):2989-2990 6. Perfect JR: Cryptococcosis (Cryptococcus neoformans and Cryptococcus gattii).
In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of
PLFA Cryptococcus Antigen Screen, Lateral Flow Assay, Pleural

42396 Fluid
Clinical Information: Cryptococcosis is an invasive fungal infection caused by Cryptococcus
particularly weathered pigeon droppings. C gattii was previously associated with tropical and subtropical
regions only; however, more recently this organism has also been found to be endemic in British
Columbia, along the Pacific Northwest, and in the Southeastern United States. Infection is usually
acquired via the pulmonary route. Patients are often unaware of any exposure history. Approximately half
of the patients with symptomatic disease have a predisposing immunosuppressive condition such as
AIDS, steroid therapy, lymphoma, or sarcoidosis. Symptoms may include fever, headache, dizziness,
ataxia, somnolence, and cough. While the majority of C neoformans infections occur in
immunocompromised patient populations, C gattii has a higher predilection for infection of healthy
individuals. In addition to the lungs, cryptococcal infections frequently involve the central nervous system
(CNS), particularly in patients infected with HIV. Mortality among patients with CNS cryptococcosis
may approach 25% despite antibiotic therapy. Untreated CNS cryptococcosis is invariably fatal.
Disseminated disease may affect any organ system and usually occurs in immunosuppressed individuals.
Useful For: Diagnosis of infection with Cryptococcus species

Interpretation: The presence of cryptococcal antigen in pleural fluid is indicative of infection with
Cryptococcus species. Monitoring cryptococcal antigen levels as a means to determine response to
therapy is discouraged, as antigen levels may persist despite adequate treatment and disease resolution. A
negative result indicates lack of infection; however, rare cases of false-negative results have been
reported. Fungal culture should always be ordered alongside antigen testing.
Reference Values:
Negative
Clinical References: 1. Binnicker MJ, Jespersen DJ, Bestrom JE, Rollins LO: Comparison of four
assays for the detection of cryptococcal antigen. J Clin Micro. 2012;19(12):1988-1990 2. Howell SA,
Hazen KC, Brandt ME: Candida, cryptococcus, and other yeast of medical importance. In: Manual of
Clinical Microbiology. 11th ed. ASM Press; 2015: 1984-2014
ULFA Cryptococcus Antigen Screen, Lateral Flow Assay, Random,

604095 Urine
Clinical Information: Cryptococcosis is an invasive fungal infection caused by Cryptococcus
neoformans or Cryptococcus gattii. The organism has been isolated from several sites in nature,
particularly weathered pigeon droppings. Infection is usually acquired via the pulmonary route. Patients
are often unaware of any exposure history. Approximately half of the patients with symptomatic disease
have a predisposing immunosuppressive condition such as AIDS, steroid therapy, lymphoma, or
sarcoidosis. Symptoms may include fever, headache, dizziness, ataxia, somnolence, and cough. While the
majority of C neoformans infections occur in immunocompromised patient populations, C gattii has a
predilection for infection of healthy individuals. In addition to the lungs, cryptococcal infections
frequently involve the central nervous system (CNS), particularly in HIV-infected patients. Mortality
associated with CNS cryptococcosis approaches 25% despite antifungal therapy, while untreated CNS
cryptococcosis is invariably fatal. Disseminated disease may affect any organ system and usually occurs
in immunosuppressed individuals.
Useful For: Aiding in the diagnosis of infection with Cryptococcus neoformans or Cryptococcus
gattii This test should not be used as a test of cure. This test should not be used as a screening procedure
for the general population.
Interpretation: The presence of cryptococcal antigen (CrAg) in any body fluid is strongly
suggestive of infection with Cryptococcus neoformans or Cryptococcus gattii. Declining titers are
suggestive of clinical response to therapy. However, monitoring CrAg titers should not be used as a test
of cure, as low level titers may persist for extended periods of time following appropriate therapy and
disease resolution. In addition to testing for CrAg, patients with presumed disease due to C neoformans
or C gattii should have appropriate clinical specimens (eg, blood, bronchoalveolar lavage fluid)
submitted for routine smear and fungal culture.
Reference Values:
Negative
Clinical References: 1. Hazen KC, Howell SA: Candida, Cryptococcus, and other yeasts of
medical importance. In: Murray PR, ed. Manual of Clinical Microbiology. 9th ed. ASM Press; 2007:
1762-1788 2. Bruner KT, Franco-Paredes C, Henao-Martinez A, et al: Cryptococcus gattii complex
infections in HIV-infected patients, Southeastern United States. EID. 2018 Nov;24(11). doi:
10.3201/eid2411.180787
PLFAT Cryptococcus Antigen Titer, Lateral Flow Assay, Pleural Fluid

particularly weathered pigeon droppings. C gattii was previously associated with tropical and
subtropical regions only; however, more recently this organism has also been found to be endemic in
British Columbia, along the Pacific Northwest and in the Southeastern United States. Infection is
usually acquired via the pulmonary route. Patients are often unaware of any exposure history.
Approximately half of the patients with symptomatic disease have a predisposing immunosuppressive
condition such as AIDS, steroid therapy, lymphoma, or sarcoidosis. Symptoms may include fever,
headache, dizziness, ataxia, somnolence, and cough. While the majority of C neoformans infections
occur in immunocompromised patient populations, C gattii has a higher predilection for infection of
healthy individuals. In addition to the lungs, cryptococcal infections frequently involve the central
nervous system (CNS), particularly in patients infected with HIV. Mortality among patients with CNS
cryptococcosis may approach 25% despite antibiotic therapy. Untreated CNS cryptococcosis is
Useful For: Diagnosis of infection with Cryptococcus species

Interpretation: The presence of cryptococcal antigen in pleural fluid is indicative of infection with
Cryptococcus species. Monitoring cryptococcal antigen levels as a means to determine response to
therapy is discouraged, as antigen levels may persist despite adequate treatment and disease resolution.
A negative result indicates lack of infection; however rare cases of false-negative results have been
reported. Fungal culture should always be ordered alongside antigen testing.
Reference Values:
Only orderable as a reflex. For more information see PLFA / Cryptococcus Antigen Screen, Lateral
Flow Assay, Pleural Fluid.
Clinical References: 1. Binnicker MJ, Jespersen DJ, Bestrom JE, Rollins LO: Comparison of four
assays for the detection of cryptococcal antigen. J Clin Micro. 2012;19(12):1988-1990 2. Howell SA,
Hazen KC, Brandt ME: Candida, cryptococcus, and other yeast of medical importance. In: Manual of
Clinical Microbiology. 11th ed. ASM Press; 2015:1984-2014
SLFAT Cryptococcus Antigen Titer, Lateral Flow Assay, Serum

particularly weathered pigeon droppings. C gattii was previously associated with tropical and subtropical
regions only, however, more recently this organism has also been found to be endemic in British
Columbia and among the Pacific Northwest United States and is associated with several different trees
infections occur in immunocompromised patient populations, C gattii has a higher predilection for
Useful For: Monitoring Cryptococcus antigen titers in serum Aiding in the diagnosis of cryptococcosis
This test should not be used as a test of cure or to guide treatment decisions.
Interpretation: The presence of cryptococcal antigen in any body fluid (serum or cerebrospinal fluid:
CSF) is indicative of cryptococcosis. Disseminated infection is usually accompanied by a positive serum
test. Declining titers may indicate regression of infection. However, monitoring titers to cryptococcal
antigen should not be used as a test of cure or to guide treatment decisions. Low-level titers may persist
for extended periods of time following appropriate therapy and resolution of infection.(3,4)
Reference Values:
Negative
Clinical References: 1. Speed B, Dunt D: Clinical and host differences between infections with the
two varieties of Cryptococcus neoformans. Clin Infect Dis. 1995;21(1):28-34 2. Chen S, Sorrell T,
Cryptococcus neoformans in Australia and New Zealand. Australasian Cyrptococcoal Study Group. Clin
Infect Dis. 2000;31(2):499-505 3. Lu H, Zhou Y, Yin Y, et al: Cryptococcal antigen test revisited:
significance for cryptococcal meningitis therapy monitoring in a tertiary Chinese hospital. J Clin
Microbiol. 2005 June;43(6):2989-2990 4. Perfect JR, Dismukes WE, Dromer F, et al: Clinical practice
guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of
America. Clin Infect Dis. 2010;50:291-322 5. Binnicker MJ, Jespersen DJ, Bestrom JE, Rollins LO: A
comparison of four assays for detection of cryptococcal antigen. Clin Vaccine Immunol. 2012
Dec;19(12):1988-1990 6. Warren NG, Hazen KC: Candida, Cryptococcus, and other yeasts of medical
importance. In: Murray PR, ed. Manual of Clinical Microbiology. 7th ed. ASM Press; 1999: 1184-1199
CLFAT Cryptococcus Antigen Titer, Lateral Flow Assay, Spinal Fluid

neoformans or Cryptococcus gattii. Cryptococcus neoformans has been isolated from several sites in
nature, particularly weathered pigeon droppings. C gatti was previously associated with tropical and
subtropical regions only, however, more recently this organism has also been found to be endemic in
British Columbia and among the Pacific Northwest United States and is associated with several different
trees species. Infection is usually acquired via the pulmonary route. Patients are often unaware of any
exposure history. Approximately half of the patients with symptomatic disease have a predisposing
infections occur in immunocompromised patient populations, C gattii is has a higher predilection for
immunosuppressed individuals. Note: According to the College of American Pathologists (CAP,
IMM.41840), cerebrospinal fluid (CSF) samples submitted for initial diagnosis that test positive by the
lateral flow assay should also be submitted for routine fungal culture. Fungal cultures are not required for
CSF samples that are submitted to monitor Cryptococcus antigen titers during treatment.
Useful For: Monitoring Cryptococcus antigen titers in cerebrospinal fluid Aiding in the diagnosis of
cryptococcosis This test should not be used as a test of cure or to guide treatment decisions.
Interpretation: The presence of cryptococcal antigen in any body fluid (serum or cerebrospinal
fluid: CSF) is indicative of cryptococcosis. Disseminated infection is usually accompanied by a positive
serum test. Declining titers may indicate regression of infection. However, monitoring titers to
cryptococcal antigen should not be used as a test of cure or to guide treatment decisions. Low-level
titers may persist for extended periods of time following appropriate therapy and resolution of
infection.(3,4) CSF specimens submitted for initial diagnosis that test positive by the lateral flow assay,
should also be submitted for routine fungal culture. Culture can aid to differentiate between the 2
common Cryptococcus species causing disease (Cryptococcus neoformans and Cryptococcus gattii) and
can be used for antifungal susceptibility testing, if necessary. CSF specimens submitted to monitor
antigen levels during treatment do not need to be cultured.
Reference Values:
Negative
Clin Infect Dis. 2000;31(2):499-505 3. Lu H, Zhou Y, Yin Y, et al: Cryptococcal antigen test revisited:
significance for cryptococcal meningitis therapy monitoring in a tertiary Chinese hospital. J Clin
Microbiol. 2005 June;43(6):2989-2990 4. Perfect JR, Dismukes WE, Dromer F, et al: Clinical practice
guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society
of America. Clin Infect Dis. 2010;50:291-322 5. Warren NG, Hazen KC: Candida, Cryptococcus, and
other yeasts of medical importance. In: Marrya PR, ed. Manual of Clinical Microbiology. 7th ed. ASM
Press; 1999: 1184-1199 6. Perfect JR: Cryptococcosis (Cryptococcus neoformans and Cryptococcus
ULFAT Cryptococcus Antigen Titer, Lateral Flow Assay, Urine

neoformans or Cryptococcus gattii. The organism has been isolated from several sites in nature,
particularly weathered pigeon droppings. Infection is usually acquired via the pulmonary route. Patients
are often unaware of any exposure history. Approximately half of the patients with symptomatic disease
have a predisposing immunosuppressive condition such as AIDS, steroid therapy, lymphoma, or
sarcoidosis. Symptoms may include fever, headache, dizziness, ataxia, somnolence, and cough. While
the majority of C neoformans infections occur in immunocompromised patient populations, C gattii has
a predilection for infection of healthy individuals. In addition to the lungs, cryptococcal infections
frequently involve the central nervous system (CNS), particularly in HIV-infected patients. Mortality
associated with CNS cryptococcosis approaches 25% despite antifungal therapy, while untreated CNS
cryptococcosis is invariably fatal. Disseminated disease may affect any organ system and usually occurs
in immunosuppressed individuals.
Useful For: Aiding in the diagnosis of infection with Cryptococcus neoformans or Cryptococcus gattii
This test should not be used as a test of cure.
Interpretation: The presence of cryptococcal antigen (CrAg) in any body fluid is strongly suggestive
of infection with Cryptococcus neoformans or Cryptococcus gattii. Declining titers are suggestive of
clinical response to therapy. However, monitoring CrAg titers should not be used as a test of cure, as low
level titers may persist for extended periods of time following appropriate therapy and disease resolution.
In addition to testing for CrAg, patients with presumed disease due to C neoformans or C gattii should
have appropriate clinical specimens (eg, blood, bronchoalveolar lavage fluid) submitted for routine smear
and fungal culture.
Reference Values:
Only orderable as a reflex. For more information see ULFA / Cryptococcus Antigen Screen, Lateral Flow
Assay, Urine.
Clinical References: 1. Hazen KC, Howell SA: Candida, Cryptococcus, and other yeasts of medical
importance. In: Murray PR, ed. Manual of Clinical Microbiology. 9th ed. ASM Press; 2007:1762-1788 2.
Bruner KT, Franco-Paredes C, Henao-Martinez A, et al: Cryptococcus gattii complex infections in
HIV-infected patients, Southeastern United States. EID. 2018 Nov;24(11) doi: 10.3201/eid2411.180787
LFACX Cryptococcus Antigen with Reflex, Spinal Fluid

particularly weathered pigeon droppings. C gattii was previously only associated with tropical and
subtropical regions, however, more recently this organism has also been found to be endemic in British
Columbia and among the Pacific Northwest United States, and is associated with several different trees
infections occur in immunocompromised patient populations, C gattii has a higher predilection for
infection of healthy hosts.(1,2) In addition to the lungs, cryptococcal infections frequently involve the
central nervous system (CNS), particularly in patients infected with HIV. Mortality among patients with
CNS cryptococcosis may approach 25% despite antibiotic therapy. Untreated CNS cryptococcosis is
immunosuppressed individuals. Note: According to the College of American Pathologists (CAP,
IMM.41840), cerebrospinal fluid (CSF) samples submitted for initial diagnosis, which test positive by the
lateral flow assay, should also be submitted for routine fungal culture. Fungal cultures are not required for
CSF samples that are submitted to monitor Cryptococcus antigen titers during treatment.
Useful For: Aiding in the diagnosis of cryptococcosis This test should not be used as a test of cure or
to guide treatment decisions. This test should not be performed as a screening procedure for the general
population.
Interpretation: The presence of cryptococcal antigen in any body fluid (serum or cerebrospinal fluid:
CSF) is indicative of cryptococcosis. Specimens that are positive by the lateral flow assay (LFA) screen
are automatically repeated by the same method utilizing dilutions in order to generate a titer value. CSF
specimens submitted for initial diagnosis, which test positive by LFA, should also be submitted for
routine fungal culture. Culture can aid to differentiate between the 2 common Cryptococcus species
causing disease (Cryptococcus neoformans and Cryptococcus gattii) and can be used for antifungal
susceptibility testing, if necessary. CSF specimens submitted to monitor antigen levels during treatment
do not need to be cultured. Disseminated infection is usually accompanied by a positive serum test.
Higher Cryptococcus antigen titers appear to correlate with more severe infections. Declining titers may
indicate regression of infection. However, monitoring titers to cryptococcal antigen should not be used as
a test of cure or to guide treatment decisions, as low level titers may persist for extended periods of time
following appropriate therapy and the resolution of infection.
Reference Values:
CRYPTOCOCCUS ANTIGEN SCREEN WITH TITER
Negative
CRYPTOCOCCUS ANTIGEN TITER, LFA

Negative
FUNGAL CULTURE
Negative
If positive, fungus will be identified.
Clin Infect Dis. 2000;31(2):499-505 3. Perfect JR, Dismukes WE, Dromer F, et al: Clinical practice
guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society
of America. Clin Infect Dis. 2010;50:291-322 4. Warren NG, Hazen KC: Candida, Cryptococcus, and
other yeasts of medical importance. In: Murray PR, ed. Manual of Clinical Microbiology. 7th ed. ASM
Press; 1999: 1184-1199 5. Lu H, Zhou Y, Yin Y, et al: Cryptococcal antigen test revisited: significance
for cryptococcal meningitis therapy monitoring in a tertiary Chinese hospital. J Clin Microbiol. 2005
June;43(6):2989-2990 6. Perfect JR: Cryptococcosis (Cryptococcus neoformans and Cryptococcus
CRYPS Cryptosporidium Antigen, Feces

80335 Clinical Information: Cryptosporidia are small apicomplexan protozoan parasites that infect the
intestinal tract of humans and animals. They were conventionally categorized as coccidia but are now
known to be more closely related to the gregarines. Many species may infect humans, with the most
common being Cryptosporidium hominis and Cryptosporidium parvum. Infected humans and animals
shed small (4-6 micrometer in diameter) infectious oocysts in their stool, and these can subsequently
contaminate and survive in recreational and drinking water supplies. Infection of humans occurs by the
fecal-oral route or via ingestion of contaminated water or food. Infection is easily acquired, with an
infectious dose of approximately 100 oocysts. Waterborne transmission is a primary mode of
transmission and is commonly responsible for human outbreaks. This is due to the fact that
Cryptosporidium species oocysts are resistant to cold temperatures and chlorine and require extensive
filtration or water treatment to remove them from drinking water. The incubation period is typically 7 to
10 days following exposure. While most patients have symptoms, approximately 30% of infected
individuals are asymptomatic. When symptoms are present, they usually include profuse watery
diarrhea, malaise, anorexia, nausea, crampy abdominal pain, and low-grade fever. Infection is usually
self-limited in immunocompetent individuals, with resolution of symptoms in 10 to 14 days. However,
diarrhea can be prolonged and life-threatening in immunocompromised patients such as those with
AIDS, infants, and older adults, and result in severe dehydration and wasting. The fecal ova and parasite
examination is an insensitive method for detecting Cryptosporidium, given the small size of the oocysts
and their lack of trichrome staining. Instead, use of this test or the multiplex gastrointestinal polymerase
chain reaction (PCR) panel (GIP / Gastrointestinal Pathogen Panel, PCR, Feces) is recommended for
sensitive and specific detection. This antigen test is ideal for situations in which cryptosporidiosis is
highly suspected (eg outbreak scenarios), whereas the PCR panel allows for simultaneous detection of
multiple parasitic, viral, and bacterial causes of diarrhea. For more information about diagnostic tests
that may be of value in evaluating patients with diarrhea see the following algorithms: -Parasitic
Investigation of Stool Specimens Algorithm -Laboratory Testing for Infectious Causes of Diarrhea
Useful For: Establishing the diagnosis of intestinal cryptosporidiosis

Interpretation: A positive enzyme-linked immunosorbent assay (ELISA) indicates the presence of
antigens of cryptosporidium and is interpreted as evidence of infection with that organism. The
sensitivity, specificity, and positive and negative predictive value (PPV and NPV) of the ELISA were
98%, 98%,98% PPV and 98.5% NPV, respectively, as determined by examination of 130 fecal specimens
by conventional microscopy and by ELISA.
Reference Values:
Negative
Clinical References: Centers for Disease Control and Prevention (CDC): Parasites-Cryptosporidium
(also known as "Crypto"). CDC; Updated July 1, 2019. Accessed October 16, 2019. Available at
www.cdc.gov/parasites/crypto/index.html
SFC Crystal Identification, Synovial Fluid

8719 Clinical Information: Birefringent crystals are found in the synovial fluid of more than 90% of
patients with acutely inflamed joints. Monosodium urate crystals are seen in gouty fluids and calcium
pyrophosphate crystals are seen in chondrocalcinosis. The urates are usually needle-shaped, and the
calcium crystals are often rhomboidal. Cholesterol crystals may also be observed.
Useful For: Identifying the presence and type of crystals in synovial fluid
Interpretation: Positive identification of crystals provides a definitive diagnosis for joint disease.
Reference Values:
None seen
If present, crystals are identified.
Clinical References: Hussong JW, Kjeldsberg CR: Kjeldsberg's Body Fluid Analysis. First edition.
ASCP Press 2015
CSF3R CSF3R Exon 14 and 17 Mutation Detection by Sanger

Clinical Information: CSF3R encodes the receptor for colony-stimulating factor 3, a cytokine that
controls the production, differentiation, and function of granulocytes. Somatic CSF3R mutations were
recently described in 50% to 80% of chronic neutrophilic leukemia (CNL) patients. Their association with
atypical chronic myelogenous leukemia (aCML) remains controversial. They have also been reported as
somatic events in severe congenital neutropenia (SCN) patients. There are 2 types of CSF3R mutations:
extracellular domain/membrane proximal point mutations (most commonly p.T618I) and cytoplasmic tail
truncation mutations. They demonstrated sensitivity to JAK kinase inhibitors and Src kinase inhibitors,
respectively, in in vitro assays. In CNL, the most common mutation is p.T618I, although cytoplasmic
truncation mutation can also occur. Somatic cytoplasmic truncation mutations have been reported in
approximately 30% of SCN patients and 80% of SCN patients with leukemic transformation, who are
often on granulocyte-colony stimulating factor (GCSF) therapy. However, their role in leukemic
transformation is uncertain.
Useful For: Evaluation and classification of chronic neutrophilia Aids in the diagnosis of chronic
neutrophilic leukemia (CNL) Identification of mutations that may suggest the class of kinase inhibitor to
which the neoplasm may be sensitive
Interpretation: The results will be given as positive or negative for CSF3R mutation and, if positive,
the mutation will be described.
Reference Values:
Clinical References: 1. Maxson JE, Gotlib J, Pollyea DA, et al: Oncogenic CSF3R mutations in
chronic neutrophilic leukemia and atypical CML. N Engl J Med 2013;368:1781-1790 2. Pardanani A,
Lasho TL, Laborde RR, et al: CSF3R T618I is a highly prevalent and specific mutation in chronic
neutrophilic leukemia. Leukemia 2013;27:1870-1873 3. Tefferi A, Thiele J, Vannucchi AM, et al: An
overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for
myeloproliferative neoplasms. Leukemia 2014;1:1-7 4. Vandenberghe P, Beel K: Severe congenital
neutropenia, a genetically heterogeneous disease group with an increased risk of AML/MDS. Pediatr Rep
2011;3(s2):e9
CSTB CSTB Gene, Repeat Expansion Analysis, Varies

616515 Clinical Information: CSTB-related progressive myoclonic epilepsy (PME), also known as
progressive myoclonic epilepsy type 1 (EPM1) or Unverricht-Lundborg disease, is the most common
and least severe of the collective progressive myoclonic epilepsies. CSTB-related PME is inherited in
an autosomal recessive pattern and is associated with inter- and intrafamilial variability. Individuals
with CSTB-related PME have normal early development with onset of symptoms typically in the first or
second decade of life. CSTB-related PME is characterized by involuntary myoclonus that is action- or
stimulus-precipitated. Individuals with the condition are at increased risk for seizures, including
tonic-clonic, absence, psychomotor and focal motor. The condition is progressive, leading to wheelchair
dependence in some individuals. Later symptoms may also include ataxia, incoordination, intention
tremor, dysarthria, mood disorders, and mild cognitive decline. CSTB-related PME is caused by
disease-causing variants in the CSTB gene. An expansion of a dodecamer repeat sequence in the
promoter region of the CSTB gene accounts for approximately 90% of disease-causing variants (99% in
Finnish individuals). Full penetrance CSTB expansions are greater than or equal to 30 repeats, while
normal alleles are typically 2 or 3 repeats. Allele sizes between 5 and 29 repeats are of unclear
significance. The remainder of disease-causing variants are sequence variants including missense,
nonsense, splice site variants, and small deletions and duplications. Genotype/phenotype correlation
suggests that individuals who are homozygous for nonexpansion variants or compound heterozygous for
one expansion allele and one nonexpansion allele have earlier onset and more severe symptoms than
those individuals with biallelic expansion alleles. Instability of the repeat expansion has been reported
with vertical transmission, including both minimal expansion and contraction of repeat sizes. Alleles in
the uncertain range are not associated with symptoms of CSTB-related PME but may demonstrate
instability with transmission. Since repeat alleles in this size range have rarely been reported, the risk of
repeat expansion into the full penetrance allele range (>29 repeats) is not fully understood. Additionally,
correlation of repeat size with onset of symptoms is unclear.
Useful For: Molecular confirmation of clinically suspected CSTB-related progressive myoclonic

epilepsy Identifying full penetrance dodecamer repeat expansions within CSTB known to cause
CSTB-related progressive myoclonic epilepsy, allowing for predictive testing of at-risk family members
Impacting patient treatment and management through the identification of a specific underlying etiology
for epilepsy (eg, directing appropriate use of anti-epileptic drugs and other treatment modalities)

Reference Values:
Normal: <5 dodecamer repeats
Repeat Size of Uncertain Significance: 5-29 dodecamer repeats
Full Penetrance Expansion: >29 dodecamer repeats
Clinical References: 1. Lehesjoki AE, Koskimiemi M: Progressive myoclonus epilepsy of

Unverricht-Lundborg type. Epilepsia. 1999;40 Suppl 3:23-28 2. Hypponen J, Aikia M, Joensuu T, et al:
Refining the phenotype of Unverricht-Lundborg disease (EPM1): a population-wide Finnish study.
Neurology. 2015 Apr 14;84(15):1529-1536 3. Canafoglia L, Gennaro E, Capovilla G, et al:
Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg
disease carrying compound heterozygous CSTB point and indel mutations. Epilepsia. 2012
Dec;53(12):2120-2127
FCUIP CU (Chronic Urticaria) Index Panel
Anti-Thyroid Peroxidase IgG:Â Â Â Â <35 IU/mL
Anti-Thyroglobulin IgG:Â Â Â Â Â Â Â Â Â Â Â Â <40 IU/mL
TSH (Thyrotropin):Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â 0.4-4.0 uIU/mL
CU Index:Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â <10.0
The CU Index test is the second generation Functional Anti-FceR test. Patients with a CU Index greater
than or equal to 10 have basophil reactive factors in their serum which supports and autoimmune basis for
disease.
FCUIX CU Index
57549 Clinical Information: Patients with a chronic form of urticaria who are positive (>10) with the CU
index have an autoimmune basis for their disease. A positive result does not indicate which autoantibody
(anti-IgE, anti-FceRI or anti-FCERII) is present.
Reference Values:
< 10.0
The CU Index test is the second generation Functional Anti-FceR test. Patient with a CU Index greater
than or equal to 10 have basophil reactive factors in their serum which supports an autoimmune basis for
disease.
FCUKG Cucumber IgG

Reference Values:
CUKE Cucumber, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cucumber Defining the allergen responsible for
Reference Values:
0 Negative

apply to all ages.
OATC Cultivated Oat, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cultivated oat Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
CRYE Cultivated Rye, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to cultivated rye


Reference Values:

0 Negative

apply to all ages.
WHTC Cultivated Wheat, IgE, Serum
Useful For: Establishing a diagnosis of an allergy to cultivated wheat


Reference Values:
0 Negative

apply to all ages.
CULAF Culture for Genetic Testing, Amniotic Fluid

35244 Clinical Information: Fetal cells obtained by amniocentesis (amniocytes) are used for a wide range
of laboratory tests. Prior to testing, the cells may need to be cultured to obtain adequate numbers of
amniocytes.
Useful For: Producing amniocyte cultures that can be used for genetic analysis
Reference Values:
Not applicable
Clinical References: The AGT Cytogenetics Laboratory Manual Fourth edition. Edited by MS
Arsham, MJ Barch, HJ Lawce. John Wiley and Sons Inc, Hoboken, NJ, 2017
FUNID Culture Referred for Identification, Fungus

8223 Clinical Information: Organisms are referred for identification or to confirm an identification made
elsewhere. This may provide helpful information regarding the significance of the organism, its role in the
disease process, and its possible origin.
Useful For: Identification of pure isolates of filamentous fungi and yeast

Interpretation: Genus and species are reported on fungal isolates whenever possible.
Reference Values:
Not applicable
Clinical References: Ashbee HR: General approaches for direction detection and identification of
fungi. In: Carroll KC, Pfaller MA, Landry ML, et al, eds. Manual of Clinical Microbiology. 12th ed. Vol
1. ASM Press; 2019:2035-2055
TBIDS Culture Referred for Identification, Mycobacterium and

64714 Nocardia with Antimicrobial Susceptibility Testing, Varies
Clinical Information: There are nearly 200 recognized species of mycobacteria and more than 100
Nocardia species. Many are human pathogens and, therefore, identification to the species level is
important to help guide patient care. In addition, there are other aerobic actinomycete genera that can be
human pathogens including, but not limited to, Tsukamurella, Rhodococcus, and Gordonia species.
Nucleic acid hybridization probes are utilized that identify specific ribosomal RNA sequences of
Mycobacterium tuberculosis complex, Mycobacterium avium complex, and Mycobacterium gordonae.
Other Mycobacteria species, Nocardia species, and other aerobic actinomycete genera are identified using
matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI TOF MS) or nucleic
acid sequencing of a 500-base pair region of the 16S ribosomal RNA gene. After identification,
antimicrobial susceptibility testing is performed following Clinical and Laboratory Standards Institute
(CLSI) M24 guidelines using either broth dilution or critical concentration methods as appropriate for the
species.
Useful For: Rapid identification to the species level and susceptibility testing for Mycobacterium
species, Nocardia species, and other aerobic actinomycete genera and species from pure culture isolates
Interpretation: Organisms growing in pure culture are identified to the species level whenever
possible.
Reference Values:
Not applicable
Clinical References: 1. Pfyffer GE: Mycobacterium: general characteristics, laboratory detection,

and staining procedures. In: Jorgensen JH, Pfaller MA, eds. Manual of Clinical Microbiology. 11th ed.
Vol 1. ASM Press; 2015:536-569 2. Clinical and Laboratory Standards Institute: Susceptibility Testing of
Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes. 2nd ed. CLSI document M24-A2. Clinical
and Laboratory Standards Institute; 2011
CTBID Culture Referred for Identification, Mycobacterium and

80278 Nocardia, Varies
Clinical Information: There are approximately 200 recognized species of mycobacteria and more
than 100 Nocardia species. Many of these species are human pathogens and, therefore, identification to
the species level is important to help guide patient care. In addition, there are other aerobic actinomycete
genera that can be human pathogens including, but not limited to, Tsukamurella, Rhodococcus, and
Gordonia species. Nucleic acid hybridization probes are utilized that identify specific ribosomal RNA
sequences of Mycobacterium tuberculosis complex, Mycobacterium avium complex, and Mycobacterium
gordonae. Other Mycobacteria species, Nocardia species and other aerobic actinomycete genera are
identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
(MALDI-TOF MS) or nucleic acid sequencing of a 500-base pair region of the 16S ribosomal RNA gene.
Useful For: Rapid identification to the species level for Mycobacterium species, Nocardia species,
and other aerobic actinomycete genera and species from pure culture isolates
Interpretation: Organisms growing in pure culture are identified to the species level whenever
possible.
Reference Values:
Not applicable
Clinical References: 1. Martin I, Pfyffer GE, Parrish N: Mycobacterium: General characteristics,

laboratory detection and staining procedures. In: Carroll KC, Pfaller MA, Landry ML, et al, eds.
Manual of Clinical Microbiology. 12th ed. Vol 1.Â ASM Press; 2019:558-575 2. Warshauer DM,
Salfinger M, Desmond E, Lin SYG: Mycobacterium tuberculosis complex. In: Carroll KC, Pfaller MA,
Landry ML, et al, eds. Manual of Clinical Microbiology. 12th ed. Vol 1.Â ASM Press; 2019:576-594 3.
Caulfield AJ, Richter E, Brown-Elliott BA, Wallace RJ Jr, Wengenack NL: Mycobacterium: Laboratory
characteristics of slowly growing mycobacteria other than Mycobacterium tuberculosis. In: Carroll KC,
Pfaller MA, Landry ML, et al, eds. Manual of Clinical Microbiology. 12th ed. Vol 1. ASM Press;
2019:595-611 Â 4. Brown-Elliott BA, Wallace RJ Jr: Mycobacterium: Clinical and laboratory
characteristics of rapidly growing mycobacteria. In: Carroll KC, Pfaller MA, Landry ML, et al, eds.
Manual of Clinical Microbiology. 12th ed. Vol 1.Â ASM Press; 2019:612-629 5. Conville PS,
Brown-Elliott BA, Witebsky FG: Nocarida, Rhodococcus, Gordonia, Actinomadura, Streptomyces and
other eerobic Actinomycetes. In: Carroll KC, Pfaller MA, Landry ML, et al, eds. Manual of Clinical
Microbiology. 12th ed. Vol 1.Â ASM Press; 2019:525-557
VRID2 Culture Referred for Identification, Virus

5190 Clinical Information: Viruses are responsible for a broad spectrum of clinical symptoms and
diseases. The most commonly isolated viruses are adenovirus, cytomegalovirus (CMV), enteroviruses,
herpes simplex virus (HSV), influenza virus, parainfluenza virus (types 1-3), respiratory syncytial virus
(RSV), and varicella-zoster virus (VZV). Some viral infections can be treated with antiviral drugs. Early
laboratory diagnosis by isolation may be helpful in the medical management of these patients. Viruses
that may be recovered in cell culture include adenovirus, CMV, enterovirus, HSV, VZV, RSV,
influenza virus, and parainfluenza virus. HSV and enterovirus are the most commonly recovered
viruses. A number of viruses are not routinely detected in cell culture. These include Epstein-Barr virus
(EBV), rubella virus (must order serology), human papillomavirus (HPV), Norwalk or norovirus, and
West Nile virus.
Useful For: Viral identification and confirmation

Interpretation: A positive result indicates that virus was present in the specimen submitted. Clinical
correlation is necessary to determine the significance of the result. Negative results may be seen in a
number of situations including absence of viral disease, inability of the virus to grow in culture
(examples of organisms not detected by culture include Epstein-Barr virus, rubella virus, human
papilloma virus, norovirus and West Nile virus), and nonviable organisms submitted. Parainfluenza
virus type 4 also may not be detected by viral culture.
Reference Values:
Not applicable
Clinical References: 1. Clinical and Laboratory Standards Institute (CLSI). Viral Culture.
Proposed Guideline. 2005 CLSI document M41-P. CLSI, Wayne, PA 2. Ginocchio CC, Van Horn G,
Harris PC: In Manual of Clinical Microbiology. Chapter 80: Reagents, stains, and cell culture: virology.
11th edition. Edited by J Versalovic, KC Carroll, et al. Washington, DC, ASM Press, 2015, pp
1422-1431
CURR Curry, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to curry Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
CURL Curvularia lunata, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Curvularia lunata


Reference Values:
0 Negative

apply to all ages.
FCURV Curvularia spicifera/Bipolaris IgE

57898 Interpretation: Class IgE (kU/L) Comment 0 <.10 Negative 0/1 0.10 Ã¢â‚¬â€œ 0.34
Equivocal/Borderline 1 0.35 Ã¢â‚¬â€œ 0.69 Low Positive 2 0.70 Ã¢â‚¬â€œ 3.49 Moderate Positive 3
3.50 Ã¢â‚¬â€œ 17.49 High Positive 4 17.50 Ã¢â‚¬â€œ 49.99 Very High Positive 5 50.00 Ã¢â‚¬â€œ
99.9 Very High Positive 6 >99.99 Very High Positive
Reference Values:
<0.35 kU/L
CGPH Custom Gene Panel, Hereditary, Next-Generation Sequencing,

605198 Varies
Clinical Information: This test can be used to customize genetic testing panels offered at Mayo
Clinic Laboratories. Individual genes can be added or removed to an existing genetic testing panel.
Additionally, this test can be used to create your own custom single gene or multi-gene panel or to
combine existing panels within the same disease state. Note: any genes added to the custom panel must
be from the same disease state. Only one Gene List ID may be submitted per Custom Gene Panel,
Hereditary order. The Gene List ID can be created using the Custom Gene Ordering tool (see Ordering
Guidance).
Useful For: Customization of existing next-generation sequencing panels offered through Mayo Clinic
Laboratories Detection single nucleotide and copy number variants in a custom gene panel Identification
of a pathogenic variant may assist with diagnosis, prognosis, clinical management, familial screening, and
genetic counseling for a hereditary condition
significance.
Reference Values:
May;17(5):405-424. doi: 10.1038/gim.2015.30
CIB Cutaneous Direct Immunofluorescence Assay, Varies

607602 Clinical Information: Skin or mucosal tissue from patients with autoimmune bullous diseases,
connective tissue disease, vasculitis, lichen planus, and other inflammatory conditions often contains
bound immunoglobulin, complement, or fibrinogen. Biopsy specimens are examined for the presence of
bound IgG, IgM, IgA, third component of complement (C3), fibrinogen, and IgG4.
Useful For: Confirming a diagnosis of bullous pemphigoid, cicatricial pemphigoid, pemphigoid

gestationis and other variants of pemphigoid, all types of pemphigus, including paraneoplastic pemphigus
(paraneoplastic multiorgan syndrome), dermatitis herpetiformis, linear IgA bullous dermatosis, chronic
bullous disease of childhood, epidermolysis bullosa acquisita, porphyria cutanea tarda, bullous eruption of
lupus erythematosus, and atypical or mixed forms of bullous disease, systemic lupus erythematosus,
cutaneous lupus erythematosus, or other variants, vasculitis, lichen planus, and other inflammatory
diseases This test is not useful for diagnosis of malignancies involving the skin.
Interpretation: A board-certified Dermatopathologist will review and interpret the test results in
correlation with other clinical findings as provided.
Reference Values:
Clinical References: 1. Jain S, Basavaraj V, Vimala MG: Utility of Direct Immunofluorescence

Studies in Subclassification of Autoimmune Sub-Epidermal Bullous Diseases: A 2-Year Study in a
Tertiary Care Hospital. Turk Patoloji Derg. 2016;32(2):91-98. doi: 10.5146/tjpath.2015.01345 2. Diercks
GF, Pas HH, Jonkman MF: Immunofluorescence of Autoimmune Bullous Diseases. Surg Pathol Clin.
2017 Jun;10(2):505-512. doi: 10.1016/j.path.2017.01.011 3. Kershenovich R, Hodak E, Mimouni D:
Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014
Apr-May;13(4-5):477-481. doi: 10.1016/j.autrev.2014.01.011 4. Buschman KE, Seraly M, Thong HY,
Deng JS, Draviam RP, Abernethy JL: A predominant IgG4 subclass may be responsible for false-negative
direct immunofluorescence in bullous pemphigoid. J Cutan Pathol. 2002 May;29(5):282-286. doi:
10.1034/j.1600-0560.2002.290504.x 5. Lamb PM, Patton T, Deng JS: The predominance of IgG4 in
prodromal bullous pemphigoid. Int J Dermatol. 2008 Feb;47(2):150-153. doi:
10.1111/j.1365-4632.2008.03361.x
CIFS Cutaneous Immunofluorescence Antibodies (IgG), Serum
8052 Clinical Information: IgG anti-basement membrane zone (BMZ) antibodies are produced by
patients with pemphigoid. In most patients with bullous pemphigoid, serum contains IgG anti-BMZ
antibodies, while in cicatricial pemphigoid circulating IgG anti-BMZ antibodies are found in a minority
of cases. Sensitivity of detection of anti-BMZ antibodies is increased when serum is tested using sodium
chloride-split primate skin as substrate. Circulating IgG anti-BMZ antibodies are also detected in
patients with epidermolysis bullosa acquisita and bullous eruption of lupus erythematosus. IgG anti-cell
surface (CS) antibodies are produced by patients with pemphigus. The titer of anti-CS antibodies
generally correlates with disease activity of pemphigus.
Useful For: Confirming a diagnosis of pemphigoid, pemphigus, epidermolysis bullosa acquisita, or

bullous lupus erythematosus
Interpretation: Indirect immunofluorescence (IF) testing may be diagnostic when histologic or

direct IF studies are only suggestive, nonspecific, or negative. Anti-cell surface antibodies correlate with
a diagnosis of pemphigus. Anti-basement membrane zone (BMZ) antibodies correlate with a diagnosis
of bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita (EBA), or bullous
eruption of lupus erythematosus (LE). If serum contains anti-BMZ antibodies, the pattern of
fluorescence on sodium chloride (NaCl)-split skin substrate helps distinguish pemphigoid from EBA
and bullous LE. Staining of the roof (epidermal side) or both epidermal and dermal sides of NaCl-split
skin correlate with the diagnosis of pemphigoid, while fluorescence localized only to the dermal side of
the split-skin substrate correlates with either EBA or bullous LE.
Reference Values:
Report includes presence and titer of circulating antibodies. If serum contains basement zone (BMZ)
antibodies on split-skin substrate, patterns will be reported as:
1) Epidermal pattern, consistent with pemphigoid
2) Dermal pattern, consistent with epidermolysis bullosa acquisita
Negative in normal individuals
Clinical References: 1. Beutner EH, Chorzelski TP, Kumar V, eds: Immunopathology of the Skin.
3rd ed. Wiley Medical Publication; 1987 2. Gammon WR, Briggaman RA, Inman AO 3rd, Queen LL,
Wheeler CE: Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by
indirect immunofluorescence on 1.0 M sodium chloride-separated skin. J Invest Dermatol. 1984
Feb;82(2):139-144 3. Tirumalae R, Kalegowda IY: Role of BIOCHIP indirect immunofluorescence test
in cutaneous vesiculobullous diseases. Am J Dermatopathol. 2020 May;42(5):322-328
CIFA Cutaneous Immunofluorescence Antibodies, IgA, Serum

610627 Clinical Information: Immunoglobulin A anti-basement membrane zone (BMZ) antibodies are
produced by patients with pemphigoid. In most patients with bullous pemphigoid, serum contains IgA
anti-BMZ antibodies, while in cicatricial pemphigoid circulating IgA anti-BMZ antibodies are found in
a minority of cases. Sensitivity of detection of anti-BMZ antibodies is increased when serum is tested
using sodium chloride-split primate skin as substrate. Circulating IgA anti-BMZ antibodies are also
detected in patients with epidermolysis bullosa acquisita and bullous eruption of lupus erythematosus.
IgA anti-cell surface (CS) antibodies are produced by patients with pemphigus. The titer of anti-CS
antibodies generally correlates with disease activity of pemphigus.
Useful For: Confirming a diagnosis of pemphigoid, pemphigus, epidermolysis bullosa acquisita, or

bullous lupus erythematosus
Interpretation: Indirect immunofluorescence (IF) testing may be diagnostic when histologic or

direct IF studies are only suggestive, nonspecific, or negative. Anti-cell surface antibodies correlate with
a diagnosis of pemphigus. Anti-basement membrane zone (BMZ) antibodies correlate with a diagnosis
of bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita (EBA), or bullous
eruption of lupus erythematosus (LE). If serum contains anti-BMZ antibodies, the pattern of
fluorescence on sodium chloride (NaCl)-split skin substrate helps distinguish pemphigoid from EBA
and bullous LE. Staining of the roof (epidermal side) or both epidermal and dermal sides of NaCl-split
skin correlates with the diagnosis of pemphigoid, while fluorescence localized only to the dermal side of
the split-skin substrate correlates with either EBA or bullous LE.
Reference Values:
Report includes presence and titer of circulating antibodies. If serum contains basement membrane zone
(BMZ) antibodies on split-skin substrate, patterns will be reported as:
1) Epidermal pattern, consistent with pemphigoid
2) Dermal pattern, consistent with epidermolysis bullosa acquisita
Negative in normal individuals
Clinical References: 1. Caux F, Kirtschig G, Lemarchand-Venencie F, et al: IgA-epidermolysis

bullosa acquisita in a child resulting in blindness. Br J Dermatol. 1997 Aug;137(2):270-275 2. Chorzelski
TP, Jablonska S: IgA linear dermatosis of childhood (chronic bullous disease of childhood). Br J
Dermatol. 1979 Nov;101(5):535-542 3. Guide SV, Marinkovich MP: Linear IgA bullous dermatosis. Clin
Dermatol. 2001 Nov-Dec;19(6):719-727 4. Hashimoto T, Ebihara T, Nishikawa T: Studies of
autoantigens recognized by IgA anti-keratinocyte cell surface antibodies. J Dermatol Sci. 1996
Apr;12(1):10-17 5. Lally A, Chamberlain A, Allen J, Dean D, Wojnarowska F: Dermal-binding linear IgA
disease: an uncommon subset of a rare immunobullous disease. Clin Exp Dermatol. 2007
Sep;32(5):493-498 6. Tsuruta D, Ishii N, Hamada T, et al: IgA pemphigus. Clin Dermatol. 2011
Jul-Aug;29(4):437-442 7. Vodegel RM, de Jong MCJM, Pas HH, Jonkman MF: IgA-mediated
epidermolysis bullosa acquisita: two cases and review of the literature. J Am Acad Dermatol. 2002
Dec;47(6):919-925 8. Willsteed E, Bhogal BS, Black MM, McKee P, Wojnarowska F: Use of 1M NaCl
split skin in the indirect immunofluorescence of the linear IgA bullous dermatoses. J Cutan Pathol. 1990
Jun;17(3):144-148 9. Wilson BD, Beutner EH, Kumar V, Chorzelski TP, Jablonska S: Linear IgA bullous
dermatosis. An immunologically defined disease. Int J Dermatol. 1985 Nov;24(9):569-574 10.
Wojnarowska F, Collier PM, Allen J, Millard PR: The localization of the target antigens and antibodies in
linear IgA disease is heterogeneous, and dependent on the methods used. Br J Dermatol. 1995
May;132(5):750-757 11. Tirumalae R, Kalegowda IY: Role of BIOCHIP indirect immunofluorescence
test in cutaneous vesiculobullous diseases. Am J Dermatopathol. 2020 May;42(5):322-328
CXC13 CXCL13 Immunostain, Technical Component Only

113163 Clinical Information: CXCL13 (CXC motif chemokine ligand 13) is useful in the classification of
nodal T-cell lymphomas with T-follicular helper (TFH) phenotype, and the diagnosis of follicular
dendritic cell sarcoma.
Useful For: Assessment of CXCL13 (CXC motif chemokine ligand 13) expression
control tissue is available upon request, call 855-516-8404. Interpretation of this test should be performed
in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.
Clinical References: 1. Basha BM, Bryant SC, Rech KL, et al: Application of a 5 marker panel to
the routine diagnosis of peripheral T-cell lymphoma with T-follicular helper phenotype. Am J Surg
Pathol. 2019; 43(9):1282-1290 2. Kurita D, Miyoshi H, Yoshida N, et al: A clinicopathologic study of
Lennert lymphoma and possible prognostic factors. Am J Surg Pathol. 2016;40(9):1249-1260 3. Park J,
Han J, Kang H, Lee ES, Chan Kim Y: Expression of follicular helper T-cell markers in primary cutaneous
T-cell lymphoma. Am J Dermatopathol. 2014;36(6):465-470
CXLPL CXCR4 Mutation Analysis, Somatic, Lymphoplasmacytic

64759 Lymphoma/Waldenstrom Macroglobulinemia, Varies
Clinical Information: Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia
(LPL/WM) is a B-cell lymphoma characterized by an aberrant accumulation of malignant
lymphoplasmacytic cells in the bone marrow, lymph nodes, and spleen. It is a B-cell neoplasm that can
exhibit excess production of serum IgM symptoms related to hyperviscosity, tissue filtration, and
autoimmune-related pathology. CXCR4 mutations are identified in approximately 30% to 40% of
patients with LPL/WM and are almost always associated with MYD88 L265P, which is highly
prevalent in this neoplasm. The status of CXCR4 va mutations riants in the context of MYD88 L265P is
clinically relevant as important determinants of clinical presentation, overall survival, and therapeutic
response to ibrutinib. A MYD88-L265P/CXCR4-WHIM (C-terminus nonsense/frameshift mutations)
molecular signature is associated with intermediate to high bone marrow disease burden and serum IgM
levels, less adenopathy, and intermediate response to ibrutinib in previously treated patients. A
MYD88-L265P/CXCR4-WT (wild type) molecular signature is associated with intermediate bone
marrow disease burden and serum IgM levels, more adenopathy, and highest response to ibrutinib in
previously treated patients. A MYD88-WT/CXCR4-WT molecular signature is associated with inferior
overall survival, lower response to ibrutinib therapy in previously treated patients, and lower bone
marrow disease burden in comparison to those harboring a MYD88-L265 variant.
Useful For: Aiding in the prognosis and clinical management of lymphoplasmacytic

lymphoma/Waldenstrom macroglobulinemia
Interpretation: Mutations detected or not detected. An interpretive report will be issued.

Reference Values:
Variants present or absent in the test region of the CXCR4 gene (NCBI NM_003467.2, GRCh37).
Clinical References: 1. Hunter Z, Xu L, Yang G, et al: The genomic landscape of Waldenstrom

macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations,
and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014 Mar
13;123(11):1637-1646. doi: 10.1182/blood-2013-09-525808 2. Landgren O, Tageja N: MYD88 and
beyond: novel opportunities for diagnosis, prognosis and treatment in Waldenstrom's
Macroglobulinemia. Leukemia. 2014 Sep;28(9):1799-1803. doi: 10.1038/leu.2014.88 3. Poulain S,
Roumier C, Venet-Caillault A, et al: Genomic Landscape of CXCR4 Mutations in Waldenstrom
Macroglobulinemia. Clin Cancer Res. 2016 Mar 15;22(6):1480-1488. doi:
10.1158/1078-0432.CCR-15-0646 4. Roccaro A, Sacco A, Jimenez C, et al: C1013G/CXCR4 acts as a
driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic
lymphoma. Blood. 2014 Jun 26;123(26):4120-4131. doi: 10.1182/blood-2014-03-564583 5. Schmidt J,
Federmann B, Schindler N, et al: MYD88 L265P and CXCR4 mutations in lymphoplasmacytic
lymphoma identify cases with high disease activity. Br J Haematol. 2015 Jun;169(6):795-803. doi:
10.1111/bjh.13361 6. Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR: Somatic mutations in
MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom
macroglobulinemia. Blood. 2014 May 1;123(18):2791-2796. doi: 10.1182/blood-2014-01-550905 7.
Treon SP, Tripsas CK, Meid K, et al: Ibrutinib in previously treated Waldenstrom's macroglobulinemia.
N Engl J Med. 2015 Apr 9;372(15):1430-1440. doi: 10.1056/NEJMoa1501548 8. Xu L, Hunter ZR,
Tsakmaklis N, et al: Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom
Macroglobulinaemia. Br J Haematol. 2016 Mar;172(5):735-744. doi: 10.1111/bjh.13897
FCYNB Cyanide, Blood Test

Normal: Up to 0.05 mcg/mL
Potentially toxic: 0.50 mcg/mL and greater
Potentially lethal: 2.0 mcg/mL and greater
CARU Cyclic Adenosine Monophosphate (cAMP), Urinary Excretion,

609739 Serum and Urine
Clinical Information: Adenosine cyclic 3',5'-monophosphate (cAMP) functions as an intracellular
"second messenger" regulating the activity of intracellular enzymes or proteins in response to a variety of
hormones (eg, parathyroid hormone). Urinary cAMP is elevated in about 85% of patients with
hyperparathyroidism.
Useful For: Differential diagnosis of hypercalcemia Adjunct to serum parathyroid hormone

measurements, especially in the diagnosis of parathyroid hormone resistance states, such as
pseudohypoparathyroidism
Interpretation: Urinary adenosine cyclic 3',5'-monophosphate (cAMP) is elevated in about 85% of

patients with hyperparathyroidism and in about 50% of patients with humoral hypercalcemia of
malignancy.
Reference Values:
CYCLIC AMP
1.3-3.7 nmol/dL of glomerular filtrate
CREATININE, SERUM
Males
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-14 years: 0.35-0.86 mg/dL
> or =15 years: 0.74-1.35 mg/dL
Females
0-11 months: 0.17-0.42 mg/dL
1-5 years: 0.19-0.49 mg/dL
6-10 years: 0.26-0.61 mg/dL
11-15 years: 0.35-0.86 mg/dL
> or =16 years: 0.59-1.04 mg/dL
CREATININE, URINE
No reference values apply. Interpret with other clinical data.
Clinical References: 1. Aurbach GD, Marx SJ, Spiegel AM: Parathyroid hormone, calcitonin, and
the calciferols. In: Wilson JD, Foster DW, eds. Williams Textbook of Endocrinology. 8th ed. WB
Saunders Company; 1992:1413-1415 2. Badiu C MD, PhD. In: Melmed S, Auchus RJ, Goldfine AB, et
al, eds. Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020
CCP Cyclic Citrullinated Peptide Antibodies, IgG, Serum

84182 Clinical Information: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease
characterized by interactions between the environment, specific genetic risk factors, and the human
immune system. It affects about 0.6% of the US population with a global prevalence of 0.24%.(1)
Clinically, RA is typified by progressive damage of synovial joints, inflammation, production of diverse
autoantibodies, and variable extra-articular manifestations.(2-4) Patients with RA may be categorized
based on the phase of disease (early versus established), presence or absence of antibodies (seropositive
versus seronegative), clinical manifestations (joint erosion, interstitial lung disease, or cardiovascular), or
specific risks (genes, gender, or smoking).(2-4) Delayed diagnosis of RA is associated with joint erosion,
destruction or deformities, poor response to treatment with ultimate increase in morbidity, and
mortality.(3,4) Although late RA prognosis may be linked to adverse consequences, early diagnosis has
been reported to improve outcomes; notably reduced joint destruction or deformity, delayed radiologic
progression, and decreased functional disability.(3-5) To facilitate early diagnosis, the American College
of Rheumatology/European League Against Rheumatism 2010 RA classification criteria recommend
testing for rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA).(2) RF is an
autoantibody directed against the Fc portion of immunoglobulin while ACPA are directed against
peptides and proteins containing citrulline, a modified form of the amino acid arginine.(6,7) In addition to
the use of RA and ACPA IgG to diagnose RA, RF and ACPA isotype antibodies and other serologic
biomarkers have been used to predict if, and when, an individual who has inflammatory arthritis (IA) may
develop future clinically apparent IA and access genetic and/or environmental risks.(3,4,8,9) Compared to
early serologic tests for RA including RF, several studies have demonstrated that ACPA have much
improved specificity for RA.(4,6,10) A systemic review and meta-analysis of 33 studies including patients
with RA and healthy or disease controls demonstrated the sensitivity of anti-mutated citrullinated
vimentin, anticyclic citrullinated peptide, and RF of 71%, 71%, 77%, with the specificity of 89%, 95%,
73%, and the area under the curve of the summary receiver operating characteristic of 89%, 95%, 82%,
respectively.(10) Based on these studies, there exist a subset of patients with RA who are negative for RF
and ACPA IgG (seronegative) who must be diagnosed clinically or with use of emerging diagnostic
tests.(4,7,9) See Connective Tissue Disease Cascade (CTDC).
Useful For: Evaluating patients suspected of having rheumatoid arthritis (RA) Differentiating RA
from other inflammatory arthritis or connective tissue diseases
Interpretation: A positive result for cyclic citrullinated peptide (CCP) antibodies may be suggestive
of rheumatoid arthritis (RA) if compatible clinical features of disease are present. Significantly elevated
levels of CCP antibodies may be useful to identify RA patients with erosive joint disease. A Mayo
Clinic prospective clinical evaluation of the CCP antibody test showed a diagnostic sensitivity for RA
of 78% with fewer than 5% false positive results in healthy controls (see Cautions).
Reference Values:
<20.0 U (negative)
20.0-39.9 U (weak positive)
> or =60.0 U (strong positive)
Clinical References: 1. Cross M, Smith E, Hoy D, et al: The global burden of rheumatoid arthritis:
estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 Jul;73(7):1316-1322 2.
Aletaha D, Neogi T, Silman AJ, et al: 2010 Rheumatoid arthritis classification criteria: an American
College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis
Rheum. 2010 Sep;62(9):2569-2581 3. Burgers LE, Raza K, van der Helm-van Mil AH: Window of
opportunity in rheumatoid arthritis - definitions and supporting evidence: from old to new perspectives.
RMD Open. 2019 Apr 3;5(1):e000870 4. Deane KD, Holers VM: Rheumatoid arthritis pathogenesis,
prediction, and prevention: An emerging paradigm shift. Arthritis Rheumatol. 2021 Feb;73(2):181-193
5. Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS: Early referral
recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical
guide. Ann Rheum Dis. 2002 Apr;61(4):290-297 6. Schellekens GA, Visser H, de Jong BA, et al: The
diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide.
Arthritis Rheum. 2000 Jan;43(1):155-163 7. Derksen VFAM, Huizinga TWJ, van der Woude D: The
role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017
Jun;39(4):437-446 8. Hedstrom AK, Ronnelid J, Klareskog L, Alfredsson L: Complex relationships of
smoking, HLA-DRB1 genes, and serologic profiles in patients with early rheumatoid arthritis: Update
from a Swedish population-based case-control study. Arthritis Rheumatol. 2019 Sep;71(9):1504-1511 9.
Verheul MK, Bohringer S, van Delft MAM, et al: Triple positivity for anti-citrullinated protein
autoantibodies, rheumatoid factor, and anti-carbamylated protein antibodies conferring high specificity
for rheumatoid arthritis: Implications for very early identification of at-risk individuals. Arthritis
Rheumatol. 2018 Nov;70(11):1721-1731 10. Zhu JN, Nie LY, Lu XY, Wu HX: Meta-analysis:
compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the
rheumatoid arthritis classification criteria? Clin Chem Lab Med. 2019 Oct 25;57(11):1668-1679
CYC1 Cyclin D1 Immunostain, Technical Component Only

70411 Clinical Information: Cyclin D1 is a protein that regulates entry of the cell into cell cycle. It drives
the transition between G0 and G1 phase. In normal tissues, basal epithelial cells, endothelial cells, and
stromal cells are often cyclin D1 positive. As a result of a translocation involving the cyclin D1 gene
and IgH, t(11;14), the vast majority of mantle cell lymphomas overexpress cyclin D1. This is a useful
feature in the classification of low-grade B-cell lymphomas.
Useful For: Classification of low-grade B-cell lymphomas

Clinical References: 1. Salem Amir M, et al:Â Prognostic value of combined; Cox-2, cyclin D1 and
P21 expression in colorectal cancer (CRC) patients: An immunohistochemical study. Open J Pathol.
2018;8(3):106-121 2. Parvin T, et al: Prognostic utility of cyclin D1 in invasive breast carcinoma. Indian J
Surg Oncol. 2019;10(1):167-173 3. Li Z, et al: Prognostic significance of cyclin D1 expression in renal
cell carcinoma: a systematic review and meta-analysis. Pathol Oncol Res. 2020;26(3):1401-1409
FFLEX Cyclobenzaprine (Flexeril)

Reference Range: 10 - 30 ng/mL
CYCL Cyclospora Stain, Feces

81506 Clinical Information: Cyclospora cayetanensis is an apicomplexan protozoan parasite that causes
watery diarrhea, anorexia, malaise, and weight loss. The extent of symptoms depends on the age and
condition of the host and the infectious dose. The infection is usually self-limited, but symptoms can be
severe and prolonged, particularly in immunocompromised patients. Cyclosporal diarrheal disease is
endemic in many parts of the world, including Asia, India, Southeast Asia, and Latin America. Although
most cases of cyclosporiasis have been seen in travelers to developing countries, outbreaks in the United
States have been noted due to contaminated fruits and vegetables from Latin America. Transmission is via
fecally contaminated food or water. If untreated, symptoms typically last for 10 to 12 weeks, and may
follow a relapsing course. The infection usually responds to treatment with a
sulfamethoxazole-trimethoprim drug combination. Cyclospora cayetanensis oocysts are traditionally
detected by modified acid-fast staining, in which the oocysts stain bright pink-red. However, the modified
safranin stain has been shown to provide increased sensitivity over modified acid-fast method and
produces a more rapid result. It is the method used in our laboratory to detect Cyclospora cayetanensis
oocysts in fecal sediment. See Laboratory Testing for Infectious Causes of Diarrhea and Parasitic
Investigation of Stool Specimens Algorithm for other diagnostic tests that may be of value in evaluating
patients with diarrhea.
Useful For: The identification of Cyclospora cayetanensis as a cause of infectious gastroenteritis

Interpretation: A report of Cyclospora cayetanensis detected indicates the presence of this parasite in
the patient's feces.
Reference Values:
Negative
If positive, reported as Cyclospora cayetanensis detected.
Clinical References: 1. Chacin-Bonilla L: Epidemiology of Cyclospora cayetanensis: A review

focusing in endemic areas. Acta Trop 2010;115(3):181-193 2. Ortega YR, Sanchez R: Update on
Cyclospora cayetanensis, a food-borne and waterborne parasite. Clin Microbiol Rev 2010;23(1):218-234
CYSPR Cyclosporine, Blood

35143
Clinical Information: Cyclosporine is a lipophilic polypeptide used to prevent rejection after solid
organ transplantation; it suppresses T-cell activation by inhibiting calcineurin to decrease interleukin-2
(IL-2) production. There is substantial interpatient variability in absorption, half-life, and other
pharmacokinetic parameters. Cyclosporine is extensively metabolized by cytochrome P450 (CYP) 3A4
to at least 30 less-active metabolites, many of which are detected by immunoassays. Cyclosporine is
known for many drug interactions, including increased neuro- and nephrotoxicity when coadministered
with antibiotics, antifungals, or other immunosuppressants. Cyclosporine has a narrow therapeutic range
with frequent adverse effects making therapeutic drug monitoring essential. With 80% of cyclosporine
sequestered in erythrocytes, whole blood is the preferred specimen for analysis. Dose is adjusted
initially (up to 2 months posttransplant) to maintain concentrations generally between 150 and 400
ng/mL. Target trough concentrations vary according to clinical protocol and depend on type of allograft,
risk of rejection, concomitant immunosuppressive drugs, and toxicity. After the first 2 postoperative
months, the target range is generally lower, between 75 and 300 ng/mL. Conversion between
formulations is generally done at the same dose but with drug monitoring.
Useful For: Monitoring whole blood cyclosporine concentration during therapy, particularly in
individuals coadministered cytochrome P450 (CYP) 3A4 substrates, inhibitors, or inducers Adjusting
dose to optimize immunosuppression while minimizing toxicity Evaluating patient compliance
Interpretation: Most individuals display optimal response to cyclosporine with trough whole blood
levels 100 to 400 ng/mL. Preferred therapeutic ranges may vary by transplant type, protocol, and
comedications. Therapeutic ranges are based on specimens collected at trough (ie, immediately before
the next scheduled dose). Higher results will be obtained when the blood is drawn at other times. This
test may also be used to analyze cyclosporine levels 2 hours after dosing (C2 concentrations); trough
therapeutic ranges do not apply to C2 specimens. The assay is specific for cyclosporine; it does not
cross-react with cyclosporine metabolites, sirolimus, sirolimus metabolites, tacrolimus, or tacrolimus
metabolites. Results by liquid chromatography with detection by tandem mass spectrometry are
approximately 30% less than by immunoassay.
Reference Values:
100-400 ng/mL (Trough)
Target steady-state trough concentrations vary depending on the type of transplant, concomitant
immunosuppression, clinical/institutional protocols, and time post-transplant. Results should be
interpreted in conjunction with this clinical information and any physical signs/symptoms of
rejection/toxicity.
Clinical References: 1. Moyer TP, Post GR, Sterioff S, Anderson CF: Cyclosporine
nephrotoxicity is minimized by adjusting dosage on the basis of drug concentration in blood. Mayo Clin
Proc. 1988 March;63(3):241-247 2. Kahan BD, Keown P, Levy GA, Johnston A: Therapeutic drug
monitoring of immunosuppressant drugs in clinical practice. Clin Ther. 2002 March;24(3):330-350 3.
Dunn CJ, Wagstaff AJ, Perry CM, Plosker GL, Goa KL: Cyclosporin: an updated review of the
pharmacokinetic properties, clinical efficacy, and tolerability of a microemulsion-based formulation
(neoral) 1 in organ transplantation. Drugs. 2001;61(13):1957-2016 4. Milone MC, Shaw LM:
Therapeutic drugs and their management. In: Rifai N, Chiu RWK, Young I, Burnham CAD, eds. Tietz
Textbook of Laboratory Medicine. 7th ed. Elsevier; 2023:420-453
CYCPK Cyclosporine, Peak, Blood

42427 Clinical Information: Cyclosporine is a lipophilic polypeptide used to prevent rejection after solid
organ transplantation; it suppresses T-cell activation by inhibiting calcineurin to decrease interleukin-2
(IL-2) production. There is substantial interpatient variability in absorption, half-life, and other
pharmacokinetic parameters. Cyclosporine is extensively metabolized by cytochrome P450 (CYP) 3A4
to at least 30 less-active metabolites, many of which are detected by immunoassays. Cyclosporine is
known for many drug interactions, including increased neuro- and nephrotoxicity when coadministered
with antibiotics, antifungals, or other immunosuppressants. Cyclosporine has a narrow therapeutic range
with frequent adverse effects making therapeutic drug monitoring essential. With 80% of cyclosporine
sequestered in erythrocytes, whole blood is the preferred specimen for analysis.
Useful For: Monitoring whole blood peak cyclosporine concentration during therapy, particularly in
individuals coadministered cytochrome P450 (CYP) 3A4 substrates, inhibitors, or inducers Adjusting
dose to optimize immunosuppression while minimizing toxicity Evaluating patient compliance
Interpretation: No definitive therapeutic or toxic ranges have been established for postdose peak
monitoring. Preferred therapeutic ranges may vary by transplant type, protocol, and comedications. The
2-hour postdose cyclosporine ranges listed for this test are only suggested guidelines. This assay is
specific for cyclosporine; it does not cross-react with cyclosporine metabolites, sirolimus, sirolimus
metabolites, tacrolimus, or tacrolimus metabolites. Results by liquid chromatography with detection by
tandem mass spectrometry are approximately 30% less than by immunoassay.
Reference Values:
No definitive therapeutic or toxic ranges have been established.
Optimal blood drug levels are influenced by type of transplant, patient response, time posttransplant,
coadministration of other drugs, and drug formulation.
The following 2-hour postdose cyclosporine ranges are only suggested guidelines:
Kidney transplant: 800-1700 ng/mL
Liver transplant: 600-1000 ng/mL
Target steady-state peak concentrations vary depending on the type of transplant, concomitant
immunosuppression, clinical/institutional protocols, and time posttransplant. Results should be interpreted
in conjunction with this clinical information and any physical signs/symptoms of rejection/toxicity.
Clinical References: 1. Milone MC, Shaw LM: Therapeutic drugs and their management. In: Rifai
N, Chiu RWK, Young I, Burnham CAD, eds. Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier;
2023:420-453 2. Moyer TP, Post GR, Sterioff S, Anderson CF: Cyclosporine nephrotoxicity is minimized
by adjusting dosage on the basis of drug concentration in blood. Mayo Clin Proc. 1988
March;63(3):241-247 3. Kahan BD, Keown P, Levy GA, Johnston A: Therapeutic drug monitoring of
immunosuppressant drugs in clinical practice. Clin Ther. 2002 March;24(3):330-350 4. Dunn CJ,
Wagstaff AJ, Perry CM, Plosker GL, Goa KL: Cyclosporin: an updated review of the pharmacokinetic
properties, clinical efficacy, and tolerability of a microemulsion-based formulation (neoral) 1 in organ
transplantation. Drugs. 2001;61(13):1957-2016
2D66Z CYP2D6 3' Gene Duplication/Multiplication (Bill Only)

2D65Z CYP2D6 5' Gene Duplication/Multiplication (Bill Only)

2D61Z CYP2D6 Full Gene Sequence (Bill Only)

2D62Z CYP2D6 Gene CYP2D6-2D7 Hybrid (Bill Only)
2D63Z CYP2D6 Gene CYP2D7-2D6 Hybrid (Bill Only)

2D64Z CYP2D6 Nonduplicated Gene (Bill Only)

CSTCE Cystatin C with Estimated Glomerular Filtration Rate (eGFR),

614154 Serum
Clinical Information: Cystatin C is a low-molecular weight (13,250 kDa) cysteine proteinase
inhibitor that is produced by all nucleated cells and found in body fluids, including serum. Since it is
formed at a constant rate and freely filtered by the kidneys, its serum concentration is inversely
correlated with the glomerular filtration rate (GFR); that is, a high concentration indicates a low GFR,
while a lower concentration indicates a higher GFR, similar to creatinine. The renal handling of cystatin
C differs from creatinine. While both are freely filtered by glomeruli, once filtered cystatin C, unlike
creatinine, is reabsorbed and metabolized by proximal renal tubules. Therefore, under normal
conditions, cystatin C does not enter the final excreted urine to any significant degree. The serum
concentration of cystatin C is not greatly affected by body mass, age, sex, or race. Thus, in certain cases,
cystatin C may be a more reliable marker of renal function (GFR) than creatinine. GFR can be estimated
(eGFR) from serum cystatin C utilizing an equation that includes the age and sex of the patient. The
CKD-EPI cystatin C equation was developed by Inker et al(1) and demonstrated good correlation with
measured iothalamate clearance in patients with all common causes of kidney disease, including kidney
transplant recipients. Cystatin C eGFR may have advantages over creatinine eGFR in certain patient
groups in whom muscle mass is abnormally high or low (for example quadriplegics, much older adults,
or malnourished individuals). Blood levels of cystatin C also equilibrate more quickly than creatinine,
and therefore, serum cystatin C may be more accurate than serum creatinine when kidney function is
rapidly changing (for example amongst hospitalized individuals).(2) The same group also developed an
eGFR equation that uses serum creatinine and cystatin C, in addition to age, sex, and race.(1) This
equation may be useful to average out potential confounders of creatinine versus cystatin C.
Useful For: Assessing renal function in patients suspected of having kidney disease Monitoring
treatment response in patients with kidney disease An index of glomerular filtration rate (GFR),
especially in patients where serum creatinine may be misleading (eg, very obese, older adults, or
malnourished patients) Calculation of CKD-EPI cystatin CÂ estimated GFR for patients where serum
creatinine may be misleading (eg, very obese, older adults, or malnourished patients)
Interpretation: Cystatin C: Cystatin C inversely correlates with the glomerular filtration rate (GFR),
that is, elevated levels of cystatin C indicate decreased GFR. Cystatin C may provide more accurate
assessment of GFR for very obese, older adults, or malnourished patients than creatinine. Cystatin C
equation does not require patient ethnic data and can be used for those patients with this information
unavailable. Due to immaturity of renal function, cystatin C levels are higher in neonates less than 3
months of age.(3) Estimated GFR: Chronic kidney disease (CKD) is defined as the presence of:
persistent and usually progressive reduction in GFR (GFR <60 mL/min/1.73 m[2]) and/or albuminuria
(>30 mg of urinary albumin per gram of urinary creatinine), regardless of GFR. According to the
National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) classification,
among patients with CKD, irrespective of diagnosis, the stage of disease should be assigned based on
the level of kidney function(4) Stage Description GFR mL/min/BSA 1 Kidney damage with normal or
increased GFR 90 2 Kidney damage with mild decrease in GFR 60-89 3A Mild to moderate decrease in
GFR 45-59 3B Moderate to severe decrease in GFR 30-44 4 Severe decrease in GFR 15-29 5 Kidney
failure <15 (or dialysis)
Reference Values:
Cystatin C:
18-49 years: 0.63-1.03 mg/L
> or =50 years: 0.67-1.21 mg/L
0-17 years: Reference values have not been established. Refer to estimated glomerular filtration rate
(eGFR).
Estimated GFR:
>60 mL/min/BSA
Adult eGFR: Estimated GFR calculated using CKD-EPI Cystatin C equation.(1)
Pediatric eGFR: Estimated GFR calculated using Schwartz Cystatin C equation.)(1)
Clinical References: 1. Inker LA, Schmid CH, Tighiouart H, CKD-EPI Investigators, et al:
Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012
Jul;367(1):20-29 2. Frazee E, Rule AD, Lieske JC, et al: Cystatin C-guided vancomycin dosing in
critically ill patients: A quality improvement project. Am J Kidney Dis. 2017 May;69(5):658-666. doi:
10.1053/j.ajkd.2016.11.016 3. Buehrig CK, Larson TS, Bergert JH, et al: Cystatin C is superior to serum
creatinine for the assessment of renal function. J Am Soc Nephrol. 2001;12:194A 4. KDOQI US
Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of
CKD. Am J Kidney Dis. 2014;63:713-735. 5. Grubb AO: Cystatin C--properties and use as a diagnostic
marker. Adv Clin Chem. 2000;35:63-99 6. Coll E, Botey A, Alvarez L, et al: Serum cystatin C as a new
marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment.
Am J Kidney Dis. 2000 Jul;36(1):29-34 7. Larsson A, Hansson LO, Flodin M, Katz R, Shlipak MG:
Calibration of the Siemens cystatin C immunoassay has changed over time. Clin Chem. 2011
May;57(5):777-778 8. Voskoboev NV, Larson TS, Rule AD, Lieske JC: Importance of cystatin C assay
standardization. Clin Chem. 2011 Aug;57(8):1209-1211 9. Nitsch D, Sandling JK, Byberg L et al: Fetal,
developmental, and parental influences on cystatin C in childhood: the Uppsala Family Study. Am J
Kidney Dis. 2011 Jun;57(6):863-872 10. Voskoboev NV, Larson TS, Rule AD, Lieske JC: Analytic and
clinical validation of a standardized cystatin C particle enhanced turbidimetric assay (PETIA) to estimate
glomerular filtration rate. Clin Chem Lab Med. 2012 Mar;50(9):1591-1596 11. Finney H, Newman DJ,
Thakkar H, Fell JM, Price CP: Reference ranges for the plasma cystatin C and creatinine measurements in
premature infants, neonates, and older children. Arch Dis Child. 2000 Jan;82(1):71-75 12. Schwartz GJ,
Schneider MF, Maier PS, et al: Improved equations estimating GFR in children with chronic kidney
disease using an immunonephelometric determination of cystatin C. Kidney Int. 2012 Aug;82(4):445-53.
doi: 10.1038/ki.2012.169
CFP Cystic Fibrosis Mutation Analysis, 106-Mutation Panel, Varies

35386 Clinical Information: Cystic fibrosis (CF), in the classic form, is a severe autosomal recessive
disorder characterized by a varied degree of chronic obstructive lung disease and pancreatic enzyme
insufficiency. The incidence of CF varies markedly among different populations, as does the variant
detection rate for the variant screening assay. To date, over 1500 variants have been described within the
CF gene, named cystic fibrosis transmembrane conductance regulator (CFTR). The most common variant,
deltaF508, accounts for approximately 67% of the variants worldwide and approximately 70% to 75% in
a North American White population. Most of the remaining variants are rather rare, although some show a
relatively higher prevalence in certain ethnic groups or in some atypical presentations of CF such as
congenital bilateral absence of the vas deferens (CBAVD). Variants detected by this assay include the 23
variants recommended by the American College of Medical Genetics and Genomics as well as 83 other
variants. Of note, CFTR potentiator therapies may improve clinical outcomes for patients with a clinical
diagnosis of CF and at least one copy of the G178R, G551S, G551D, S549N, S549R, G1244E, S1251N,
S1255P, or G1349D variant. The G178R, S549N, S549R, S551D, and S1251N variants are included in
this test. These 106 variants account for approximately 91% of CF chromosomes in a Northern European
White population. Detection rates for several ethnic and racial groups are listed in the table below. Note
that interpretation of test results and risk calculations are also dependent on clinical information and
family history. Racial or ethnic group Carrier frequency Variant detection rate* African American 1/65
81% Ashkenazi Jewish 1/25 97% Asian American (excluding individuals of Japanese ancestry) 1/90 54%
Mixed European 1/25 82% Eastern European 1/25 77% French Canadian 1/25 91% Hispanic American
1/46 82% Northern European 1/25 91% Southern European 1/25 79% *Rates are for classical CF. Rates
are lower for atypical forms of CF and for CBAVD. CFTR variants listed below are included in this
panel. Deletion exons 2-3 Exon 11: R553X Intron 2: 296+2 T>A Exon 11: A559T Exon 3: E60X Exon
11: R560T Exon 3: R75X Intron 11: 1811+1.6kb A>G Exon 3: G85E Intron 11: 1812-1 G>A Exon 3:
394_395delTT Intron 12: 1898+1 G>A Intron 3: 405+1 G>A Intron 12: 1898+1 G>T Intron 3: 406-1
G>A Intron 12: 1898+1 G>C Exon 4: E92X Intron 12: 1898+5 G>T Exon 4: 444delA Exon 12: P574H
Exon 4: 457TAT>G Exon 13: 1949del84 Exon 4: R117H Exon 13: 2043delG Exon 4: R117C Exon 13:
2055del9>A Exon 4: Y122X Exon 13: 2105del13ins5 Exon 4: 574delA Exon 13: 2108delA Intron 4:
621+1 G>T Exon 13: 2143delT Exon 5: 663delT Exon 13: 2183_2184delAAinsG Exon 5: G178R Exon
13: 2184delA Intron 5: 711+1 G>T Exon 13: 2184insA Intron 5: 711+5 G>A Exon 13: R709X Intron 5:
712-1 G>T Exon 13: K710X Exon 6a: H199Y Exon 13: 2307insA Exon 6a: P205S Exon 13: R764X
Exon 6a: L206W Intron 14b: 2789+5 G>A Exon 6a: 852del22 Exon 15: 2869insG Exon 6b: 935delA
Exon 15: Q890X Exon 6b: 936delTA Intron 16: 3120+1 G>A Exon 7: deltaF311 Exon 17a: 3171delC
Exon 7: 1078delT Exon 17a: 3199del6 Exon 7: G330X Exon 17b: R1066C Exon 7: R334W Exon 17b:
W1089X (TGG>TAG) Exon 7: T338I Exon 17b: Y1092X (C>G) Exon 7: R347P Exon 17b: Y1092X
(C>A) Exon 7: R347H Exon 17b: M1101K Exon 7: R352Q Exon 17b: M1101R Exon 7: Q359K Exon 18:
D1152H Exon 7: T360K Exon 19: R1158X Exon 8: 1288insTA Exon 19: R1162X Exon 9: A455E Exon
19: 3659delC Exon 10: S466X (C>A) Exon 19: 3667del4 Exon 10: S466X (C>G) Exon 19: S1196X Exon
10: G480C Exon 19: W1204X (TGG>TAG) Exon 10: Q493X Exon 19: 3791delC Exon 10: deltaI507
Exon 19: Q1238X Exon 10: deltaF508 Intron 19: 3849+10kb C>T Exon 10: 1677delTA Exon 20:
3876delA Exon 10: C524X Exon 20: S1251N Intron 10: 1717-1 G>A Exon 20: S1255X Exon 11: G542X
Exon 20: 3905insT Exon 11: S549N Exon 20: W1282X (TGG>TGA) Exon 11: S549R (T>G) Exon 21:
4016insT Exon 11: G551D Exon 21: N1303K (C>A) Exon 11:Q552X Exon 21: N1303K (C>G) See
Cystic Fibrosis Molecular Diagnostic Testing Algorithm in Special Instructions for additional
information.
Useful For: Confirmation of a clinical diagnosis of cystic fibrosis Risk refinement via carrier
screening for individuals in the general population Prenatal diagnosis or familial variant testing when
the familial variants are included in the 106-variant panel listed in Clinical Information Risk refinement
via carrier screening for individuals with a family history when familial mutations are not available
Identification of patients who may respond to CFTR potentiator therapy

Reference Values:
Clinical References: 1. Quint A, Lerer I, Sagi M, Abeliovich D: Mutation spectrum in Jewish

cystic fibrosis patients in Israel: implication to carrier screening. Am J Med Genet A.
2005;136(3):246-248. doi: 10.1002/ajmg.a.30823 2. Bobadilla JL, Macek M, Fine FP, Farrell PM:
Cystic fibrosis: a worldwide analysis of CFTR mutations-correlation with incidence data and
application to screening. Hum Mutat. 2002;19(6):575-606. doi: 10.1002/humu.10041 3. Sugarman EA,
Rohlfs EM, Silverman LM, Alitto BA: CFTR mutation distribution among U.S. Hispanic and African
American individuals: evaluation in cystic fibrosis patient and carrier screening populations. Genet
Med. 2004;6(5):392-399. doi: 10.1097/01.gim.0000139503.22088.66 4. Watson MS, Cutting GR,
Desnick RJ, et al: Cystic fibrosis population carrier screening: 2004 revision of American College of
Medical Genetics mutation panel. Genet Med. 2004;6(5):387-391. doi:
10.1097/01.gim.0000139506.11694.7c 5. Heim RA, Sugarman EA, Allitto BA: Improved detection of
cystic fibrosis mutations in the heterozygous U.S. population using an expanded, pan-ethnic mutation
panel. Genet Med. 2001;3(3):168-176. doi: 10.1097/00125817-200105000-00004 6. De Boeck K,
Munck A, Walker S, et al: Efficacy and safety of ivacaftor in patients with cystic fibrosis and a
non-G551D gating mutation. J Cyst Fibros. 2014 Dec;13(6):674-680. doi: 10.1016/j.jcf.2014.09.005
CYSTS Cysticercosis Antibody, IgG, Serum

65872 Clinical Information: Cysticercosis is caused by infection with Taenia solium, a tapeworm (cestode).
In this form of infection, humans and pigs serve as the intermediate host and have the cystic larval form in
their tissues. Humans can also serve as the definitive host for T solium and have the adult form in their
intestine (known as taeniasis). Humans acquire cysticercosis by ingesting microscopic T solium eggs in
contaminated food, water, or on fomites. The eggs enter the environment when they are shed in stool from
a person with the intestinal form of infection; this could be the same patient (autoinfection) or a different
patient. Once ingested, the eggs hatch in the intestine to release oncospheres, which invade the intestinal
wall and disseminate via the blood to muscles, liver, brain, and other tissues where they form cysts
(cysticerci). Taeniasis occurs when cysticerci are ingested in the undercooked flesh of an infected
intermediate host (eg, pig). In the small intestine, cysticerci will evaginate and attach via a scolex to the
intestinal wall. They then grow to become mature adult tapeworms. Adults can reside in the intestine for
years and grow from 2 to 7 meters with over 500 proglottids, each filled with 50,000 eggs. While
cysticercosis and taeniasis occur globally, in the United States, infections are predominantly encountered
in immigrants from Latin and Central America who acquired the infection locally. The symptoms
associated with cysticercosis depend on where the cysticerci localize, their size, number, and stage
(degenerating, calcified, etc). The time between initial infection and symptom onset may vary from
several months to years. The presence of cysts in the brain or spinal cord, referred to as
neurocysticercosis, is the most serious form of disease and, while some individuals may be asymptomatic,
many present with seizures (70%-90%), headache, confusion, and difficulty with balance. Cysts present in
striated muscle are typically asymptomatic. Diagnosis of cysticercosis relies on both imaging studies and
serologic testing results. Importantly, detection of T solium eggs or proglottids in stool by an ova and
parasite exam is diagnostic for taeniasis, not cysticercosis. Individuals with taeniasis should be evaluated
for cysticercosis by serology since autoinfection can occur. Due to imperfect sensitivity and specificity of
commercially available enzyme-linked immunosorbent assays (ELISA) for cysticercosis, it is
recommended that both positive and negative results by commercial ELISA be confirmed by a
cysticercosis immunoblot offered through the Centers for Disease Control and Prevention
(www.cdc.gov/dpdx/cysticercosis/index.html) for patients strongly suspected to have cysticercosis.
Currently available antibody detection assays are unable to distinguish between active and inactive
infections.
Useful For: Aiding in the diagnosis of infection with Taenia solium (cysticercosis)
Interpretation: Positive: Results suggest infection with Taenia solium (cysticercosis). Confirmatory
testing through the Centers for Disease Control and Prevention is recommended. False-positive results
may occur in patients with other helminth infections (eg, Echinococcus). Negative: No antibodies to
Taenia solium (cysticercosis) detected. A negative result may not rule-out infection as the sample may
have been collected prior to the development of a detectable level of antibodies. Sensitivity is negatively
impacted by the presence of few cysticerci or location in areas less accessible to the immune system.
Repeat testing on a new sample is recommended for patients at high risk of cysticercosis.
Reference Values:
Negative
Clinical References: 1. Garvey BT, Moyano LM, Ayvar V, et al: Neurocysticercosis among people
living near pigs heavily infected with cysticercosis in rural endemic Peru. Am J Trop Med Hyg. 2018
Feb;98(2):558-564 2. Rodriguez S, Wilkins P, Dorny P: Immunological and molecular diagnosis of
cysticercosis. Pathog Glob Health. 2012 Sep;106(5):286-298
FCAEC Cysticercus Antibody (IgG), ELISA, CSF

75587 Clinical Information: Cysticercosis is caused by infection with the larval form (cysticercus) of the
pork tapeworm, Taenia solium. A negative test result does not exclude the diagnosis of
neurocysticercosis, particularly if only a single brain lesion is present. Test sensitivity increases from 50%
or less for a solitary brain cyst to greater than 90% if 3 or more cysts are present. Antibodies from other
parasitic infection, particularly results by the cysticercus IgG antibody Western blot is thus recommended.
Reference Values:
Reference Range: <0.75
Interpretive Criteria:
<0.75 Antibody Not Detected
> or =0.75 Antibody Detected
Diagnosis of central nervous system infections can be accomplished by demonstrating the presence of
intrathecally-produced specific antibody. Interpretation of results may be complicated by low antibody
levels found in CSF, passive transfer of antibody from blood, and contamination via bloody taps.
Antibodies to other parasitic infections, particularly echinococcosis, may crossreact in the cysticercus
IgG ELISA. Confirmation of positive ELISA results by the cysticercus IgG antibody Western blot is
thus recommended.
CYSGP Cystinuria Gene Panel, Varies

608027 Clinical Information: Cystinuria is an inborn error of metabolism resulting from poor absorption
and reabsorption of the amino acid cystine in the intestines and kidneys. This leads to an accumulation
of poorly soluble cystine and dibasic amino acids (lysine, arginine, and ornithine) in the urine and
results in the production of kidney stones (urolithiasis). Symptoms may include acute episodes of
abdominal or lower back pain, presence of blood in the urine (hematuria), and recurrent episodes of
kidney stones may result in frequent urinary tract infections, which may ultimately result in renal
insufficiency. The combined incidence of cystinuria has been estimated to be 1 in 7000. Cystinuria is an
autosomal recessive disease, but some heterozygous carriers have an autosomal dominant, incomplete
penetrance appearance with elevated, but typically non-disease causing, urinary cystine and dibasic
amino acid excretion. Some heterozygotes do tend to have higher levels of lysine and cystine versus
arginine and ornithine as compared to patients with homozygous variants, who excrete large amounts of
cysteine and all 3 dibasic amino acids. Cystinuria is caused by variants in genes, SLC3A1 and PREPL
on chromosome 2p and SLC7A9 on chromosome 19q. Initially, the disease was classified into subtypes
I, II, and III (type II and III are also referred as nontype I) based on the amount of urinary cystine
excreted in heterozygous parental specimens. A new classification system has been proposed to
distinguish the various forms of cystinuria: type A, due to variants in the SLC3A1 gene; type B, due to
variants in the SLC7A9 gene; and type AB, due to 1 variant in each SLC3A1 and SLC7A9 gene. A
contiguous gene deletion involving both SLC3A1 and PREPL gene is associated with an autosomal
recessive hypotonia-cystinuria syndrome, presenting with dysmorphic features, severe neonatal
hypotonia, myasthenic syndrome, failure to thrive in infancy with transition to hyperphagia in late
childhood, and nephrolithiasis with excretion of cystine, lysine, arginine and ornithine. Variants in the
PREPL gene are associated with autosomal recessive congenital myasthenic syndrome 22 (CMS22),
which does not present with cystinuria. Urinary measurement of cystine, lysine, ornithine, and arginine
(CYSQN / Cystinuria Profile, Quantitative, 24 Hour, Urine or CYSR / Cystinuria Profile, Quantitative,
Random, Urine) is recommended as a first-tier test to screen for cystinuria prior to molecular genetics
testing. Treatment/management options for cystinuria include a high fluid intake, alkali and dietary
modifications, and administration of oral tiopronin to prevent formation of cystine stones.
Useful For: Follow up for abnormal biochemical results suggestive of cystinuria Establishing a
molecular diagnosis for patients with cystinuria Identifying variants within genes known to be
associated with cystinuria, allowing for predictive testing of at-risk family members
known significance.
Reference Values:
May;17(5):405-424 2. PalacÃn M, Goodyer P, Nunes V, et al: Cystinuria. In: Valle D, Antonarakis S,
Ballabio A, Beaudet A, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited
Disease: McGraw-Hill; 2019. Accessed January 07, 2020. Available at
http://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225555540 3. Eggermann T,
Spengler S, Venghaus A, et al: 2p21 Deletions in hypotonia-cystinuria syndrome. Eur JMed Genet.
2012;55(10)561-563 4. Regal L, Shen XM, Selcen D, et al: PREPL deficiency with or without cystinuria
causes a novel myasthenic syndrome. Neurology. 2014;82(14)1254-1260
CYSQN Cystinuria Profile, Quantitative, 24 Hour, Urine

8376 Clinical Information: Cystinuria is an inborn error of metabolism resulting from poor absorption and
reabsorption of the amino acid cystine in the intestines and kidneys. This leads to an accumulation of
poorly soluble cystine in the urine and results in the production of kidney stones (urolithiasis). Symptoms
may include acute episodes of abdominal or lower back pain, presence of blood in the urine (hematuria),
and recurrent episodes of kidney stones may result in frequent urinary tract infections, which may
ultimately result in renal insufficiency. The combined incidence of cystinuria has been estimated to be 1
in 7000. Cystinuria is an autosomal recessive disease, but some heterozygous carriers have an autosomal
dominant, incomplete penetrance appearance with elevated, but typically nondisease causing, urinary
cystine excretion. Cystinuria is caused by variants in genes, SLC3A1 on chromosome 2p and SLC7A9 on
chromosome 19q. Initially, the disease was classified into subtypes I, II, and III (type II and III are also
referred as nontype-I) based on the amount of urinary cystine excreted in heterozygous parental
specimens. A new classification system has been proposed to distinguish the various forms of cystinuria:
type A, due to variants in the SLC3A1 gene; type B, due to variants in the SLC7A9 gene; and type AB,
due to 1 variant in each SLC3A1 and SLC7A9 gene.
Useful For: Diagnosis of cystinuria

Interpretation: Homozygotes or compound heterozygotes with cystinuria excrete large amounts of
cystine in urine, but the amount varies markedly. Urinary excretion of other dibasic amino acids (arginine,
lysine, and ornithine) is also typically elevated. Plasma concentrations are generally normal or slightly
decreased. Individuals who are homozygous and heterozygous for nontype I cystinuria can be
distinguished by the pattern of urinary amino acids excretion: homozygous individuals secrete large
amounts of cystine and all 3 dibasic amino acids, whereas heterozygous individuals secrete more lysine
and cystine than arginine and ornithine.
Reference Values:
CYSTINE
3-15 years: 11-53 mcmol/24 hours
> or =16 years: 28-115 mcmol/24 hours
LYSINE
ORNITHINE
ARGININE
Conversion Formulas:
Result in mcmol/24 hours x 0.24=result in mg/24 hours
Result in mg/24 hours x 4.17=result in mcmol/24 hours
Clinical References: 1. Saravakos P, Kokkinou V, Giannatos E: Cystinuria: current diagnosis and

management. Urology. 2014 Apr;83(4):693-699 2. Palacin, M, Goodyer, P, Nunes V, Gasparini P:
Cystinuria. Palacin M, Goodyer P, Nunes V, Gasparini P: Cystinuria. In: Valle DL, Antonarakis S,
Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited
Disease. McGraw-Hill; 2019. Accessed April 27, 2022. Available at
CYSR Cystinuria Profile, Quantitative, Random, Urine

81067 Clinical Information: Cystinuria is an inborn error of metabolism resulting from poor absorption
and reabsorption of the amino acid cystine in the intestines and kidneys. This leads to an accumulation
of poorly soluble cystine in the urine and results in the production of kidney stones (urolithiasis).
Symptoms may include acute episodes of abdominal or lower back pain, presence of blood in the urine
(hematuria), and recurrent episodes of kidney stones may result in frequent urinary tract infections,
which may ultimately result in renal insufficiency. The combined incidence of cystinuria has been
estimated to be 1 in 7000. Cystinuria is an autosomal recessive disease, but some heterozygous carriers
have an autosomal dominant, incomplete penetrance appearance with elevated, but typically nondisease
causing, urinary cystine excretion. Cystinuria is caused by variants in genes, SLC3A1 on chromosome
2p and SLC7A9 on chromosome 19q. Initially, the disease was classified into subtypes I, II, and III
(type II and III are also referred as nontype-I) based on the amount of urinary cystine excreted in
heterozygous parental specimens. A new classification system has been proposed to distinguish the
various forms of cystinuria: type A, due to variants in the SLC3A1 gene; type B, due to variants in the
SLC7A9 gene; and type AB, due to 1 variant in each SLC3A1 and SLC7A9 gene.
Useful For: Biochemical diagnosis and monitoring of cystinuria

Interpretation: Homozygotes or compound heterozygotes with cystinuria excrete large amounts of
cystine in urine, but the amount varies markedly. Urinary excretion of other dibasic amino acids
(arginine, lysine, and ornithine) is also typically elevated. Plasma concentrations are generally normal or
slightly decreased. Individuals who are homozygous and heterozygous for nontype I cystinuria can be
distinguished by the pattern of urinary amino acids excretion: homozygous individuals secrete large
amounts of cystine and all 3 dibasic amino acids, whereas heterozygous individuals secrete more lysine
and cystine than arginine and ornithine.
Reference Values:
Â < or =12 13-35 months 3-6 years 7-8 years 9-17 years > or =18 years
months
Arginine Arg 10-560 20-395 14-240
Ornithine Orn
Cystine Cys 12-504 11-133 10-98
Lysine Lys 19-1988 25-743 14-307 17-276 10-240 15-271 All

results reported
as nmol/mg
creatinine.
Clinical References: 1. Saravakos P, Kokkinou V, Giannatos E: Cystinuria: current diagnosis and

management. Urology. 2014 Apr;83(4):693-699 2. Palacin M, Goodyer P, Nunes V, Gasparini P:
Cystinuria. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online
Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed April 27, 2022.
Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225555540&bookid=2709
METR1 Cytochrome b5 Reductase Enzyme Activity, Blood

65609 Clinical Information: Cytochrome b5 reductase (CYB5R), also called methemoglobin reductase, is
the enzyme within the erythrocyte that maintains hemoglobin in the reduced (non-methemoglobin) state.
A deficiency of CYB5R in erythrocytes is an autosomal recessive disorder resulting from variants in the
CYB5R3 or the CYB5A genes. Persons who are heterozygous for CYB5R genetic variants have no
clinical or laboratory abnormalities, are not cyanotic, and have normal methemoglobin concentrations in
their blood. However, they hold an increased risk for more severely symptomatic acute episodes of
methemoglobinemia with exposure to inducing agents. Persons who are homozygous for CYB5R genetic
variants have normal arterial oxygen saturation but have varying quantities of methemoglobin in their
blood, generally 15% to 20%, and are quite cyanotic. Paradoxically, homozygotes typically have normal
blood counts; the condition only rarely causes polycythemia. The presence of methemoglobin shifts the
hemoglobin-O2 dissociation curve to the right, so although the transport of oxygen is diminished, the
delivery of oxygen to tissues is normal. Because of the chronicity, the homozygous condition is usually
compensated and, therefore, quite benign, but it may cause concern to parents of affected children, be a
cosmetic embarrassment to the children, and alarm the attending physician. The cyanosis may be treated
with methylene blue.
Useful For: Evaluation of patients with cyanosis Confirming cases of suspected cytochrome b5
reductase (methemoglobin reductase) deficiency Functional studies in families with cytochrome b5
reductase deficiency
Interpretation: Cytochrome b5 reductase (methemoglobin reductase) activity in neonates (0-6 weeks)

is normally 60% of the normal adult value. Adult values are attained by 2 to 3 months of age.
Heterozygotes have results slightly lower than the reference range. Homozygotes demonstrate little to no
cytochrome b5 reductase activity and increased levels of methemoglobin.
Reference Values:
> or =12 months of age: 7.8-13.1 U/g Hb
Clinical References: 1. Agarwal AM, Prchal JT: Methemoglobinemia and other

dyshemoglobinemias. In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. Williams Hematology. 9th
ed. McGraw-Hill; 2016:789-800 2. Percy MJ, Barnes C, Crighton G, et al: Methemoglobin reductase
deficiency: Novel mutation is associated with a disease phenotype of intermediate severity. J Pediatr
Haematol Oncol. 2012;34:457-460
1A2Q Cytochrome P450 1A2 Genotype, Varies

610041 Clinical Information: The cytochrome P450 (CYP) family is involved in the primary metabolism of
many drugs. The CYPs are a group of oxidative/dealkylating enzymes localized in the microsomes of
many tissues including the intestines and liver. One of these CYP enzymes, CYP1A2, is wholly or
partially responsible for the hydroxylation or dealkylation of many commonly prescribed drugs.
CYP1A2-mediated drug metabolism is highly variable. A number of variants have been identified in the
CYP1A2 gene that results in increased, diminished, or abolished catalytic activity and substrate
metabolism. The frequency of these variants varies by ethnicity. Dosing of drugs that are metabolized
through CYP1A2 may require adjustment based on the CYP1A2 genotype. Individuals who are poor
metabolizers may require lower than usual doses to achieve optimal response, whereas individuals who
are ultrarapid metabolizers may benefit from increased doses. CYP1A2 phenotype is predicted based
upon the number of functional, partially functional, nonfunctional, and inducible alleles present in a
sample. In the absence of clear guidance on dosing for various metabolizer phenotypes, patients with
either rapid or poor metabolism also may benefit by switching to another comparable drug that is not
primarily metabolized by CYP1A2 or by therapeutic drug monitoring where applicable. The following
table outlines the relationship between the variations (star alleles) detected in this assay and the effect on
the activity of the enzyme produced by that allele. CYP1A2 allele Nucleotide change (legacy
nomenclature) cDNA nucleotide change (NM_000761.4) Effect on enzyme metabolism(a) *1 None (wild
type) None (wild type) Normal (extensive) activity *1F -163C>A c.-9-154C>A Increased inducibility
*1K -729C>T c.-10+113C>T Decreased activity and decreased inducibility *6 5090C>T c.1291C>T No
activity *7 3533G>A c.1253+1G>A No activity a. Effect of a specific allele on the activity of the
CYP1A2 enzyme can only be estimated since the literature does not provide precise data.(1-5) A
complicating factor in correlating CYP1A2 genotype to CYP1A2 phenotype is that some drugs or their
metabolites are inhibitors of CYP1A2 catalytic activity. These drugs may reduce CYP1A2 catalytic
activity. Consequently, an individual may require a dose decrease greater than predicted based upon
genotype alone. Another complicating factor is that CYP1A2 is inducible by several drugs and
environmental agents (eg, cigarette smoke) and the degree of inducibility is under genetic control. It is
important to interpret the results of testing in the context of other coadministered drugs and environmental
factors.
Useful For: Identifying individuals who are poor, intermediate, normal (extensive) or rapid
metabolizers of drugs metabolized by cytochrome P450 1A2 to assist drug therapy decision making
Interpretation: An interpretive report will be provided. The genotype, with associated star alleles, is
assigned using standard allelic nomenclature as published by the Pharmacogene Variation (PharmVar)
Consortium.(6) CYP1A2 activity is also dependent upon hepatic function status, as well as age. Renal
function may be important for drugs that are excreted in urine. Patients may develop drug toxicity if
hepatic or renal function is decreased. Drug metabolism is known to decrease with age. It is important
to interpret the results of testing and dose adjustments in the context of hepatic and renal function and
age. For additional information regarding pharmacogenomic genes and their associated drugs, see
Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information
regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.
Reference Values:
Clinical References: 1. Ito M, Katono Y, Oda A, Hirasawa N, Hiratsuka M: Functional

characterization of 20 allelic variants of CYP1A2. Drug Metab Pharmacokinet. 2015
Jun;30(3):247-252. doi: 10.1016/j.dmpk.2015.03.001 2. Zhou H, Josephy PD, Kim D, Guengerich FP:
Functional characterization of four allelic variants of human cytochrome P450 1A2. Arch Biochem
Biophys. 2004 Feb;422(1):23-30. doi: 10.1016/j.abb.2003.11.019 3. Murayama N, Soyama A, Saito Y,
et al: Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally
occurring variant enzymes. J Pharmacol Exp Ther. 2004 Mar;308(3):1219 4. Murayama N, Soyama A,
Saito Y, et al: J Pharmacol Exp Ther. 2004;308(1):300-306. doi: 10.1124/jpet.103.055798 5. Saito Y,
Hanioka N, Maekawa K, et al. Functional analysis of three CYP1A2 variants found in a Japanese
population. Drug Metab Dispos. 2005;33(12):1905-1910. doi: 10.1124/dmd.105.005819 6. PharmVar.
Pharmacogene Variation Consortium. Updated March 3, 2021. Accessed March 22, 2021. Available at
www.pharmvar.org/
2B6Q Cytochrome P450 2B6 Genotype, Varies

610042 Clinical Information: The cytochrome P450 (CYP) family of enzymes is a group of
oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and
liver. CYP2B6 is wholly or partially responsible for the metabolism of several commonly prescribed
drugs. The CYP2B6 gene is highly variable with over 38 named alleles. The gene can have multiple
sequence variations. Alleles thought to have an impact upon CYP2B6 enzyme function at the time that
this test was developed are included in this test (see Table). Individuals without a detectable gene
alteration will be reported as CYP2B6*1/*1, but it is possible that these individuals harbor unknown
variants that may impact metabolism. In addition, some individuals have genes that are hybrids of
CYP2B6 and the CYP2B7 pseudogene. The frequency of these hybrids is unknown, and this assay does
not test for these hybrids. Phenotyping is derived from the Pharmacogene Variation Consortium
website(1), an exhaustive review of the CYP2B6 literature, the Clinical Pharmacogenetics
Implementation Consortium website(2), and published guidelines.(3) CYP2B6 genotype results are used
to predict metabolizer phenotypes. A CYP2B6 phenotype is predicted based upon the number of
functional, partially functional, and nonfunctional alleles present in a sample. In rare instances where
alleles with unknown function are present in a homozygous or compound heterozygous state, an
unknown phenotype occurs. It should be noted that other laboratories may use different phenotype
prediction methods as there is no consensus on this at this time. However, the method used here
represents the findings of the majority of literature available. Several medications act as substrates of
CYP2B6. CYP2B6-metabolized medications with the highest quality of data for the impact of various
CYP2B6 alleles on metabolism are: -Bupropion -Efavirenz -Ketamine -Methadone -Nevirapine Other
enzymes may be involved in the metabolism of these drugs. For example, bupropion is also metabolized
by CYP2D6. Efavirenz is also metabolized by CYP2A6, although CYP2B6 is the major metabolizing
enzyme. Ketamine is also metabolized by CYP2A6, and nevirapine is also metabolized by CYP3A4 and
CYP3A5. CYP2A6 testing is not available clinically at the time this document was written, but
CYP2D6 (2D6Q / Cytochrome P450 2D6 Comprehensive Cascade, Varies), CYP3A4 (3A4Q /
Cytochrome P450 3A4 Genotype, Varies), and CYP3A5 (3A5Q / Cytochrome P450 CYP3A5
Genotype, Varies) testing is available. There is a variable degree of substrate specificity exhibited by
CYP2B6 alleles on these medications. This means that the same allele (ie, *6) may not metabolize all
substrates at exactly the same rate. Drugs that are metabolized by CYP2B6 may require dosage
adjustment based on the individual patient's genotype. For example, patients who are poor metabolizers
may require much lower than usual doses to achieve optimal response in the case of drugs that are
inactivated by the CYP2B6 enzyme. Alternatively, patients who are ultrarapid metabolizers may benefit
from increased doses in the case of drugs that are inactivated by CYP2B6 enzyme. In the absence of
clear guidance from the FDA on dosing for various metabolizer phenotypes, patients with either
ultrarapid or poor metabolism may benefit by switching to comparable alternate medications that are not
primarily metabolized by CYP2B6 or by therapeutic drug monitoring where applicable. Table. Enzyme
Activity of Individual Star Alleles Enzyme activity Examples of CYP2B6 star alleles Normal
(extensive) activity *1, *5 Increased activity *4, *22 Decreased activity *6, *7, *9, *11, *14, *15, *19,
*20, *26, *27, *36 No or null activity *8, *12, *13, *16 (also known as *18.002), *18, *35, *38
Unknown activity Â *27
Useful For: Aiding in determining therapeutic strategies for drugs that are metabolized by cytochrome
P450 (CYP) 2B6 Providing information relevant to bupropion, efavirenz, ketamine, methadone, and
nevirapine, as well as other medications metabolized by CYP2B6 Determining the genotype if
genotype-phenotype discord is encountered clinically after testing with a less comprehensive genotyping
method has occurred Identifying genotype when required for drug trials and research protocols
Consortium.(1) For additional information regarding pharmacogenomic genes and their associated drugs,
see Pharmacogenomic Associations Tables. This resource also includes information regarding enzyme
inhibitors and inducers, as well as potential alternate drug choices.
Reference Values:
Clinical References: 1. PharmVar. Pharmacogene Variation Consortium. Updated March 3, 2021.

Accessed March 22, 2021. Available at www.pharmvar.org/ 2. Clinical Pharmacogenetics Implementation
Consortium (CPIC). Accessed October 14, 2020. Available at https://cpicpgx.org/ 3. Desta Z, Gammal
RS, Gong L, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6
and Efavirenz-Containing Antiretroviral Therapy. Clin Pharmacol Ther. 2019;106(4):726-733. doi:
10.1002/cpt.1477 4. U.S National Library of Medicine: DailyMed. National Institutes of Health. Accessed
October 14, 2020. Available at https://dailymed.nlm.nih.gov/dailymed/index.cfm
2C19R Cytochrome P450 2C19 Genotype, Varies

610043 Clinical Information: Primary metabolism of many drugs is performed by the cytochrome P450
(CYP) enzymes, a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues
including the intestines and liver. One of these CYP enzymes, CYP2C19, participates in the metabolism
of a wide variety of drugs, including the activation of the anticoagulant clopidogrel and the inactivation of
citalopram. CYP2C19 drug metabolism is variable among individuals. Some individuals have CYP2C19
genetic variants that lead to severely diminished or absent CYP2C19 catalytic activity (ie, poor
metabolizers). The frequency of CYP2C19 variants (formerly known as polymorphisms) depends on
ethnicity. CYP2C19 variants that produce poor metabolizers are found with frequencies of 2% to 5% in
the White population, 4% in African Americans, 13% to 23% in Asians, and 38% to 79% in Polynesians
and Micronesians. The following table displays the CYP2C19 variants detected by this assay, the
corresponding star allele, and the effect on CYP2C19 enzyme activity. Table. Enzyme Activity of
Individual Star Alleles CYP2C19a allele cDNA nucleotide change (NM_000769.1) Effect on enzyme
activity *1 None (wild type) Normal (extensive) activity *2 c.681G>A No activity *3 c.636G>A No
activity *4 c.1A>G No activity *5 c.1297C>T No activity *6 c.395G>A No activity *7 c.819+2T>A No
activity *8 c.358T>C No activity *9 c.431G>A Decreased activity *10 c.680C>T Decreased activity *17
c.-806C>T Enhanced activity *35 c.332-23A>G in the absence of c.681G>A No activity CYP2C19 drug
metabolism is dependent on the specific genotype detected and also on the number and type of drugs
administered to the patient. Phenotyping is derived from the Pharmacogene Variation Consortium
website(1), the Clinical Pharmacogenetics Implementation Consortium website(2), published
guidelines(3-8), and an exhaustive review of the CYP2C19 literature(9-10). Individuals without a
detectable CYP2C19 variant will have the predicted phenotype of an extensive drug metabolizer and are
designated as CYP2C19*1/*1. If an individual is homozygous or compound heterozygous for alleles with
no activity, the individual is predicted to be a poor metabolizer. If an individual is heterozygous for an
allele with no activity, the individual is predicted to be an intermediate metabolizer. Individuals with the
CYP2C19*17 allele (in the absence of any inactive or decreased activity alleles) may have enhanced
metabolism of drugs. In some cases, a range of potential phenotypes may be given, depending on the
combination of alleles identified. Patients who are poor metabolizers may benefit from dose alteration or
selection of a comparable drug that is not primarily metabolized by CYP2C19. It is important to interpret
the results of testing in the context of other coadministered drugs.
Useful For: Identifying patients who may be at risk for altered metabolism of drugs that are modified
by cytochrome P450 2C19 Predicting anticoagulation response to clopidogrel
Consortium.(1) For additional information regarding pharmacogenomic genes and their associated
drugs, see Pharmacogenomic Associations Tables. This resource also includes information regarding
enzyme inhibitors and inducers, as well as potential alternate drug choices. Drug-drug interactions and
drug-metabolite inhibition must be considered when treating intermediate metabolizers. It is important
to interpret the results of testing and dose adjustments in the context of hepatic and renal function and
patient age.
Reference Values:
Clinical References: 1. PharmVar: Pharmacogene Variation Consortium. Updated March 3, 2021.

Accessed March 22, 2021. Available at www.pharmvar.org/ 2. Clinical Pharmacogenetics
Implementation Consortium (CPIC). Accessed October 14, 2020. Available at https://cpicpgx.org/ 3.
Scott SA, Sangkuhl K, Stein CM, et al: Clinical Pharmacogenetics Implementation Consortium
guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013
Sep;94(3):317-323. doi: 10.1038/clpt.2013.105 4. Lima JJ, Thomas CD, Barbarino J, et al: Clinical
Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump
Inhibitor Dosing. Clin Pharmacol Ther. 2020 Aug;10.1002/cpt.2015. doi: 10.1002/cpt.2015 5.
Moriyama B, Obeng AO, Barbarino J, et al: Clinical Pharmacogenetics Implementation Consortium
(CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther. 2018
Feb;103(2):349 6. Moriyama B, Obeng AO, Barbarino J, et al: Clinical Pharmacogenetics
Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin
Pharmacol Ther. 2017;102(1):45-51. doi: 10.1002/cpt.583 7. Hicks JK, Bishop JR, Sangkuhl K, et al:
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19
Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther.
2015;98(2):127-134. doi: 10.1002/cpt.147 8. Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical
pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes
and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37-44. doi:
10.1002/cpt.597 9. Blaisdell J, Mohrenweiser H, Jackson J, et al: Identification and functional
characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics.
2002;12(9):703-711. doi: 10.1097/00008571-200212000-00004 10. Mega JL, Close SL, Wiviott SD, et
al: Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med.
2009;360(4):354-362. doi: 10.1056/NEJMoa0809171
2C9QT Cytochrome P450 2C9 Genotype, Varies

610044 Clinical Information: Primary metabolism of many drugs is performed by the cytochrome P450
(CYP) enzymes, a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues,
but primarily in the intestines and liver. One of these CYP enzymes, CYP2C9, participates in the
metabolism of a wide variety of drugs including warfarin and phenytoin. CYP2C9-mediated drug
metabolism is variable among individuals. Some individuals have CYP2C9 genetic variants that lead to
severely diminished or absent CYP2C9 catalytic activity (ie, poor metabolizers). These individuals may
metabolize various drugs at a slower rate than normal and may require dosing adjustments to prevent
adverse drug reactions. A number of specific CYP2C9 variants have been identified that result in
enzymatic deficiencies. The following information outlines the relationship between the variants detected
in the assay and their effect on enzyme activity: Table. Enzyme Activity of Individual Star Alleles
CYP2C9 allele cDNA nucleotide change (NM_000771.3) Effect on enzyme metabolism *1 None (wild
type) Normal activity *2 c.430C>T Reduced activity *3 c.1075A>C No activity *4 c.1076T>C Reduced
activity *5 c.1080C>G Reduced activity *6 c.818delA No activity *8 c.449G>A Reduced activity *9
c.752A>G Normal activity *11 c.1003C>T Reduced activity *12 c.1465C>T Reduced activity *13
c.269C>T No activity *14 c.374G>A Reduced activity *15 c.485C>A No activity *16 c.895A>G
Reduced activity *17 c.1144C>T Reduced activity *18 c.1190A>C No activity *25 c.353_362del No
activity *26 c.389C>G Reduced activity *28 c.641A>T Reduced activity *30 c.1429G>A Reduced
activity *33 c.395G>A No activity *35 c.374G>T;430C>T No activity CYP2C9 drug metabolism is
dependent on the specific genotype detected and also on the number and type of drugs administered to the
patient. Phenotyping is derived from the Pharmacogene Variation Consortium website(1), the Clinical
Pharmacogenetics Implementation Consortium website (2), published guidelines (3-5), and an exhaustive
review of the CYP2C9 literature (6-7). Individuals without a detectable CYP2C9 variant will have the
predicted phenotype of an extensive drug metabolizer and are designated as CYP2C9 *1/*1. If an
individual is homozygous or compound heterozygous for an allele with no activity, the individual is
predicted to be a poor metabolizer. If an individual is heterozygous for an allele with no activity, the
individual is predicted to be an intermediate metabolizer. In some cases, a range of potential phenotypes
may be given, depending on the combination of alleles identified. Patients who are poor metabolizers may
benefit from dose alteration or selection of a comparable drug that is not primarily metabolized by
CYP2C9. It is important to interpret the results of testing in the context of other coadministered drugs.
Useful For: Identifying individuals who may be at risk for altered metabolism of drugs that are
modified by cytochrome P450 2C9
see Pharmacogenomic Associations Tables. This resource also includes information regarding enzyme
inhibitors and inducers, as well as potential alternate drug choices. Drug-drug interactions and
drug/metabolite inhibition must be considered in the case of all metabolizer categories except poor
metabolizer. It is important to interpret the results of testing and dose adjustments in the context of hepatic
and renal function and patient age.
Reference Values:

Consortium (CPIC). Accessed October 14, 2020. Available at https://cpicpgx.org/ 3. Karnes JH, Rettie
AE, Somogyi AA, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for
CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clin Pharmacol Ther. 2021
Feb;109(2):302-309. doi: 10.1002/cpt.2008 4. Johnson JA, Caudle KE, Gong L, et al: Clinical
Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin
Dosing: 2017 Update. Clin Pharmacol Ther. 2017 Sep;102(3):397-404. doi: 10.1002/cpt.668 5. Theken
KN, Lee CR, Gong L, et al: Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for
CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther. 2020 Aug;108(2):191-200.
doi: 10.1002/cpt.1830 6. Niemi M, Cascorbi I, Timm R, Kroemer HK, Neuvonen PJ, Kivisto KT:
Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin
Pharmacol Ther. 2002;72(3):326-332. doi: 10.1067/mcp.2002.127495 7. Blaisdell J, Jorge-Nebert LF,
Coulter S, et al: Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics.
2004;14(8):527-537. doi: 10.1097/01.fpc.0000114759.08559.51
2D6Q Cytochrome P450 2D6 Comprehensive Cascade, Varies

610045 Clinical Information: The cytochrome P450 (CYP) family of enzymes is a group of
oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and
liver. One of the CYP enzymes, CYP2D6, is wholly or partially responsible for the metabolism of many
commonly prescribed drugs. The CYP2D6 gene is highly variable with over 100 named alleles. The
gene may be deleted, duplicated, and multiplied, and can have multiple sequence variations. In addition,
some individuals have genes that are hybrids of CYP2D6 and the CYP2D7 pseudogene. Some
individuals have CYP2D6 variants that result in synthesis of an enzyme with decreased or absent
catalytic activity. These individuals may process CYP2D6-metabolized medications more slowly.
CYP2D6 duplications and multiplications involving active alleles may result in ultrarapid metabolism
of CYP2D6-metabolized drugs. CYP2D6 genotype results are used to predict metabolizer
phenotypes.(See Table 1) Table 1. Enzyme Activity of Individual Star Alleles Enzyme activity
Examples of CYP2D6 star alleles Normal (extensive) metabolism *1, *2, *2A, *35 Decreased activity
*9, *10, *14, *17, *29, and *41 No or null activity *3, *4, *4N, *5, *6, *7, *8, *11, *12, *13, *15, *36,
*68, *114 CYP2D6 phenotype is predicted based upon the number of functional, partially functional,
and nonfunctional alleles present in a sample. Phenotyping is derived from the Pharmacogene Variation
Consortium website (1), the Clinical Pharmacogenetics Implementation Consortium website (2),
published guidelines (3-8), and an exhaustive review of the CYP2D6 literature (9-10). There are
instances where a precise phenotype prediction is not possible, and in these instances, a range of
possible phenotypes will be given. Individuals without a detectable gene alteration will have the
predicted phenotype of an extensive drug metabolizer and are designated as CYP2D6*1/*1. Drugs that
are metabolized through CYP2D6 may require dosage adjustment based on the individual patient's
genotype. Patients who are poor metabolizers may require lower than usual doses to achieve optimal
response in the case of drugs that are inactivated by the CYP2D6 enzyme and higher than usual doses in
the case of drugs that are activated by CYP2D6 enzyme. Alternatively, patients who are ultrarapid
metabolizers may benefit from increased doses in the case of drugs that are inactivated by CYP2D6
enzyme and lower doses in the case of drugs that are activated by CYP2D6. In the absence of clear
guidance from FDA on dosing for various metabolizer phenotypes, patients with either ultrarapid or
poor metabolism may benefit by switching to comparable alternate medications not primarily
metabolized by CYP2D6 or by therapeutic drug monitoring where applicable. Overall, this test provides
a comprehensive CYP2D6 genotype result for patients, ensuring a more accurate phenotype prediction.
This assay has clinical significance for patients taking or considering medications activated (eg,
codeine, tramadol, and tamoxifen) or inactivated (eg, antidepressants and antipsychotics) by the
CYP2D6 enzyme. Sequential tier testing associated with this test will be initiated until the least
ambiguous phenotype possible is determined.
Useful For: Providing information relevant to tamoxifen, codeine, and tramadol, as well as other
medications metabolized by cytochrome P450 2D6 Determining the exact genotype when other
methods fail to generate this information or if genotype-phenotype discord is encountered clinically
Identifying precise genotype when required (eg, drug trials, research protocols) Identifying novel
variants that may interfere with drug metabolism (when reflex to sequencing is performed)
Interpretation: A comprehensive interpretive report will be provided, which combines the results of
all tier testing utilized to obtain the final genotype. The genotype, with associated star alleles, is
Consortium.(1) For the CYP2D6 copy number variation assay, the reportable copy number range is 0 to
4 copies for each of the CYP2D6 region assessed. Novel variants will be classified based on known,
predicted, or possible effect on gene function and reported with interpretive comments detailing their
potential or known significance. For additional information regarding pharmacogenomic genes and their
associated drugs, see Pharmacogenomic Associations Tables in Special Instructions. This resource also
includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug
choices.
Reference Values:
A comprehensive interpretive report will be provided.

Consortium (CPIC). Accessed October 14, 2020. https://cpicpgx.org/ 3. Brown JT, Bishop JR, Sangkuhl
K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450
(CYP)2D6 Genotype and Atomoxetine Therapy. Clin Pharmacol Ther. 2019;106(1):94-102. doi:
10.1002/cpt.1409 4. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics
Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014
update. Clin Pharmacol Ther. 2014;95(4):376-382. doi: 10.1038/clpt.2013.254 5. Bell GC, Caudle KE,
Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for
CYP2D6 genotype and use of ondansetron and tropisetron. Clin Pharmacol Ther. 2017;102(2):213-218.
doi: 10.1002/cpt.598 6. Goetz MP, Sangkuhl K, Guchelaar HJ, et al. Clinical Pharmacogenetics
Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol
Ther. 2018;103(5):770-777. doi: 10.1002/cpt.1007 7. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical
Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes
and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98(2):127-134. doi:
10.1002/cpt.147 8. Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical pharmacogenetics implementation
consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic
antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37-44. doi: 10.1002/cpt.597 9. Black JL
3rd, Walker DL, O'Kane DJ, Harmandayan M. Frequency of undetected CYP2D6 hybrid genes in clinical
samples: impact on phenotype prediction [published correction appears in Drug Metab Dispos. 2012
Jun;40(6):1238]. Drug Metab Dispos. 2012;40(1):111-119. doi: 10.1124/dmd.111.040832 10. Kirchheiner
J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution
of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004;9(5):442-473. doi:
10.1038/sj.mp.4001494 11. Crews KR, Monte AA, Huddart R, et al: Clinical Pharmacogenetics
Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid
Therapy. Clin Pharmacol Ther. 2021 Jan 2. doi: 10.1002/cpt.2149. Epub ahead of print

610046 Clinical Information: CYP3A4 is a member of the CYP3A family of genes located on chromosome
7. The cytochrome P450 (CYP) 3A subfamily of enzymes is responsible for the metabolism of more than
50% of medications that undergo hepatic metabolism and first-pass metabolism in intestinal epithelial
cells, including some lipid-lowering drugs. The CYP3A4 enzyme activity is highly variable.
Interindividual differences in enzyme expression may be due to several factors including: variable
homeostatic control mechanisms, disease states that alter homeostasis, up- or down-regulation by
environmental stimuli, and genetic variation.(1) One variant, CYP3A4*22 (c.522-191C>T), has been
studied extensively. This variant affects hepatic expression of CYP3A4 and response to statin drugs. The
CYP3A4*22 allele is associated with reduced CYP3A4 activity, which may result in a better response to
lipid-lowering drugs, such as simvastatin, atorvastatin, or lovastatin. However, reduced CYP3A4 activity
may also be associated with statin-induced myopathy, especially for simvastatin. Studies show that in
livers with the reference (wild-type) genotype (homozygous C or CC) the CYP3A4 mRNA level and
enzyme activity were 1.7- and 2.5-fold greater than in CYP3A4*22 heterozygotes (CT) and homozygotes
(TT), respectively. In 235 patients taking stable doses of drugs for lipid control, carriers of the T allele
required significantly lower statin doses for optimal lipid control than did non-T carriers.(2) These results
indicate that CYP3A4*22 markedly affects expression of CYP3A4 and could serve as a biomarker for
CYP3A4 metabolizer phenotype. The reported allele frequency of CYP3A4*22 is 5% to 8% in the white
population and 4.3% in African American and Chinese populations. Other alleles have not been as
extensively studied in clinical trials but are expected to have similar impacts on statin metabolism and the
metabolism of other drugs primarily metabolized by CYP3A4. The following table displays the CYP3A4
variants detected by this assay, the corresponding star allele, and the effect on CYP3A4 enzyme activity.
Individuals without a detectable CYP3A4 variant are designated as CYP3A4*1/*1. CYP3A4 allele cDNA
nucleotide change (NM_017460.5) Effect on enzyme activity *1 None (wild type) Normal activity *8
c.389G>A No activity *11 c.1088C>T Reduced activity *12 c.1117C>T Reduced activity *13 c.1247C>T
No activity *16 c.554C>G Minimal activity *17 c.566T>C No activity *18 c.878T>C Reduced activity
*22 c.522-191C>T Reduced activity *26 c.802C>T No activity Genotype to phenotype predictions are
based on the Pharmacogene Variation Consortium website (3) and review of the CYP3A4 literature.
Useful For: Aids in determining therapeutic strategies for drugs that are metabolized by cytochrome
P450 3A4, including atorvastatin, simvastatin, and lovastatin This test is not useful for managing
patients receiving fluvastatin, rosuvastatin, or pravastatin since these drugs are not metabolized
appreciably by CYP3A4.
Consortium.(3) For additional information regarding pharmacogenomic genes and their associated
drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also
includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug
choices.
Reference Values:
Clinical References: 1. Evans WE, Relling MV. Pharmacogenomics: translating functional

genomics into rational therapeutics. Science. 1999;286(5439):487-491. doi:
10.1126/science.286.5439.487 2. Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic
polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics
J. 2011;11(4):274-286. doi:10.1038/tpj.2010.28 3. PharmVar: Pharmacogene Variation Consortium.
Updated March 3, 2021. Accessed March 22, 2021. Available at www.pharmvar.org/ 4. Lamba JK, Lin
YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism.
Adv Drug Deliv Rev. 2002;54(10):1271-1294. doi: 10.1016/s0169-409x(02)00066-2 5. Elens L, Becker
ML, Haufroid V, et al. Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with
simvastatin-mediated cholesterol reduction in the Rotterdam Study. Pharmacogenet Genomics.
2011;21(12):861-866. doi: 10.1097/FPC.0b013e32834c6edb 6. Elens L, van Schaik RH, Panin N, et al.
Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and
trough blood levels in stable renal transplant patients. Pharmacogenomics. 2011;12(10):1383-1396. doi:
10.2217/pgs.11.90 7. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed October
14, 2020. https://cpicpgx.org/

610047 Clinical Information: CYP3A5 is a member of the CYP3A family of genes located on
chromosome 7. The cytochrome P450 (CYP) 3A subfamily of enzymes responsible for the metabolism
of more than 50% of medications that undergo hepatic metabolism and first-pass metabolism in
intestinal epithelial cells. The CYP3A5 expression level and enzymatic activity can be modulated by
genetic variation. CYP3A5 allelic frequency depends upon ethnicity. For example, in individuals of
European descent the most common allele is the CYP3A5*3 allele (c.219-237A>G), which results in a
splicing defect and absence of enzyme activity. In individuals of African descent, the *1 allele
(functional enzyme) is most common. The distribution of CYP3A5*3 allele frequencies ranges from
0.14 among sub-Saharan Africans to 0.95 in European populations. CYP3A5 testing is commonly
ordered for patients receiving tacrolimus. Tacrolimus is an immunosuppressive calcineurin inhibitor
used in transplant recipients. Tacrolimus has a low therapeutic index with a wide range of side effects
and large interindividual variability in its pharmacokinetics, particularly in the dose required to reach
target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical
practice. Tacrolimus dose requirements are most closely associated with CYP3A5 genotype even
though the drug is metabolized by both CYP3A4 and CYP3A5. According to existing literature and
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, individuals with at least one
copy of fully functional CYP3A5 (ie, *1/*1 and *1/*3) require a higher dose of tacrolimus to reach the
targeted whole blood concentrations than those without a copy of a fully functional CYP3A5 allele (ie,
*3/*3) (2-5). CYP3A5 genotyping may predict dose requirements for tacrolimus but does not replace
the need for therapeutic monitoring to guide tacrolimus dose adjustments. For a patient with the
CYP3A5*3/*3 genotype, initiating tacrolimus therapy with a standard (normal) dose is recommended.
One of the complications in interpreting CYP3A5 genotyping results and the effect of genotype on drug
dosing is the fact that most individuals involved in drug trials have been of European decent.
Individuals of European decent are more likely to have the CYP3A5*3/*3 genotype, which predicts a
poor metabolizer phenotype. Dosing requirements were derived from these clinical trials so individuals
with 1 or 2 copies of CYP3A5*1, will functionally behave as though they have increased activity and
may require higher doses of CYP3A5 metabolized drugs. The following table displays the CYP3A5
variants detected by this assay, the corresponding star allele, and the effect on CYP3A5 enzyme
activity: CYP3A5 allele cDNA nucleotide change (NM_000777.4) Effect on enzyme activity *1 None
(wild type) Normal activity *3 c.219-237A>G No activity *5 c.432+2T>C No activity *6 c.624G>A No
activity *7 c.1035dup No activity *8 c.82C>T Reduced activity *9 c.1009G>A Reduced activity
Useful For: Aids in optimizing treatment with tacrolimus and other drugs metabolized by cytochrome
P450 3A5
assigned using standard allelic nomenclature as published by Pharmacogene Variation (PharmVar)
see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes
information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.
Reference Values:

Accessed March 22, 2021. Available at www.pharmvar.org/ 2. Birdwell KA, Decker B, Barbarino JM, et
al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and
Tacrolimus Dosing. Clin Pharmacol Ther. 2015;98(1):19-24. doi: 10.1002/cpt.113 3. Thervet E, Loriot
MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin
Pharmacol Ther. 2010;87(6):721-726. doi: 10.1038/clpt.2010.17 4. Lamba J, Hebert JM, Schuetz EG,
Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for CYP3A5.
Pharmacogenet Genomics. 2012;22(7):555-558. doi: 10.1097/FPC.0b013e328351d47f 5. Clinical
Pharmacogenetics Implementation Consortium (CPIC). Accessed October 14, 2020. https://cpicpgx.org/
FCYTP Cytokine Panel 13

75139 Interpretation: Results are used to understand the pathophysiology of immune, infectious, or
inflammatory disorders, or may be used for research purposes.
Reference Values:
Tumor Necrosis Factor-alpha 7.2Â pg/mL or less
Interleukin 2 2.1 pg/mL or less
Interleukin 2 Receptor Soluble 175.3 pg/mL to 858.2 pg/mL
Interleukin 12 1.9 pg/mL or less
Interferon gamma 4.2 pg/mL or less
Interleukin 4 2.2Â pg/mL or less
Interleukin 1 beta 6.7Â pg/mL or less
CYPAN Cytokine Panel, Plasma

610259 Clinical Information: Cytokines are important mediators of cell-to-cell communication within the
innate and adaptive immune systems. The expression of most cytokines is highly regulated and
generally occurs in response to foreign or self-antigenic stimulation. The functions of cytokines are
extremely varied, with many cytokines also displaying pleiotropic effects, depending on their cellular
target. Some cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1 beta, IL-6, interferon
(IFN)-alpha and beta, IL-10, and IL-18 are particularly important in the innate immune response. For
example, TNF, IL-1 beta, and IL-6 induce expression of acute phase proteins in the liver. TNF and IL-1
beta also lead to endothelial activation and are critical regulators of the hypothalamus, which can result
in elevated body temperature. IL-6, in comparison, is a bridge to the adaptive immune response, by
acting on B cells to induce proliferation. In contrast, IFN-alpha and IFN-beta (members of the type I
IFN family) are key components of the innate immune response to viral infections. IFN-gamma, which
is a type II IFN, has roles in both the innate and adaptive immune responses, including macrophage
activation, induction of B-cell isotype switching, and T helper type 1 cell differentiation. Other
cytokines, such as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory
protein-1alpha (MIP-1alpha), are categorized as chemokines because they function primarily to attract
leukocytes to the site of inflammation. Further, some cytokines act on hematopoietic stem cells to
induce differentiation of various leukocytes. For example, granulocyte-monocyte colony stimulating
factor (GM-CSF) induces myeloid progenitor cells to differentiate into neutrophils and monocytes.
Lastly, for some cytokines, soluble forms of the receptor can be found in the peripheral circulation. The
IL-2 soluble receptor is produced from proteolytic cleavage of the membrane-bound receptor, which
occurs during T-cell activation. As a group, cytokines and their receptors represent a highly complex
and critical regulator of a normal immune response.
Useful For: Understanding the etiology of infectious or chronic inflammatory diseases, when used in
conjunction with clinical information and other laboratory testing Research studies in which an
assessment of cytokine responses is needed
Interpretation: Elevated cytokine concentrations could be consistent with the presence of infection
or other inflammatory process.
Reference Values:
Tumor necrosis factor: <10.0 pg/mL
Interleukin (IL)-6: <5.0 pg/mL
Interferon (IFN)-beta: <20.0 pg/mL
IL-10: <7.0 pg/mL
Monocyte chemoattractant protein-1: < or =198 pg/mL
IL-1 beta: <20.0 pg/mL
IFN-gamma: <60.0 pg/mL
Macrophage inflammatory protein-1 alpha: <220 pg/mL
Granulocyte-monocyte colony stimulating factor: <15.0 pg/mL
IL-2 receptor alpha soluble: < or =959 pg/mL
IFN-alpha: <20.0 pg/mL
IL-18: < or =468 pg/mL
Clinical References: 1. Bozza FA, Salluh JI, Japiassu AM, et al: Cytokine profiles as markers of
disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11(2):R49. doi: 10.1186/cc5783.Â 2.
Milman N, Karsh J, Booth RA: Correlation of a multi-cytokine panel with clinical disease activity in
patients with rheumatoid arthritis. Clin Biochem. 2010;43(16-17):1309-1314. doi:
10.1016/j.clinbiochem.2010.07.012. 3. Teijara JR: Type I interferons in viral control and immune
regulation. Curr Opin Virol. 2016;16: 31-40. doi: 10.1016/j.coviro.2016.01.001. 4. Tisoncki JR, Korth
MJ, Simmons CP, Farrar J, Martin TR, Katze MG: Into the eye of the cytokine storm. Microbiol Mol
Biol Rev. 2010;76(1):16-32. doi: 10.1128/MMBR.05015-11.Â 5. Garcia Borrega J, Godel P, Ruger,
MA, et al: In the eye of the storm: Immune-mediated toxicities associated with CAR-T cell therapy.
Hemasphere. 2019;3(2):e191. doi: 10.1097/HS9.0000000000000191.Â
CFNPC Cytology FNA (Bill Only)

CTPPC Cytology Touch Prep (Bill Only)

CTAPC Cytology Touch Prep Additional (Bill Only)

CMVG Cytomegalovirus (CMV) Antibodies, IgG, Serum

34970 Clinical Information: Cytomegalovirus (CMV) is a member of the Herpesviridae family of viruses
and usually causes asymptomatic infection after which it remains latent in patients, primarily within bone
marrow-derived cells.(1) Primary CMV infection in immunocompetent individuals may also manifest as a
mononucleosis-type syndrome, similar to primary Epstein-Barr virus infection, with fever, malaise, and
lymphadenopathy. CMV is a significant cause of morbidity and mortality among bone marrow or solid
organ transplant recipients, individuals with AIDS, and other immunosuppressed patients due to virus
reactivation or from a newly acquired infection.(2,3) Infection in these patient populations can affect
almost any organ and lead to multiorgan failure. CMV is also responsible for congenital disease among
newborns and is one of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella,
CMV, and herpes simplex virus). CMV seroprevalence increases with age. In the United States the
prevalence of CMV specific antibodies increases from approximately 36% to over 91% in children
between the ages of 6 to 11 and adults over 80 years old, respectively.(4)
Useful For: Determining whether a patient (especially transplant recipients, organ and blood donors)
has had a recent infection or previous exposure to cytomegalovirus
Interpretation: Positive cytomegalovirus (CMV) IgG results indicate past or recent CMV infection.
These individuals may transmit CMV to susceptible individuals through blood and tissue products.
Equivocal CMV IgG results may occur during acute infection or may be due to nonspecific binding
reactions. Submit an additional sample for testing if clinically indicated. Individuals with negative CMV
IgG results are presumed to not have had prior exposure or infection with CMV and are, therefore,
considered susceptible to primary infection.
Reference Values:
Negative (reported as positive, negative, or equivocal)
Clinical References: 1. Soderberg-Naucler C, Fish KN, Nelson JA: Reactivation of latent human
cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. 1997 Oct
3;91(1):119-126. 2. Kusne S, Shapiro R, Fung J: Prevention and treatment of cytomegalovirus infection
in organ transplant recipients. Transpl Infect Dis. 1999;1(3):187-203 3. Rubin RH: Importance of CMV
in the transplant population. Transpl Infect Dis. 1999;1(1):3-7 4. Staras SA, Dollard SC, Radford KW,
Flanders WD, Pass RF, Cannon MJ: Seroprevalence of cytomegalovirus infection in the United States,
1998-1994. Clin Infect Dis 2006;43(9):1143-151 5. Bruminhent J, Thongprayoon C, Dierkhising RA,
Kremers WK, Theel ES, Razonable RR: Risk factors for cytomegalovirus reactivation after liver
transplantation: can pre-transplant cytomegalovirus antibody titers predict outcome? Liver Transpl.
2015;21(4):539-546 6. Dioverti MV, Razonable RR: Cytomegalovirus. Microbiol Spectr. 2016;4(4).
doi: 10.1128/microbiolspec.DMIH2-0022-2015.
CMVP Cytomegalovirus (CMV) Antibodies, IgM and IgG, Serum

and usually causes asymptomatic infection after which it remains latent in patients, primarily within
bone marrow derived cells. Primary CMV infection in immunocompetent individuals may manifest as a
mononucleosis-type syndrome, similar to primary Epstein-Barr virus infection, with fever, malaise and
reactivation or from a newly acquired infection. Infection in these patient populations can affect almost
any organ and lead to multiorgan failure. CMV is also responsible for congenital disease among
newborns and is one of the TORCH infections (toxoplasmosis, other infections including syphilis,
rubella, CMV, and herpes simplex virus). CMV seroprevalence increases with age. In the United States,
the prevalence of CMV-specific antibodies increases from approximately 36% to over 91% in children
between 6 to 11 years of age and adults over 80 years old, respectively.
Useful For: Aiding in the diagnosis of acute or past infection with cytomegalovirus (CMV)
Determination of prior exposure to CMV This test should not be used for screening blood or plasma
donors.
Interpretation: IgM: A negative cytomegalovirus (CMV) IgM result suggests that the patient is not
experiencing acute or active infection. However, a negative result does not rule-out primary CMV
infection. It has been reported that CMV-specific IgM antibodies were not detectable in 10% to 30% of
cord blood sera from infants demonstrating infection in the first week of life. In addition, up to 23%
(3/13) of pregnant women with primary CMV infection did not demonstrate detectable CMV IgM
responses within 8 weeks postinfection. In cases of primary infection where the time of seroconversion
is not well defined as high as 28% (10/36) of pregnant women did not demonstrate CMV IgM antibody.
Positive CMV IgM results indicate a recent infection (primary, reactivation, or reinfection). IgM
antibody responses in secondary (reactivation) CMV infections have been demonstrated in some CMV
mononucleosis patients, in a few pregnant women, and in renal and cardiac transplant patients. Levels
of antibody may be lower in transplant patients with secondary rather than primary infections. IgG:
Positive CMV IgG results indicate past or recent CMV infection. These individuals may transmit CMV
to susceptible individuals through blood and tissue products. Individuals with negative CMV IgG results
are presumed to not have had prior exposure or infection with CMV and are, therefore, considered
susceptible to primary infection. Equivocal CMV IgM or IgG results may occur during acute infection
or may be due to nonspecific binding reactions. Submit an additional sample for testing if clinically
indicated.
Reference Values:
CYTOMEGALOVIRUS IgM:
Negative
CYTOMEGALOVIRUS IgG:
Negative
Clinical References: 1. Soderberg-Naucler C, Fish NK, Nelson JA: Reactivation of latent human
cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997 Oct
3;91(1):119-126 2. Bruminhent J, Thongprayoon C, Dierkhising RA, Kremers WK, Theel ES, Razonable
RR: Risk factors for cytomegalovirus reactivation after liver transplantation: can pre-transplant
cytomegalovirus antibody titers predict outcome? Liver Transpl. 2015;21(4):539-546 3. Dioverti MV,
Razonable RR: Cytomegalovirus. Microbiol Spectr. 2016;4(4) 4. Staras SA, Dollard SC, Radford KW,
Flanders WD, Pass RF, Cannon MJ: Seroprevalence of cytomegalovirus infection in the United States,
1998-1994. Clin Infect Dis. 2006;43(9):1143
CMVM Cytomegalovirus (CMV) Antibodies, IgM, Serum

and usually causes asymptomatic infection after which it remains latent in patients, primarily within bone
marrow-derived cells. Primary CMV infection in immunocompetent individuals may also manifest as a
mononucleosis-type syndrome, similar to primary Epstein-Barr virus infection, with fever, malaise, and
reactivation or from a newly acquired infection. Infection in these patient populations can affect almost
any organ and lead to multiorgan failure. CMV is also responsible for congenital disease among newborns
and is 1 of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and
herpes simplex virus). CMV seroprevalence increases with age. In the United States, the prevalence of
CMV specific antibodies increases from approximately 36% to over 91% in children between the ages of
6 to 11 and adults over 80 years old, respectively.
Useful For: Aiding in the diagnosis of acute infection with cytomegalovirus This test should not be
used for screening blood or plasma donors.
Interpretation: A negative cytomegalovirus (CMV) IgM result suggests that the patient is not
experiencing acute or active infection. However, a negative result does not rule-out primary CMV
infection. It has been reported that CMV-specific IgM antibodies were not detectable in 10% to 30% of
cord blood sera from infants demonstrating infection in the first week of life. In addition, up to 23%
(3/13) of pregnant women with primary CMV infection did not demonstrate detectable CMV IgM
responses within 8 weeks postinfection. In cases of primary infection where the time of seroconversion is
not well defined as high as 28% (10/36) of pregnant women did not demonstrate CMV-IgM antibody.
Positive CMV IgM results indicate a recent infection (primary, reactivation, or reinfection). IgM antibody
responses in secondary (reactivation) CMV infections have been demonstrated in some CMV
mononucleosis patients, in a few pregnant women, and in renal and cardiac transplant patients. Levels of
antibody may be lower in transplant patients with secondary, rather than primary, infections. Equivocal
CMV IgM results may occur during acute infection or may be due to nonspecific binding reactions.
Submit an additional sample for testing if clinically indicated.
Reference Values:
Negative
Clinical References: 1. Soderberg-Naucler C, Fish KN, Nelson JA: Reactivation of latent human
cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. 1997 Oct 3;91(1):119-126.
2. Bruminhent J, Thongprayoon C, Dierkhising RA, Kremers WK, Theel ES, Razonable RR: Risk factors
for cytomegalovirus reactivation after liver transplantation: can pre-transplant cytomegalovirus antibody
titers predict outcome? Liver Transpl. 2015;21(4):539-546 3. Dioverti MV, Razonable RR:
Cytomegalovirus. Microbiol Spectr. 2016;4(4). doi: 10.1128/microbiolspec.DMIH2-0022-2015. 4. Staras
SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ: Seroprevalence of cytomegalovirus
infection in the United States, 1998-1994. Clin Infect Dis 2006;43(9):1143-1151
CMVQN Cytomegalovirus (CMV) DNA Detection and Quantification by
601954 Real-Time PCR, Plasma
Clinical Information: Cytomegalovirus (CMV) is a common and major cause of opportunistic
infection in organ transplant recipients, causing significant morbidity and mortality. CMV infection and
disease typically occur during the first year after organ transplantation after cessation of antiviral
prophylaxis. Such infection usually manifests as fever, leukopenia, hepatitis, colitis, or retinitis. Other
manifestations of CMV infection in this population may be more subtle and include allograft injury and
loss, increased susceptibility to infections with other organisms, and decreased patient survival (ie,
indirect effects). The risk of CMV disease is highest among organ recipients who are CMV seronegative
prior to transplantation and receive allografts from CMV-seropositive donors (ie, CMV D+/R-
mismatch). The infection is transmitted via latent CMV present in the transplanted organ donor and the
virus subsequently reactivates, causing a primary CMV infection in the recipient. CMV disease may
also occur from reactivation of the virus already present within the recipients. Factors, such as the type
of organ transplanted, intensity of the antirejection immunosuppressive therapy, advanced age, and
presence of comorbidities in the recipient, are also associated with increased risk for CMV disease after
allograft transplantation. Lung, heart, small intestine, pancreas, and kidney-pancreas transplant
recipients are at greater risk for CMV infection than kidney and liver transplant recipients. Among the
various clinical laboratory diagnostic tests currently available to detect CMV infection, nucleic acid
amplification tests (eg, polymerase chain reaction: PCR) are the most sensitive and specific detection
methods. In addition, quantification of CMV DNA level in peripheral blood (ie, CMV viral load) is
used routinely to determine when to initiate preemptive antiviral therapy, diagnose active CMV disease,
and monitor response to antiviral therapy. A number of factors can affect CMV viral load results,
including the specimen type (whole blood versus plasma), biologic properties of CMV, performance
characteristics of the quantitative assay (eg, limit of detection, limits of quantification, linearity, and
reproducibility), degree of immunosuppression, and intensity of antiviral therapy. In general, higher
CMV viral loads are associated with tissue-invasive disease, while lower levels are associated with
asymptomatic infection. However, the viral load in the peripheral blood compartment may be low or
undetectable in some cases of tissue-invasive disease. Since a wide degree of overlap exists in CMV
viral load and disease, a rise in viral load over time is more important in predicting CMV disease than a
single viral load result at a given time point. Therefore, serial monitoring (eg, weekly intervals) of organ
transplant recipients with quantitative CMV PCR is recommended in such patients at risk for CMV
disease. Since changes in viral load may be delayed by several days in response to antiviral therapy and
immunosuppression, viral load should not be monitored more frequently than a weekly basis. Typically,
CMV viral load changes of greater than 0.5 log IU/mL are considered biologically significant changes
in viral replication. Patients with suppression of CMV replication (ie, viral load of <35 or <1.54 log
IU/mL at days 7, 14, and 21 of treatment) had shorter times to resolution of clinical disease than those
without viral suppression. No degree of relative viral load reduction from pretreatment level was
associated with faster resolution of CMV disease.
Useful For: Detection and quantification of cytomegalovirus (CMV) viremia Monitoring CMV
disease progression and response to antiviral therapy
log IU/mL), with a 95% or higher limit of detection at 35 IU/mL. A result of "Undetected" indicates the
absence of cytomegalovirus (CMV) DNA in the plasma (see Cautions below). A result of "<35 IU/mL
(<1.54 log IU/mL)" indicates that CMV DNA is detected in the plasma, but the assay cannot accurately
quantify the CMV DNA present below this level. A quantitative value (reported in IU/mL and log
IU/mL) indicates the level of CMV DNA (ie, viral load) present in the plasma. A result of ">10,000,000
IU/mL (>7.00 log IU/mL)" indicates that CMV DNA level present in plasma is above 10,000,000
IU/mL (7.00 log IU/mL), and the assay cannot accurately quantify CMV DNA present above this level.
Reference Values:
Undetected
Clinical References: 1. Kotton CN, Kumar D, Caliendo AM, et al: International consensus
guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010
Apr 15;89(7):779-795 2. Kraft CS, Armstrong WS, Caliendo AM: Interpreting quantitative
cytomegalovirus DNA testing: understanding the laboratory perspective. Clin Infect Dis. 2012
Jun;54(12):1793-1797 3. Razonable RR, Asberg A, Rollag H, et al: Virologic suppression measured by
a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization international standard
is predictive of CMV disease resolution in transplant recipients. Clin Infect Dis. 2013
Jun;56(11):1546-1553
CMVNG Cytomegalovirus (CMV) Drug Resistance, Next-Generation

603607 Sequencing, Plasma
Clinical Information: Cytomegalovirus (CMV) is a DNA virus with a seroprevalence of
approximately 50% in the United States. Acute infection can be asymptomatic or cause a
mononucleosis-like illness in immunocompetent individuals. After acute infection, the virus enters a
latent state. Reactivation of the virus can occur, particularly if a patient becomes immunosuppressed.
Immunosuppressed patients are also at higher risk of severe acute infection. CMV disease may range from
congenital disease, retinitis, inflammation of the gastrointestinal tract, encephalitis, and pneumonia.
Treatment for CMV typically involves antiviral drugs as well as decreasing the degree of
immunosuppression (if applicable and medically advisable). Currently, anti-CMV drugs bind and inhibit
either a viral kinase (UL97 gene product) or a viral DNA polymerase (UL54 gene product). There are a
number of assays available to test for the presence of CMV. Quantitative assays report the concentration
of CMV DNA present and can be used to monitor the viral load in patients who are at risk of CMV
disease as well as assess response to antiviral therapy. A rising CMV viral load (ie, increase of 0.5 log or
more between samples) correlates with an increased risk of CMV disease and may indicate treatment
failure (ie, due to antiviral resistance) if the patient is on appropriate therapy. Variants in UL97 and UL54
have been associated with antiviral resistance. This test uses next-generation sequencing (NGS) to analyze
the sequence of UL97 and UL54. Identified variants are reported if they have been previously associated
with CMV antiviral resistance and are present in at least 15% of the sequences analyzed. This assay uses a
database of known resistance-associated variants that is periodically updated with new variants that are
reported in the scientific literature.
Useful For: Detecting variants in the cytomegalovirus genes, UL97 and UL54, which are associated
with antiviral resistance This test is not useful for the initial diagnosis of CMV infection
Interpretation: If a resistance-associated variant is detected, a patient's antiviral regimen may need to

be adjusted for optimal response. If no resistance-associated variants are detected, it is still important to
assess the patient's clinical response and quantitative viral load before determining that the infecting virus
is susceptible to a treatment regimen (see Cautions). Predicted drug resistance is reported separately for
each antiviral drug. Predicted resistance to one antiviral may or may not be associated with predicted
cross-resistance to other drugs.
Reference Values:
None Detected/Not Predicted
Clinical References: 1. Chou S, Ercolani RJ, Sahoo MK, et al: Improved detection of emerging
drug-resistant mutant cytomegalovirus subpopulations by deep sequencing. Antimicrob Agents
Chemother. 2014 Aug;58(8):4697-4702 2. Garrigue I, Moulinas R, Recordon-Pinson P, et al:
Contribution of next generation sequencing to early detection of cytomegalovirus UL97 emerging mutants
and viral subpopulations analysis in kidney transplant recipients. J Clin Virol. 2016 Jul;80:74-81 3.
Razonable RR: Drug-resistant cytomegalovirus: clinical implications of specific mutations. Curr Opin
Organ Transplant. 2018 Aug;23(4):388-394 4. Houldcroft CJ, Bryant JM, Depledge DP, et al: Detection
of low frequency multi-drug resistance and novel putative maribavir resistance in immunocompromised
pediatric patients with cytomegalovirus. Front Microbiol. 2016 Sep 9;7:1317
CMVI Cytomegalovirus (CMV) Immunostain, Technical Component

70406 Only
Clinical Information: Cytomegalovirus (CMV) stain visualizes the intranuclear and cytoplasmic
viral inclusions of CMV-infected cells. CMV can cause severe systemic infection (primary or reactivated
infection) in patients who are immunocompromised. Antibodies to cytomegalovirus fail to react with any
normal human tissue.
Useful For: Identification of cytomegalovirus infection

the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist
interpretation is required, order PATHC / Pathology Consultation for a full diagnostic evaluation or
second opinion of the case. The positive and negative controls are verified as showing appropriate
included on the slide, a scanned image of the relevant quality control tissue is available upon request,
call 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical
Clinical References: 1. Johnson J, Affolter K, Boynton K, et al: CMV disease in IBD:

Comparison of diagnostic tests and correlation with disease outcome. Inflamm Bowel Dis. 2018 Jun
8;24(7):1539-1546. doi: 10.1093/ibd/izy045 2. Agnarsdottir M, Popova S, Alafuzoff I: Expression of
CMV protein pp65 in cutaneous malignant melanoma. PLoS One. 2019 Oct 11;14(10):e0223854. doi:
10.1371/journal.pone.0223854 3. Jung KH, Kim J, Lee HS, et al: Clinical Implications of the
CMV-Specific T-Cell Response and Local or Systemic CMV Viral Replication in Patients With
Moderate to Severe Ulcerative Colitis. Open Forum Infect Dis. 2019 Dec 18;6(12):ofz526. doi:
10.1093/ofid/ofz526
LCMV Cytomegalovirus (CMV), Molecular Detection, PCR, Varies

81240 Clinical Information: Infection with cytomegalovirus (CMV) is a significant cause of morbidity
and mortality in transplant recipients and other immunocompromised hosts. Specific neurologic
syndromes associated with CMV infection include subacute radiculomyelopathy, peripheral neuropathy,
and encephalitis. CMV-associated central nervous system (CNS) disease occurs most commonly in
immunocompromised patients. Histologic evidence of CMV infections in autopsy brain tissue was
identified in 20% to 40% of AIDS patients. In 2 separate studies, CMV (DNA) was the most common
herpesvirus (29/181, 16/49) detected from cerebrospinal fluid of patients with AIDS. CNS infections
with CMV can also occur in immunocompetent patients. CMV is a leading cause of congenital viral
infections worldwide, and laboratory testing by real-time PCR is useful in the diagnosis of neonatal
CMV disease.
Useful For: Rapid qualitative detection of cytomegalovirus (CMV) DNA This test is not intended for
the monitoring of cytomegalovirus (CMV) disease progression.
Interpretation: Detection of cytomegalovirus (CMV) DNA in a specimen supports the clinical

diagnosis of infection due to this virus. Studies indicate that CMV DNA is not detected by PCR in
cerebrospinal fluid from patients without central nervous system disease caused by this virus.
Reference Values:
Negative
Clinical References: 1. Espy M, Binnicker MJ: Comparison of six real-time PCR assays for the
qualitative detection of cytomegalovirus in clinical specimens. J Clin Microbiol 2013:51(11):3749-3752
2. Petito CK, Cho ES, Lemann W, et al: Neuropathy of acquired immunodeficiency syndrome (AIDS):
an autopsy review. J Neuropathol Exp Neurol 1986 November;45(6):635-646 3. Cinque P, Vago L,
Dahl H, et al: Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated
opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996
August;10(9):951-958 4. Broccolo F, Iulioano R, Careddu AM, et al: Detection of lymphotropic
herpesvirus DNA by polymerase chain reaction in cerebrospinal fluid of AIDS patients with
neurological disease. Acta Virol 2000 June-August;44(3):137-143 5. Prosch S, Schielke E, Reip A, et
al: Human cytomegalovirus (HCMV) encephalitis in an immunocompetent young person and diagnostic
reliability of HCMV DNA PCR using cerebrospinal fluid of nonimmunosuppressed patients. J Clin
Microbiol 1998 December;36(12):3636-3640 6. Sia IG, Patel R: New strategies for prevention and
therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol
Rev 2000;13:83-121
FCYTG Cytomegalovirus IgG Avidity

75445 Clinical Information: Discrimination between recent (primary) and past cytomegalovirus (CMV)
infection can be an important tool in the clinical management of pregnant women. Although nearly all
individuals with recent CMV infection are positive for CMV IgM, individuals with past CMV may also
express CMV IgM due to long-term IgM persistence or viral reactivation; thus, detection of CMV IgM is
not a reliable indicator of recent CMV infection. Measurement of CMV IgG avidity can assist in
discriminating recent from past CMV infection. A low avidity index is a reliable indicator of CMV
infection within the previous 6 months, a high avidity index essentially excludes the possibility that
infection occurred within the previous 4 months. Avidity index values should be considered within the
context of other laboratory findings and clinical signs.
Interpretation: < 0.60Â Low Avidity Index 0.60 - 0.70Â Intermediate Avidity Index > 0.70Â High
Avidity Index
Reference Values:
> 0.70
ANCA2 Cytoplasmic Neutrophil Antibodies, Inflammatory Bowel

610030 Disease Panel, Serum
Clinical Information: Inflammatory bowel disease (IBD) refers to 2 diseases-ulcerative colitis (UC)
and Crohn disease (CD), both of which result from chronic inflammation in the gastrointestinal (GI)
tract.(1) CD is characterized by chronic diarrhea, abdominal pain, and fatigue.(2) In comparison, UC
frequently presents with bloody diarrhea that is of an urgent nature.(3) Inflammation in UC most
frequently affects the rectum and proximal colon and presents with continue mucosal involvement. In CD,
inflammation can affect almost any area of the GI tract and is usually evidenced as patchy, transmural
lesions. Diagnosis of IBD is primarily based on clinical evaluation, endoscopy with biopsy, and imaging
studies.(4) Because CD and UC are characterized by GI inflammation, fecal calprotectin can be used to
differentiate IBD from noninflammatory conditions such as irritable bowel syndrome (IBS). Fecal
calprotectin is useful in excluding IBD as a diagnosis and avoiding unnecessary endoscopic or imaging
procedures. CD and UC are associated with the presence of various antimicrobial and autoantibodies.(5)
Patients with UC often have measurable antineutrophil cytoplasmic antibodies (ANCA), which react with
as yet uncharacterized target antigens in human neutrophils; in contrast, patients with CD often have
measurable IgA and/or IgG antibodies, which react with cell wall mannan of Saccharomyces cerevisiae.
Despite these associations, current guidelines indicate that testing for these antibodies is not sufficiently
sensitive for use in the diagnosis of IBD.(2,3) Rather, these antibodies should be limited to distinguishing
between CD and UC in cases where the specific diagnosis is unclear based on pathologic and imaging
studies.
Useful For: Measurement of antineutrophil cytoplastic antibodies as a part of a profile to aid in

distinguishing between ulcerative colitis and Crohn disease in patients for whom the specific diagnosis is
unclear based on endoscopic, pathologic, and imaging evaluations This test is not useful for determining
the extent of disease in patients with inflammatory bowel disease or determining the response to
disease-specific therapy including surgical resection of diseased intestine.
Interpretation: The presence of antineutrophil cytoplasmic antibodies (ANCA) in the absence of IgA
and IgG anti-Saccharomyces cerevisiae antibodies (ASCA) is consistent with the diagnosis of ulcerative
colitis; the presence of IgA and IgG ASCA in the absence of ANCA is consistent with Crohn disease.
Reference Values:
Only orderable as part of a profile. For more information see IBDP2 / Inflammatory Bowel Disease
Serology Panel, Serum.
Clinical References: 1. Rose NR, Mackay IR, eds. Inflammatory bowel diseases. In: The
Autoimmune Diseases. Elsevier; 2008 2. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson
LB, Sands BE: ACG Clinical Guideline: Management of Crohn's disease in adults. Am J Gastroenterol.
2018 Apr;113(4):481-517 3. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD: ACG
Clinical Guideline: Ulcerative colitis in adults. Am J Gastroenterol. 2019 Mar;114(3):384-413 4. Clark C,
Turner J: Diagnostic modalities for inflammatory bowel disease: Serologic markers and endoscopy. Surg
Clin North Am. 2015 Dec;95(6):1123-1141 5. Zhou G, Song Y, Yang W, et al: ASCA, ANCA, ALCA
and many more: Are they useful in the diagnosis of inflammatory bowel disease? Dig Dis.
2016;34(1-2):90-97
ANCA Cytoplasmic Neutrophil Antibodies, Serum

9441 Clinical Information: Antineutrophil cytoplasmic antibodies (ANCA) can occur in patients with
small blood vessel vasculitis including granulomatosis with polyangiitis (GPA), microscopic
polyangiitis (MPA), or eosinophilic granulomatosis with polyangiitis (EGPA), collectively referred to
as ANCA-associated vasculitis (AAV).(2) Detection of ANCA is a well-established diagnostic test for
the evaluation of patients suspected of having AAV.(3) ANCA react with enzymes in the cytoplasmic
granules of human neutrophils including proteinase 3 (PR3), myeloperoxidase (MPO), elastase, and
cathepsin G amongst others. Of these, PR3-ANCA and MPO-ANCA are the best characterized in AAV.
Antibodies to PR3-ANCA occur in patients with GPA and produce a characteristic pattern of granular
cytoplasmic fluorescence on ethanol-fixed neutrophils called the cANCA pattern. Antibodies to
MPO-ANCA occur predominately in patients with MPA and produce a pattern of perinuclear
cytoplasmic fluorescence on ethanol-fixed neutrophils called the pANCA pattern.(4) EPGA may be
pANCA positive with reactivity to MPO-ANCA or negative for ANCA. The pANCA pattern may also
be observed in patients with inflammatory bowel disease, predominantly ulcerative colitis, usually in
the absence of detectable MPO-ANCA reactivity.
Useful For: Evaluating patients suspected of having ANCA-associated vasculitis (granulomatosis

with polyangiitis and microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis)
Interpretation: Positive results for antineutrophil cytoplasmic antibodies (ANCA) demonstrate two
main patterns namely; cytoplasmic (cANCA) and perinuclear (pANCA) in a compendium of small
vessel vasculitis collectively referred to as ANCA-associated vasculitis (AAV) that includes
granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with
polyangiitis. Negative ANCA results do not rule out a diagnosis of AAV or irritable bowel disease.
Reference Values:
Negative
If positive for antineutrophil cytoplasmic antibodies, results are titered.
Clinical References: 1.Savige J, Gillis D, Benson E, et al: International consensus statement on

testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol.
1999:111;507-513 2. Kitching AR, Anders HJ, Basu N, et al: ANCA-associated vasculitis. Nat Rev Dis
Primers. 2020 Aug;6(1);71 3. Ramponi G, Folci M, De Santis M, et al: The biology, pathogenetic role,
clinical implications, and open issues of serum anti-neutrophil cytoplasmic antibodies. Autoimmun Rev.
2021 Mar;20(3):102759 4. Guchelaar NAD, Waling MM, Adhin AA, et al: The value of anti-neutrophil
cytoplasmic antibodies (ANCA) testing for the diagnosis of ANCA-associated vasculitis, a systematic
review and meta-analysis. Autoimmun Rev. 2021 Jan:20;102716
DDITT D-Dimer, Plasma

40936 Clinical Information: The specific degradation of fibrin (ie, fibrinolysis) is the reactive mechanism
responding to the formation of fibrin. Plasmin is the fibrinolytic enzyme derived from inactive
plasminogen. Plasminogen is converted into plasmin by plasminogen activators. The main plasminogen
activators are tissue plasminogen activator (tPA) and pro-urokinase, which is activated into urokinase
(UK) by, among others, the contact system of coagulation. In the bloodstream, plasmin is rapidly and
specifically neutralized by alpha-2-antiplasmin, thereby restricting its fibrinogenolytic activity and
localizes the fibrinolysis on the fibrin clot. On the fibrin clot, plasmin degrades fibrin into various
products (ie, D-dimers). Antibodies specific for these products, which do not recognize fibrinogen, have
been developed. The presence of these various fibrin degradation products, among which D-dimer is the
terminal product, is the proof that the fibrinolytic system is in action in response to coagulation
activation. Elevated D-dimer levels are found in association with disseminated intravascular coagulation
(DIC), pulmonary embolism (PE), deep vein thrombosis (DVT), trauma, and bleeding. D-dimer may
also be increased in association with pregnancy, liver disease, malignancy, inflammation, or a chronic
hypercoagulable state.
Useful For: Excluding the diagnosis of acute pulmonary embolism or deep vein thrombosis,
particularly when results of a sensitive D-dimer assay are combined with clinical information, including
pretest disease probability(1-4) Diagnosis of intravascular coagulation and fibrinolysis, also known as
disseminated intravascular coagulation, especially when combined with clinical information and other
laboratory test data (eg, platelet count, assays of clottable fibrinogen and soluble fibrin monomer
complex, and clotting time assays-prothrombin time and activated partial thromboplastin time)(5)
Interpretation: A normal D-dimer result of 500 ng/mL or less fibrinogen equivalent units (FEU) on
the IL D-Dimer HS500 kit has a negative predictive value of approximately 100% (range 97%-100%) and
is FDA approved for the exclusion of acute pulmonary embolism (PE) and deep vein thrombosis (DVT)
when there is low or moderate pretest probability for PE or DVT. D-dimer concentrations increase with
age and, therefore, the specificity for DVT and PE exclusion decreases with age. For DVT or PE
exclusion, in addition to clinical pretest probability, age-adjusted D-dimer cutoffs are suggested for
patients older than 50 years of age. Recent evidence suggests using clinical pretest probability and
age-adjusted cutoffs to improve the performance of D-dimer testing in patients older than 50 years of age.
In recent studies, when compared to a fixed D-dimer cutoff, age-adjusted D-dimer cutoff values
(calculated as follows: age [years] x 10 ng/mL) resulted in equivalent outcomes and no additional false
negative findings.(6-7) Increased D-dimer values are abnormal but do not indicate a specific disease state.
D-dimer values may be increased as a result of: -Clinical or subclinical disseminated intravascular
coagulation/intravascular coagulation and fibrinolysis -Other conditions associated with increased
activation of the procoagulant and fibrinolytic mechanisms such as recent surgery, active or recent
bleeding, hematomas, trauma, or thromboembolism -Association with pregnancy, liver disease,
inflammation, malignancy, or hypercoagulable (procoagulant) states The degree of D-dimer increase does
not definitely correlate with the clinical severity of associated disease states.
Reference Values:
< or =500 ng/mL Fibrinogen Equivalent Units (FEU)
D-dimer values < or =500 ng/mL FEU may be used in conjunction with clinical pretest probability to
exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).
Clinical References: 1. Brill-Edward P, Lee A: D-dimer testing in the diagnosis of acute venous
thromboembolism. Thromb Haemost. 1999 August;82(2):688-694 2. Heit JA, Minor TA, Andrews JC,
Larson DR, Li H, Nichols WL: Determinants of plasma fibrin D-dimer sensitivity for acute pulmonary
embolism as defined by pulmonary angiography. Arch Pathol Lab Med. 1999 March;123(3):235-240. doi:
10.1043/0003-9985(1999)123. 3. Heit JA, Meyers BJ, Plumhoff EA, Larson DR, Nichols WL: Operating
characteristics of automated latex immunoassay tests in the diagnosis of angiographically-defined acute
pulmonary embolism. Thromb Haemost. 2000 June;83(6):970 4. Bates SM, Grand'Maison A, Johnston M,
Naguit I, Kovacs MJ, Ginsberg JS: A latex D-dimer reliably excludes venous thromboembolism. Arch
Intern Med. 2001 February;161(3):447-453. doi: 10.1001/archinte.161.3.447. 5. Levi M, Ten Cate H:
Disseminated intravascular coagulation. N Engl J Med. 1999 Aug 19;341(8):586-592. doi:
10.1056/NEJM199908193410807. 6. Righini M, Van Es J, Den Exter PL, et al: Age-adjusted D-dimer
cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014 Mar
19;311(11):1117-1124. doi:10.1001/jama.2014.2135 7. Schouten HJ, Geersing GJ, Koek HL, et al:
Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with
suspected venous thromboembolism: systematic review and meta-analysis. BMJ. 2012;346:f2492. doi:
10.1136/bmj.f2492. 8. Feinstein DI, Marder VJ, Colman RW: Consumptive thrombohemorrhagic
disorders. In: Colman RW, Hirsh J, Marder VJ, et al. eds. Hemostasis and Thrombosis: Basic Principles
and Clinical Practice. 3rd ed. JB Lippincott Co.; 2001;1197-1234
DIMER D-Dimer, Plasma
602174 Clinical Information: Thrombin, the terminal enzyme of the plasma procoagulant cascade, cleaves
fibrinopeptides A and B from fibrinogen, generating fibrin monomer. Fibrin monomer contains D
domains on each end of the molecule and a central E domain. Most of the fibrin monomers polymerize
to form insoluble fibrin, or the fibrin clot, by repetitive end-to-end alignment of the D domains of 2
adjacent molecules in lateral contact with the E domain of a third molecule. The fibrin clot is
subsequently stabilized by thrombin-activated factor XIII, which covalently cross-links fibrin
monomers by transamidation, including dimerization of the D domains of adjacently polymerized fibrin
monomers. The fibrin clot promotes activation of fibrinolysis by catalyzing the activation of
plasminogen (by plasminogen activators) to form plasmin enzyme. Plasmin proteolytically degrades
cross-linked fibrin, ultimately producing soluble fibrin degradation products of various sizes that
include cross-linked fragments containing neoantigenic D-dimer (DD) epitopes. Plasmin also degrades
fibrinogen to form fragments X,Y, D, and E. D-dimer immunoassays use monoclonal antibodies to DD
neoantigen and mainly detect cross-linked fibrin degradation products, whereas the fibrino(geno)lytic
degradation products-X, Y, D, and E, and their polymers may be derived from fibrinogen or fibrin.
Therefore, the blood content of D-dimer indirectly reflects the generation of thrombin and plasmin,
roughly indicating the turnover or activation state of the coupled blood procoagulant and fibrinolytic
mechanisms.(1)
Useful For: Diagnosis of intravascular coagulation and fibrinolysis (ICF), also known as
disseminated intravascular coagulation (DIC), especially when combined with clinical information and
other laboratory test data (eg, platelet count, assays of clottable fibrinogen and soluble fibrin monomer
complex, and clotting time assays-prothrombin time and activated partial thromboplastin time)
Exclusion of the diagnosis of acute pulmonary embolism or deep vein thrombosis, particularly when
results of a sensitive D-dimer assay are combined with clinical information, including pretest disease
probability
Interpretation: D-dimer values < or =500 ng/mL Â fibrinogen-equivalent units (FEU) are normal.
Within the reportable normal range (220-500 ng/mL FEU), measured values may reflect the activation
state of the procoagulant and fibrinolytic systems, but the clinical utility of such quantitation is not
established. A normal D-dimer result (< or =500 ng/mL FEU) has a negative predictive value of
approximately 95% for the exclusion of acute pulmonary embolism (PE) or deep vein thrombosis when
there is low or moderate pretest PE probability. Increased D-dimer values are abnormal but do not
indicate a specific disease state. D-dimer values may be increased as a result of: -Clinical or subclinical
disseminated intravascular coagulopathy (DIC)/intravascular coagulation and fibrinolysis (ICF). -Other
conditions associated with increased activation of the procoagulant and fibrinolytic mechanisms such as
recent surgery, active or recent bleeding, hematomas, trauma, or thromboembolism. -Association with
pregnancy, liver disease, inflammation, malignancy or hypercoagulable (procoagulant) states. The
degree of D-dimer increase does not definitely correlate with the clinical severity of associated disease
states.
Reference Values:
Only orderable as part of a profile or reflex. For more information see:
Profile, Plasma
< or =500 ng/mL Fibrinogen Equivalent Units (FEU)

D-dimer values < or =500 ng/mL FEU may be used in conjunction with clinical pretest probability to
exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).
Clinical References: 1. Legnani C, Cini M, Scarvelis D, et al: Multicenter evaluation of a new

quantitative highly sensitive D-dimer assay, the HemosIL D-dimer HS 500, in patients with clinically
suspected venous thromboembolism. Thromb Res 2010;125(5):398-401 2. Levi M, Ten Cate H:
Disseminated intravascular coagulation. N Engl J Med 1999 Aug;341(8):586-592 3. Brill-Edward P,
Lee A: D-dimer testing in the diagnosis of acute venous thromboembolism. Thromb Haemost 1999
Aug;82(2):688-694
DLAC D-Lactate, Plasma

8878 Clinical Information: D-lactate is produced by bacteria residing in the colon when carbohydrates are
not completely absorbed in the small intestine. When large amounts of D-lactate are present, individuals
can experience metabolic acidosis, altered mental status (from drowsiness to coma), and a variety of other
neurologic symptoms, in particular dysarthria and ataxia. Although a temporal relationship has been
described between elevations of plasma and urine D-lactate and the accompanying encephalopathy, the
mechanism of neurologic manifestations has not been elucidated. D-lactic acidosis is typically observed in
patients with a malabsorptive disorder, such as short-bowel syndrome, or following a jejunoileal bypass.
In addition, healthy children presenting with gastroenteritis may also develop the clinical presentation of
D-lactic acidosis. Routine lactic acid determinations in blood will not reveal abnormalities because most
lactic acid assays measure only L-lactate. Accordingly, D-lactate analysis must be specifically requested
(eg, this test). However, as D-lactate is readily excreted in urine, it is the preferred specimen for D-lactate
determinations; see DLAU / D-Lactate, Urine.
Useful For: An adjunct to urine D-lactate (preferred) for the diagnosis of D-lactate acidosis
Interpretation: Increased levels are consistent with D-lactic acidosis. However, because D-lactate is
readily excreted, urine determinations are preferred.
Reference Values:
0.0-0.25 mmol/L
Clinical References: 1. Petersen C: D-lactic acidosis. Nutr Clin Pract. 2005;20(6):634-645 2.

Kowlgi NG, Chhabra L: D-Lactic acidosis: An underrecognized complication of short bowel syndrome.
Gastroenterol Res Pract. 2015;2015:476215. doi: /10.1155/2015/476215
DLAU D-Lactate, Urine

8873 Clinical Information: D-lactate is produced by bacteria residing in the colon when carbohydrates are
not completely absorbed in the small intestine. When large amounts of D-lactate are present, individuals
can experiencemetabolic acidosis, altered mental status (from drowsiness to coma) and a variety of other
neurologic symptoms, in particular dysarthria and ataxia. Although a temporal relationship has been
described between elevations of plasma and urine D-lactate and the accompanying encephalopathy, the
mechanism of neurologic manifestations has not been elucidated. D-lactic acidosis is typically observed in
patients with a malabsorptive disorder, such as short-bowel syndrome, or following jejunoileal bypass. In
addition, healthy children presenting with gastroenteritis may also develop the clinical presentation of
D-lactic acidosis. Routine lactic acid determinations in blood will not reveal abnormalities because most
lactic acid assays measure only L-lactate. Accordingly, D-lactate analysis must be specifically requested
(eg, DLAC / D-Lactate, Plasma). However, as D-lactate is readily excreted in urine, this is the preferred
specimen for D-lactate determinations.
Useful For: Preferred test for diagnosing D-lactate acidosis, especially in patients with jejunoileal
bypass and short-bowel syndrome
Interpretation: Increased levels are diagnostic.

Reference Values:
0.0-0.25 mmol/L
Clinical References: 1. Brandt RB, Siegel SA, Waters MG, Bloch MH: Spectrophotometric assay
for D-(-)-lactate in plasma. Anal Biochem. 1980;102(1):39-46 2. Petersen C: D-lactic acidosis. Nutr Clin
Pract. 2005 Dec;20(6):634-645 3. Kowlgi NG, Chhabra L: D-Lactic acidosis: An underrecognized
complication of short bowel syndrome. Gastroenterol Res Pract. 2015;2015:476215. doi:
/10.1155/2015/476215
DAGR Dairy and Grain Allergen Profile, Serum
Useful For: Establishing a diagnosis of an allergy to dairy and grain Defining the allergen

likelihood of allergic disease as opposed to other etiologies and defines the allergens responsible for
eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the
Reference Values:
0 Negative

apply to all ages.
DAND Dandelion, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to dandelion Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
DATE Date, Fruit, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to date, fruit Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
DATRE Date, Tree, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to date, tree Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
DOCK8 Dedicator of Cytokinesis 8 (DOCK8) Deficiency, Blood

608112 Clinical Information: Dedicator of cytokinesis 8 (DOCK8) is an atypical guanine exchange factor
that plays a role in regulating actin polymerization and cytoskeletal rearrangement. DOCK8 is important
in both innate and adaptive immunity by contributing to cellular migration, cytotoxicity, antibody
production, and immunological memory. DOCK8 deficiency is a rare, combined immunodeficiency with
an autosomal recessive inheritance that typically presents in childhood. Its clinical features include atopic
disease, recurrent sinopulmonary infections, cutaneous viral infection, Staphylococcus aureus skin
infections, and cancer. DOCK8 deficiency is diagnosed based on clinical phenotype, immunologic
findings, and molecular analysis. Diseases in the differential diagnosis include Job syndrome (AD-HIES),
ZNF341 deficiency, and severe atopic dermatitis. Assessment of DOCK8 expression on immune cells is
an important component and facilitates the diagnosis of this condition and the timely treatment of the
patient.
Useful For: Aiding in the diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency This test is not
useful for assessing DOCK8 carrier status.
Interpretation: The results will be reported as the percentage of dedicator of cytokinesis 8 (DOCK8)
expression on T cells, B cells, natural killer (NK) cells, and monocytes. The absence of DOCK8
expression on all cell types will be consistent with DOCK8 deficiency. In this case, genetic analysis of
DOCK8 to confirm the diagnosis and to identify the underlying alteration will be recommended. The
expression of DOCK8 on a subset of T cells and/or NK cells could suggest somatic reversion in a patient
with DOCK8 deficiency, which can modulate disease phenotype over time.
Reference Values:
The appropriate reference values will be provided on the report.
Clinical References: 1. Engelhardt KR, McGhee S, Winkler S, et al: Large deletions and point
mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of
hyper-IgE syndrome. J Allergy Clin Immunol. 2009 Dec; 124(6):1289-302 e4. doi:
10.1016/j.jaci.2009.10.038 2. Jing H, Zhang Q, Zhang Y, et al: Somatic reversion in dedicator of
cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol. 2014
Jun;133(6):1667-1675. doi: 10.1016/j.jaci.2014.03.025 3. Pai SY, de Boer H, Massaad MJ, et al: Flow
cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency. J Allergy Clin Immunol. 2014
Jul;134(1):221-223. doi: 10.1016/j.jaci.2014.02.023 4. Engelhardt KR, Gertz ME, Keles S, et al: The
extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin
Immunol. 2015 Aug;136(2):402-412. doi: 10.1016/j.jaci.2014.12.1945 5. Su HC, Jing H, Angelus P,
Freeman AF: Insights into immunity from clinical and basic science studies of DOCK8
immunodeficiency syndrome. Immunol Rev. 2019 Jan;287(1):9-19. doi: 10.1111/imr.12723 6. Aydin SE,
Freeman AF, Al-Herz W, et al: Hematopoietic stem cell transplantation as treatment for patients with
DOCK8 deficiency. J Allergy Clin Immunol Pract. 2019 Mar;7(3):848-855. doi:
10.1016/j.jaip.2018.10.035
DHEA_
Current 81405
Dehydroepiandrosterone (DHEA), Serum
Clinical Information: Dehydroepiandrosterone (DHEA) is the principal human C-19 steroid.
DHEA has very low androgenic potency but serves as the major direct or indirect precursor for most sex
steroids. DHEA is secreted by the adrenal gland and production is at least partly controlled by
adrenocorticotropic hormone (ACTH). The bulk of DHEA is secreted as a 3-sulfoconjugate
dehydroepiandrosterone sulfate (DHEAS). Both hormones are albumin bound, but DHEAS binding is
much tighter. As a result, circulating concentrations of DHEAS are much higher (>100-fold) compared
to DHEA. In most clinical situations, DHEA and DHEAS results can be used interchangeably. In
gonads and several other tissues, most notably skin, steroid sulfatases can convert DHEAS back to
DHEA, which can then be metabolized to stronger androgens and to estrogens. During pregnancy,
DHEA/DHEAS and their 16-hydroxylated metabolites are secreted by the fetal adrenal gland in large
quantities. They serve as precursors for placental production of the dominant pregnancy estrogen,
estriol. Within weeks after birth, DHEA/DHEAS levels fall by 80% or more and remain low until the
onset of adrenarche at age 7 or 8 in girls and age 8 or 9 in boys. Adrenarche is a poorly understood
phenomenon, peculiar to higher primates, that is characterized by a gradual rise in adrenal androgen
production. It precedes puberty but is not casually linked to it. Early adrenarche is not associated with
early puberty or with any reduction in final height or overt androgenization. However, girls with early
adrenarche may be at increased risk of polycystic ovarian syndrome as adults and some boys may
develop early penile enlargement. Following adrenarche, DHEA/DHEAS levels increase until the age of
20 to a maximum roughly comparable to that observed at birth. Levels then decline over the next 40 to
60 years to around 20% of peak levels. The clinical significance of this age-related drop is unknown,
and trials of DHEA/DHEAS replacement in older individuals have not produced convincing benefits.
However, in younger and older patients with primary adrenal failure, the addition of DHEA/DHEAS to
corticosteroid replacement has been shown in some studies to improve mood, energy, and sex drive.
Elevated DHEA/DHEAS levels can cause signs or symptoms of hyperandrogenism in women. Men are
usually asymptomatic but, through peripheral conversion of androgens to estrogens, can occasionally
experience mild estrogen excess. Most mild-to-moderate elevations in DHEAS levels are idiopathic.
However, pronounced elevations of DHEA/DHEAS may be indicative of androgen-producing adrenal
tumors. In small children, congenital adrenal hyperplasia (CAH) due to 3 beta-hydroxysteroid
dehydrogenase deficiency is associated with excessive DHEA/DHEAS production. Lesser elevations
may be observed in 21-hydroxylase deficiency (the most common form of CAH) and 11
beta-hydroxylase deficiency. By contrast, steroidogenic acute regulatory protein (STAR) or 17
alpha-hydroxylase deficiency is characterized by low DHEA/DHEAS levels. For more information, see
Steroid Pathways.
Useful For: Diagnosing and differential diagnosis of hyperandrogenism (in conjunction with
measurements of other sex steroids) As an initial screen in adults with bioavailable testosterone
measurement. Depending on results, this may be supplemented with measurements of sex
hormone-binding globulin and occasionally other androgenic steroids (eg, 17-hydroxyprogesterone). An
adjunct in the diagnosis of congenital adrenal hyperplasia (CAH); DHEA/DHEAS measurements play a
secondary role to the measurements of cortisol/cortisone, 17 alpha-hydroxyprogesterone, and
androstenedione Diagnosing and differential diagnosis of premature adrenarche
Interpretation: Elevated dehydroepiandrosterone (DHEA)/dehydroepiandrosterone sulfate

(DHEAS) levels indicate increased adrenal androgen production. Mild elevations in adults are usually
idiopathic, but levels 5-fold or more of the upper limit of normal can suggest the presence of an
androgen-secreting adrenal tumor. DHEA/DHEAS levels are elevated in greater than 90% of patients
with such tumors. This is particularly true for androgen-secreting adrenal carcinomas, as they have
typically lost the ability to produce downstream androgens, such as testosterone. By contrast,
androgen-secreting adrenal adenomas may also produce excess testosterone and secrete lesser amounts
of DHEA/DHEAS. Patients with congenital adrenal hyperplasia (CAH) may show very high levels of
DHEA/DHEAS, often 5-fold to 10-fold elevations. However, with the possible exception of 3
beta-hydroxysteroid dehydrogenase deficiency, other steroid analytes offer better diagnostic accuracy
than DHEA/DHEAS measurements. Consequently, DHEA/DHEAS testing should not be used as the
primary tool for CAH diagnosis. Similarly, discovering a high DHEA/DHEAS level in an infant or
child with symptoms or signs of possible CAH should prompt additional testing, as should the
discovery of very high DHEA/DHEAS levels in an adult. In the latter case, adrenal tumors need to be
excluded and additional adrenal steroid profile testing may assist in diagnosing nonclassical CAH. For
more information, see Steroid Pathways.
Reference Values:
Premature: <40 ng/mL*
0-1 day: <11 ng/mL*
2-6 days: <8.7 ng/mL*
7 days-1 month: <5.8 ng/mL*
>1-23 months: <2.9 ng/mL*
2-5 years: <2.3 ng/mL
6-10 years: <3.4 ng/mL
11-14 years: <5.0 ng/mL
15-18 years: <6.6 ng/mL
19-30 years: <13 ng/mL
31-40 years: <10 ng/mL
41-50 years: <8.0 ng/mL
51-60 years: <6.0 ng/mL
*Source: Dehydroepiandrosterone. In: Soldin SJ, Brugnara C, Wong Ed, eds. Pediatric Reference
Ranges. 5th ed. AACC Press; 2005:75
Clinical References: 1. Ibanez L, DiMartino-Nardi J, Potau N, Saenger P: Premature

adrenarche-normal variant or forerunner of adult disease? Endocrine Rev. 2000 Dec;21(6):671-696 2.
Collett-Solberg PF: Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice,
Part I. Clin Pediatr (Phila). 2001 Jan;40(1):1-16 3. Allolio B, Arlt W: DHEA treatment: myth or reality?
Trends Endocrinol Metab. 2002 Sep;13(7):288-294 4. Salek FS, Bigos KL, Kroboth PD: The influence of
hormones and pharmaceutical agents on DHEA and DHEA-S concentrations: a review of clinical studies.
J Clin Pharmacol. 2002 Mar;42(3):247-266 5. Bertholf RL, Cooper M, Winter WE: Adrenal Cortex. In:
6th ed. Elsevier; 2018:66 6. Ebeling P, Koivisto VA: Physiological importance of
dehydro-epiandrosterone. Lancet. 1994 Jun;343(8911):1479-1481 7. Morales AJ, Nolan JJ, Nelson JC,
Yen SS: Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J
Clin Endocrinol Metab. 1994 Jun;78(6):1360-1367
DHES1 Dehydroepiandrosterone Sulfate, Serum

113595 Clinical Information: Dehydroepiandrosterone (DHEA) is the principal human C-19 steroid. DHEA
has very low androgenic potency, but serves as the major direct or indirect precursor for most sex steroids.
DHEA is secreted by the adrenal gland and production is at least partly controlled by adrenocorticotropic
hormone. The bulk of DHEA is secreted as a 3-sulfoconjugate (DHEA-S). Both hormones are albumin
bound, but binding of DHEA-S is much tighter. In gonads and several other tissues, most notably skin,
steroid sulfatases can convert DHEA-S back to DHEA, which can then be metabolized to stronger
androgens and to estrogens. During pregnancy, DHEA-S and its 16-hydroxylated metabolites are secreted
by the fetal adrenal gland in large quantities. They serve as precursors for placental production of the
dominant pregnancy estrogen, estriol. Within weeks after birth, DHEA-S levels fall by 80% or more and
remain low until the onset of adrenarche. Adrenarche is a poorly understood phenomenon peculiar to
higher primates, which is characterized by a gradual rise in adrenal androgen production. It precedes
puberty but is not causally linked to it. Early adrenarche is not associated with early puberty or with any
reduction in final height or overt androgenization and is generally regarded as a benign condition, not
needing intervention. However, girls with early adrenarche may be at increased risk of polycystic ovarian
syndrome as adults, and some boys may develop early penile enlargement. Following adrenarche,
DHEA-S levels increase until the age of 20, up to maximum levels roughly comparable to that observed at
birth. Levels then decline over the next 40 to 60 years to around 20% of peak levels. The clinical
significance of this age-related drop is unknown and trials of DHEA-S replacement in the elderly have not
produced convincing benefits. However, in young and old patients with primary adrenal failure, the
addition of DHEA-S to corticosteroid replacement has been shown in some studies to improve mood,
energy, and sex drive. Elevated DHEA-S levels can cause symptoms or signs of hyperandrogenism in
women. Men are usually asymptomatic, but through peripheral conversion of androgens to estrogens can
occasionally experience mild estrogen excess. Most mild to moderate elevations in DHEA-S levels are
idiopathic. However, pronounced elevations of DHEA-S may be indicative of androgen-producing
adrenal tumors. In small children, congenital adrenal hyperplasia (CAH) due to 3 beta-hydroxysteroid
deficiency is associated with excessive DHEA-S production. Lesser elevations may be observed in
21-hydroxylase deficiency (the most common form of CAH) and 11 beta-hydroxylase deficiency. By
contrast, steroidogenic acute regulatory protein or 17 alpha-hydroxylase deficiencies are characterized by
low DHEA-S levels. An initial workup in adults might also include total and bioavailable testosterone
(TTBS / Testosterone, Total and Bioavailable, Serum) measurements. Depending on results, this may be
supplemented with measurements of sex hormone-binding globulin (SHBG /Sex Hormone-Binding
Globulin [SHBG], Serum) and, occasionally other androgenic steroids (eg, 17-hydroxyprogesterone).
Useful For: Diagnosis and differential diagnosis of hyperandrogenism (in conjunction with
measurements of other sex steroids) An adjunct in the diagnosis of congenital adrenal hyperplasia
Diagnosis and differential diagnosis of premature adrenarche
Interpretation: Elevated dehydroepiandrosterone sulfate (DHEA-S) levels indicate increased

adrenal androgen production. Mild elevations in adults are usually idiopathic, but levels of 600 mcg/dL
or more can suggest the presence of an androgen-secreting adrenal tumor. DHEA-S levels are elevated
in more than 90% of patients with such tumors, usually well above 600 mcg/dL. This is particularly true
for androgen-secreting adrenal carcinomas, as they have typically lost the ability to produce
down-stream androgens, such as testosterone. By contrast, androgen-secreting adrenal adenomas may
also produce excess testosterone and secrete lesser amounts of DHEA-S. Patients with congenital
adrenal hyperplasia (CAH) may show very high levels of DHEA-S, often 5- to 10-fold elevations.
However, with the possible exception of 3 beta-hydroxysteroid dehydrogenase deficiency, other steroid
analytes offer better diagnostic accuracy than DHEA-S measurements. Consequently, DHEA-S testing
should not be used as the primary tool for CAH diagnosis. Similarly, discovering a high DHEA-S level
in an infant or child with symptoms or signs of possible CAH should prompt additional testing, as
should the discovery of very high DHEA-S levels in an adult. In the latter case, adrenal tumors need to
be excluded and additional adrenal steroid profile testing may assist in diagnosing nonclassical CAH.
Girls below the age of 7 to 8 and boys before age 8 to 9, who present with early development of pubic
hair, or, in boys, penile enlargement, may be suffering from either premature adrenarche or premature
puberty or both. Measurement of DHEA-S (DHES / Dehydroepiandrosterone Sulfate [DHEA-S],
Serum), dehydroepiandrosterone (DHEA_ / Dehydroepiandrosterone [DHEA], Serum), and
androstenedione (ANST / Androstenedione, Serum), alongside determination of sensitive estradiol
(EEST / Estradiol, Serum), testosterone and bioavailable (TTBS / Testosterone, Total and Bioavailable,
Serum), or free testosterone (TGRP / Testosterone, Total and Free, Serum), sex hormone-binding
globulin (SHBG / Sex Hormone-Binding Globulin [SHBG], Serum), and luteinizing hormone (LH /
Luteinizing Hormone [LH], Serum)/follicle-stimulating hormone (FSH / Follicle-Stimulating Hormone
[FSH], Serum) levels will allow correct diagnosis in most cases. In premature adrenarche, only the
adrenal androgens, chiefly DHEA-S, will be above prepubertal levels, whereas early puberty will also
show a fall in SHBG levels and variable elevations of gonadotropins and gonadal sex-steroids above the
prepuberty reference range. Levels of DHEA-S do not show significant diurnal variation. Many drugs
and hormones can result in changes in DHEA-S levels. Whether any of these secondary changes in
DHEA-S levels are of clinical significance and how they should be related to the established normal
reference ranges is unknown. In most cases, the drug-induced changes are not large enough to cause
diagnostic confusion, but when interpreting mild abnormalities in DHEA-S levels, drug and hormone
interactions should be taken into account. Examples of drugs and hormones that can reduce DHEA-S
levels include: insulin, oral contraceptive drugs, corticosteroids, central nervous system agents that
induce hepatic enzymes (eg, carbamazepine, clomipramine, imipramine, phenytoin), many antilipemic
drugs (eg, statins, cholestyramine), domapinergic drugs (eg, levodopa/dopamine, bromocryptine), fish
oil, and vitamin E. Drugs that may increase DHEA-S levels include: metformin, troglitazone, prolactin,
(and by indirect implication many neuroleptic drugs), danazol, calcium channel blockers (eg, diltiazem,
amlodipine), and nicotine.
Reference Values:
Mean Age Reference Range (mcg/dL)
Stage I >14 days 11-120
Stage II 11.5 years 14-323
Stage III 13.6 years 5.5-312
Stage IV 15.1 years 29-412
Stage V 18.0 years 104-468 *Puberty onset (transition from

Tanner stage I to Tanner stage II) occurs for
boys at a median age of 11.5 (+/-) 2 years.
For boys, there is no proven relationship
between puberty onset and body weight or
ethnic origin. Progression through Tanner
stages is variable. Tanner stage V (adult) is
usually reached by age 18. 18-30 years:
105-728 mcg/dL 31-40 years: 57-522
mcg/dL 41-50 years: 34-395 mcg/dL 51-60
years: 20-299mcg/dL 61-70 years: 12-227
mcg/dL > or =71 years: 6.6-162 mcg/dL
FEMALES 1-14 days: DHEA-S levels in
newborns are very elevated at birth but fall
to prepubertal levels within a few days.
Tanner Stages*Â
Mean Age Reference Range (mcg/dL)
Stage I >14 days 16-96
Stage II 10.5 years 22-184
Stage III 11.6 years 11-296
Stage V 14.5 years 57-395 *Puberty onset (transition from

Tanner stage I to Tanner stage II) occurs
for girls at a median age of 10.5 (+/-) 2
years. There is evidence that it may occur
up to 1 year earlier in obese girls and in
African American girls. Progression
through Tanner stages is variable. Tanner
stage V (adult) is usually reached by age
18. 18-30 years: 83-377 mcg/dL 31-40
years: 45-295 mcg/dL 41-50 years: 27-240
mcg/dL 51-60 years: 16-195 mcg/dL
61-70 years: 9.7-159 > or =71 years:
5.3-124 mcg/dL
Clinical References: 1. Kricka L. Interferences in immunoassays - still a threat. Clin Chem

2000;46:1037-1038 2. Bjerner J, et al. Immunometric assay interference: incidence and prevention. Clin
Chem 2002;48:613-621 3. Sciarra F, Tosti-Croce C, Toscano V: Androgen-secreting adrenal tumors.
Minerva Endocrinol 1995;20:63-68 4. Young WF Jr: Management approaches to adrenal
incidentalomas-a view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;21:671-696
5. Ibanez L, DiMartino-Nardi J, Potau N, Saenger P: Premature adrenarche-normal variant or forerunner
of adult disease? Endocrine Reviews 2001;40:1-16 6. Collett-Solberg P: Congenital adrenal hyperplasia:
from genetics and biochemistry to clinical practice, part I. Clin Pediatr 2001;40:1-16 7. Allolio B, Arlt
W: DHEA treatment: myth or reality? Trends Endocrinol Metab 2002;13:288-294 8. Salek FS, Bigos
KL, Kroboth PD: The influence of hormones and pharmaceutical agents on DHEA and DHEA-S
concentrations: a review of clinical studies. J Clin Pharmacol 2002;42:247-266 9. Elmlinger MW,
Kuhnel W, Ranke MB: Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH),
estradiol (E2), prolactin, progesterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone
sulfate (DHEA-S), cortisol and ferritin in neonates, children, and young adults. Clin Chem Lab Med
2002;40(11):1151-1160
DLL3 Delta-Like 3 Protein (SP347), Semi-Quantitative

603332 Immunohistochemistry, Manual, Tissue
Clinical Information: Delta-like 3 protein (DLL3) is an atypical Notch ligand induced by the
neuroendocrine transcription factor, ASCL-1.Â DLL3 is expressed on the cell membrane and in the
cytoplasm of tumor cells.Â
Useful For: Diagnosis of small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma
(LCNEC), amongst other tumors
Interpretation: Positivity for this test will require 50% or more of the tumor cells within a specimen
to express delta-like 3 protein with an intensity ranging from 1 to 3+.
Clinical References: 1. Saunders LR, Bankovich AJ, Anderson WC, et al: A DLL3-targeted
antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
Sci Transl Med. 2015 Aug;7(302):302ra136 2. Xie H, Boland JM, Maleszewski JJ, et al: Expression of
delta-like protein 3 is reproducibly present in a subset of small cell lung carcinomas and pulmonary
carcinoid tumors. Lung Cancer. 2019 Sep;135:73-79. doi: 10.1016/j.lungcan.2019.07.016 3. Xie H,
Kaye FJ, Isse K, et al: Delta-like protein 3 expression and targeting in merkel cell carcinoma.
Oncologist. 2020 Sep 1;10:810-817. doi: 10.1634/theoncologist.2019-0877
DMS2 Dementia, Autoimmune/Paraneoplastic Evaluation, Serum

92114 Clinical Information: The rapid identification of subacute cognitive decline as autoimmune
dementia facilitates optimum treatment with immunotherapy and an expedited search for a limited stage
of cancer in some patients. Traditionally, neurologists have been reluctant to consider a diagnosis of an
autoimmune cognitive disorder in the absence of delirium. However, some recent case series and
clinical-serologic observations have suggested a growing appreciation for autoimmune neurologic
disorders presenting with features of a rapidly progressive dementia rather than delirium. These
disorders can affect all age groups. Unfortunately, these potentially reversible conditions may be
misdiagnosed as being progressive neurodegenerative (currently irreversible) disorders with devastating
consequences for the patient. In the evaluation of a patient with cognitive decline, clinicians should
consider the possibility of an autoimmune etiology on their list of differential diagnoses. The
importance of not overlooking this possibility rests in the experience that these patients have a
potentially immunotherapy-responsive, reversible disorder. The development and widespread
availability of neural antibody marker testing has changed this perspective so that other presenting
symptoms such as personality change, executive dysfunction, and psychiatric symptoms are
increasingly recognized in an autoimmune context. Clues that are helpful in identifying patients with an
autoimmune dementia can be summarized as a triad of: -Suspicious clinical features (a subacute onset
of symptoms, a rapidly progressive course, and fluctuating symptoms) and radiological findings
-Detection of cerebrospinal fluid (CSF) or serological biomarkers of autoimmunity -Response to
immunotherapy Detection of neural autoantibodies in serum or CSF serves 2 purposes; to inform the
physician of a likely autoimmune etiology and to raise suspicion for a paraneoplastic cause. The
neurological associations of neural autoantibodies tend to be diverse and multifocal, although certain
syndromic associations may apply. For example, LGI1 (leucine-rich, glioma inactivated 1) antibody
was initially considered to be specific for autoimmune limbic encephalitis, but over time other
presentations have been reported, including rapidly progressive course of cognitive decline mimicking
neurodegenerative dementia. Since neurological presentations are often multifocal and diverse,
comprehensive antibody testing is usually more informative than testing for 1 or 2 selected antibodies.
Some of the antibodies are highly predictive of an unsuspected underlying cancer. For example,
small-cell lung carcinoma (antineuronal nuclear antibody-type 1 [ANNA-1]; collapsin
response-mediator protein-5 neuronal [CRMP-5-IgG]), ovarian teratoma (N-methyl-D-aspartate
receptor: NMDA-R), and thymoma (CRMP-5 IgG). Also, a profile of seropositivity for multiple
autoantibodies may be informative for cancer type. For example, in a patient presenting with a rapidly
progressive dementia who has CRMP-5-IgG, and subsequent reflex reveals muscle acetylcholine
receptor (AChR) binding antibody, the findings should raise a high suspicion for thymoma. If an
associated tumor is found, its resection or ablation optimizes the neurological outcome. Antibody
testing on CSF is additionally helpful, particularly when serum testing is negative, though in some
circumstances testing both serum and CSF simultaneously is pertinent. Testing of CSF is recommended
for some antibodies in particular (such as NMDA-R antibody and glial fibrillary acidic protein
[GFAP]-IgG) because CSF testing is both more sensitive and specific.
Useful For: Investigating new onset dementia and cognitive impairment plus 1 or more of the
following using serum specimens: -Rapid onset and progression -Fluctuating course -Psychiatric
accompaniments (psychosis, hallucinations) -Movement disorder (myoclonus, tremor, dyskinesias)
-Headache -Autoimmune stigmata (personal history or family history or signs of diabetes mellitus, thyroid
disorder, vitiligo, poliosis [premature graying], myasthenia gravis, rheumatoid arthritis, systemic lupus
erythematosus) -Smoking history (over 20 pack-years) or other cancer risk factors -History of cancer
-Inflammatory cerebrospinal fluid -Neuroimaging findings atypical for degenerative etiology
Interpretation: Antibodies specific for neuronal, glial, or muscle proteins are valuable serological
markers of autoimmune epilepsy and of a patient's immune response to cancer. These autoantibodies are
not found in healthy subjects and are usually accompanied by subacute neurological symptoms and signs.
It is not uncommon for more than 1 of the following autoantibodies to be detected in patients with
autoimmune dementia: -Plasma membrane antibodies (N-methyl-D-aspartate [NMDA] receptor;
2-amino-3-[5-methyl-3-oxo-1,2-oxazol-4-yl] propanoic acid [AMPA] receptor; gamma-amino butyric
acid [GABA-B] receptor). These autoantibodies are all potential effectors of dysfunction. -Neuronal
nuclear autoantibody, type 1 (ANNA-1) or type 3 (ANNA-3). -Neuronal or muscle cytoplasmic antibodies
(amphiphysin, Purkinje cell antibody-type 2 [PCA-2], collapsin response-mediator protein-5 neuronal
[CRMP-5-IgG], or glutamic acid decarboxylase [GAD65] antibody).
Reference Values:
ADMSI Dementia, Interpretation, S Medical interpretation NA
ANN1S Anti-Neuronal Nuclear Ab, IFA

Type 1

Type 2

Type 3
DPPIS DPPX Ab IFA, S IFA Negative
GD65S GAD65 Ab Assay, S RIA < or =0.02 nmol/L Reference

values apply to all ages.
GFAIS GFAP IFA, S IFA Negative
IG5IS IgLON5 IFA, S IFA Negative
GL1IS mGluR1 Ab IFA, S IFA Negative
NIFIS NIF IFA, S IFA Negative
PCAB2 Purkinje Cell Cytoplasmic Ab IFA

Type 2
PCATR Purkinje Cell Cytoplasmic Ab IFA Reflex Information:

Type Tr
ARBI ACh Receptor (Muscle) RIA < or =0.02 nmol/L

Binding Ab
AINCS Alpha Internexin CBA, S CBA Negative
AMPIS AMPA-R Ab IF Titer Assay, IFA

S
AMIBS Amphiphysin Immunoblot, SIB Negative
CRMWS CRMP-5-IgG Western Blot, WB Negative

S
DPPTS DPPX Ab IFA Titer, S IFA

Assay, S
IG5CS IgLON5 CBA, S CBA Negative
IG5TS IgLON5 IFA Titer, S IFA
GL1TS mGluR1 Ab IFA Titer, S IFA

NFHCS NIF Heavy Chain CBA, S CBA Negative
NIFTS NIF IFA Titer, S IFA
NFLCS NIF Light Chain CBA, S CBA Negative

Assay, S
PCABP Purkinje Cell Cytoplasmic IFA

Ab Type 1
abbreviations used:
Immunofluorescence assay (IFA)
Cell-binding assay (CBA) Western
blot (WB) Radioimmunoassay
(RIA) Immunoblot (IB)
Neuron-restricted patterns of IgG
staining that do not fulfill criteria
for ANNA-1, ANNA-2,
CRMP-5-IgG, PCA-1, PCA-2, or
PCA-Tr may be reported as
"unclassified anti-neuronal IgG."
reported as "uninterpretable." Note:
CRMP-5 titers lower than 1:240 are
detectable by recombinant CRMP-5
Western blot analysis. CRMP-5
Western blot analysis will be done
on request on stored serum (held 4
weeks). This supplemental testing is
recommended in cases of chorea,
vision loss, cranial neuropathy, and
myelopathy. Call the
Neuroimmunology Laboratory at
800-533-1710 to request CRMP-5
Western blot.
Clinical References: 1. McKeon A, Lennon VA, Pittock SJ: Immunotherapy responsive dementias
and encephalopathies. Continuum (Minneap Minn). 2010 Apr;16(2):80-101. doi:
10.1212/01.CON.0000368213.63964.34 2. Flanagan EP, McKeon A, Lennon VA, et al: Autoimmune
dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010
Oct;85(10):881-897 3. Geschwind MD, Tan KM, Lennon VA, et al: Voltage-gated potassium channel
autoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol. 2008 Oct;65(10):1341-1346 4.
Lancaster E, Martinez-Hernandez E, Dalmau J: Encephalitis and antibodies to synaptic and neuronal cell
surface proteins. Neurology. 2011 Jul;77(2):179-189 5. Klein CJ, Lennon VA, Aston PA, et al: Insights
from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol. 2013
Feb;70(2):229-234
DMC2 Dementia, Autoimmune/Paraneoplastic Evaluation, Spinal Fluid

92115 Clinical Information: The rapid identification of subacute cognitive decline as autoimmune dementia
facilitates optimum treatment with immunotherapy and an expedited search for a limited stage of cancer
in some patients. Traditionally, neurologists have been reluctant to consider a diagnosis of an autoimmune
cognitive disorder in the absence of delirium. However, some recent case series and clinical-serologic
observations have suggested a growing appreciation for autoimmune neurologic disorders presenting with
features of a rapidly progressive dementia rather than delirium. These disorders can affect all age groups.
Unfortunately, these potentially reversible conditions may be misdiagnosed as being progressive
neurodegenerative (currently irreversible) disorders with devastating consequences for the patient. In the
evaluation of a patient with cognitive decline, clinicians should consider the possibility of an autoimmune
etiology on their list of differential diagnoses. The importance of not overlooking this possibility rests in
the experience that these patients have a potentially immunotherapy-responsive, reversible disorder. The
development and widespread availability of neural antibody marker testing has changed this perspective
so that other presenting symptoms such as personality change, executive dysfunction, and psychiatric
symptoms are increasingly recognized in an autoimmune context. Clues that are helpful in identifying
patients with an autoimmune dementia can be summarized as a triad of: -Suspicious clinical features (a
subacute onset of symptoms, a rapidly progressive course, and fluctuating symptoms) and radiological
findings -Detection of cerebrospinal fluid (CSF) or serological biomarkers of autoimmunity -Response to
immunotherapy Detection of neural autoantibodies in serum or CSF serves 2 purposes; to inform the
physician of a likely autoimmune etiology and to raise suspicion for a paraneoplastic cause. The
neurological associations of neural autoantibodies tend to be diverse and multifocal, although certain
syndromic associations may apply. For example, LGI1 (leucine-rich, glioma inactivated 1) antibody was
initially considered to be specific for autoimmune limbic encephalitis, but over time other presentations
have been reported, including rapidly progressive course of cognitive decline mimicking
neurodegenerative dementia. Since neurological presentations are often multifocal and diverse,
comprehensive antibody testing is usually more informative than testing for 1 or 2 selected antibodies.
Some of the antibodies are highly predictive of an unsuspected underlying cancer. For example, small-cell
lung carcinoma (antineuronal nuclear antibody-type 1 [ANNA-1]; collapsin response-mediator protein-5
neuronal [CRMP-5-IgG]), ovarian teratoma (N-methyl-D-aspartate receptor: NMDA-R), and thymoma
(CRMP-5 IgG). Also, a profile of seropositivity for multiple autoantibodies may be informative for cancer
type. For example, in a patient presenting with a rapidly progressive dementia who has CRMP-5-IgG, and
subsequent reflex reveals muscle acetylcholine receptor (AChR) binding antibody, the findings should
raise a high suspicion for thymoma. If an associated tumor is found, its resection or ablation optimizes the
neurological outcome. Antibody testing on CSF is additionally helpful particularly when serum testing is
negative, though in some circumstances testing both serum and CSF simultaneously is pertinent. Testing
of CSF is recommended for some antibodies in particular (such as NMDA-R antibody and glial fibrillary
acidic protein [GFAP]-IgG) because CSF testing is both more sensitive and specific.
Useful For: Investigating new onset dementia and cognitive impairment plus 1 or more of the
following accompaniments using cerebrospinal fluid specimens: -Rapid onset and progression
-Fluctuating course -Psychiatric accompaniments (psychosis, hallucinations) -Movement disorder
(myoclonus, tremor, dyskinesias) -Headache -Autoimmune stigmata (personal history or family history
or signs of diabetes mellitus, thyroid disorder, vitiligo, poliosis [premature graying], myasthenia gravis,
rheumatoid arthritis, systemic lupus erythematosus) -Smoking history (over 20 pack-years) or other
cancer risk factors -History of cancer -Inflammatory cerebrospinal fluid -Neuroimaging findings
atypical for degenerative etiology
not found in healthy subjects and are usually accompanied by subacute neurological symptoms and
signs. It is not uncommon for more than 1 of the following autoantibodies to be detected in patients with
autoimmune dementia: -Plasma membrane antibodies (N-methyl-D-aspartate [NMDA] receptor;
2-amino-3-[5-methyl-3-oxo-1,2- oxazol-4-yl] propanoic acid [AMPA] receptor; gamma-amino butyric
acid [GABA]-B receptor). These autoantibodies are all potential effectors of dysfunction. -Neuronal
nuclear autoantibody type 1 (ANNA-1) or type 3 (ANNA-3). -Neuronal or muscle cytoplasmic
antibodies (amphiphysin, Purkinje cell antibody-type 2 [PCA-2], collapsin response-mediator protein-5
neuronal [CRMP-5-IgG], or glutamic acid decarboxylase [GAD65] antibody).
Reference Values:
Test ID Reporting name Methodology* Reference value
ADMCI Dementia, Interpretation, CSF Medical interpretation NA
AMPCC AMPA-R Ab CBA, CSF CBA Negative
AMPHC Amphiphysin Ab, CSF IFA
AGN1C Anti-Glial Nuclear Ab, Type 1 IFA
ANN1C Anti-Neuronal Nuclear Ab, IFA

Type 1

Type 2

Type 3
CS2CC CASPR2-IgG CBA, CSF CBA Negative
CRMC CRMP-5-IgG, CSF IFA
DPPIC DPPX Ab IFA, CSF IFA Negative
GABCC GABA-B-R Ab CBA, CSF CBA Negative
GD65C GAD65 Ab Assay, CSF RIA < or =0.02 nmol/L Reference

GFAIC GFAP IFA, CSF IFA Negative
IG5IC IgLON5 IFA, CSF IFA Negative
LG1CC LGI1-IgG CBA, CSF CBA Negative
GL1IC mGluR1 Ab IFA, CSF IFA Negative
NIFIC NIF IFA, CSF IFA Negative
NMDCC NMDA-R Ab CBA, CSF CBA Negative
PCTRC Purkinje Cell Cytoplasmc Ab IFA

Type Tr
PCA2C Purkinje Cell Cytoplasmic Ab IFA Reflex Information:

Type 2
AGNBC AGNA-1 Immunoblot, CSF IB Negative
AINCC Alpha Internexin CBA, CSFCBA Negative
AMPIC AMPA-R Ab IF Titer IFA

Assay, CSF
AMIBC Amphiphysin Immunoblot, IB Negative

CSF
AN1BC ANNA-1 Immunoblot, CSF IB Negative
CRMWC CRMP-5-IgG Western Blot, WB Negative

CSF
DPPCC DPPX Ab CBA, CSF CBA Negative
DPPTC DPPX Ab IFA Titer, CSF IFA
GABIC GABA-B-R Ab IF Titer IFA

Assay, CSF
GFACC GFAP CBA, CSF CBA Negative
GFATC GFAP IFA Titer, CSF IFA
IG5CC IgLON5 CBA, CSF CBA Negative
IG5TC IgLON5 IFA Titer, CSF IFA
GL1CC mGluR1 Ab CBA, CSF CBA Negative
GL1TC mGluR1 Ab IFA Titer, CSF IFA
NFHCC NIF Heavy Chain CBA, CBA Negative

CSF
NIFTC NIF IFA Titer, CSF IFA
NFLCC NIF Light Chain CBA, CSF CBA Negative
NMDIC NMDA-R Ab IF Titer IFA

Assay, CSF
PC1BC PCA-1 Immunoblot, CSF IB Negative
PCTBC PCA-Tr Immunoblot, CSF IB Negative
PCA1C Purkinje Cell Cytoplasmic IFA *Methodology abbreviations:

Ab Type 1 Immunofluorescence assay (IFA)
for ANNA-1, ANNA-2, ANNA-3,
reported as "uninterpretable."
Note: CRMP-5 titers lower than
1:2 are detectable by recombinant
CRMP-5 Western blot analysis.
CRMP-5 Western blot analysis
will be done on request on stored
spinal fluid (held 4 weeks). This
supplemental testing is
Western blot.
Clinical References: 1. McKeon A, Lennon VA, Pittock SJ: Immunotherapy-responsive

dementias and encephalopathies. Continuum (Minneap Minn). 2010 Apr;16(2):80-101 2. Flanagan EP,
McKeon A, Lennon VA, et al: Autoimmune dementia: clinical course and predictors of immunotherapy
response. Mayo Clin Proc. 2010 Oct;85(10):881-897 3. Geschwind MD, Tan KM, Lennon VA, et al:
Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol.
2008 Oct;65(10):1341-1346 4. Lancaster E, Martinez-Hernandez E, Dalmau J: Encephalitis and
antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011 Jul 12;77(2):179-189 5.
Klein CJ, Lennon VA, Aston PA, et al: Insights from LGI1 and CASPR2 potassium channel complex
autoantibody subtyping. JAMA Neurol. 2013 Feb;70(2):229-234
DCME Dendritic Cell and Monocyte Enumeration, Blood

609795 Clinical Information: Dendritic cells (DC) play a critical role in both innate and adaptive immune
responses. DC include 2 major subsets: myeloid (or conventional) dendritic cells (mDC) and
plasmacytoid dendritic cells (pDC). mDC can capture and present antigens to CD4+ T cells and
cross-present them to CD8+ T cells. They are also a source of inflammatory cytokines. pDC take part in
priming of antiviral T cells and are the major source of type I interferons; as such they act as a primary
defense against viremia. Monocytes are the archetypal myeloid mononuclear cells. Although human
monocytes do have phenotypic heterogeneity, the majority are CD14+ and are classified as classical or
inflammatory monocytes. The list of conditions where this test can be used as part of the assessment
include, but are not limited to, GATA-binding protein 2 deficiency, IKZF1 deficiency, IRF8 deficiency,
STAT3 gain-of-function disease, HYOU1 deficiency, reticular dysgenesis due to AK2 variants, WHIM
syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), dedicator of cytokinesis 8
(DOCK8) deficiency, IRF7 deficiency, and Hermansky-Pudlak syndrome type II. In addition,
unexplained monocytopenia can be a relevant clue in detecting DC deficiency.
Useful For: Aiding in the diagnosis of patients suspected of defects in innate immunity, particularly
those involving monocyte and dendritic cell development This test has not been validated for the
diagnosis of hematologic malignancies.
Interpretation: Interpretive comments will be provided, where applicable, to complement the reported
plasmacytoid dendritic cells, myeloid (or conventional) dendritic cells, and monocyte counts, and their
respective reference ranges.
Reference Values:
The appropriate reference values will be provided on the report.
Clinical References: 1. Bigley V, Cytlak U, Collin M: Human dendritic cell immunodeficiencies.

Semin Cell Dev Biol. 2019 Feb;86:50-61 2. Ciancanelli MJ, Huang SX, Luthra P, et al: Infectious disease.
Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science. 2015
Apr 24;348(6233):448-453 3. Cytlak U, Resteu A, Bogaert D, et al: Ikaros family zinc finger 1 regulates
dendritic cell development and function in humans. Nat Commun. 2018 Mar 27;9(1):1239 4. Dickinson
RE, Griffin H, Bigley V, et al: Exome sequencing identifies GATA-2 mutation as the cause of dendritic
cell, monocyte, B and NK lymphoid deficiency. Blood. 2011 Sep 8;118(10):2656-2658 5. Haapaniemi
EM, Fogarty CL, Keskitalo S, et al: Combined immunodeficiency and hypoglycemia associated with
mutations in hypoxia upregulated 1. J Allergy Clin Immunol. 2017 Apr;139(4):1391-1393 6. Haapaniemi
EM, Kaustio M, Rajala HL, et al: Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and
mycobacterial disease in patients with activating mutations in STAT3. Blood. 2015 Jan;125(4):639-648 7.
Hambleton S, Salem S, Bustamante J, et al: IRF8 mutations and human dendritic-cell immunodeficiency.
N Engl J Med. 2011 Ju3 14;365(2):127-138 8. Keles S, Jabara HH, Reisli I, et al: Plasmacytoid dendritic
cell depletion in DOCK8 deficiency: rescue of severe herpetic infections with IFN-alpha 2b therapy. J
Allergy Clin Immunol. 2014 Jun;133(6):1753-1755 9. Pannicke U, Honig M, Hess I, et al: Reticular
dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2.
Nat Genet. 2009 Jan;41(1):101-105 10. Prandini A, Salvi V, Colombo F, et al: Impairment of dendritic
cell functions in patients with adaptor protein-3 complex deficiency. Blood. 2016 Jun;127(26):3382-3386
11. Reizis B: Plasmacytoid dendritic cells: Development, regulation, and function. Immunity. 2019 Jan
15;50(1):37-50 12. Tassone L, Moratto D, Vermi W, et al: Defect of plasmacytoid dendritic cells in warts,
hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients. Blood. 2010 Dec
2;116(23):4870-4873 13. Vuckovic S, Gardiner D, Field K, et al: Monitoring dendritic cells in clinical
practice using a new whole blood single-platform TruCOUNT assay. J Immunol Methods. 2004
Jan;284(1-2):73-87
DENGM Dengue Virus Antibody, IgG and IgM, Serum

83865 Clinical Information: Dengue virus (DV) is a globally distributed flavivirus with 4 distinct serotypes
(DV-1, -2, -3, -4) and is primarily transmitted by the Aedes aegypti mosquito, which is found throughout
the tropical and subtropical regions of over 100 countries. DV poses a significant worldwide public health
threat with approximately 2.5 to 3 billion people residing in DV endemic areas, among whom 100 to 200
million individuals will be infected and approximately 30,000 patients will succumb to the disease
annually. Following dengue infection, the incubation period varies from 3 to 7 days and, while some
infections remain asymptomatic, the majority of individuals will develop classic dengue fever.
Symptomatic patients become acutely febrile and present with severe musculoskeletal pain, headache,
retro-orbital pain, and a transient macular rash, most often observed in children. Fever defervescence
signals disease resolution in most individuals. However, children and young adults remain at increased
risk for progression to dengue hemorrhagic fever and dengue shock syndrome, particularly during repeat
infection with a new DV serotype. Detection of dengue-specific IgM and IgG-class antibodies remains the
most commonly utilized diagnostic method. Seroconversion occurs approximately 3 to 7 days following
exposure and, therefore, testing of acute and convalescent sera may be necessary to make the diagnosis.
As an adjunct to serologic testing, identification of early DV infection may be made by detection of the
DV nonstructural protein 1 (NS1) antigen. NS1 antigenemia is detectable within 24 hours of infection and
up to 9 days following symptom onset. The DV NS1 antigen can be detected by ordering DNSAG /
Dengue Virus NS1 Antigen, Serum.
Useful For: Aiding in the diagnosis of dengue virus infection

Interpretation: The presence of IgG-class antibodies to dengue virus (DV) is consistent with exposure
to this virus sometime in the past. By 3 weeks following exposure, nearly all immunocompetent
individuals should have developed IgG antibodies to DV. The presence of IgM-class antibodies to DV is
consistent with acute-phase infection. IgM antibodies become detectable 3 to 7 days following infection
and may remain detectable for up to 6 months or longer following disease resolution. The absence of
IgM-class antibodies to DV is consistent with lack of infection. However, specimens collected too soon
following exposure may be negative for IgM antibodies to DV. If DV remains suspected, a second
specimen, collected approximately 10 to 12 days following exposure should be tested.
Reference Values:
IgG: negative
IgM: negative
Clinical References: 1. Bhatt S, Gething PW, Brady OJ, et al: The global distribution and burden
of dengue. Nature. 2013 Apr 25;496:504-507. doi: 10.1038/nature12060 2. Dengue--an infectious
disease of staggering proportions. Lancet. 2013 Jun 22;381(9884):2136 doi:
10.1016/S0140-6736(13)61423-3 3. Rigau-Perez JG, Clark GG, Gubler DJ, et al: Dengue and dengue
haemorrhagic fever. Lancet. 1998 Sep 19;352:971-977 4. Tang KF, Ooi EE: Diagnosis of dengue: an
update. Expert Rev Anti Infect. Ther 2012 Aug;10:895-907 doi: 10.1586/eri.12.76 5. Guzman MG,
Kouri G: Dengue diagnosis, advances and challenges. Int J Infect Dis. 2004 Mar;8:69-80
DENVP Dengue Virus Antibody/Antigen Panel, Serum

62869 Clinical Information: Dengue virus (DV) is a globally distributed flavivirus with 4 distinct
serotypes (DV-1, -2, -3, -4) and is primarily transmitted by the Aedes aegypti mosquito, which is found
throughout the tropical and subtropical regions of over 100 countries. DV poses a significant worldwide
public health threat with approximately 2.5 to 3 billion people residing in DV endemic areas, among
whom 100 to 200 million individuals will be infected and approximately 30,000 patients will succumb
to the disease annually. Following dengue infection, the incubation period varies from 3 to 7 days and
while some infections remain asymptomatic, the majority of individuals will develop classic dengue
fever. Symptomatic patients become acutely febrile and present with severe musculoskeletal pain,
headache, retro-orbital pain, and a transient macular rash, most often observed in children. Fever
defervescence signals disease resolution in most individuals. However, children and young adults
remain at increased risk for progression to dengue hemorrhagic fever and dengue shock syndrome,
particularly during repeat infection with a new DV serotype. Detection of dengue-specific IgM and
IgG-class antibodies remains the most commonly utilized diagnostic method. Seroconversion occurs
approximately 3 to 7 days following exposure and therefore testing of acute and convalescent sera may
be necessary to make the diagnosis. Detection of the DV nonstructural protein 1 (NS1) has emerged as
an alternative biomarker to both serologic- and molecular-based techniques for diagnosis of acute DV
infection. NS1 antigenemia is detectable within 24 hours and up to 9 days following symptoms onset.
This overlaps with the DV viremic phase and NS1 is often detectable prior to IgM seroconversion.
Concurrent evaluation (as performed in this profile) for the NS1 antigen alongside testing for IgM- and
IgG-class antibodies to DV provides optimal diagnostic potential for both early and late dengue disease.
Useful For: Aiding in the diagnosis of dengue virus infection by detection of IgM and IgG antibodies
and the nonstructural protein 1 (NS1)
Interpretation: The presence of IgG-class antibodies to dengue virus (DV) is consistent with
exposure to this virus sometime in the past. By 3 weeks following exposure, nearly all
immunocompetent individuals should have developed IgG antibodies to DV. The presence of IgM-class
antibodies to DV is consistent with acute-phase infection. IgM antibodies become detectable 3 to 7 days
following infection and may remain detectable for up to 6 months or longer following disease
resolution. The absence of IgM-class antibodies to DV is consistent with lack of infection. However,
specimens collected too soon following exposure may be negative for IgM antibodies to DV. If DV
remains suspected, a second specimen, collected approximately 10 to 12 days following exposure
should be tested. The presence of dengue nonstructural protein 1 (NS1) antigen is consistent with
acute-phase infection with dengue virus. The NS1 antigen is typically detectable within 1 to 2 days
following infection and up to 9 days following symptom onset. NS1 antigen may also be detectable
during secondary dengue virus infection, but for a shorter duration of time (1-4 days following symptom
onset). The absence of dengue NS1 antigen is consistent with the lack of acute-phase infection. The
NS1 antigen may be negative is samples collected immediately following dengue virus infection
(<24-48 hours) and is rarely detectable following 9 to 10 days of symptoms.
Reference Values:
IgG: negative
IgM: negative
NS1: negative
Clinical References: 1. Bhatt S, Gething PW, Brady OJ, et al: The global distribution and burden of
dengue. Nature. 2013 Apr 25;496:504-507 doi: 10.1038/nature12060 2. Dengue--an infectious disease of
staggering proportions. Lancet. 2013 Jun 22;381(9884):2136 doi: 10.1016/S0140-6736(13)61423-3 3.
Rigau-Perez JG, Clark GG, Gubler DJ, et al: Dengue and dengue haemorrhagic fever. Lancet. 1998 Sep
19;352:971-977 4. Tang KF, Ooi EE: Diagnosis of dengue: an update. Expert Rev Anti Infect Ther. 2012
Aug;10:895-907 doi: 10.1586/eri.12.76 5. Guzman MG, Kouri G: Dengue diagnosis, advances and
challenges. Int J Infect Dis. 2004 Mar;8:69-80
DNSAG Dengue Virus NS1 Antigen, Serum

36781 Clinical Information: Dengue virus (DV) is a globally distributed flavivirus with 4 distinct serotypes
(DV-1, -2, -3, -4) and is primarily transmitted by the Aedes aegypti mosquito, found throughout the
tropical and subtropical regions of over 100 countries. DV poses a significant worldwide public health
threat with approximately 2.5 to 3 billion people residing in DV endemic areas, among whom 100 to 200
million individuals will be infected, and approximately 30,000 patients will succumb to the disease,
annually. Following dengue infection, the incubation period varies from 3 to 7 days, and while some
infections remain asymptomatic, the majority of individuals will develop classic dengue fever.
Symptomatic patients become acutely febrile and present with severe musculoskeletal pain, headache,
retro-orbital pain, and a transient macular rash, most often observed in children. Fever defervescence
signals disease resolution in most individuals. However, children and young adults remain at increased
risk for progression to dengue hemorrhagic fever and dengue shock syndrome, particularly during repeat
infection with a new DV serotype. Detection of the DV nonstructural protein 1 (NS1) has emerged as an
alternative biomarker to both serologic and molecular based techniques for diagnosis of acute DV
infection. NS1 antigenemia is detectable within 24 hours and up to 9 days following symptoms onset.
This overlaps with the DV viremic phase and NS1 is often detectable prior to IgM seroconversion.
Concurrent evaluation for the NS1 antigen alongside testing for IgM- and IgG-class antibodies to DV
(DENGM / Dengue Virus Antibody, IgG and IgM, Serum) provides optimal diagnostic potential for both
early and late dengue disease.
Useful For: Aiding in the diagnosis of dengue virus infection

Interpretation: Positive: The presence of dengue nonstructural protein 1 (NS1) antigen is consistent
with acute-phase infection with dengue virus. The NS1 antigen is typically detectable within 1 to 2 days
following infection and up to 9 days following symptom onset. NS1 antigen may also be detectable
during secondary dengue virus infection, but for a shorter duration of time (1-4 days following symptom
onset). Negative: The absence of dengue NS1 antigen is consistent with the lack of acute-phase infection.
The NS1 antigen may be negative if specimen is collected immediately following dengue virus infection
(<24-48 hours) and is rarely detectable following 9 to 10 days of symptoms.
Reference Values:
Negative
dengue. Nature. 2013;496:504-507 2. Dengue--an infectious disease of staggering proportions. Lancet.
2013 Jun 22;381(9884):2136 3. Rigau-Perez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ, Vorndam
AV: Dengue and dengue haemorrhagic fever. Lancet 1998;352:971-977 4. Tang KF, Ooi EE: Diagnosis
of dengue: an update. Expert Rev Anti Infect Ther. 2012;10:895-907 5. Guzman MG, Kouri G: Dengue
diagnosis, advances and challenges. Int J Infect Dis. 2004;8:69-80
DENGS Dengue Virus, Molecular Detection, PCR, Serum
serotypes (DV-1, -2, -3, -4) and is primarily transmitted by the Aedes aegypti mosquito, found
to the disease, annually. Following dengue infection, the incubation period varies from 3 to 7 days and
headache, retro-orbital pain, and a transient macular rash most often observed in children. Fever
particularly during repeat infection with a new DV serotype. Detection of DV nucleic acid in serum is a
marker of acute infection with this virus. Importantly, the period of time that the virus can be detected in
serum is brief and, therefore, molecular testing should be performed within the first week following
onset of symptoms. After this time, serologic testing is the preferred method for diagnosis of DV
infection.
Useful For: Aiding in the diagnosis of acute infection caused by dengue virus
Interpretation: Positive: The detection of dengue virus nucleic acid in serum is consistent with
acute-phase infection. Dengue virus nucleic acid may be detectable during the first 1 to 7 days
following the onset of symptoms. Negative: The absence of dengue nucleic acid in serum is consistent
with the lack of acute-phase infection. Dengue virus nucleic acid may not be detected if the serum
specimen is collected immediately following dengue virus infection (<24-48 hours) and is rarely
detectable following 7 days of symptoms.
Reference Values:
Negative
Clinical References: 1. Bhatt S, Gething PW, Brady OJ, et al: The global distribution and burden
of dengue. Nature 2013;496:504-507 2. Dengue--an infectious disease of staggering proportions. Lancet
2013 Jun 22;381(9884):2136 3. Rigau-Perez JG, Clark GG, Gubler DJ, et al: Dengue and dengue
haemorrhagic fever. Lancet 1998;352:971-977 4. Tang KF, Ooi EE: Diagnosis of dengue: an update.
Expert Rev Anti Infect Ther 2012;10:895-907 5. Guzman MG, Kouri G: Dengue diagnosis, advances
and challenges. Int J Infect Dis 2004;8:69-80
DENGC Dengue Virus, Molecular Detection, PCR, Spinal Fluid

serotypes (DV-1, -2, -3, -4) and is primarily transmitted by the Aedes aegypti mosquito, found
to the disease, annually. Following dengue infection, the incubation period varies from 3 to 7 days and
headache, retro-orbital pain, and a transient macular rash, most often observed in children. Fever
particularly during repeat infection with a new DV serotype. Detection of DV nucleic acid in
cerebrospinal fluid (CSF) is a marker for central nervous system infection caused by this virus.
Importantly, the period of time that the virus can be detected in serum and CSF is brief and, therefore,
molecular testing should be performed within the first week following onset of symptoms. After this
time, serologic testing is the preferred method for diagnosis of DV infection.
Useful For: Aiding in the diagnosis of central nervous system infection caused by dengue virus
Interpretation: Positive: The detection of dengue virus nucleic acid in cerebrospinal fluid (CSF) is
consistent with acute-phase infection of the central nervous system. Dengue virus nucleic acid may be
detectable during the first 1 to 7 days following the onset of symptoms. Negative: The absence of dengue
nucleic acid in CSF is consistent with the lack of acute-phase infection. Dengue virus nucleic acid may
not be detected if the CSF specimen is collected immediately following dengue virus infection (<24-48
hours) and is rarely detectable following 7 days of symptoms.
Reference Values:
Negative
dengue. Nature 2013;496:504-507 2. Dengue--an infectious disease of staggering proportions. Lancet
2013 Jun 22;381(9884):2136 3. Rigau-Perez JG, Clark GG, Gubler DJ, et al: Dengue and dengue
haemorrhagic fever. Lancet 1998;352:971-977 4. Tang KF, Ooi EE: Diagnosis of dengue: an update.
Expert Rev Anti Infect Ther 2012;10:895-907 5. Guzman MG, Kouri G: Dengue diagnosis, advances and
challenges. Int J Infect Dis 2004;8:69-80
DRPL Dentatorubral-Pallidoluysian Atrophy (DRPLA) Gene Analysis,

35402 Varies
Clinical Information: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant
neurodegenerative disorder characterized by ataxia, choreoathetosis, dementia, and psychiatric
disturbance in adults and ataxia, myoclonus, seizures, and progressive intellectual deterioration in
children. Characteristic neuropathologic observations include degeneration of the dentatorubral and
pallidoluysian systems of the central nervous system. The prevalence of DRPLA depends on the
geographic and ethnic origin of the population being studied. DRPLA was first described in a European
individual without a family history; however, it is predominantly found as an inherited condition and is
most prevalent in Japan (0.2-0.7 per 100,000). Although rare, DRPLA has been identified in other
populations including Europe and North America. DRPLA is caused by an expansion of the CAG
trinucleotide repeat in the ATN1 (DRPLA) gene. This trinucleotide repeat is polymorphic in the general
population, with the number of repeats ranging from 7 to 35. In affected individuals the CAG expansion
ranges from 48 to 93 repeats. As with other trinucleotide repeat disorders, anticipation is frequently
observed, and larger CAG expansions are associated with earlier onset and a more severe and rapid
clinical course. In DRPLA, the observed anticipation appears to be significantly greater in paternal
transmissions.
Useful For: Molecular confirmation of a diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA)

for symptomatic patients Predictive testing for individuals with a family history of DRPLA and a
documented expansion in the ATN1 gene in an affected family member

Reference Values:
Normal alleles: 7-35 CAG repeats
Abnormal alleles: 49-93 CAG repeats
Clinical References: 1. Ikeuchi T, Onodera O, Oyake M, et al: Dentatorubral-pallidoluysian atrophy

(DRPLA): close correlation of CAG repeat expansions with the wide spectrum of clinical presentations
and prominent anticipation. Semin Cell Biol 1995;6:37-44 2. Tsuji S: Dentatorubral-pallidoluysian
atrophy: clinical aspects and molecular genetics. Ad Neurol 2002;89:231-239 3. Oyanagi S: Hereditary
dentatorubral-pallidoluysian atrophy. Neuropathology 2000 20 Suppl:S42-6
FDCU Deoxypyridinoline Crosslinks, Urine

Current 58048
Reference Values:
Deoxypyridinoline Urine-ratio to CRT Adult Male: 2.3 Ã¢â‚¬â€œ 8.7 nmol/mmol
Premenopausal Adult Female: 3.1 Ã¢â‚¬â€œ 8.7 nmol/mmol
Creatinine, Urine Ã¢â‚¬â€œ per volume No reference interval
The target value for treated post-menopausal adult females is the same as the Premenopausal reference
interval.
DEXT Dermatopathology Consultation, Wet Tissue

70596 Clinical Information: Dermatopathology involves histologic examination of skin biopsy and oral
mucosal specimens.
Useful For: Histologic diagnosis and differential diagnosis of cutaneous diseases

Interpretation: Histologic diagnosis is based primarily on interpretation of hematoxylin and
eosin-stained sections. Special histochemical stains, such as alcian blue, Giemsa, or periodic acid-Schiff
may be necessary in some cases. Interpretation is based on evaluation of patterns including architectural
and cytologic details, which are included in a microscopic description.
Reference Values:
Diagnosis and description of microscopic findings
Clinical References: 1. Lever WF, Schaumburg-Lever G: Histopathology of the Skin. 7th ed.
Philadelphia, JB Lippincott; 1990 2. Elder D, Elenitsas R, Rubin A, et al, eds: Atlas of
Dermatopathology Synopsis and Atlas of Leverâ€™s Histopathology of the Skin. 4th ed. Lippincott
Williams and Wilkins; 2020
DMIC Dermatophagoides microceras, IgE, Serum

immune response to allergen that may be associated with allergic disease. The allergens chosen for
bronchospasm) in infants and children 5 years due to food sensitivity (milk, egg, soy, and wheat
Useful For: Establishing a diagnosis of an allergy to Dermatophagoides microceras

Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â
Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Defining the allergen

Reference Values:

0 Negative

apply to all ages.
DCP Des-Gamma-Carboxy Prothrombin, Serum

61844 Clinical Information: Des-gamma-carboxy prothrombin (DCP), also known as the protein induced
by vitamin K absence or antagonist II (PIVKA-II), is an abnormal form of the coagulation protein,
prothrombin. DCP is a nonfunctional prothrombin resulting from a lack of carboxylation of 10 glutamic
acid residues in the N-terminal portion of the molecule. In normal liver, prothrombin undergoes
post-translational carboxylation before release into the peripheral blood. The carboxylation converts
specific amino-terminal glutamic acid residues to gamma-carboxyglutamic acid. The vitamin K dependent
carboxylase responsible for the carboxylation is absent in many hepatocellular carcinoma (HCC) cells,
and an abnormal prothrombin with all or some of unconverted glutamic acid is secreted. Therefore, this
noncarboxylated form (DCP) has been used as an HCC biomarker. DCP is considered a complementary
biomarker to alpha fetoprotein (AFP) and third electrophoretic form of lentil lectin-reactive AFP%
(AFP-L3%) for assessing the risk of developing HCC. The elevation of both AFP-L3 and DCP indicate
progression of HCC, albeit they reflect different features of the progression. In a prospective study of
patients in the United States with an established diagnosis of HCC, the sensitivities for AFP, AFP-L3%,
and DCP were 68%, 62%, and 73%, respectively. When the 3 markers were combined, the sensitivity was
86%. In another study, DCP levels were shown to correlate with tumor size and metastatic HCC. In this
study, compared to AFP and AFP-L3%, DCP had the highest sensitivity (87%) and the highest positive
predictive value (87%) in patients with HCC due to chronic hepatitis B and C infections. A number of
studies have shown that elevated serum DCP is significantly related to portal vein invasion and/or
intrahepatic metastasis, which significantly affect prognosis for patients with HCC. DCP can be elevated
in other conditions besides HCC. Conditions such as obstructive jaundice, intrahepatic cholestasis causing
chronic decrease in vitamin K, and ingestion of drugs such as warfarin or wide-spectrum antibiotics can
result in high concentrations of DCP. In addition, 25% to 50% of patients with HCC will have a DCP
value within the reference range. Because of this, a normal DCP value does not rule out HCC.
Useful For: Risk assessment of patients with chronic liver disease for development of hepatocellular
carcinoma (HCC) Aiding in the monitoring of HCC patients post therapy if des-gamma-carboxy
prothrombin (DCP) level was elevated prior to therapy
Interpretation: In patients with an elevated des-gamma-carboxy prothrombin (DCP) result (> or =7.5
ng/mL), the risk of developing hepatocellular carcinoma (HCC) is 36.5% (95% CI 23.5%-49.6%). The
risk of developing HCC with a negative DCP result (<7.5 ng/mL) is 7.6% (95% CI 4.4%-10.8%). For
patients with HCC and an elevated DCP level prior to therapy, an elevated DCP level posttherapy is
associated with an increased risk of HCC recurring.
Reference Values:
<7.5 ng/mL
Clinical References: 1. Lai Q, Iesari S, Levi Sandri GB, Lerut J: Des-gamma-carboxy prothrombin
in hepatocellular cancer patients waiting for liver transplant: a systematic review and meta-analysis. Int J
Biol Markers. 2017 Oct 31;32(4):e370-e374. doi: 10.5301/ijbm.5000276 2. Zhu R, Yang J, Xu L, et al:
Diagnostic Performance of Des-gamma-carboxy Prothrombin for Hepatocellular Carcinoma: A
Meta-Analysis. Gastroenterol Res Pract. 2014;2014:529314. doi: 10.1155/2014/529314 3. De J, Shen Y,
Qin J, et al: A Systematic Review of Des-gamma-Carboxy Prothrombin for the Diagnosis of Primary
Hepatocellular Carcinoma. Medicine (Baltimore). 2016 Apr;95(17):e3448. doi:
10.1097/MD.0000000000003448
DESPR Desipramine, Serum

37123 Clinical Information: Desipramine is a tricyclic antidepressant; it also is a metabolite of
imipramine. These drugs have also been employed in the treatment of enuresis (involuntary urination)
in childhood and severe obsessive-compulsive neurosis. Desipramine is the antidepressant of choice in
patients where maximal stimulation is indicated. The therapeutic concentration of desipramine is 100 to
300 ng/mL. About 1 to 3 weeks of treatment are required before therapeutic effectiveness becomes
apparent. The most frequent side effects are those attributable to anticholinergic effects: dry mouth,
constipation, dizziness, tachycardia, palpitations, blurred vision, and urinary retention. These occur at
blood concentrations in excess of 400 ng/mL, although they may occur at therapeutic concentrations in
the early stage of therapy. Cardiac toxicity (first-degree heart block) is usually associated with blood
concentrations in excess of 400 ng/mL.
Useful For: Monitoring serum concentration of desipramine during therapy Evaluating potential
desipramine toxicity The test may also be useful to evaluate patient compliance
Interpretation: Most individuals display optimal response to desipramine with serum levels of 100
to 300 ng/mL. Some individuals may respond well outside of this range or may display toxicity within
the therapeutic range; thus, interpretation should include clinical evaluation. Risk of toxicity is
increased with levels above 400 ng/mL.
Reference Values:
dose).
Levels may be elevated in non-trough specimens.
monitoring and toxicology of antidepressants. Crit Rev Clin Lab Sci. 2008;45(1):25-89Â Â Â Â 2.
Thanacoody HK, Thomas SH: Antidepressant poisoning. Clin Med. 2003;3(2):114-118 3. Hiemke C,
Baumann P, Bergemann N, et al: AGNP Consensus Guidelines for Therapeutic Drug Monitoring in
Psychiatry: Update 2011. Pharmacopsychiatry. 2011;44(6):195-235 4. Burtis CA, Ashwood ER, Bruns
ED, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 5th ed. Elsevier; 2012
DESMN Desmin Immunostain, Technical Component Only

70421 Clinical Information: Desmin is an intermediate filament protein in striated and smooth muscle
cells. In neoplastic tissues, the antibody reacts with tumors of myogenic origin such as those arising
from smooth muscle (leiomyosarcomas) and those derived from striated muscle (rhabdomyosarcomas).
Useful For: Identification of striated and smooth muscle cells and tumors derived from this cell type
Clinical References: 1. Pawlak A, Rejmak-Kozicka E, Gil KE, Ziemba A, Kaczmarek L, Gil RJ:
Patterns of desmin expression in idiopathic dilated cardiomyopathy are related to the desmin mRNA and
ubiquitin expression. J Investig Med. 2019 Jan;67(1):11-19. doi: 10.1136/jim-2017-000707 2.
Bermudez-Jimenez FJ, Carriel V, Brodehl A, et al: Novel desmin mutation p.Glu401Asp impairs filament
formation, disrupts cell membrane integrity, and causes severe arrhythmogenic left ventricular
cardiomyopathy/dysplasia. Circulation. 2018 Apr 10;137(15):1595-1610. doi:
10.1161/CIRCULATIONAHA.117.028719 3. Ekinci O, Ogut B, Celik B, Dursun A: Compared with
elastin stains, h-caldesmon and desmin offer superior detection of vessel invasion in gastric, pancreatic,
and colorectal adenocarcinomas. Int J Surg Pathol. 2018 Jun;26(4):318-326. doi:
10.1177/1066896917752442
DSGAB Desmoglein 1 (DSG1) and Desmoglein 3 (DSG3), IgG

606818 Antibodies, Serum
Clinical Information: Pemphigus includes a group of often fatal autoimmune blistering diseases
characterized by intraepithelial lesions. Pemphigus vulgaris and its variants may present with oral or
mucosal lesions alone or with mucosal plus skin lesions. Pemphigus foliaceous and variants present with
skin lesions alone. Indirect immunofluorescence (IIF) studies reveal that both forms of pemphigus are
caused by autoantibodies to cell surface antigens of stratified epithelia or mucous membranes and skin.
These antibodies bind to calcium-dependent adhesion molecules in cell surface desmosomes, notably
desmoglein 1 (DSG1) in pemphigus foliaceus and desmoglein 3 (DSG3) and/or DSG1 in pemphigus
vulgaris. Desmogleins are protein substances located in and on the surface of keratinocytes. These
proteins have been shown to be a critical factor in cell-to-cell adhesion. Antibodies to desmogleins can
result in loss of cell adhesion, the primary cause of blister formation in pemphigus. The diagnosis of
pemphigus depends on biopsy and serum studies that characterize lesions and detect the autoantibodies
that cause them. Originally, the serum studies were performed by IIF using primate esophagus and other
tissue substrates. The identification of the reactive antigens as DSG1 and DSG3 has made it possible to
develop highly specific and sensitive enzyme-linked immunosorbent assay methods.
Useful For: Preferred screening test for patients suspected to have an autoimmune blistering disorder
of the skin or mucous membranes (pemphigus) Aiding in the diagnosis of pemphigus
Interpretation: Antibodies to desmoglein 1 (DSG1) and desmoglein 3 (DSG3) have been shown to be
present in patients with pemphigus. Many patients with pemphigus foliaceus, a superficial form of
pemphigus have antibodies to DSG1. Patients with pemphigus vulgaris, a deeper form of pemphigus,
have antibodies to DSG3 and sometimes DSG1 as well. Antibody titer correlates in a semiquantitative
manner with disease activity in many patients. Patients with severe disease can usually be expected to
have high titers of antibodies to DSG. Titers are expected to decrease with clinical improvement. Our
experience demonstrates a very good correlation between DSG1 and DSG3 results and the presence of
pemphigus. Adequate sensitivities and specificity for disease are documented. However, in those patients
strongly suspected to have pemphigus either by clinical findings or by routine biopsy, and in whom the
DSG assay is negative, indirect immunofluorescence testing is recommended. For more information see
CIFS / Cutaneous Immunofluorescence Antibodies [IgG], Serum.
Reference Values:
DESMOGLEIN 1:
DESMOGLEIN 3:
Clinical References: 1. Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T: The clinical

phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol.
1999 Feb;40(2 Pt 1):167-170 2. Amagai M, Komai A, Hashimoto T, et al: Usefulness of enzyme-linked
immunoabsorbent assay using recombinant desmogleins 1 and 3 for sero-diagnosis of pemphigus. Brit J
Dermatol. 1999 Feb;140(2):351-357 3. Harman KE, Gratian MJ, Bhogal BS, Challacombe SJ, Black M:
The clinical significance of autoantibodies to desmoglein 1 in 78 cases of pemphigus vulgaris. J Invest
Derm. 1999;112(4):568. Abstract 273 4. Harman KE, Gratian MJ, Seed PT, Bhogal BS, Challacombe SJ,
Black MM: Diagnosis of pemphigus by ELISA: a critical evaluation of two ELISAs for the detection of
antibodies to the major pemphigus antigens, desmoglein 1 and 3. Clin Exp Dermatol. 2000
May;25(3):236-240 5. Prussmann W, Prussmann J, Koga H, et al: Prevalence of pemphigus and
pemphigoid autoantibodies in the general population. Orphanet J Rare Dis. 2015 May 15;10:63 6. Toosi
S, Collins JW, Lohse CM, et al: Clinicopathologic features of IgG/IgA pemphigus in comparison with
classic (IgG) and IgA pemphigus. Int J Dermatol. 2016 Apr;55(4):e184-e190 7. Montagnon CM,
Tolkachjov SN, Murrell DF, Camilleri MJ, Lehman JS: Intraepithelial autoimmune blistering dermatoses:
Clinical features and diagnosis. J Am Acad Dermatol. 2021 Jun;84(6):1507-1519
DESG3 Desmoglein 3 (DSG3) Immunostain, Technical Component

70420 Only
Clinical Information: Desmoglein 3 (DSG3) is a calcium-binding transmembrane glycoprotein
component of desmosomes in vertebrate epithelial cells. Currently, three desmoglein subfamily
members have been identified and all are members of the cadherin cell adhesion molecule superfamily.
Positivity for DSG3 in a non-small cell lung carcinoma supports a diagnosis of squamous cell
carcinoma.
Useful For: Classification of squamous cell carcinomas

Clinical References: 1. Funahashi SI, Kawai S, Fujii E, et al: Generation of an anti-desmoglein 3

antibody without pathogenic activity of pemphigus vulgaris for therapeutic application to squamous cell
carcinoma. J Biochem. 2018 Dec;164(6):471-481. doi: 10.1093/jb/mvy074 2. Xiao J, Lu X, Chen X, et
al: Eight potential biomarkers for distinguishing between lung adenocarcinoma and squamous cell
carcinoma. Oncotarget. 2017 Sep 22;8(42):71759-71771. doi: 10.18632/oncotarget.17606 3. Brown L,
Wan H: Desmoglein 3: a help or a hindrance in cancer progression? Cancers (Basel). 2015
Mar;7(1):266-286. doi: 10.3390/cancers7010266
DEXA Dexamethasone, Serum

609439 Clinical Information: Synthetic glucocorticoids are widely used and have an important clinical
utility both as antiinflammatory and immunosuppressive agents. The medical use of these agents, as
well as their surreptitious use, can sometimes lead to a confusing clinical presentation. Patients exposed
to these steroids may present with clinical features of Cushing syndrome but with suppressed cortisol
levels and evidence of hypothalamus-pituitary-adrenal axis suppression.
Useful For: Confirming the presence of dexamethasone in serum Confirming the cause of secondary
adrenal insufficiency This test is not useful as the sole basis for a diagnosis or treatment decisions.
Interpretation: This test will screen for, and quantitate if present, the synthetic glucocorticoid,
dexamethasone. The presence of this synthetic glucocorticoid in serum indicates the current or recent
use of this compound.
Reference Values:
Baseline: <30 ng/dL
8:00 a.m. following 1 mg Dexamethasone, previous evening: >100 ng/dL
8:00 a.m. following 8 mg Dexamethasone, (4 x 2 mg doses) previous day: >800 ng/dL
Clinical References: Genere N, Kaur RJ, Athimulam S, et al: Interpretation of abnormal

dexamethasone suppression test is enhanced with use of synchronous free cortisol assessment. J Clin
Endocrinol Metab. 2021 Oct 14;dgab724. doi: 10.1210/clinem/dgab724. Epub ahead of print
FDXAP Dexedrine (Dextroamphetamine)

FCDU8 Dextro/Levo Methorphan, Umbilical Cord Tissue

Units: ng/g
FDM Dextromethorphan (DM), Serum

DBS1 Diabetes Mellitus Type 1 Evaluation, Serum

48400 Clinical Information: Islet cell autoantibodies have been known to be associated with type 1 diabetes
mellitus since the 1970s. Since 1988, several autoantigens against which islet antibodies are directed have
been identified. These include the insulinoma-associated protein 2 (IA-2), glutamic acid decarboxylase 65
(GAD65), insulin and, most recently, the zinc transporter ZnT8.(1) Only 4% to 7% of patients with type 1
diabetes are autoantibody negative, fewer than 10% have only 1 marker, and around 70% have 3 or 4
markers. These findings have been confirmed in multiple specialty laboratories internationally. One or
more of these autoantibodies are detected in 93% to 96% of patients with type 1 diabetes, both adults and
children. These antibodies are also detectable in relatives of type 1 diabetic patients at risk for developing
diabetes, before clinical onset.(2) Some patients with type 1 diabetes are initially diagnosed as having type
2 diabetes because of symptom-onset in adulthood, societal obesity, and initial insulin-independence.
These patients with either "latent autoimmune diabetes in adulthood" or type 1 diabetes mellitus may be
distinguished from those patients with type 2 diabetes by detection of 1 or more islet autoantibodies
(including ZnT8 antibody). Patients with gestational diabetes can also be stratified for future diabetes risk
by detection of 1 or more islet autoantibodies.
Useful For: Distinguishing type 1 from type 2 diabetes mellitus Identifying individuals at risk of type 1
diabetes (including high-risk relatives of patients with diabetes) Predicting future insulin requirement
treatment in patients with adult-onset diabetes
Interpretation: Seropositivity for 1 or more islet cell autoantibodies is supportive of: -A diagnosis of
type 1 diabetes. Only 2% to 4% of patients with type 1 diabetes are antibody negative; 90% have more
than 1 antibody marker, and 70% have 3 or 4 markers.(1) Patients with gestational diabetes who are
antibody seropositive are at high risk for diabetes postpartum. Rarely, diabetic children test seronegative,
which may indicate a diagnosis of maturity-onset diabetes of the young in clinically suspicious cases. -A
high risk for future development of diabetes. Among 44 first-degree relatives of patients with type 1
diabetes, those with 3 antibodies had a 70% risk of developing type 1 diabetes within 5 years.(2) -A
current or future need for insulin therapy in patients with diabetes. In the UK Prospective Diabetes Study,
84% of those classified clinically as having type 2 diabetes and seropositive for glutamic acid
decarboxylase 65 required insulin within 6 years, compared to 14% that were antibody negative.(3)
Reference Values:
GLUTAMIC ACID DECARBOXYLASE (GAD65) ANTIBODY
< or =0.02 nmol/L
INSULIN ANTIBODIES
< or =0.02 nmol/L
ISLET ANTIGEN 2 (IA-2) ANTIBODY
< or =0.02 nmol/L
ZINC Transporter 8 (ZnT8) ANTIBODY
< 15.0 U/mL
Clinical References: 1. Bingley PJ: Clinical applications of diabetes antibody testing. J Clin
Endocrinol Metab 2010;95:25-33 2. Bingley PJ, Gale EA: Progression to type 1 diabetes in islet cell
antibody-positive relatives in the European Nicotinamide Diabetes Intervention Trial: the role of
additional immune, genetic and metabolic markers of risk. Diabetologia 2006;49:881-890 3. Turner R,
Stratton I, Horton V, et al: UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid
decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study
Group. Lancet 1997;350:1288-1293
DIA Diazepam and Nordiazepam, Serum

8629 Clinical Information: Diazepam, a benzodiazepine derivative, is an anxiolytic agent that reduces
neuronal depolarization resulting in decreased action potentials. It enhances the action of gamma-amino
butyric acid (GABA) by tightly binding to A-type GABA receptors, thus opening the membrane
channels and allowing the entry of chloride ions. It is also used as a muscle relaxant, procedural
sedation agent, and sedative-hypnotic agent to treat withdrawal states (ie, ethanol), along with other
conditions (seizures). Diazepam is metabolized to several metabolites in the liver including temazepam,
oxazepam, and nordiazepam (desmethyldiazepam), and the clearance of the drug is reduced
considerably in older individuals and in patients with hepatic disease. Therapeutic assessment typically
includes measurement of both the parent drug (diazepam) and the active metabolite (nordiazepam).
Useful For: Assessing compliance Monitoring for appropriate therapeutic level Assessing diazepam
toxicity
Interpretation: For seizures: Serum concentrations are not usually monitored during early therapy
because response to the drug can be monitored clinically as seizure control. If seizures resume despite
adequate therapy, another anticonvulsant must be considered. Toxicity is commonly seen when
diazepam plus nordiazepam concentrations exceed 3000 ng/mL. Adverse effects of benzodiazepines in
therapeutic doses usually reflect the drug's pharmacology and include sedation, slurred speech, and
ataxia. Respiratory depression/arrest may occur with large overdoses or following rapid intravenous
injection with short-acting benzodiazepines.
Reference Values:
Therapeutic concentrations
Diazepam and Nordiazepam: 200-2,500 ng/mL
Clinical References: 1. Langman LJ, Bechtel L, Holstege CP: Clinical toxicology. In: Burtis CA,
Ashwood ER, Bruns DE, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics.. WB
Saunders Company; 2011:1109-1188 2. Burtis CA, Ashwood ER, Bruns DE, eds. Tietz Textbook of
Clinical Chemistry and Molecular Diagnostics. WB Saunders Company; 2011:Table 60.2
FDGTX Digitoxin, Serum
Digitoxin
Therapeutic Range:Â 10 - 30 ng/mL
FRDIG Digoxin, Free, Serum

82130 Clinical Information: Digoxin, a widely prescribed cardiac drug, has a narrow therapeutic window (a
very small difference exists between therapeutic and toxic tissue concentrations). While excess digoxin
can have serious side effects (eg, cardiac dysrhythmias, heart failure, seizures, death), it is one of the few
therapeutic drugs for which antidotal therapy is available.(1) In toxic situations, antibody fragment
therapy, which involves the administration of antibodies to digoxin (eg, Digibind, Digoxin Immune Fab),
is indicated. In manufacturing of Digibind, papain cleaves digoxin-specific IgG antibody into 2 antigen
binding-site fragments (Fab fragments). These fragments bind to digoxin, block the active site of the
digoxin molecule, and make it unavailable to its receptor molecule and biologically inactive. The Fab
fragment-digoxin complex is then excreted by the kidney. Total digoxin concentration in blood increases
approximately 10 to 30 fold after administration of Fab fragments. On the other hand, the unbound (free)
fraction, which is responsible for its pharmacological activity, decreases. Traditional digoxin assays
performed by immunoassay (eg, DIG / Digoxin, Serum) measure both Fab fragment-bound (inactive)
digoxin and free (active) digoxin (ie, total digoxin), and are unsuitable for managing patients when
digoxin-specific Fab fragment therapy has been administered. Assays for measurement of free digoxin
levels only are necessary in such situations. The kidneys provide the main route of Fab fragment
elimination from the body. In patients with normal renal function, digoxin-specific Fab fragments are
excreted in the urine with a biological half-life of 15 to 20 hours. Ordinarily, improvement in signs or
symptoms of digoxin intoxication begins within a half hour or less after initiation of Fab fragment
therapy. Clearance may be delayed in patients with renal failure. In such patients, toxicity may recur if
previously bound drug is released from the Fab fragments, resulting in increased levels of free digoxin.
Digoxin-like immunoreactive factors (DLIFs) are endogenous substances that can cross-react with testing
antibodies used in some digoxin immunoassays, causing erroneous results. DLIFs may be seen in certain
volume-expanded patients such as neonates, patients with renal or liver disease, and in women in the third
trimester of pregnancy being treated with digoxin.(2) DLIFs are strongly bound to proteins and, in this
assay, are removed prior to testing. The following ordering guidelines are offered: -When creatinine
clearance is less than 30 mL/min/surface area: order free digoxin levels daily for 12 days (or until
dismissal) -When creatinine clearance is equal to or above 30 mL/min/surface area (and the patient is not
on renal-replacement therapy): order free levels daily for 72 hours, as long as the last level is not
supratherapeutic (these patients are expected to have good clearance and a lower risk for reintoxication)
-Also order total digoxin levels every other day during the time periods above, with a goal of determining
whether there is correlation between changes in free and total levels.
Useful For: Evaluating recrudescent (breakthrough) digoxin toxicity in renal-failure patients Assessing
the need for more antidigoxin Fab to be administered Deciding when to reintroduce digoxin therapy
Monitoring patients with possible digoxin-like immunoreactive factors (DLIFs)
Interpretation: The target therapeutic level is 0.4 to 0.9 ng/mL. Toxicity may be seen when free
digoxin concentrations are 3.0 ng/mL or higher. Pediatric patients may tolerate higher concentrations.
Therapeutic concentrations for free digoxin are 25% lower than therapeutic values for total digoxin due to
the separation of protein-bound digoxin in the assay.
Reference Values:
<16 years:
Therapeutic ranges have not been established for patients who are under 16 years of age. In adults, the
suggested serum free digoxin therapeutic range is 0.4-0.9 ng/mL.
Toxic concentration: > or =3.0
> or =16 years:

0.4-0.9 ng/mL
Toxic concentration: > or =3.0 ng/ mL
Clinical References: 1. Jortani SA, Pinar A, Johnson NA, Valdes R Jr: Validity of unbound
digoxin measurements by immunoassays in presence of antidote (Digibind). Clin Chim Acta.
1999;283:159-169 2. DIGIBIND Digoxin Immune FAB (Ovine). Package insert. GlaxoSmithKline;
2003 3. Moyer TP, Boeckx RL, eds: Applied Therapeutic Drug Monitoring. Vol 2. American
Association for Clinical Chemistry Press; 1984 4. Jortani SA, Voldes R Jr: Digoxin and its related
endogenous factors. Crit Rev Clin Lab Sci. 1997;34:225-274 5. Datta P, Hinz V, Klee G: Comparison
four digoxin immunoassays with respect to interference from digoxin-like immunoreactive factors. Clin
Biochem. 1996;29(6):541-547 6. Soldin SJ: Free drug measurements. When and why? An overview.
Arch Pathol Lab Med. 1999;123:822-823 7. Dickstein K, Cohen-Solal A, Filippatos G, et al: ESC
guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for
the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of
Cardiology. Eur Heart J. 2008;29:2388-2442 8. Milone MC, Shaw LM: Therapeutic drugs and their
management. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics 6th ed. Elsevier; 2018800-831
DIG Digoxin, Serum

8674 Clinical Information: Compounds in the digitalis family of glycosides consist of a steroid nucleus,
a lactone ring, and a sugar. Digoxin is widely prescribed for the treatment of congestive heart failure
and various disturbances of cardiac rhythm. Digoxin improves the strength of myocardial contraction,
and results in the beneficial effects of increased cardiac output, decreased heart size, decreased venous
pressure, and decreased blood volume. Digoxin therapy also results in stabilized and slowed ventricular
pulse rate. These therapeutic effects are produced through a network of direct and indirect interactions
upon the myocardium, blood vessels, and the autonomic nervous system. Digoxin is well absorbed after
oral administration and is widely distributed to tissues, especially the heart, kidney, and liver. A number
of factors can alter normal absorption, distribution, and bioavailability of the drug, including naturally
occurring enteric bacteria in the bowel, presence of food in the gut, strenuous physical activity,
ingestion of quinine or quinidine, and concomitant use of a wide range of drugs. Children generally
require higher concentrations of digoxin. After oral administration, there is an early rise in serum
concentration. Equilibration of serum and tissue levels occurs at approximately 6 to 8 hours. For this
reason, blood specimens for digoxin analysis should be drawn at least 6 to 8 hours after drug
administration. Digoxin is excreted primarily in the urine. The average elimination half-life is 36 to 40
hours but may be considerably prolonged in those with renal disease, causing digoxin accumulation and
toxicity. Symptoms of digoxin toxicity often mimic the cardiac arrhythmia's for which the drug was
originally prescribed (eg, heart block and heart failure). Other typical symptoms of toxicity include
gastrointestinal effects, such as anorexia, nausea, vomiting, abdominal pain and diarrhea, and
neuropsychologic symptoms, such as fatigue, malaise, dizziness, clouded or blurred vision, visual and
auditory hallucination, paranoid ideation, and depression. Toxicity of digoxin may reflect several
factors: the drug has a narrow therapeutic window (a very small difference exists between therapeutic
and toxic tissue levels); individuals vary in their ability to metabolize and respond to digoxin;
absorption of various oral forms of digoxin may vary over a 2-fold range; susceptibility to digitalis
toxicity apparently increases with age.
Useful For: Monitoring digoxin therapy

Interpretation: The therapeutic range is 0.6 to 1.2 ng/mL. Levels of 4.0 ng/mL and above may be
potentially life-threatening.
Reference Values:
<16 years:
Therapeutic ranges have not been established for patients who are less than 16 years of age.
> or =16 years:

Therapeutic range: 0.6-1.2 ng/mL
Toxic concentration: > or =4.0 ng/mL
Clinical References: 1. Datta P, Hinz V, Klee G: Comparison four digoxin immunoassays with
respect to interference from digoxin-like immunoreactive factors. Clin Biochem. 1996;29(6):541-547 2.
Moyer TP, Boeckx RL, eds: Applied Therapeutic Drug Monitoring. Vol 2.Â American Association for
Clinical Chemistry; 1984 3. Jortani SA, Voldew R Jr: Digoxin and its related endogenous factors. Crit
Rev Clin Lab Sci. 1997;34:225-274 4. Dickstein K, Cohen-Solal A, Filippatos G, et al: ESC guidelines
for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis
and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Eur Heart J.
2008;29:2388-2442 5. Milone MC, Shaw LM: Therapeutic drugs and their management. In: Rifai N,
Elsevier; 2018:800-831
DPYDQ Dihydropyrimidine Dehydrogenase Genotype, Varies

610052 Clinical Information: 5-Fluorouracil (5-FU) and its orally administered prodrug, capecitabine, are
fluoropyrimidine-based chemotherapeutic agents that are widely used for the treatment of colorectal
cancer and other solid tumors. The dihydropyrimidine dehydrogenase (DPYD) gene encodes the
rate-limiting enzyme for fluoropyrimidine catabolism and eliminates over 80% of administered 5-FU.
Dihydropyrimidine dehydrogenase (DPYD) activity is subject to wide variability, mainly due to genetic
variation. This results in a broad range of enzymatic deficiency from partial (3%-5% of population) to
complete loss (0.2% of population) of enzyme activity.(2-5) Patients who are deficient in DPYD are at an
increased risk for side effects and toxicity when undergoing 5-FU treatment.(6) In addition, pathogenic
homozygous or compound heterozygous variants within DPYD are associated with dihydropyrimidine
dehydrogenase (DPD) deficiency. DPD deficiency shows large phenotypic variability, ranging from no
symptoms to a convulsive disorder with motor and intellectual disabilities. The following table displays
the DPYD variants detected by this assay, the corresponding star allele, and the effect on DPYD enzyme
activity. Other or novel variations, besides those listed here, may also impact fluoropyrimidine-related
side effects and tumor response. Table. Enzyme Activity of Individual Star Alleles DPYD allele cDNA
nucleotide change Effect on enzyme activity *1 None (wild type) Normal activity *2A 1905+1G>A No
activity *7 299_302delTCAT No activity *8 703C>T No activity *10 2983G>T No activity *13
1679T>G No activity rs67376798 2846A>T Decreased activity rs75017182 1129-5923C>G Decreased
activity rs115232898 557A>G Decreased activity
Useful For: Identifying individuals with genetic variants in DPYD who are at increased risk of toxicity
when prescribed 5-fluorouracil (5-FU) or capecitabine chemotherapy treatment
Interpretation: An interpretive report will be provided. For additional information regarding

pharmacogenomic genes and their associated drugs, see Pharmacogenomic Associations Tables. This
resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate
drug choices.
Reference Values:
Clinical References: 1. OMIM: Dihydropyrimidine dehydrogenase; DPYD. 2009. Updated

December 22, 2017.Â Accessed October 14, 2020. Available at www.omim.org/entry/612779 2. Amstutz
U, Henricks LM, Offer SM, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC)
Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update.
Clin Pharmacol Ther. 2018 Feb;103(2):210-216. doi:10.1002/cpt.911 3. Lunenburg CATC, van der
Wouden CH, Nijenhuis M, et al: Dutch Pharmacogenetics Working Group (DPWG) guideline for the
gene-drug interaction of DPYD and fluoropyrimidines. Eur J Hum Genet. 2020 Apr;28(4):508-517. doi:
10.1038/s41431-019-0540-0 4. Morel A, Boisdron-Celle M, Fey L, et al: Clinical relevance of different
dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol
Cancer Ther. 2006 Nov;5(11):2895-2904. doi: 10.1158/1535-7163.MCT-06-0327 5. Offer SM, Fossum
CC, Wegner NJ, Stuflesser AJ, Butterfield GL, Diasio RB: Comparative functional analysis of DPYD
variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res. 2014
May 1;74(9):2545-2554. doi: 10.1158/0008-5472.CAN-13-24826 6. U.S. Food and Drug Administration:
Table of Pharmacogenomic Biomarkers in Drug Labeling. FDA; Updated August 18, 2020. Accessed
October 14, 2020. Available at
www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
DPYDG Dihydropyrimidine Dehydrogenase, DPYD Full Gene

Clinical Information: 5-Fluorouracil (5-FU) and its orally administered prodrug, capecitabine, are
fluoropyrimidine-based chemotherapeutic agents that are widely used for the treatment of colorectal
cancer and other solid tumors. The dihydropyrimidine dehydrogenase (DPYD) gene encodes the
rate-limiting enzyme for fluoropyrimidine catabolism and eliminates over 80% of administered 5-FU.
Dihydropyrimidine dehydrogenase (DPYD) activity is subject to wide variability, mainly due to genetic
variation (table 1). This results in a broad range of enzymatic deficiency from partial (3%-5% of
population) to complete loss (0.2% of population) of enzyme activity.(2,3) Patients who are deficient in
DPYD are at an increased risk for side effects and toxicity when undergoing 5-FU treatment.(4) In
addition, pathogenic homozygous or compound heterozygous variants within DPYD are associated with
dihydropyrimidine dehydrogenase (DPD) deficiency. DPD deficiency shows large phenotypic
variability, ranging from no symptoms to a convulsive disorder with motor and intellectual disabilities.
Table 1. Known Genetic Variations Associated with Fluoropyrimidine Treatment Gene cDNA
numbering Alternative name Enzyme activity Phenotype? DPYD No variations identified *1
c.1905+1G->A *2A No activity or significantly reduced activity High risk for fluoropyrimidine toxicity
c.1679T->G *13 c.1898delC *3 c.299_302delTCAT *7 c.1156G->T *12 c.2846A->T rs67376798
Reduced activity Increased risk for fluoropyrimidine toxicity c.1129-5923C->G rs75017182 c.703C->T
*8 Probable reduced function Increased risk for fluoropyrimidine toxicity c.2983G->T *10 c.1003G->T
*11 c.557A->G rs115232898 c.1601C->T *4 Normal activity** Normal risk for fluoropyrimidine
toxicity c.1627A->G *5 c.2194C->T *6 c.85T->C *9A *Other or novel variations, besides those listed
here, may also impact fluoropyrimidine-related side effects and tumor response and will be reported if
detected. **Alleles that are categorized as having normal enzyme activity (eg, *4, *5, *6, *9A) will not
be reported if detected because variants with normal enzyme activity are not expected to impact
fluoropyrimidine-related side effects and tumor response. The DPYD gene is located on chromosome 1
and contains 2 transcripts. The longer transcript (NM_000110.3) contains 23 exons, and the shorter
transcript (NM_001160301.1) contains 6 exons, with exon 6 being unique to this transcript. All exons
from the longer transcript (NM_000110.3) and exon-intron boundaries are assessed. Genetic variations
involved in the metabolic pathway of fluoropyrimidines have been shown to contribute to the
differences in clinical outcomes including toxicity and tumor response.
Useful For: Identifying individuals at increased risk of toxicity when considering 5-fluorouracil and
capecitabine chemotherapy treatment May be useful in identifying variants associated with decreased or
absent dihydropyrimidine dehydrogenase enzyme activity for an individual with this deficiency
suspected
published American College of Medical Genetics and Genomics recommendations as a guideline.(5)
Variants are classified based on known, predicted, or possible pathogenicity and reported with
interpretive comments detailing their potential or known significance. For additional information
regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations
Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and
inducers, as well as potential alternate drug choices.
Reference Values:
Clinical References: 1. OMIM: 274270 Dihydropyrimidine dehydrogenase deficiency.. Johns

Hopkins University; 1986. Updated April 18, 2012. Accessed December 4, 2020. Available from
https://www.omim.org/entry/274270 2. Caudle KE, Thorn CF, Klein TE, et al: Clinical
Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase
genotype and fluoropyrimidine dosing. Clin Pharmacol Ther. 2013;94(6):640-645 3. Morel A,
Boisdron-Celle M, Fey L, et al: Clinical relevance of different dihyropyrimidine dehydrogenase gene
single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther. 2006
Nov;5(11):2895-2904 4. U.S. Food and Drug Administration (FDA): Table of Pharmacogenomic
Biomarkers in Drug Labeling. FDA; Updated June 2020, Accessed December 4, 2020. Available at:
www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm 5. Richards S,
Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint
consensus recommendation of the American College of Medical Genetics and Genomics and the
Association for Molecular Pathology. Genet Med. 2015;17(5):405-424 6. Offer SM, Fossum CC,
Wegner NJ, et al: Comparative functional analysis of DPYD variants of potential clinical relevance to
dihydropyrimidine dehydrogenase activity. Cancer Res. 2014;74(9):2545-2554
DHRF Dihydrorhodamine Flow Cytometric

62766 N-Formyl-Methionyl-Leucyl-Phenylalanine Test, Blood
Clinical Information: This assay can be used for the diagnostic evaluation of RAC2 deficiency,
which is a neutrophil defect that causes profound neutrophil dysfunction with decreased chemotaxis,
polarization, superoxide anion production, azurophilic granule secretion. This disease is caused by
inhibitory variants in the RAC2 gene, which encodes a Rho family GTPase essential to neutrophil
activation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function.(1) Patients with
RAC2 deficiency have been shown to have normal neutrophil oxidative burst when stimulated with
phorbol myristate acetate (PMA), indicating normal NADPH oxidase activity, but abnormal neutrophil
responses to N-formyl-methionyl-leucyl-phenylalanine (fMLP), which is a physiological activator of
neutrophils. The defective oxidative burst to fMLP, but not to PMA, is consistent with RAC2
deficiency.(2) By contrast, gain of function variants in RAC2 would lead to a an exaggerated response to
fMLP.(3)
Useful For: Evaluation of RAC2 deficiency and RAC2 gain of function

Interpretation: An interpretive report will be provided, in addition to the quantitative values described
in Clinical Information. Interpretation of the results of the quantitative dihydrorhodamine (DHR) flow
cytometric assay has to include both the proportion of positive neutrophils for DHR after
N-formyl-methionyl-leucyl-phenylalanine stimulation, and the mean fluorescence intensity.
Reference Values:
Result name Unit Cutoff for defining normal
% fMLP ox-DHR+ % > or =10%
MFI fMLP ox-DHR+ MFI > or =2
Control % fMLP ox-DHR+ % > or =10%
Control MFI fMLP ox-DHR+ MFI > or =2 fMLP = N-formyl-methionyl-leucyl-phenylalanine

DHR = dihydrorhodamine MFI = mean fluorescence intensity
The appropriate age-related reference values for Absolute
Neutrophil Count will be provided on the report.
Clinical References: 1. Ambruso DR, Knall C, Abell AN, et al: Human neutrophil
immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A.
2000 Apr 25;97(9):4654-4659 2. Accetta D, Syverson G, Bonacci B, et al: Human phagocyte defect
caused by a RAC2 mutation detected by means of neonatal screening for T cell lymphopenia. J Allergy
Clin Immunol. 2011 Feb;127(2):535-538 3. Hsu AP, Donko A, Arrington ME, et al: Dominant activating
RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood. 2019 May
2;133(18):1977-1988
DHRP Dihydrorhodamine Flow Cytometric Phorbol Myristate Acetate

62765 Test, Blood
Clinical Information: Chronic granulomatous disease (CGD) is caused by genetic alterations in the
gene components that encode the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
enzyme complex. These alterations result in an inability to produce superoxide anions required for
killing of bacterial and fungal organisms. Other clinical features include a predisposition to systemic
granulomatous complications and autoimmunity.(1) There are 6 known genes associated with the
clinical phenotype of CGD.(2) The gene defects include disease-causing variants in the CYBB gene,
encoding the gp91phox protein, which is X-linked and accounts for approximately 70% of CGD cases.
Other genetic causes are autosomal recessive in inheritance and occur in one of the following genes:
NCF1 (p47phox), NCF2 (p67phox), CYBA (p22phox), NCF4 (p40phox) and CYBC1(3). Typically,
patients with X-linked CGD have the most severe disease, while patients with p47phox defects tend to
have the best outcomes. Disease-causing variants in NCF4 and CYBC1 have been the most recently
described rare causes of disease.(3,4) There is significant clinical variability even among individuals
with similar variants, in terms of NADPH oxidase function, indicating that there can be several
modulating factors including the genetic alteration, infection history, and granulomatous and
autoimmune complications. There appears to be a correlation between very low NADPH superoxide
production and worse outcomes. CGD can be treated with hematopoietic cell transplantation, which can
be effective for the inflammatory and autoimmune manifestations. It has been shown that survival of
patients with CGD was strongly associated with residual reactive oxygen intermediate (ROI)
production, independent of the specific gene alteration.(5) Measurement of NADPH oxidase activity
through the dihydrorhodamine (DHR) flow cytometry assay contributed to the assessment of ROI. The
diagnostic laboratory assessment for CGD includes evaluation of NADPH oxidase function in
neutrophils, using historically the nitroblue tetrazolium test or currently the more analytically sensitive
DHR test, as described here. Activation of neutrophils with phorbol myristate acetate (PMA) results in
oxidation of DHR to a fluorescent compound, rhodamine 123, which can be measured by flow
cytometry. Flow cytometry can distinguish between the different genetic forms of CGD.(6,7) Complete
myeloperoxidase (MPO) deficiency can cause a false-positive result for CGD in the DHR flow
cytometric assay (8); however, there is a difference between the percent DHR+ neutrophils and the
mean fluorescence intensity after PMA stimulation that allows discrimination between true X-linked
CGD and complete MPO deficiency. Further, the addition of recombinant human MPO enhances the
DHR signal in MPO-deficient neutrophils but not in CGD neutrophils.(8) It is important to have
quantitative measures in the DHR flow cytometry assay to effectively use the test for diagnosis of the
different forms of CGD as well as for monitoring chimerism and NADPH oxidase activity
post-hematopoietic cell transplantation. These quantitative measures include assessment of the relative
proportion (%) of neutrophils that are positive for DHR fluorescence after PMA stimulation and the
relative fluorescence intensity of DHR on neutrophils after activation. Female carriers of X-linked CGD
can become symptomatic for CGD due to skewed lyonization (X chromosome inactivation).(9)
Age-related acquired skewing of lyonization can also cause increased susceptibility to infections in
carriers of X-linked CGD.(10) While inherited disease-causing variants are more common in CGD,
there have been reports of de novo, variants in the CYBB gene, causing X-linked CGD in male patients
whose mothers are not carriers for the affected allele. Additionally, somatic mosaicism has been
reported in patients with X-linked CGD who have small populations of normal cells.(11) There are also
reports of triple somatic mosaicism in female carriers (12,13) as well as late-onset disease in an adult
female who was a somatic mosaic for a novel variant in the CYBB gene.(14) Therefore, the clinical,
genetic, and age spectrum of CGD is varied and laboratory assessment of NADPH oxidase activity after
neutrophil stimulation, coupled with appropriate interpretation, is critical to achieving an accurate
diagnosis or for monitoring patients posttransplant.
Useful For: Evaluating chronic granulomatous disease (CGD), X-linked and autosomal recessive
forms, complete myeloperoxidase deficiency Monitoring chimerism and nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase function post-hematopoietic cell transplantation Assessing
residual NADPH oxidase activity pretransplant Identifying of female carriers for X-linked CGD
Assessing changes in lyonization with age in female carriers
Interpretation: An interpretive report will be provided, in addition to the quantitative values

described in Clinical Information. Interpretation of the results of the quantitative dihydrorhodamine
(DHR) flow cytometric assay has to include both the proportion of positive neutrophils for DHR after
phorbol myristate acetate stimulation, and the mean fluorescence intensity. Additionally, visual
assessment of the pattern of DHR fluorescence is helpful in discriminating between the various genetic
defects associated with chronic granulomatous disease and complete myeloperoxidase deficiency.
Reference Values:
Result Name Unit Cutoff for defining normal
% PMA ox-DHR+ % > or =95%
MFI PMA ox-DHR+ MFI > or =60
Control % PMA ox-DHR+ % > or =95%
Control MFI PMA ox-DHR+ MFI > or =60 MFI = mean fluorescence intensity
PMA = phorbol myristate acetate DHR =
dihydrorhodamine The appropriate age-related
reference values for Absolute Neutrophil
Count will be provided on the report.
Clinical References: 1.. Kang EM, Marciano BE, DeRavin SS, et al: Chronic granulomatous
disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011
Jun;127(6):1319-1326 2. Segal BH, DeCarlo ES, Kwon-Chung KJ, et al: Aspergillus nidulans infection in
chronic granulomatous disease. Medicine. 1998 Sep;77(5):345-354 3. Arnadottir GA, Norddahl GL,
Gudmundsdottir S, et al. A homozygous loss-of-function mutation leading to CYBC1 deficiency causes
chronic granulomatous disease. Nat Commun. 2018 Oct 25;9(1):4447 4. van de Geer A, Nieto-Patlan A,
Kuhns DB, et al. Inherited p40phox deficiency differs from classic chronic granulomatous disease. J Clin
Invest. 2018;128(9):3957-3975. doi:10.1172/JCI97116 5. Kuhns DB, Alvord WG, Heller T, et al:
Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med.
2010;363:2600-2610 6. Vowells SJ, Fleisher TA, Sekhsaria S, et al: Genotype-dependent variability in
flow cytometric evaluation of reduced NADPH oxidase function in patients with chronic granulomatous
disease. J Pediatr. 1996 Jan;128:104(1)-107 7. Vowells SJ, Sekhsaria S, Malech H, et al: Flow cytometric
analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes. J Immunol
Methods. 1995 Jan 13;178(1):89-97 8. Mauch L, Lun A, O'Gorman MRG, et al: Chronic granulomatous
disease (CGD) and complete myeloperoxidase deficiency both yield strongly reduced DHR 123 test
signals but can be easily discerned in routine testing for CGD. Clin Chem. 2007 May;53(5):890-896 9.
Roesler J: Carriers of X-linked chronic granulomatous disease at risk. Clin Immunol. 2009
Feb;130(2):233; author reply 234. doi: 10.1016/j.clim.2008.09.013 10. Rosen-Wolff A, Soldan W, Heyne
K, et al: Increased susceptibility of a carrier of X-linked chronic granulomatous disease (CGD) to
Aspergillus fumigatus infection associated with age-related skewing of lyonization. Ann Hematol. 2001
Feb;80(2):113-115 11. Yamada M, Okura Y, Suzuki Y, et al: Somatic mosaicism in two unrelated
patients with X-linked chronic granulomatous disease characterized by the presence of a small population
of normal cells. Gene. 2012 Apr 10;497(1):110-115 12. de Boer M, Bakker E, Van Lierde S, Roos
D:Somatic triple mosaicism in a carrier of X-linked chronic granulomatous disease. Blood. 1998
Jan;91(1):252-257 13. Noack D, Heyworth PG, Kyono W, et al: A second case of somatic triple
mosaicism in the CYBB gene causing chronic granulomatous disease. Hum Genet. 2001
Aug;109(2):234-238 14. Wolach B, Scharf Y, Gavrieli R, et al: Unusual late presentation of X-linked
chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB.
Blood. 2005 Jan 1;105(1):61-66 15. Kuhns DB: Diagnostic testing for chronic granulomatous disease.
Methods Mol Biol. 2019;1982:543-571 16. Delmonte OM, Fleisher TA: Flow cytometry: Surface markers
and beyond. J Allergy Clin Immunol. 2019 Feb;143(2):528-537 17. Knight V, Heimall JR, Chong H, et
al: A toolkit and framework for optimal laboratory evaluation of individuals with suspected primary
immunodeficiency. J Allergy Clin Immunol Pract. 2021 Sep;9(9):3293-3307.e6
DHR Dihydrorhodamine Flow Cytometric Test, Blood

62764 Clinical Information: Chronic granulomatous disease (CGD) is caused by genetic alterations in the
gene components that encode the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme
complex. These alterations result in an inability to produce superoxide anions required for killing bacterial
and fungal organisms. Other clinical features include a predisposition to systemic granulomatous
complications and autoimmunity.(1) There are 6 known genes associated with the clinical phenotype of
CGD.(2) The gene defects include disease-causing variants in the CYBB gene, encoding the gp91phox
protein, which is X-linked and accounts for approximately 70% of CGD cases. Other genetic causes are
autosomal recessive in inheritance and occur in one of the following genes: NCF1 (p47phox), NCF2
(p67phox), CYBA (p22phox), NCF4 (p40phox) and CYBC1.(3) Typically, patients with X-linked CGD
have the most severe disease, while patients with p47phox defects tend to have the best outcomes.
Disease-causing variants s in NCF4 and CYBC1 have been the most recently described rare causes of
disease(3,4). There is significant clinical variability even among individuals with similar variants, in terms
of NADPH oxidase function, indicating that there can be several modulating factors including the genetic
alteration, infection history, and granulomatous and autoimmune complications. There appears to be a
correlation between very low NADPH superoxide production and worse outcomes. CGD can be treated
with hematopoietic cell transplantation, which can be effective for the inflammatory and autoimmune
manifestations. It has been shown that survival of patients with CGD was strongly associated with
residual reactive oxygen intermediate (ROI) production, independent of the specific gene alteration.(5)
Measurement of NADPH oxidase activity through the dihydrorhodamine (DHR) flow cytometry assay
contributed to the assessment of ROI. The diagnostic laboratory assessment for CGD includes evaluation
of NADPH oxidase function in neutrophils, using historically the nitroblue tetrazolium test or currently
the more analytically sensitive DHR test, as described here. Activation of neutrophils with phorbol
myristate acetate (PMA) results in oxidation of DHR to a fluorescent compound, rhodamine 123, which
can be measured by flow cytometry. Flow cytometry can distinguish between the different genetic forms
of CGD.(6,7) Complete myeloperoxidase (MPO) deficiency can cause a false-positive result for CGD in
the DHR flow cytometric assay (8); however, there is a difference between the percent DHR+ neutrophils
and the mean fluorescence intensity after PMA stimulation that allows discrimination between true
X-linked CGD and complete MPO deficiency. Further, the addition of recombinant human MPO
enhances the DHR signal in MPO-deficient neutrophils but not in CGD neutrophils.(8) It is important to
have quantitative measures in the DHR flow cytometry assay to effectively use the test for diagnosis of
the different forms of CGD as well as for monitoring chimerism and NADPH oxidase activity post-
hematopoietic cell transplantation. These quantitative measures include assessment of the relative
proportion (%) of neutrophils that are positive for DHR fluorescence after PMA stimulation and the
relative fluorescence intensity of DHRÂ on neutrophils after activation. This assay can also be used for
the diagnostic evaluation of RAC2 deficiency, which is a neutrophil defect that causes profound
neutrophil dysfunction with decreased chemotaxis, polarization, superoxide anion production, azurophilic
granule secretion. This disease is caused by inhibitory variants in the RAC2 gene, which encodes a Rho
family GTPase essential to neutrophil activation and NADPH oxidase function.(9) Patients with RAC2
deficiency have been shown to have normal neutrophil oxidative burst when stimulated with PMA,
indicating normal NADPH oxidase activity, but abnormal neutrophil responses to
N-formyl-methionyl-leucyl-phenylalanine (fMLP), which is a physiological activator of neutrophils. The
defective oxidative burst to fMLP, but not to PMA, is consistent with RAC2 deficiency.(10) By contrast,
gain of function variants in RAC2 would lead to a an exaggerated response to fMLP.(11) Female carriers
of X-linked CGD can become symptomatic for CGD due to skewed lyonization (X chromosome
inactivation).(12) Age-related acquired skewing of lyonization can also cause increased susceptibility to
infections in carriers of X-linked CGD.(13) While inherited pathogenic variants are more common in
CGD, there have been reports of de novo variants in the CYBB gene, causing X-linked CGD in male
patients whose mothers are not carriers for the affected allele. Additionally, somatic mosaicism has been
reported in patients with X-linked CGD who have small populations of normal cells.(14) There are also
reports of triple somatic mosaicism in female carriers (15,16) as well as late-onset disease in an adult
female who was a somatic mosaic for a novel variant in the CYBB gene.(17) Therefore, the clinical,
genetic, and age spectrum of CGD is varied and laboratory assessment of NADPH oxidase activity after
neutrophil stimulation, coupled with appropriate interpretation, is critical to achieving an accurate
diagnosis or for monitoring patients posttransplant.
Useful For: Evaluation of chronic granulomatous disease (CGD), X-linked and autosomal recessive
forms, RAC2 deficiency, complete myeloperoxidaseÂ deficiency Monitoring chimerism and
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function post-hematopoietic cell
transplantation Assessing residual NADPH oxidase activity pretransplant Identifying female carriers for
X-linked CGD Assessing changes in lyonization with age in female carriers
Interpretation: An interpretive report will be provided, in addition to the quantitative values.
Interpretation of the results of the quantitative dihydrorhodamine (DHR) flow cytometric assay has to
include both the proportion of positive neutrophils for DHR after phorbol myristate acetate and/or
N-formyl-methionyl-leucyl-phenylalanine stimulation, and the mean fluorescence intensity .Additionally,
visual assessment of the pattern of DHR fluorescence is helpful in discriminating between the various
genetic defects associated with chronic granulomatous disease and complete myeloperoxidase deficiency.
Reference Values:
Result name Unit Cutoff for defining normal
% PMA ox-DHR+ % > or =95%
MFI PMA ox-DHR+ MFI > or =60
% fMLP ox-DHR+ % > or =10%
MFI fMLP ox-DHR+ MFI > or =2
Control % PMA ox-DHR+ % > or =95%
Control MFI PMA ox-DHR+ MFI > or =60

Control % fMLP ox-DHR+ % > or =10%
Control MFI fMLP ox-DHR+ MFI > or =2 PMA = phorbol myristate acetate DHR =
dihydrorhodamine MFI = mean fluorescence intensity fMLP =
N-formyl-methionyl-leucyl-phenylalanine The appropriate
age-related reference values for Absolute Neutrophil Count
will be provided on the report.
Clinical References: 1. Kang EM, Marciano BE, DeRavin SS, et al: Chronic granulomatous disease:
Overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011
Jun;127(6):1319-1326 2. Segal BH, DeCarlo ES, Kwon-Chung KJ, et al: Aspergillus nidulans infection in
chronic granulomatous disease. Medicine. 1998 Sep;77(5):345-354 3. Arnadottir GA, Norddahl GL,
Gudmundsdottir S, et al. A homozygous loss-of-function mutation leading to CYBC1 deficiency causes
chronic granulomatous disease. Nat Commun. 2018 Oct 25;9(1):4447 4.van de Geer A, Nieto-Patlan A,
Kuhns DB, et al. Inherited p40phox deficiency differs from classic chronic granulomatous disease. J Clin
Invest. 2018 Aug 31;128(9):3957-3975. doi:10.1172/JCI97116 5. Kuhns DB, Alvord WG, Heller T, et al:
Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010 Dec
30;363(27):2600-2610 6. Vowells SJ, Fleisher TA, Sekhsaria S, et al: Genotype-dependent variability in
flow cytometric evaluation of reduced NADPH oxidase function in patients with chronic granulomatous
disease. J Pediatr. 1996 Jan;128(1):104-107 7. Vowells SJ, Sekhsaria S, Malech H, et al: Flow cytometric
analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes. J Immunol
Methods. 1995 Jan;178(1):89-97 8. Mauch L, Lun A, O'Gorman MRG, et al: Chronic granulomatous
disease (CGD)and complete myeloperoxidase deficiency both yield strongly reduced DHR 123 test
signals but can be easily discerned in routine testing for CGD. Clin Chem. 2007 May;53(5):890-896 9.
Ambruso DR, Knall C, Abell AN, et al: Human neutrophil immunodeficiency syndrome is associated
with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 2000 Apr;97(9):4654-4659 10. Accetta D,
Syverson G, Bonacci B, et al: Human phagocyte defect caused by a RAC2 mutation detected by means of
neonatal screening for T cell lymphopenia. J Allergy Clin Immunol. 2011 Feb;127(2):535-538 11. Hsu
AP, Donko A, Arrington ME, et al: Dominant activating RAC2 mutation with lymphopenia,
immunodeficiency, and cytoskeletal defects. Blood. 2019 May 2;133(18):1977-1988 12. Roesler J:
Carriers of X-linked chronic granulomatous disease at risk. Clin Immunol 2009 Feb;130(2):233. doi:
10.1016/j.clim.2008.09.013 13. Rosen-Wolff A, Soldan W, Heyne K, et al: Increased susceptibility of a
carrier of X-linked chronic granulomatous disease (CGD) to Aspergillus fumigatus infection associated
with age-related skewing of lyonization. Ann Hematol.. 2001 Feb:80(2):113-115 14. Yamada M, Okura
Y, Suzuki Y, et al: Somatic mosaicism in two unrelated patients with X-linked chronic granulomatous
disease characterized by the presence of a small population of normal cells. Gene. 2012 Apr
10:497(1):110-115 15. de Boer M, Bakker E, Van Lierde S, et al: Somatic triple mosaicism in a carrier of
X-linked chronic granulomatous disease. Blood. 1998 Jan 1;91(1):252-257 16. Noack D, Heyworth PG,
Kyono W, Cross AR: A second case of somatic triple mosaicism in the CYBB gene causing chronic
granulomatous disease. Hum Genet. 2001 Aug;109(2):234-238 17. Wolach B, Scharf Y, Gavrieli R, et al:
Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic
mosaic for a novel mutation in CYBB. Blood. 2005 Jan 1;105:61-66 18. Kuhns DB: Diagnostic testing for
chronic granulomatous disease. Methods Mol Biol. 2019;1982:543-571. 19. Delmonte OM, Fleisher TA:
Flow cytometry: Surface markers and beyond. J Allergy Clin Immunol. 2019 Feb;143(2):528-537 20.
Knight V, Heimall JR, Chong H, et al: A toolkit and framework for optimal laboratory evaluation of
individuals with suspected primary immunodeficiency. J Allergy Clin Immunol Pract. 2021
Sep;9(9):3293-3307.e6
DHTS Dihydrotestosterone, Serum

81479 Clinical Information: The principal prostatic androgen is dihydrotestosterone (DHT). Levels of
DHT remain normal with aging, despite a decrease in the plasma testosterone, and are not elevated in
benign prostatic hyperplasia (BPH).(1) DHT is generated by reduction of testosterone by 5-alpha
reductase. Two isoenzymes of 5-alpha reductase have been discovered. Type 1 is present in most tissues
in the body where 5-alpha reductase is expressed, and is the dominant form in sebaceous glands. Type 2
is the dominant isoenzyme in genital tissues, including the prostate. Androgenetic alopecia (AGA;
male-pattern baldness) is a hereditary and androgen-dependent progressive thinning of the scalp hair
that follows a defined pattern.(2) While the genetic involvement is pronounced, but poorly understood,
major advances have been achieved in understanding the principal elements of androgen metabolism
that are involved. DHT may be related to baldness. High concentrations of 5-alpha reductase have been
found in frontal scalp and genital skin and androgen-dependent processes are predominantly due to the
binding of DHT to the androgen receptor (AR). Since the clinical success of treatment of AGA with
modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic
follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss,
is considered a possible cofactor in the complex etiology of AGA. Currently available AGA treatment
modalities with proven efficacy are oral finasteride, a competitive inhibitor of 5-alpha reductase type 2,
and topical minoxidil, an adenosine triphosphate-sensitive potassium channel opener that has been
reported to stimulate the production of vascular endothelial growth factor in cultured dermal papilla
cells. Currently, many patients with prostate disease receive treatment with a 5-alpha reductase inhibitor
such as finasteride (Proscar) to diminish conversion of DHT from testosterone. See Steroid Pathways in
Special Instructions.
Useful For: Monitoring patients receiving 5-alpha reductase inhibitor therapy or chemotherapy
Evaluating patients with possible 5-alpha reductase deficiency
Interpretation: Patients taking 5-alpha reductase inhibitor have decreased dihydrotestosterone

(DHT) serum levels. Patients with genetic 5-alpha reductase deficiency (a rare disease) also have
reduced DHT serum levels. DHT should serve as the primary marker of peripheral androgen production.
However, because it is metabolized rapidly and has a very high affinity for sex hormone-binding
globulin (SHBG), DHT does not reflect peripheral androgen action. Instead, its distal metabolite,
3-alpha, 17-beta-androstanediol glucuronide, serves as a better marker of peripheral androgen action.
See Steroid Pathways in Special Instructions.
Reference Values:
Mean Age Reference range (pg/mL)
Stage I (>6 months and prepubertal) 7.1 years < or =50
Stage II 12.1 years < or =200
Stage III 13.6 years 80-330
Stage V 18 years 240-650 >19 years: 112-955 pg/mL Females

Cord blood: < or =50 pg/mL < or =6 months:
< or =1,200 pg/mL Tanner StagesÂ
Mean Age Reference range (pg/mL)

Stage I (>6 months and prepubertal) 7.1 years < or =50
Stage II 10.5 years < or =300
Stage III 11.6 years < or =300
Stage IV 12.3 years < or =300
Stage V 14.5 years < or =300 20-55 years: < or =300 pg/mL
>55 years: < or =128 pg/mL 1. Pang S,
Levine LS, Chow D, et al:
Dihydrotestosterone and its relationship to
testosterone in infancy and childhood. J Clin
Endocrinol Metab 1979;48:821-826 2.
Stanczyk FZ: Diagnosis of hyperandrogenism:
biochemical criteria. Best Pract Res Clin
Endocrinol Metab 2006;20(2):177-191
Clinical References: 1. Bartsch G, Rittmaster RS, Klocker H: Dihydrotestosterone and the

concept of 5 alpha-reductase inhibition in human benign prostatic hyperplasia. World J Urol
2002;19(6):413-425 2. Trueb RM: Molecular mechanisms of androgenetic alopecia. Exp Gerontol
2002;37(8-9):981-990 3. Singh SM, Gauthier S, Labrie F: Androgen receptor antagonists
(antiandrogens): structure-activity relationships. Curr Med Chem 2000;7(2):211-247 4. Rhodes L,
Harper J, Uno H, et al: The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum
testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides). J
Clin Endocrinol Metab 1994;79:991-996 5. Gustafsson O, Norming U, Gustafsson S, et al:
Dihydrotestosterone and testosterone levels in men screened for prostate cancer: a study of a
randomized population. Br J Urol 1996;77:433-440 6. van der Veen A, van Faassen M, de Jong WHA,
et al: Development and validation of a LC-MS/MS method for the establishment of reference intervals
and biological variation for five plasma steroid hormones. Clin Biochem. 2019 Jun;68:15-23. doi:
10.1016/j.clinbiochem.2019.03.013
DCMGP Dilated Cardiomyopathy Multi-Gene Panel, Next-Generation

63159 Sequencing, Blood
Clinical Information: The cardiomyopathies are a group of disorders characterized by disease of the
heart muscle. Cardiomyopathy can be caused by inherited, genetic factors, or by nongenetic (acquired)
causes such as infection or trauma. When the presence or severity of the cardiomyopathy observed in a
patient cannot be explained by acquired causes, genetic testing for the inherited forms of cardiomyopathy
may be considered. Overall, the cardiomyopathies are some of the most common genetic disorders. The
inherited forms of cardiomyopathy include hypertrophic cardiomyopathy, dilated cardiomyopathy
(DCM), arrhythmogenic right ventricular cardiomyopathy, and left ventricular noncompaction. DCM is
established by the presence of left ventricular enlargement and systolic dysfunction. DCM may present
with heart failure with symptoms of congestion, arrhythmias and conduction system disease, or
thromboembolic disease (stroke). The most recent estimates of the incidence of DCM suggest that the
condition affects approximately 1 in every 250 people. These estimates are higher than originally reported
due to subclinical phenotypes and underdiagnosis. After exclusion of nongenetic causes such as ischemic
injury, DCM is traditionally referred to as "idiopathic" dilated cardiomyopathy. Approximately 20% to
50% of individuals with idiopathic DCM may have an identifiable genetic cause for their disease.
Families with 2 or more affected individuals are diagnosed with familial DCM. The majority of familial
DCM is inherited in an autosomal dominant manner; however, autosomal recessive and X-linked forms
have also been reported. At least 28 genes have been reported in association with DCM, including genes
encoding the cardiac sarcomere and other proteins involved in proteins responsible for cardiac muscle
contraction. Some genes associated with DCM also cause other forms of hereditary cardiomyopathy,
cardiac channelopathies, skeletal myopathies, or metabolic defects. See table for details regarding the
genes tested by this panel and associated diseases. Genes included in this gene panel Gene Protein
Inheritance Disease association ABCC9 ATP-Binding cassette, subfamily C, member 9 AD DCM, Cantu
syndrome ACTC1 Actin, alpha, cardiac muscle AD CHD, DCM, HCM, LVNC ACTN2 Actinin, alpha-2
AD DCM, HCM ANKRD1 Ankyrin repeat domain-containing protein 1 AD HCM, DCM CRYAB
Crystallin, alpha-B AD, AR DCM, myofibrillar myopathy CSRP3 Cysteine-and glycine-rich protein 3
AD HCM, DCM DES Desmin AD, AR DCM, ARVC, myofibrillar myopathy, RCM with AV block,
neurogenic scapuloperoneal syndrome Kaeser type, LGMD LAMA4 Laminin, alpha-4 AD DCM LAMP2
Lysosome-associated membrane protein 2 X-linked Danon disease LDB3 LIM domain-binding 3 AD
DCM, LVNC, myofibrillar myopathy LMNA Lamin A/C AD, AR DCM, EMD, LGMD, congenital
muscular dystrophy (see OMIM for full listing) MYBPC3 Myosin-binding protein-C, cardiac AD HCM,
DCM MYH6 Myosin, heavy chain 6, cardiac muscle, alpha HCM, DCM MYH7 Myosin, heavy chain 7,
cardiac muscle, beta AD HCM, DCM, LVNC, myopathy MYPN Myopalladin AD HCM, DCM NEXN
Nexilin AD HCM, DCM PLN Phospholamban AD HCM, DCM RAF1 V-raf-1 murine leukemia viral
oncogene homolog 1 AD Noonan/multiple lentigines syndrome, DCM RBM20 RNA-binding motif
protein 20 AD DCM SCN5A Sodium channel, voltage gated, type V, alpha subunit AD Brugada
syndrome, DCM, Heart block, LQTS, SSS, SIDS SGCD Sarcoglycan, delta AD, AR DCM, LGMD TAZ
Tafazzin X-linked Barth syndrome, LVNC, DCM TCAP Titin-CAP (Telethonin) AD, AR HCM, DCM,
LGMD TNNC1 Troponin C, slow AD HCM, DCM TNNI3 Troponin I, cardiac AD, AR DCM, HCM,
RCM TNNT2 Troponin T2, cardiac AD HCM, DCM, RCM, LVNC TPM1 Tropomyosin 1 AD HCM,
DCM, LVNC TTN Titin AD, AR HCM, DCM, ARVC myopathy TTR Transthyretin AD
Transthyretin-related amyloidosis VCL Vinculin AD HCM, DCM Abbreviations: Hypertrophic
cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular
cardiomyopathy (ARVC), left ventricular noncompaction cardiomyopathy (LVNC), restrictive
cardiomyopathy (RCM), limb-girdle muscular dystrophy (LGMD), Emory muscular dystrophy (EMD),
congenital heart defects (CHD), sudden infant death syndrome (SIDS), long QT syndrome (LQTS), sick
sinus syndrome (SSS), autosomal dominant (AD), autosomal recessive (AR)
history suggestive of hereditary dilated cardiomyopathy (DCM) Establishing a diagnosis of a hereditary
DCM, and in some cases, allowing for appropriate management and surveillance for disease features
based on the gene involved Identifying a pathogenic variant within a gene known to be associated with
disease features that allows for predictive testing of at-risk family members
Reference Values:
May;17(5):405-424 2. Hershberger RE, Morales A: Dilated cardiomyopathy overview. In: Adam MP,
Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2007.
Updated July 29, 2021. Accessed September 21, 2021. Available at
www.ncbi.nlm.nih.gov/books/NBK1309/ 3. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005
guideline update for the diagnosis and management of chronic heart failure in the adult. Circulation.
2005;112:e154-e235 4. Callis TE, Jensen BC, Weck KE, Willis MS: Evolving molecular diagnostics for
familial cardiomyopathies: at the heart of it all. Expert Rev Mol Diagn. 2010 April;10:3:329-351 5.
Herman DS, Lam L, Taylor MR, et al: Truncations of titin causing dilated cardiomyopathy. N Engl J
Med. 2012;366(7):619-628 6. Dhandapany PS, Razzaque MA, Muthusami U, et al: RAF1 mutations in
childhood-onset dilated cardiomyopathy. Nat Genet. 2014;46(6):635-639 7. Ackerman M, Priori SG,
Willems S, et al: HRS/EHRA expert consensus statement on the state of genetic testing for the
channelopathies and cardiomyopathies. Heart Rhythm. 2011;8:1308-1339
DILL Dill, IgE, Serum
Useful For: Establishing the diagnosis of an allergy to dill Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
FDILT Diltiazem (Cardizem, Dilacor)

DRVI3 Dilute Russell Viper Venom Time (DRVVT) Confirmation Ratio,

602181 Plasma
Clinical Information: Lupus anticoagulants (LA) are immunoglobulins (IgG, IgM, IgA, or a
combination of these) of autoimmune type that are specifically directed against antigenic complexes of
negatively charged phospholipids (such as phosphatidylserine or phosphatidylethanolamine) and
coagulation-related proteins such as beta-2-glycoprotein I (beta-2-GPI) or clotting factors including
prothrombin (factor II) or factor X, and cause prolongation of phospholipid-dependent clotting time
tests due to inhibition. LA are functionally and clinically distinct members of a broader group of
antiphospholipid autoantibodies (APA) that includes immunologically detectable anticardiolipin
antibodies or antibodies against other phospholipid-protein complexes. LA interfere with specific
coagulation factor-phospholipid interactions, typically causing prolongation of one or more
phospholipid-dependent clotting time tests (eg, activated partial thromboplastin time: APTT, dilute
Russell viper venom time: DRVVT) due to inhibition. This characteristic in vitro inhibition can be
overcome by addition of excess phospholipid. Because of the heterogeneous nature of LA antibodies, no
single coagulation test can identify or exclude all LA. Currently, the International Society on
Thrombosis and Haemostasis and the Clinical and Laboratory Standards Institute recommend testing for
LA with at least 2 phospholipid-dependent clotting time assays based on different coagulation pathways
and principles (eg, lupus-sensitive APTT and DRVVT). In addition, given the potential for
false-positive results in patients on anticoagulants, a profile or panel of coagulation tests is performed,
including the prothrombin time (PT), APTT, thrombin time (TT) and DRVVT. If the PT, APTT, and/or
DRVVT are prolonged, additional testing may include mixing tests with normal plasma (to evaluate for
inhibition) and the use of excess phospholipid in appropriate assay systems to evaluate for
phospholipid-dependent inhibition. Additional reflexive testing helps determine presence or absence of
anticoagulants and/or inhibitors to other factors. The diagnosis of LA requires performance and
interpretation of complex coagulation testing, as well as correlation with available clinical information,
including evidence of persistence of LA over time (> or =12 weeks). Â The venom obtained from
Russell's viper (Vipera russelli) contains enzymes that directly activate coagulation factors V and X,
bypassing the activation of factors VII, VIII, IX, XI, and XII, and, therefore, the effect of deficiencies or
inhibitors of these factors. Diluting the phospholipid necessary for the clotting factor interactions
increases the sensitivity to LA and the likelihood of identifying a phospholipid-dependent inhibitor that
may not be detected by other coagulation tests with higher phospholipid content (eg, LA-insensitive
APTT reagents). The DRVVT screen ratio test is one of several available in vitro tests that may be used
to screen and confirm for presence of LA or to help exclude LA. DRVVT testing is used in conjunction
with other appropriate coagulation tests (reflexive testing panels) to assist in detection and confirmation
of LA, or to help exclude their presence. The DRVVT may be abnormally prolonged (DRVVT screen
ratio > or =1.20) by LA as well as coagulation factor deficiencies, anticoagulant effects, or other types
of coagulation factor inhibitors. Specimens with abnormal results (DRVVT screen ratio > or =1.20) are
subjected to reflexive testing. With the reflexive testing, the sensitivity of DRVVT testing for LA
diagnosis is approximately 65% to 70% and the specificity is 95% or higher. It is advisable to use the
DRVVT screen, mix, and confirm ratio results in conjunction with other appropriate coagulation tests
(reflexive testing panels) to diagnose or exclude LA. Although LA cause prolonged clotting times in
vitro, there is a strong association with thrombosis risk. However, not all patients with persisting LA
develop thrombosis.
Useful For: Confirming the presence or helping to exclude the presence of lupus anticoagulants (LA)
Identifying LA that do not prolong the activated partial thromboplastin time (APTT) Evaluating
unexplained prolongation of the APTT or prothrombin time clotting tests Distinguishing LA from a
specific coagulation factor inhibitor or coagulation factor deficiencies
Interpretation: Dilute Russell viper venom time (DRVVT) screen ratio (<1.20): A normal DRVVT
screen ratio (<1.20) indicates that lupus anticoagulant (LA) is not present or not detectable by this
method (but might be detected with other methods). An abnormal DRVVT screen ratio (DRVVT screen
ratio > or =1.20) may suggest presence of LA, however, other possibilities include: -Deficiencies or
dysfunction of factors I (fibrinogen), II, V, or X, congenital or acquired -Inhibitors of factor V, or
occasionally by inhibitors of factor VIII, or other specific or nonspecific inhibitors -Anticoagulation
therapy effects (see Cautions) Further evaluation consists of performing mixing studies with an equal
volume of normal pooled plasma (DRVVT 1:1 mix) to investigate the possibility of coagulation factor
deficiency (suggested by DRVVT mix ratio <1.20) and to evaluate inhibition (suggested by DRVVT
mix ratio > or =1.20) and mixing patient plasma with DRVVT reagent enriched in phospholipid
(DRVVT confirmatory reagent) (DRVVT mix and DRVVT confirmation ratios). Possible combination
of results include the following: -DRVVT screen ratio > or =1.20, DRVVT mix ratio <1.20, and
DRVVT confirmation ratio <1.20: No evidence of LA. These data may reflect anticoagulation therapy
effects or other (congenital or acquired) coagulopathy. -DRVVT screen ratio > or =1.20, DRVVT mix
ratio > or =1.20, and DRVVT confirmation ratio <1.20: The prolonged and inhibited DRVVT (DRVVT
screen and mix ratios) may reflect presence of a specific factor inhibitor (eg, factor V inhibitor),
anticoagulation therapy effects or other nonspecific inhibitors as can be seen with monoclonal protein
disorders, lymphoproliferative disease etc. Although LA cannot be conclusively excluded, the DRVVT
confirmation ratio of < or =1.20 makes this less likely. -DRVVT screen ratio > or =1.20, DRVVT mix
ratio <1.20, and DRVVT confirmation ratio > or =1.20: Although mixing study of the prolonged
DRVVT screen and mix ratios provides no evidence of inhibition, additional phospholipid shortens the
clotting time (DRVVT confirmation ratio), suggesting presence of LA. -DRVVT screen ratio > or
=1.20, DRVVT mix ratio > or =1.20, and DRVVT confirmation ratio > or =1.20: The data are
consistent with presence of LA, provided anticoagulant effect can be excluded (see Cautions) DRVVT
assays ordered as a single, stand-alone test should be interpreted within patient clinical context and
close attention to medication use by patient (see Cautions).
Reference Values:
Only orderable as part of a reflex. For more information see DRVI1 / Dilute Russell Viper Venom Time
(DRVVT), with Reflex, Plasma.
<1.20
Normal ranges for children: not clearly established, but similar to normal ranges for adults, except for
newborn infants whose results may not reach adult values until 3 to 6 months of age.
Clinical References: 1. Proven A, Bartlett RP, Moder KG, et al: Clinical importance of positive test
results for lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 2004 April;79(4):467-475
2. Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ: Lupus anticoagulant: an analysis of the clinical
and laboratory features of 219 cases. Am J Hematol 1985 Jul;19(3):265-275 3. Brandt JT, Triplett DA,
Alving B, Sharrer I: Criteria for the diagnosis of lupus anticoagulant: an update. On behalf of the
Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardization
Committee of the ISTH. Thromb Haemost 1995 Oct;74(4);1185-1190 4. Arnout J, Vermylen J: Current
status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease. J
Thromb Haemost 2003 May;1(5):931-942 5. Pengo V, Tripodi A, Reber G, Rand JH, et al: Update of the
guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid
Antibody of the Scientific and Standardization Committee of the International Society on Thrombosis and
Haemostasis. J Thromb Haemost 2009;7:1737-1740. doi: 10.1111/j.1538-7836.2009.03555.x 6. CLSI
Laboratory Testing for Lupus Anticoagulant; Approved Guideline. CLSI document H60-A. Wayne, PA:
Clinical and Laboratory Standards Institute; 2014
DRV3 Dilute Russell Viper Venom Time (DRVVT) Confirmation,

602178 Plasma
Clinical Information: Dilute Russell viper venom time (DRVVT) confirmation is only performed
when the DRVVT screen is abnormally prolonged. Refer to DRV1 / Dilute Russell Viper Venom Time
(DRVVT), Plasma for interpretation of results.
Useful For: Confirming the presence or absence of lupus anticoagulants (LA) Identifying LA that do
not prolong the activated partial thromboplastin time (APTT) Evaluating unexplained prolongation of the
APTT or prothrombin time clotting tests Distinguishing LA from a specific coagulation factor inhibitor or
coagulation factor deficiencies
screen ratio (<1.20) indicates that lupus anticoagulant (LA) is not present or not detectable by this method
(but might be detected with other methods). An abnormal DRVVT screen ratio (DRVVT screen ratio
>1.20) may suggest presence of LA, however, other possibilities include: -Deficiencies or dysfunction of
factors I (fibrinogen), II, V, or X, congenital or acquired -Inhibitors of factor V, or occasionally by
inhibitors of factor VIII, or other specific or nonspecific inhibitors -Anticoagulation therapy effects (see
Cautions) Further evaluation consists of performing mixing studies with an equal volume of normal
pooled plasma (DRVVT 1:1 mix) to investigate the possibility of coagulation factor deficiency (suggested
by DRVVT mix ratio <1.20) and to evaluate inhibition (suggested by DRVVT mix ratio > or =1.20) and
mixing patient plasma with DRVVT reagent enriched in phospholipid (DRVVT confirmatory reagent)
(DRVVT mix and DRVVT confirmation ratios). Possible combination of results include the following:
-DRVVT screen ratio > or =1.20, DRVVT mix ratio <1.20, and DRVVT confirmation ratio <1.20: No
evidence of LA. These data may reflect anticoagulation therapy effects or other (congenital or acquired)
coagulopathy. -DRVVT screen ratio > or =1.20, DRVVT mix ratio > or =1.20, and DRVVT confirmation
ratio <1.20: The prolonged and inhibited DRVVT (DRVVT screen and mix ratios) may reflect presence
of a specific factor inhibitor (eg, factor V inhibitor), anticoagulation therapy effects or other nonspecific
inhibitors as can be seen with monoclonal protein disorders, lymphoproliferative disease etc. Although
LA cannot be conclusively excluded, the DRVVT confirmation ratio of < or =1.20 makes this less likely.
-DRVVT screen ratio > or =1.20, DRVVT mix ratio <1.20, and DRVVT confirmation ratio > or =1.20:
Although mixing study of the prolonged DRVVT screen and mix ratios provides no evidence of
inhibition, additional phospholipid shortens the clotting time (DRVVT confirmation ratio), suggesting
presence of LA. -DRVVT screen ratio > or =1.20, DRVVT mix ratio > or =1.20, and DRVVT
confirmation ratio > or =1.20: The data are consistent with presence of LA, provided anticoagulant effect
can be excluded (see Cautions). Additional tests to evaluate abnormal DRVVT results include activated
partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time. Abnormalities observed
with these tests may be further evaluated with normal plasma mixing studies, the platelet neutralization
procedure (for APTT), and coagulation factor assays may sometimes be needed. All of these reflexive
testing procedures, together with Coagulation Consultant interpretation, are included in Mayo Clinic's
Coagulation Consultation test panels: ALUPP / Lupus Anticoagulant Profile, Plasma ALBLD / Bleeding
Diathesis Profile, Limited, Plasma AATHR / Thrombophilia Profile, Plasma APROL / Prolonged Clot
Time Profile, Plasma ADIC / Disseminated Intravascular Coagulation/Intravascular Coagulation and
Fibrinolysis (DIC/ICF) Profile, Plasma DRVVT assays ordered as a single, stand-alone test should be
interpreted within patient clinical context and close attention to medication use by patient (see Cautions).
Reference Values:
Only orderable as part of a reflex. For more information see:
Profile, Plasma
<1.20
Clinical References: 1. Proven A, Bartlett RP, Moder KG, et al: Clinical importance of positive
test results for lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 2004
April;79(4):467-475 2. Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ: Lupus anticoagulant: an
analysis of the clinical and laboratory features of 219 cases. Am J Hematol 1985 Jul;19(3):265-275 3.
Brandt JT, Triplett DA, Alving B, Sharrer I: Criteria for the diagnosis of lupus anticoagulant: an update.
On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific
and Standardisation Committee of the ISTH. Thromb Haemost 1995 Oct;74(4);1185-1190 4. Arnout J,
Vermylen J: Current status and implications of autoimmune antiphospholipid antibodies in relation to
thrombotic disease. J Thromb Haemost 2003 May;1(5):931-942 5. Pengo V, Tripodi A, Reber G, et al:
Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus
Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the
International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009;7:1737-1740. doi:
10.1111/j.1538-7836.2009.03555.x 6. CLSI Laboratory Testing for Lupus Anticoagulant; Approved
Guideline. CLSI document H60-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2014
DRVI4
Current
603310as of July 20, 2022 12:05 pm CDT 800-533-1710 or 507-266-5700 or mayocliniclabs.com Page 903
Dilute Russell Viper Venom Time (DRVVT) Interpretation
Clinical Information: Lupus anticoagulants (LA) are immunoglobulins (IgG, IgM, IgA, or a
prothrombin (factor II) or factor X, and which cause prolongation of phospholipid-dependent clotting time
coagulation factor-phospholipid interactions, typically causing prolongation of 1 or more
single coagulation test can identify or exclude all LA. Currently, the International Society on Thrombosis
and Haemostasis and the Clinical and Laboratory Standards Institute recommend testing for LA with at
least 2 phospholipid-dependent clotting time assays based on different coagulation pathways and
principles (eg, lupus-sensitive APTT and DRVVT). In addition, given the potential for false-positive
results in patients on anticoagulants, a profile or panel of coagulation tests is performed, including the
prothrombin time (PT), APTT, thrombin time (TT) and DRVVT. If the PT, APTT, or DRVVT are
prolonged, additional testing may include mixing tests with normal plasma (to evaluate for inhibition) and
the use of excess phospholipid in appropriate assay systems to evaluate for phospholipid-dependent
inhibition. Additional reflexive testing helps determine presence or absence of anticoagulants and
inhibitors to other factors. The diagnosis of LA requires performance and interpretation of complex
coagulation testing, as well as correlation with available clinical information, including evidence of
persistence of LA over time (> or =12 weeks). Â The venom obtained from Russell's viper (Vipera
russelli) contains enzymes that directly activate coagulation factors V and X, bypassing the activation of
factors VII, VIII, IX, XI, and XII, and therefore, the effect of deficiencies or inhibitors of these factors.
Diluting the phospholipid necessary for the clotting factor interactions increases the sensitivity to LA and
the likelihood of identifying a phospholipid-dependent inhibitor that may not be detected by other
coagulation tests with higher phospholipid content (eg, LA-insensitive APTT reagents). The DRVVT
screen ratio test is one of several available in vitro tests that may be used to screen and confirm for
presence of LA or to help exclude LA. DRVVT testing is used in conjunction with other appropriate
coagulation tests (reflexive testing panels) to assist in detection and confirmation of LA, or to help
exclude their presence. The DRVVT may be abnormally prolonged (DRVVT Screen Ratio > or =1.20) by
LA as well as coagulation factor deficiencies, anticoagulant effects, or other types of coagulation factor
inhibitors. Specimens with abnormal results (DRVVT screen ratio > or =1.20) are subjected to reflexive
testing. With a reflexive testing algorithm, the sensitivity of DRVVT testing for LA diagnosis is
approximately 65% to 70% and the specificity is 95% or higher. It is advisable to use the DRVVT screen,
mix and confirm ratio results in conjunction with other appropriate coagulation tests (reflexive testing
panels) to diagnose or exclude LA. Although LA cause prolonged clotting times in vitro, there is a strong
association with thrombosis risk. However, not all patients with persisting LA develop thrombosis.
Useful For: Interpreting mixing and confirmation assays for lupus anticoagulants (LA)
(but might be detected with other methods).Â An abnormal DRVVT screen ratio (DRVVT screen ratio >
or =1.20) may suggest presence of LA, however, other possibilities include: -Deficiencies or dysfunction
of factors I (fibrinogen), II, V, or X, congenital or acquired -Inhibitors of factor V, or occasionally by
(DRVVT mix and DRVVT confirmation ratios). Possible combination of results include the following:Â
inhibition, additional phospholipid shortens the clotting time (DRVVT confirm ratio), suggesting
can be excluded (see Cautions) Because no single coagulation test can identify or exclude all LAs, and
because of the complexity of testing LA, one ofÂ the following Coagulation Consultation reflexive panel
procedures are recommended if clinically indicated: ALUPP / Lupus Anticoagulant Profile, Plasma
AATHR / Thrombophilia Profile, Plasma APROL / Prolonged Clot Time Profile, Plasma DRVVT assays
ordered as a single, stand-alone test should be interpreted within patient clinical context and close
attention to medication use by patient (see Cautions).
Reference Values:
Only orderable as a part of a profile. For more information see DRVI1 / Dilute Russell Viper Venom
Time (DRVVT), with Reflex, Plasma.
thrombotic disease. J Thromb Haemost 2003 May;1(5):931-942 5. Pengo V, Tripodi A, Reber G, Rand
JH, et al: Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus
DRVI2 Dilute Russell Viper Venom Time (DRVVT) Mix Ratio, Plasma
602180 Clinical Information: Lupus anticoagulants (LA) are immunoglobulins (IgG, IgM, IgA, or a
coagulation-related proteins such as beta-2-glycoprotein I (beta[2]GPI) or clotting factors including
prothrombin (factor II) or factor X, and which cause prolongation of phospholipid-dependent clotting
time tests due to inhibition. LA are functionally and clinically distinct members of a broader group of
phospholipid-dependent clotting time tests (eg, activated partial thromboplastin time [APTT], dilute
Russell viper venom time [DRVVT]) due to inhibition. This characteristic in vitro inhibition can be
Thrombosis and Haemostasis and the Clinical and Laboratory Standards Institute recommend testing for
LA with at least 2 phospholipid-dependent clotting time assays based on different coagulation pathways
and principles (eg, lupus-sensitive APTT and DRVVT). In addition, given the potential for
false-positive results in patients on anticoagulants, a profile or panel of coagulation tests is performed,
including the prothrombin time (PT), APTT, thrombin time (TT), and DRVVT. If the PT, APTT, and/or
DRVVT are prolonged, additional testing may include mixing tests with normal plasma (to evaluate for
inhibition) and the use of excess phospholipid in appropriate assay systems to evaluate for
phospholipid-dependent inhibition. Additional reflexive testing helps determine presence or absence of
anticoagulants and/or inhibitors to other factors. The diagnosis of LA requires performance and
including evidence of persistence of LA over time (> or =12 weeks). The venom obtained from
bypassing the activation of factors VII, VIII, IX, XI, and XII, and therefore, the effect of deficiencies or
may not be detected by other coagulation tests with higher phospholipid content (eg, LA-insensitive
subjected to reflexive testing. With the reflexive testing, the sensitivity of DRVVT testing for LA
diagnosis is approximately 65% to 70% and the specificity is 95% or higher. It is advisable to use the
DRVVT screen, mix and confirm ratio results in conjunction with other appropriate coagulation tests
(reflexive testing panels) to diagnose or exclude LA. Although LA cause prolonged clotting times in
vitro, there is a strong association with thrombosis risk. However, not all patients with persisting LA
develop thrombosis.
Useful For: Detecting the presence or helping to exclude the presence of lupus anticoagulants (LA)
unexplained prolongation of the activated partial thromboplastin time (APTT) or prothrombin time
clotting tests Distinguishing LA from a specific coagulation factor inhibitor or coagulation factor
deficiencies
(but might be detected with other methods). An abnormal DRVVT screen ratio (DRVVT screen ratio > or
=1.20) may suggest presence of LA, however, other possibilities include: -Deficiencies or dysfunction of
can be excluded (see Cautions) Because no single coagulation test can identify or exclude all LAs, and
because of the complexity of testing LA, one of the following Coagulation Consultation reflexive panel
procedures are recommended if clinically indicated: ALUPP / Lupus Anticoagulant Profile, Plasma
AATHR / Thrombophilia Profile, Plasma APROL / Prolonged Clot Time Profile, Plasma DRVVT assays
ordered as a single, stand-alone test should be interpreted within patient clinical context and close
attention to medication use by patient (see Cautions).
Reference Values:
Only orderable as part of a reflex. For more information see DRVI1 / Dilute Russell Viper Venom Time
(DRVVT), with Reflex, Plasma.
<1.20
International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009 Oct;7:1737-1740. doi:
DRV2 Dilute Russell Viper Venom Time (DRVVT) Mix, Plasma

coagulation factor-phospholipid interactions, typically causing prolongation of 1or more
Thrombosis and Haemostasis and the Clinical and Laboratory Standards Institute (CLSI) recommend
testing for LA with at least 2 phospholipid-dependent clotting time assays based on different
coagulation pathways and principles (eg, lupus-sensitive APTT and DRVVT). In addition, given the
potential for false-positive results in patients on anticoagulants, a profile or panel of coagulation tests is
performed, including the prothrombin time (PT), APTT, thrombin time (TT) and DRVVT. If the PT,
APTT, and/or DRVVT are prolonged, additional testing may include mixing tests with normal plasma
(to evaluate for inhibition) and the use of excess phospholipid in appropriate assay systems to evaluate
for phospholipid-dependent inhibition. Additional reflexive testing helps determine presence or absence
of anticoagulants and/or inhibitors to other factors. The diagnosis of LA requires performance and
bypassing the activation of factors VII, VIII, IX, XI, and XII, and, therefore, the effect of deficiencies or
may not be detected by other coagulation tests with a higher phospholipid content (eg, LA-insensitive
subjected to reflexive testing. With the reflexive testing algorithm, the sensitivity of DRVVT testing for
LA diagnosis is approximately 65% to 70% and the specificity is 95% or higher. Although LA cause
prolonged clotting times in vitro, there is a strong association with thrombosis risk. However, not all
patients with persisting LA develop thrombosis.
Useful For: Detecting the presence or helping to exclude the presence of lupus anticoagulants (LA)
(but might be detected with other methods). An abnormal DRVVT screen ratio (DRVVT screen ratio
>1.20) may suggest presence of LA, however, other possibilities include: -Deficiencies or dysfunction of
can be excluded (see Cautions) Additional tests to evaluate abnormal DRVVT results include activated
Coagulation Consultation test panels: ALUPP / Lupus Anticoagulant Profile, Plasma ALBLD / Bleeding
Diathesis Profile, Limited, Plasma AATHR / Thrombophilia Profile, Plasma APROL / Prolonged Clot
Time Profile, Plasma ADIC / Disseminated Intravascular Coagulation/Intravascular Coagulation and
Fibrinolysis (DIC/ICF) Profile, Plasma DRVVT assays ordered as a single, stand-alone test should be
Reference Values:
Only orderable as part of a reflex. For more information see:
Profile, Plasma
<1.20
DRV1 Dilute Russell Viper Venom Time (DRVVT), Plasma

coagulation factor-phospholipid interactions, typically causing prolongation of 1or more
coagulation pathways and principles (eg, lupus-sensitive APTT and DRVVT). In addition, given the
potential for false-positive results in patients on anticoagulants, a profile or panel of coagulation tests is
performed, including the prothrombin time (PT), APTT, thrombin time (TT) and DRVVT. If the PT,
APTT, and/or DRVVT are prolonged, additional testing may include mixing tests with normal plasma
(to evaluate for inhibition) and the use of excess phospholipid in appropriate assay systems to evaluate
for phospholipid-dependent inhibition. Additional reflexive testing helps determine presence or absence
of anticoagulants and/or inhibitors to other factors. The diagnosis of LA requires performance and
bypassing the activation of factors VII, VIII, IX, XI, and XII, and therefore, the effect of deficiencies or
may not be detected by other coagulation tests with a higher phospholipid content (eg, LA-insensitive
subjected to reflexive testing (see Testing Algorithm). With the reflexive testing algorithm, the
sensitivity of DRVVT testing for LA diagnosis is approximately 65% to 70% and the specificity is 95%
or higher. Although LA cause prolonged clotting times in vitro, there is a strong association with
thrombosis risk. However, not all patients with persisting LA develop thrombosis.
Useful For: Detecting and confirming or helping to exclude the presence of lupus anticoagulants (LA)
(but might be detected with other methods). An abnormal DRVVT screen ratio (DRVVT screen ratio > or
=1.20) may suggest presence of LA, however, other possibilities include: -Deficiencies or dysfunction of
(DRVVT mix and DRVVT confirmation ratios). Possible combination of results include the following:Â
can be excluded (see Cautions) Additional tests to evaluate abnormal DRVVT results include activated
Coagulation Consultation test panels:ALUPP / Lupus Anticoagulant Profile), Plasma ALBLD / Bleeding
Diathesis Profile, Limited), Plasma AATHR / Thrombophilia Profile), Plasma APROL / Prolonged Clot
Time Profile), Plasma ADIC / Disseminated Intravascular Coagulation/Intravascular Coagulation and
Fibrinolysis (DIC/ICF) Profile), Plasma DRVVT assays ordered as a single, stand-alone test should be
Reference Values:
Only orderable as part of a profile or reflex. For more information see:
ALUPP / Lupus Anticoagulant Profile), Plasma
AATHR / Thrombophilia Profile), Plasma
APROL / Prolonged Clot Time Profile), Plasma
ALBLD / Bleeding Diathesis Profile, Limited), Plasma
Profile), Plasma
< 1.20
Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation
Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and
Haemostasis. J Thromb Haemost 2009;7:1737-1740. doi: 10.1111/j.1538-7836.2009.03555.x 6. CLSI
DRVI1 Dilute Russell Viper Venom Time (DRVVT), with Reflex, Plasma
prothrombin (factor II) or factor X, and cause prolongation of phospholipid-dependent clotting time
coagulation pathways and principles (eg, lupus sensitive APTT and DRVVT). In addition, given the
potential for false-positive results in patients on anticoagulants, a profile or panel of coagulation testing
is recommended, including the prothrombin time (PT), APTT, thrombin time (TT), and the DRVVT. If
the PT, APTT, or DRVVT are prolonged, additional testing may include mixing tests with normal
plasma (to evaluate for inhibition) and the use of excess phospholipid in appropriate assay systems to
evaluate for phospholipid-dependent inhibition. Additional reflexive testing helps determine the
presence or absence of anticoagulants or inhibitors to other factors. The diagnosis of LA requires
performance and interpretation of complex coagulation testing, as well as correlation with available
clinical information, including evidence of persistence of LA over time (> or =12 weeks). The venom
obtained from the Russell viper (Vipera russelli) contains enzymes that directly activate coagulation
factors V and X, bypassing the activation of factors VII, VIII, IX, XI, and XII, and, therefore, the effect
of deficiencies or inhibitors of these factors. Diluting the phospholipid necessary for the clotting factor
interactions increases the sensitivity to LA and the likelihood of identifying a phospholipid-dependent
inhibitor that may not be detected by other coagulation tests that have a higher phospholipid content (eg,
LA-insensitive APTT reagents). The DRVVT screen ratio test is one of several available in vitro tests
that may be used to screen and confirm the presence of LA or to help exclude LA. DRVVT testing is
used in conjunction with other appropriate coagulation tests (reflexive testing panels) to assist in
detection and confirmation of LA, or to help exclude their presence. The DRVVT may be abnormally
prolonged (DRVVT screen ratio > or =1.20) by LA as well as coagulation factor deficiencies,
anticoagulant effects, or other types of coagulation factor inhibitors. Specimens with abnormal results
(DRVVT screen ratio > or =1.20) are subjected to reflexive testing (see Testing Algorithm). With the
reflexive testing algorithm, the sensitivity of DRVVT testing for LA diagnosis is approximately 65% to
70% and the specificity is 95% or higher. It is advisable to use the DRVVT screen, mix and confirm
ratio results in conjunction with other appropriate coagulation tests (reflexive testing panels) to diagnose
or exclude LA. Although LA cause prolonged clotting times in vitro, there is a strong association with
thrombosis risk. However, not all patients with persisting LA develop thrombosis.
Useful For: Detecting and confirming or helping to exclude the presence of lupus anticoagulants
(LA) Identifying LA that do not prolong the activated partial thromboplastin time (APTT) Evaluating
screen ratio (<1.20) indicates that lupus anticoagulants (LA) is not present, or not detectable, by this
method (but might be detected with other methods). Abnormal DRVVT screen ratio (DRVVT screen ratio
> or =1.20) may suggest the presence of LA; however, other possibilities include: -Deficiencies or
dysfunction of factors I (fibrinogen), II, V, or X, congenital or acquired. -Inhibitors of factor V, or
occasionally by inhibitors of factor VIII, or other specific or nonspecific inhibitors -Anticoagulation
therapy effects (see Cautions) Further evaluation consists of performing mixing studies with an equal
volume of normal pooled plasma (DRVVT 1:1 mix) to investigate the possibility of coagulation factor
deficiency (suggested by DRVVT mix ratio <1.20) and to evaluate inhibition (suggested by DRVVT mix
ratio > or =1.20) and mixing patient plasma with DRVVT reagent enriched in phospholipid (DRVVT
confirmatory reagent) (DRVVT mix and DRVVT confirm ratios). Possible combinations of results
include the following: -DRVVT screen ratio > or =1.20, DRVVT mix ratio <1.20, and DRVVT confirm
ratio <1.20: No evidence of LA. This data may reflect anticoagulation therapy effects or other (congenital
or acquired) coagulopathy. -DRVVT screen ratio > or =1.20, DRVVT mix ratio > or =1.20, and DRVVT
confirm ratio <1.20: The prolonged and inhibited DRVVT (DRVVT screen and mix ratios) may reflect
presence of a specific factor inhibitor (eg, factor V inhibitor), anticoagulation therapy effects, or other
nonspecific inhibitors as can be seen with monoclonal protein disorders, lymphoproliferative disease, etc.
Although LA cannot be conclusively excluded, the DRVVT confirm ratio of < or =1.20 makes this less
likely. -DRVVT screen ratio > or =1.20, DRVVT mix ratio <1.20, andÂ DRVVT confirm ratio > or
=1.20: Although mixing study of the prolonged DRVVT screen and mix ratios provides no evidence of
inhibition, additional phospholipid shortens the clotting time (DRVVT confirm ratio), suggesting
presence of LA. -DRVVT screen ratio > or =1.20, DRVVT mix ratio > or =1.20, and DRVVT confirm
ratio > or =1.20: The data are consistent with presence of LA, provided anticoagulant effect can be
excluded (see Cautions). Because no single coagulation test can identify or exclude all LAs, and because
of the complexity of testing LA, a combination or panel of coagulation tests is recommended: ALUPP /
Lupus Anticoagulant Profile, Plasma AATHR / Thrombophilia Profile, Plasma APROL / Prolonged Clot
Time Profile, Plasma DRVVT assays ordered as a single, stand-alone test should be interpreted within
patient clinical context and close attention to medication use by patient (see Cautions).
Reference Values:
Dilute Russell viper venom time screen ratio <1.20
Normal ranges for children: Not clearly established, but similar to normal ranges for adults, except for
Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation
Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and
Haemostasis. J Thromb Haemost 2009 Oct;7:1737-1740. doi: 10.1111/j.1538-7836.2009.03555.x 6. CLSI
DIPGS Diphtheria Toxoid IgG Antibody, Serum

36664 Clinical Information: Diphtheria is an acute, contagious, febrile illness caused by the bacterium
Corynebacterium diphtheriae. The disease is classically characterized by a combination of localized
inflammation in the upper respiratory tract with the formation of a diphtheric pseudomembrane over the
oropharynx, including the tonsils, pharynx, larynx and posterior nasal passages. C diphtheriae produces a
potent diphtheria exotoxin that is absorbed systemically and can lead to cardiac failure and paralysis of
the diaphragm. The disease is preventable by vaccination with diphtheria toxoid, which stimulates
antidiphtheria toxoid antibodies. In the United States, diphtheria toxoid is administered to children as part
of the combined diphtheria, tetanus, and acellular pertussis (TDaP) vaccine. A patient's immunological
response to diphtheria toxoid vaccination can be determined by measuring antidiphtheria toxoid IgG
antibody using this enzyme immunoassay technique. An absence of antibody formation postvaccination
may relate to immune deficiency disorders, either congenital or acquired, or iatrogenic due to
immunosuppressive drugs.
Useful For: Determining a patient's immunological response to diphtheria toxoid vaccination Aiding
in the evaluation of immunodeficiency
Interpretation: Results of 0.01 IU/mL or more suggest a vaccine response. A diphtheria toxoid
booster should be considered for patients with antidiphtheria toxoid IgG values between 0.01 and less
than 0.1 IU/mL.
Reference Values:
Vaccinated: Positive (> or =0.01 IU/mL)
Unvaccinated: Negative (<0.01 IU/mL)
Clinical References: 1. Booy R, Aitken SJ, Taylor S, et al: Immunogenicity of combined

diphtheria, tetanus, and pertussis vaccine given at 2, 3, and 4 months versus 3, 5, and 9 months of age.
Lancet. 1992;339(8792):507-510 2. Maple PA, Efstratiou A, George RC, Andrews NJ, Sesardic D:
Diphtheria immunity in UK blood donors. Lancet. 1995;345(8955):963-965 3. WHO meeting report:
The Control of Diphtheria in Europe. WHO ref:EUR/ICP/EPI/024 1990 4. Wagner KS, White JM,
Lucenko I, et al: Diphtheria in the postepidemic period, Europe, 2000-2009. Emerg Infect Dis. 2012
Feb;18(2):217-225 doi: 10.3201/eid1802.110987
DTABS Diphtheria/Tetanus Antibody Panel, Serum

36670 Clinical Information: Diphtheria is an acute, contagious, febrile illness caused by the bacterium
Corynebacterium diphtheriae. The disease is classically characterized by a combination of localized
inflammation in the upper respiratory tract with the formation of a diphtheric pseudomembrane over the
oropharynx, including the tonsils, pharynx, larynx, and posterior nasal passages. C diphtheriae produces
a potent diphtheria exotoxin that is absorbed systemically and can lead to cardiac failure and paralysis
of the diaphragm. The disease is preventable by vaccination with diphtheria toxoid, which stimulates
antidiphtheria toxoid antibodies. In the United States, diphtheria toxoid is administered to children as
part of the combined diphtheria, tetanus, acellular pertussis (TDaP) vaccine. A patient's immunological
response to diphtheria toxoid vaccination can be determined by measuring antidiphtheria toxoid IgG
antibody using this enzyme immunoassay technique. An absence of antibody formation postvaccination
may relate to immune deficiency disorders, either congenital or acquired, or iatrogenic due to
immunosuppressive drugs. Tetanus results from contamination of wounds or lacerations with
Clostridium tetani spores from the environment. The spores germinate to actively replicating bacterial
cells localized within the wound and produce the heat-labile toxin, tetanospasmin. Tetanospasmin
attaches to peripheral nerve endings and travels to the central nervous system (CNS) where it blocks
inhibitory impulses to motor neurons and leads to severe, spastic muscle contractions, a classic
characteristic of tetanus. The disease is preventable by vaccination with tetanus toxoid
(formaldehyde-treated tetanospasmin), which stimulates development of antitetanus toxoid antibodies.
In the United States, tetanus toxoid is administered to children as part of the combined diphtheria,
tetanus, acellular pertussis (TDaP) vaccine. Two to 3 weeks following vaccination, a patient's
immunological response may be assessed by measuring the total antitetanus toxoid IgG antibody level
in serum. An absence of antibody formation postvaccination may relate to immune deficiency disorders,
either congenital or acquired, or iatrogenic due to immunosuppressive drugs.
Useful For: Assessment of an antibody response to tetanus and diphtheria toxoid vaccines, which
should be performed at least 3 weeks after immunization Aiding in the evaluation of immunodeficiency
This test should not be used to diagnose tetanus infection
Interpretation: Diphtheria: Results of 0.01 IU/mL or more suggest a vaccine response. A diphtheria
toxoid booster should be considered for patients with antidiphtheria toxoid IgG values between 0.01 and
less than 0.1 IU/mL Tetanus: Results of 0.01 IU/mL or more suggest a vaccine response. A tetanus
toxoid booster should strongly be considered for patients with antitetanus toxoid IgG values between
0.01 and 0.5 IU/mL. Some cases of tetanus, usually mild, have occasionally been observed in patients
who have a measurable serum level of 0.01 to 1.0 IU/mL.
Reference Values:
DIPHTHERIA TOXOID IgG ANTIBODY
TETANUS TOXOID IgG ANTIBODY

Clinical References: 1. Booy R, Aitken SJ, Taylor S, et al: Immunogenicity of combined diphtheria,
tetanus, and pertussis vaccine given at 2, 3, and 4 months versus 3, 5, and 9 months of age. Lancet.
1992;339(8792):507-510 2. Maple PA, Efstratiou A, George RC, Andrews NJ, Sesardic D: Diphtheria
immunity in UK blood donors. Lancet. 1995;345(8955):963-965 3. Bleck TP: Clostridium tetani
(tetanus). In: Mandell GL, Bennett JE, Dolin R, eds. Principals and Practice of Infectious Disease. 5th ed.
Churchill Livingstone;2000:2537-2543 4. Gergen PJ, McQuillan GM, Kiely M, Ezzati-Rice TM, Sutter
RW, Virella G: A population-based serologic survey of immunity to tetanus in the United States. N Engl J
Med. 1995;332:761-766 5. Bjorkholm B, Wahl M, Granstrom M, Hagberg L: Immune status and booster
effects of low doses of tetanus toxoid in Swedish medical personnel. Scand J Infect Dis. 1994;26:471-475
6. Ramsay ME, Corbel MJ, Redhead K, Ashworth LA, Begg NT: Persistence of antibody after accelerated
immunization with diptheria/tetanus/pertussis vaccine. Br Med J. 1991;302:1489-1491 7. Wagner KS,
White JM, Lucenko I, et al: Diphtheria in the postepidemic period, Europe, 2000-2009. Emerg Infect Dis.
2012 Feb;18(2):217-225 doi: 10.3201/eid1802.110987
DCTR Direct Antiglobulin Test (Polyspecific), Blood

113514 Clinical Information: IgG antibody or complement components secondary to the action of IgM
antibody may be present on the patient's own red blood cells (RBC) or on transfused RBC.
Useful For: Demonstrating in vivo coating of red blood cells with IgG or the complement component
C3d in the following settings: -Autoimmune hemolytic anemia -Hemolytic transfusion reactions
-Drug-induced hemolytic anemia
Interpretation: Negative: No IgG antibody or complement (C3d) detected on the surface of the red
cell. Positive: Test polyspecific direct antiglobulin testing will be ordered and performed.
Reference Values:
Negative
AABB; 2017
DSAC Disaccharidase Activity Panel, Tissue

608236 Clinical Information: Disaccharidases in the small intestines are responsible for the breakdown of
disaccharides (double sugars) into monosaccharides (simple sugars). Patients with a deficiency of 1 or
more disaccharidase enzymes can experience intolerance to foods containing complex sugars resulting in
a range of gastrointestinal symptoms including diarrhea or constipation, abdominal pain and cramping,
gas, bloating, and nausea. In addition, patients may experience malnutrition, weight loss, or failure to
thrive. Given the nonspecificity and frequency of abdominal symptoms, misdiagnosis or a diagnostic
delay of disaccharide deficiencies may occur. Primary and secondary causes of disaccharidase
deficiencies exist, and age of onset may vary from birth through adulthood. Primary causes are rare and
result from genetic alterations in a variety of genes. Secondary deficiencies typically result from small
intestinal mucosal damage. Treatment of both primary and secondary disaccharidase deficiencies involves
dietary management. While primary deficiencies require lifelong treatment, secondary disaccharidase
deficiencies may require treatment only until the intestinal lining recovers.
Useful For: Evaluation of patients who present with signs or symptoms suggestive of disaccharidase
disorders This test is not intended for carrier detection.
Interpretation: Quantitative values of lactase, sucrase, maltase, palatinase, and glucoamylase are
reported. Clinical interpretation of results is provided.
Reference Values:
Lactase: > or =14.0 nmol/min/mg protein
Sucrase: > or =19.0 nmol/min/mg protein
Maltase: > or =70.0 nmol/min/mg protein
Palatinase: > or =6.0 nmol/min/mg protein
Glucoamylase: > or =8.0 nmol/min/mg protein
Clinical References: 1. Cohen SA, Oloyede H, Gold BD, Mohammed A, Elser HE: Clinical
characteristics of disaccharidase deficiencies among children undergoing upper endoscopy. J Pediatr
Gastroenterol Nutr. 2018 Jun;66 Suppl 3:S56-S60 2. Semenza G, Auricchio S, Mantei N. :
Small-intestinal disaccharidases. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA.
eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Accessed
August 23, 2021. Available at
https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225081608
ADICI Disseminated Intravascular Coagulation/Intravascular

603182 Coagulation and Fibrinolysis (DIC/ICF) Profile Interpretation
Clinical Information: Disseminated intravascular coagulation (DIC)/intravascular coagulation and
fibrinolysis (ICF), collectively termed DIC/ICF is a consumptive hemorrhagic and microthrombotic
disorder that manifests as clinical bleeding or thrombosis. Conditions associated with DIC/ICF can
include; sepsis, trauma (head injury, severe tissue injury), obstetric complications (amniotic fluid
embolism, abruptio placentae), malignancies, vascular disorders (hemangiomas, aortic aneurysm), and
immunologic disorders.Â These disorders can cause formation of thrombin and fibrin intravascularly,
which can result in widespread fibrin deposition contributing to thrombosis and organ failure or,
conversely, can result in bleeding due to consumption of coagulation proteins and platelets. DIC/ICF is
not a disease; rather it is a syndrome that is secondary to an underlying disorder.
Useful For: Establishing laboratory evidence of disseminated intravascular coagulation (DIC)

Reference Values:
Only orderable as part of a profile. For more information see ADIC / Disseminated Intravascular
Coagulation/Intravascular Coagulation and Fibrinolysis (DIC/ICF) Profile, Plasma.
Clinical References: Boender J: A Diagnostic Approach to Mild Bleeding Disorders Journal of

Thrombosis and Haemostasis 2016;14:1507-1516
ADIC Disseminated Intravascular Coagulation/Intravascular

603306 Coagulation and Fibrinolysis (DIC/ICF) Profile, Plasma
Clinical Information: Disseminated intravascular coagulation (DIC) and intravascular coagulation
and fibrinolysis (ICF), collectively termed DIC/ICF is a consumptive hemorrhagic and microthrombotic
disorder that manifests as clinical bleeding or thrombosis. Conditions associated with DIC/ICF can
include sepsis, trauma (eg, head injury, severe tissue injury), obstetric complications (eg, amniotic fluid
embolism, abruptio placentae), malignancies, vascular disorders (eg, hemangiomas, aortic aneurysm), and
immunologic disorders. These disorders can cause formation of thrombin and fibrin intravascularly,
which can result in widespread fibrin deposition contributing to thrombosis and organ failure or,
conversely, can result in bleeding due to consumption of coagulation proteins and platelets. DIC/ICF is
not a disease, rather it is a syndrome that is secondary to an underlying disorder.
Useful For: Establishing laboratory evidence of disseminated intravascular coagulation

Reference Values:
An interpretive report is provided.
Clinical References: Boender J, Kruip MJ, Leebeek FWG: A diagnostic approach to mild bleeding
disorders. J Thromb Haemost. 2016 Aug;14(8):1507-1516. doi: 10.1111/jth.13368
FDIRU Diuretic Screen, Urine

Qualitative diuretic screen includes: benzthiazide, bumetanide, chlorothiazide, chlorthalidone, furosemide,
hydrochlorothiazide, hydroflumethiazide, and metolazone.
FDM1 DMPK DNA Test (DM1)

91592 Clinical Information: Detects CTG repeat expansions in the muscle protein kinase (DMPK) gene.
Typical presentation: Adults may present with a range of symptoms from cataracts to significant muscle
wasting, cardiac complications, ptosis and myotonia, infants may present with severe hypotonia, skeletal
deformities, developmental delay and mental retardation.
Reference Values:
CRITH DNA Double-Stranded (dsDNA) Antibodies by Crithidia luciliae

62925 IFA, IgG, Serum
Clinical Information: Double-stranded DNA (dsDNA) antibodies are systemic lupus erythematosus
(SLE)-specific antibodies and are part of the immunology domain of the 2019 European League Against
Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE (1) as
well as a previous guidance on SLE diagnosis.(2) The Crithidia luciliae indirect immunofluorescence test
(CLIFT) is widely used as a confirmatory test following a positive dsDNA IgG result obtained by a
solid-phase immunoassay due to its structural or analytical specificity.(3-5) The CLIFT (dsDNA) test is
indicated in patients who are positive for anti-cellular antibody (also known as antinuclear antibody
[ANA]) homogeneous pattern (6) using HEp-2 substrate by indirect immunofluorescence assay (IFA)
following a positive result for dsDNA IgG using a solid-phase immunoassay (eg, enzyme-linked
immunosorbent assay or multiplex bead assay).(3,4) A positive CLIFT result is usually associated with
the presence of moderate-to-high affinity dsDNA IgG antibodies. The CLIFT result may be negative and
the immunoassay positive for dsDNA IgG in SLE patients with inactive (remission) disease or in patients
with early disease.(3,4,7) Discordant results between CLIFT and solid-phase immunoassays may also be
due to differences in the structural specificities of DNA analytes as well as the absence reliable reagents to
harmonize available clinical tests.(3,5,8) A minority of SLE patients may test negative using HEp-2 by
IFA for nuclear antibodies.(9) Testing antibodies associated with the HEp-2 IFA cytoplasmic pattern such
as ribosomal P IgG autoantibodies may be useful if features of neuropsychiatric disease are present.(9)
Alternatively, patients may be tested for Smith, ribonuclear protein (RNP), sulfosalicylic acid (SSA)-52
and SSA-60 antibodies.(6,9)
Useful For: Confirmation testing for dsDNA IgG antibodies in patients with clinical features of
systemic lupus erythematosus or at-risk for disease This test may not be used independently for
monitoring treatment response or establishing remission.
Interpretation: A positive result for double-stranded DNA (dsDNA) IgG antibodies in the
appropriate clinical context is highly suggestive of systemic lupus erythematosus (SLE). The presence
of dsDNA IgG antibodies detected using the Crithidia luciliae indirect immunofluorescence test is
highly specific for SLE with moderate sensitivity. A negative result does not rule out a diagnosis of
SLE.
Reference Values:
Only orderable as reflex. For more information see ADNAR / DNA Double-Stranded (dsDNA)
Antibodies with Reflex, IgG, Serum.
Negative
Clinical References: 1. Aringer M, Costenbader K, Daikh D, et al: European league against

rheumatism/American College of Rheumatology Classification Criteria for systemic lupus
erythematosus. Arthritis Rheumatol. 2019 Sep;71(9):1400-1412. doi: 10.1002/art.40930 2. Petri M,
Orbai AM, AlarcÃ³n GS, et al: Derivation and validation of the Systemic Lupus International
Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012
Aug;64(8): 2677-2686. doi: 10.1002/art.34473 3. Enocsson H, Sjowall C, Wirestam L, et al: Four
anti-dsDNA antibody assays in relation to systemic lupus erythematosus disease specificity and activity.
J Rheumatol. 2015 May;42(5):817-825. doi: 10.3899/jrheum.140677 4. Sarbu MI, Salman-Monte TC,
Munoz PR, Lisbona MP, Bernabe MA, Carbonell J: Differences between clinical and laboratory
findings in patients with recent diagnosis of SLE according to the positivity of anti-dsDNA by the
Crithidia luciliae method. Lupus. 2015 Oct;24(11):1198-1203. doi: 10.1177/0961203315573852 5.
Rekvig OP: Autoimmunity and SLE: factual and semantic evidence-based critical analyses of
definitions, etiology, and pathogenesis. Front Immunol. 2020 Oct 6;11:569234. doi:
10.3389/fimmu.2020.569234 6. Damoiseaux J, Andrade LEC, Carballo OG, et al: Clinical relevance of
HEp-2 indirect immunofluorescent patterns: the International Consensus on ANA patterns (ICAP)
perspective. Ann Rheum Dis. 2019 Jul;78(7):879-889. doi: 10.1136/annrheumdis-2018-214436 7.
Bragazzi NL, Watad A, Damiani G, Adawi M, Amital H, Shoenfeld Y: Role of anti-DNA
auto-antibodies as biomarkers of response to treatment in systemic lupus erythematosus patients: hypes
and hopes. Insights and implications from a comprehensive review of the literature. Expert Rev Mol
Diagn. 2019 Nov;19(11):969-978. doi: 10.1080/14737159.2019.1665511 8. Fox BJ, Hockley J, Rigsby
P, Dolman C, Meroni PL, Ronnelid J: A WHO Reference Reagent for lupus (anti-dsDNA) antibodies:
international collaborative study to evaluate a candidate preparation. Ann Rheum Dis. 2019
Dec;78(12):1677-1680. doi: 10.1136/annrheumdis-2019-215845 9. Choi MY, Clarke AE, St Pierre Y, et
al: Antinuclear antibody-negative systemic lupus erythematosus in an international inception cohort.
Arthritis Care Res (Hoboken). 2019 Jul;71(7):893-902. doi: 10.1002/acr.23712
ADNAR DNA Double-Stranded (dsDNA) Antibodies with Reflex, IgG,

63073 Serum
Clinical Information: Of the systemic lupus erythematosus (SLE)-specific antibodies outlined in
the immunology domain of the 2019 European League Against Rheumatism (EULAR)/American
College of Rheumatology (ACR) classification criteria for SLE,(1) antibodies to double-stranded DNA
(dsDNA) is the most common. It is also included in the Systemic Lupus International Collaborating
Clinics classification criteria (SLICC) for SLE.(2) Detection of IgG antibodies to dsDNA is the most
used isotype clinically.(3-5) The diagnostic performance of dsDNA IgG antibodies in SLE is variable
and dependent on several factors; notably the immunological method used for their detection, the
structure of the DNA, the patientâ€™s disease state (early or active vs inactive) including specific
clinical manifestations and demographics.(3-7) Weak-positive dsDNA IgG antibodies have low affinity
and low avidity with variable clinical correlations for SLE.(3) Testing for IgG antibodies to dsDNA is
indicated in patients positive for anti-cellular antibody (ie, antinuclear antibody: ANA) homogeneous
pattern using HEp-2 substrate by indirect immunofluorescence assay (IFA) along with clinical features
compatible with SLE.(1,2,8). A minority of SLE patients may test negative using HEp-2 by IFA for
nuclear antibodies.(8,9) Testing antibodies associated with HEp-2 IFA cytoplasmic pattern such as
ribosomal P IgG autoantibodies may be useful if features of neuropsychiatric disease are present.
Alternatively, patients may be tested for Smith, ribonucleoprotein, SSA-52, and SSA-60
antibodies.(8,9) The levels of antibodies to dsDNA may fluctuate with SLE disease activity. Increasing
antibody levels may be associated with flares while decline or negative results may indicate response to
treatment or disease remission.
Useful For: Evaluating patients with clinical features or at-risk for systemic lupus erythematosus with
additional testing by indirect immunofluorescence to clarify cases of borderline enzyme-linked
immunosorbent assay results
Interpretation: A positive result for double-stranded DNA (dsDNA) IgG antibodies in the appropriate
clinical context is suggestive of systemic lupus erythematosus (SLE). The performance characteristics of
dsDNA IgG antibodies in SLE is dependent on the immunological method used for their detection, the
patientâ€™s disease state including clinical manifestations, and demographics. Weak-positive dsDNA
IgG antibody results have a low-positive predictive value for SLE. Negative results do not rule out a
diagnosis of SLE.
Reference Values:
<30.0 IU/mL (negative)
30.0-75.0 IU/mL (borderline)
>75.0 IU/mL (positive)
Negative is considered normal.
Clinical References: 1. Aringer M, Costenbader K, Daikh D, et al: 2019 European League Against
Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus
Erythematosus. Arthritis Rheumatol. 2019 Sep;71(9):1400-1412. doi: 10.1002/art.40930 2. Petri M, Orbai
AM, Alarcon GS, et al: Derivation and validation of the Systemic Lupus International Collaborating
Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012
Aug;64(8):2677-86. doi: 10.1002/art.34473 3. Infantino M, Manfredi M, Merone M, et al: Analytical
variability in the determination of anti-double-stranded DNA antibodies: the strong need of a better
definition of the old and new tests. Immunol Res. 2018 Jun;66(3):340-347. doi:
10.1007/s12026-018-8992-9 4. Fox BJ, Hockley J, Rigsby P, Dolman C, Meroni PL, Ronnelid J, et al: A
WHO Reference Reagent for lupus (anti-dsDNA) antibodies: international collaborative study to evaluate
a candidate preparation. Ann Rheum Dis. 2019 Dec;78(12):1677-1680. doi:
10.1136/annrheumdis-2019-21584 5. Ambrose N, Morgan TA, Galloway J, et al: Differences in disease
phenotype and severity in SLE across age groups. Lupus. 2016 Dec;25(14):1542-1550. doi:
10.1177/0961203316644333 6. Rekvig OP: Autoimmunity and SLE: Factual and semantic
evidence-based critical analyses of definitions, etiology, and pathogenesis. Front Immunol.
2020;11:569234. doi: 10.3389/fimmu.2020.569234 7. Bragazzi NL, Watad A, Damiani G, Adawi M,
Amital H, Shoenfeld Y: Role of anti-DNA auto-antibodies as biomarkers of response to treatment in
systemic lupus erythematosus patients: hypes and hopes. Insights and implications from a comprehensive
review of the literature. Expert Rev Mol Diagn. 2019 Nov;19(11):969-978. doi:
10.1080/14737159.2019.1665511 8. Damoiseaux J, Coelho Andrade LE, Carballo OG, et al: Clinical
relevance of HEp-2 indirect immunofluorescent patterns: the International Consensus on ANA patterns
(ICAP) perspective. Ann Rheum Dis. 2019 Jul;78(7):879-889. doi: 10.1136/annrheumdis-2018-214436 9.
Choi MY, Clarke AE, St Pierre Y, et al: Antinuclear antibody-negative systemic lupus erythematosus in
an international inception cohort. Arthritis Care Res (Hoboken). 2019 Jul;71(7):893-902. doi:
10.1002/acr.23712
ADNA DNA Double-Stranded Antibodies, IgG, Serum

8178 Clinical Information: Of the systemic lupus erythematosus (SLE)-specific antibodies outlined in the
immunology domain of the 2019 European League Against Rheumatism (EULAR)/American College of
Rheumatology (ACR) classification criteria for SLE,(1) antibodies to double-stranded DNA (dsDNA) is
the most common. It is also included in the Systemic Lupus International Collaborating Clinics
classification criteria (SLICC) for SLE.(2) Detection of IgG antibodies to dsDNA is the most used isotype
clinically.(3-5) The diagnostic performance of dsDNA IgG antibodies in SLE is variable and dependent
on several factors; notably the immunological method used for their detection, the structure of the DNA,
the patientâ€™s disease state (early or active vs inactive) including specific clinical manifestations and
demographics.(3-7) Weak-positive dsDNA IgG antibodies have low affinity and low avidity with variable
clinical correlations for SLE.(3) Testing for IgG antibodies to dsDNA is indicated in patients positive for
anti-cellular antibody (ie, antinuclear antibody: ANA) homogeneous pattern using HEp-2 substrate by
indirect immunofluorescence assay (IFA) along with clinical features compatible with SLE.(1,2,8). A
minority of SLE patients may test negative using HEp-2 by IFA for nuclear antibodies.(8,9) Testing
antibodies associated with HEp-2 IFA cytoplasmic pattern such as ribosomal P IgG autoantibodies may
be useful if features of neuropsychiatric disease are present. Alternatively, patients may be tested for
Smith, ribonucleoprotein, SSA-52, and SSA-60 antibodies.(8,9) The levels of antibodies to dsDNA may
fluctuate with SLE disease activity. Increasing antibody levels may be associated with flares while decline
or negative results may indicate response to treatment or disease remission.
Useful For: Evaluating patients with clinical features or at-risk for systemic lupus erythematosus
(SLE) An adjunct test for monitoring disease activity in SLE patients previously positive for
double-stranded DNA IgG antibodies
Interpretation: A positive result for double-stranded DNA (dsDNA) IgG antibodies in the
appropriate clinical context is suggestive of systemic lupus erythematosus (SLE). The performance
characteristics of dsDNA IgG antibodies in SLE is dependent on the immunological method used for
their detection, the patientâ€™s disease state including clinical manifestations, and demographics.
Weak-positive dsDNA IgG antibody results have a low-positive predictive value for SLE. Negative
results do not rule out a diagnosis of SLE.
Reference Values:
<30.0 IU/mL (negative)
30.0-75.0 IU/mL (borderline)
>75.0 IU/mL (positive)
Negative is considered normal.
Clinical References: 1. Aringer M, Costenbader K, Daikh D, et al: 2019 European League Against
Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus
Erythematosus. Arthritis Rheumatol. 2019 Sep;71(9):1400-1412. doi: 10.1002/art.40930 2. Petri M,
Orbai AM, Alarcon GS, et al: Derivation and validation of the Systemic Lupus International
Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012
Aug;64(8):2677-86. doi: 10.1002/art.34473 3. Infantino M, Manfredi M, Merone M, et al: Analytical
variability in the determination of anti-double-stranded DNA antibodies: the strong need of a better
definition of the old and new tests. Immunol Res. 2018 Jun;66(3):340-347. doi:
10.1007/s12026-018-8992-9 4. Fox BJ, Hockley J, Rigsby P, Dolman C, Meroni PL, Ronnelid J, et al:
A WHO Reference Reagent for lupus (anti-dsDNA) antibodies: international collaborative study to
evaluate a candidate preparation. Ann Rheum Dis. 2019 Dec;78(12):1677-1680. doi:
10.1136/annrheumdis-2019-21584 5. Ambrose N, Morgan TA, Galloway J, et al: Differences in disease
phenotype and severity in SLE across age groups. Lupus. 2016 Dec;25(14):1542-1550. doi:
10.1177/0961203316644333 6. Rekvig OP: Autoimmunity and SLE: Factual and semantic
evidence-based critical analyses of definitions, etiology, and pathogenesis. Front Immunol.
2020;11:569234. doi: 10.3389/fimmu.2020.569234 7. Bragazzi NL, Watad A, Damiani G, Adawi M,
Amital H, Shoenfeld Y: Role of anti-DNA auto-antibodies as biomarkers of response to treatment in
systemic lupus erythematosus patients: hypes and hopes. Insights and implications from a
comprehensive review of the literature. Expert Rev Mol Diagn. 2019 Nov;19(11):969-978. doi:
10.1080/14737159.2019.1665511 8. Damoiseaux J, Coelho Andrade LE, Carballo OG, et al: Clinical
relevance of HEp-2 indirect immunofluorescent patterns: the International Consensus on ANA patterns
(ICAP) perspective. Ann Rheum Dis. 2019 Jul;78(7):879-889. doi: 10.1136/annrheumdis-2018-214436
9. Choi MY, Clarke AE, St Pierre Y, et al: Antinuclear antibody-negative systemic lupus erythematosus
in an international inception cohort. Arthritis Care Res (Hoboken). 2019 Jul;71(7):893-902. doi:
10.1002/acr.23712
DNJB9 DNAJB9 Immunostain, Technical Component Only

71739 Clinical Information: DNAJB9 (Dnaj [hsp40] homolog, subfamily b, member 9) is a heat shock
protein that plays a role in protein folding. Proteomic analysis indicates that the DNAJB9 protein is
specifically identified in glomeruli of patients with fibrillary glomerulonephritis (FGN). By
immunohistochemistry there is an intense smudgy staining of extracellular glomerular deposits for
DNAJB9 in patients with FGN.
Useful For: Diagnosis of fibrillary glomerulonephritis

Clinical References: 1. Nasr SH, Vrana JA, Dasari S, et al: DNAJB9 is a specific
immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep. 2018 Jan;3(1):56-64 2.
Dasari S, Alexander MP, Vrana JA, et al: DnaJ heat shock protein family B member 9 is a novel
biomarker for fibrillary GN. J Am Soc Nephrol. 2018 Jan;29(1):51-56 3. Liang S, Chen D, Liang D, et al:
Clinicopathological characteristics and outcome of patients with fibrillary glomerulonephritis: DNAJB9 is
a valuable histologic marker. J Nephrol. 2020 Jun 18. doi: 10.1007/s40620-020-00783-4
FDKYE Dock Yellow (Rumex crispus) IgE

57528 Interpretation: Class IgE (kU/L) Comment 0 <0.10 Negative 0/1 0.10 - 0.34 Equivocal 1 0.35 - 0.69
Low Positive 2 0.70 - 3.4 Moderate Positive 3 3.5 - 17.4 High Positive 4 17.5 - 49.9 Very High Positive 5
50.0 - 99.9 Very High Positive 6 > or = 100 Very High Positive
Reference Values:
<0.35 kU/L
DOGD Dog Dander, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to dog dander Defining the allergen responsible for
Reference Values:
0 Negative

apply to all ages.
FDFEN Dog Fennel (Anthemis cotula) IgE

75547 Interpretation: Class IgE (kU/L) Comment 0 <0.35 Below Detection 1 0.35 - 0.69 Low Positive 2
0.70 - 3.49 Moderate Positive 3 3.50 - 17.49 Positive 4 17.50 - 49.99 Strong Positive 5 50.00 - 99.99
Very Strong Positive 6 >99.99 Very Strong Positive
Reference Values:
<0.35 kU/L
DOG1 DOG-1 Immunostain, Technical Component Only

70422 Clinical Information: DOG-1 (discovered on gastrointestinal stromal tumors: GIST) is a
calcium-regulated chloride channel protein that is expressed strongly on the cell surface of GIST and
rarely in other soft tissue tumors, such as uterine type retroperitoneal leiomyomas, peritoneal
leiomyomatosis, and synovial sarcomas. DOG-1 may aid in the differential diagnosis of GIST,
including KIT-negative and PDGFRA-altered GIST cases.
Useful For: Identification of gastrointestinal stromal tumors

Clinical References: 1. Khurram, SA, Speight, PM: Characterisation of DOG-1 expression in

salivary gland tumours and comparison with myoepithelial markers. Head and Neck Pathol.
2019;13(2):140-148 2. Chetty R, Serra S: Molecular and morphological correlation in gastrointestinal
stromal tumours (GISTs): an update and primer. Journal of Clin Pathol. 2016;69:754-760 3. Hemminger
J, Iwenofu, OH: Discovered on gastrointestinal stromal tumours 1 (DOG1) expression in
non-gastrointestinal stromal tumour (GIST) neoplasms. Histopathol. 2012;61(2):170-177
FDLS Donath Landsteiner

Negative
DFIR Douglas Fir, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to Douglas fir Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
DXPIN Doxepin and Nordoxepin, Serum
63507 Clinical Information: Doxepin is recommended for the treatment of psychoneurotic patients with
depression or anxiety, or with depression or anxiety associated with alcoholism or organic disease.
Nordoxepin (N-desmethyldoxepin) is the major metabolite and is usually present at concentrations
equal to doxepin. Optimal efficacy occurs at combined serum concentrations between 50 and 150
ng/mL. Like other tricyclic antidepressants, the major toxicity of doxepin is expressed as cardiac
dysrhythmias, which occur at concentrations in excess of 500 ng/mL. Other side effects include nausea,
hypotension, and dry mouth.
Useful For: Monitoring doxepin therapy Evaluating potential doxepin toxicity Evaluating patient
compliance
Interpretation: Most individuals display optimal response to doxepin when combined serum levels
of doxepin and nordoxepin are between 50 and 150 ng/mL. Some individuals may respond well outside
of this range or may display toxicity within the therapeutic range; thus, interpretation should include
clinical evaluation. Risk of toxicity is increased with combined levels are above 500 ng/mL.
Therapeutic ranges are based on specimens collected at trough (ie, immediately before the next dose).
Reference Values:
Therapeutic concentration (doxepin + nordoxepin): 50-150 ng/mL
Note: Therapeutic ranges are for specimens drawn at trough (ie, immediately before next scheduled
CDAUX Drug Abuse Panel with Confirmation, Chain of Custody,

62718 Random, Urine
Clinical Information: This assay was designed to screen for and confirm by gas
chromatography-mass spectrometry (GC-MS), gas chromatography-flame ionization detection
(GC-FID), or liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the following drugs:
-Amphetamines -Barbiturates -Benzodiazepines -Cocaine -Ethanol -Opiates -Phencyclidine
-Tetrahydrocannabinol Chain of custody is a record of the disposition of a specimen to document who
Useful For: Detecting drug abuse involving amphetamines, barbiturates, benzodiazepines, cocaine,
ethanol, marijuana, opiates, and phencyclidine This test is intended to be used in a setting where the test
results can be used definitively to make a diagnosis. Chain of custody is required whenever the results
of testing could be used in a court of law. Its purpose is to protect the rights of the individual
contributing the specimen by demonstrating that it was under the control of personnel involved with
testing the specimen at all times; this control implies that the opportunity for specimen tampering would
be limited.
Interpretation: A positive result indicates that the patient has used the drugs detected in the recent
past. See individual tests (eg, AMPHX / Amphetamines Confirmation, Chain of Custody, Urine) for
more information. For information about drug testing, including estimated detection times, see Drugs of
Abuse Testing at https://www.mayocliniclabs.com/test-info/drug-book/index.html.
Reference Values:
Negative
Screening cutoff concentrations
Amphetamines: 500 ng/mL
Benzodiazepines: 100 ng/mL
Ethanol: 10 mg/dL
Opiates: 300 ng/mL
Phencyclidine: 25 ng/mL
Clinical References: 1. Physicians Desk Reference (PDR). 60th edition. Montvale, NJ, Medical
Economics Company, 2006 2. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th
edition. Edited by LL Bruntman. New York, McGraw-Hill Book Company, 2006 3. Langman LJ, Bechtel
L, Holstege CP: Chapter 35. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited
by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, 2011, pp 1109-1188
CDA5X Drug Abuse Survey with Confirmation, Panel 5, Chain of

Clinical Information: This assay was designed to screen for and confirm by gas
chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry
(LC-MS/MS) the following drugs: -Amphetamines -Cocaine -Opiates -Phencyclidine
-Tetrahydrocannabinol Chain of custody is a record of the disposition of a specimen to document who
manner, analysis will be performed in such a way that it will withstand regular court scrutiny. Chain of
custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect
the rights of the individual contributing the specimen by demonstrating that it was under the control of
Useful For: Detecting drug abuse involving amphetamines, cocaine, marijuana, opiates, and
phencyclidine This chain-of-custody test is intended to be used in a setting where the test results can be
used definitively to make a diagnosis.
Reference Values:
Negative
Opiates: 300 ng/mL
by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, 2011, pp 1109-1188
CDAU5 Drug Abuse Survey with Confirmation, Panel 5, Random, Urine

80373 Clinical Information: This assay was designed to screen by immunoassay and confirm by gas
(LC-MS/MS) for the following drugs: -Amphetamines -Cocaine -Opiates -Phencyclidine
-Tetrahydrocannabinol This assay represents the coupling of an immunoassay screen with an automatic
confirmation of all positive results by the definitive assay available and described in each individual reflex
test (eg, AMPHU / Amphetamines Confirmation, Urine). All positive screening results are confirmed by
GC-MS or LC-MS/MS, and quantitated, before a positive result is reported.
Useful For: Detecting drug abuse involving amphetamines, cocaine, marijuana, opiates, and
phencyclidine This test is intended to be used in a setting where the test results can be used definitively
to make a diagnosis.
past. See individual tests (eg, AMPHU / Amphetamines Confirmation, Urine) for more information. For
information about drug testing, including estimated detection times, see Drugs of Abuse Testing at
Reference Values:
Negative
Opiates: 300 ng/mL
Clinical References: 1. Physician's Desk Reference (PDR). 60th edition. Montvale, NJ, Medical
edition. Edited by LL Bruntman. New York, McGraw-Hill Book Company, 2006 3. Langman LJ,
Bechtel L, Holstege CP: Chapter 35: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics.
Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, 2011, pp 1109-1188
CDA7X Drug Abuse Survey with Confirmation, Panel 9, Chain of

Clinical Information: This assay was designed to test for and confirm by gas
(LC-MS/MS) the most common classes of drugs of abuse. This test uses the simple screening technique
which involves immunologic testing for drugs by class. All positive screening results are confirmed by
GC-MS (positive alcohol by GC) or LC-MS/MS and quantitated, before a positive result is reported.
Chain of custody is a record of the disposition of a specimen to document who collected it, who handled
it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be
performed in such a way that it will withstand regular court scrutiny. Chain of custody is required
individual contributing the specimen by demonstrating that it was under the control of personnel
tampering would be limited.
Useful For: Detecting drug abuse involving alcohol, amphetamines, barbiturates, benzodiazepines,
cocaine, methadone, opiates, phencyclidine, and tetrahydrocannabinol This chain-of-custody test is
intended to be used in a setting where the test results can be used definitively to make a diagnosis.
past. See individual tests (eg, AMPHX / Amphetamines Confirmation, Chain of Custody, Urine) for
more information. For information about drug testing, including estimated detection times, see Drugs of
Abuse Testing at https://www.mayocliniclabs.com/test-info/drug-book/index.html.
Reference Values:
Negative
Ethanol: 10 mg/dL
Methadone metabolite: 300 ng/mL
Opiates: 300 ng/mL
by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Co, 2011, pp 1109-1188
CDAU7 Drug Abuse Survey with Confirmation, Panel 9, Random, Urine

chromatography-mass spectrometry (GC-MS), gas chromatography-flame ionization detection (GC-FID),
or liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the following drugs:
-Amphetamines -Barbiturates -Benzodiazepines -Cocaine -Ethanol -Opiates -Methadone -Phencyclidine
-Tetrahydrocannabinol This test represents the coupling of an immunoassay screen with an automatic
confirmation of all positive results by the definitive assay available and described in each individual reflex
test (eg, AMPHU / Amphetamines Confirmation, Urine). All positive screening results are confirmed by
GC-MS, GC-FID, or LC-MS/MS and quantitated before a positive result is reported.
Useful For: Detecting drug abuse involving, amphetamines, barbiturates, benzodiazepines, cocaine,
ethanol, methadone, opiates, phencyclidine, and tetrahydrocannabinol This test is intended to be used in a
setting where the test results can be used definitively to make a diagnosis.
Reference Values:
Negative
Ethanol: 10 mg/dL
Methadone metabolite: 300 ng/mL
Opiates: 300 ng/mL
L, Holstege CP. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA
Burtis, ER Ashwood, DE Bruns. Chapter 35. WB Saunders Co, 2011, pp 1109-1188
CDAU Drug Abuse Survey with Confirmation, Random, Urine

chromatography-mass spectrometry (GC-MS), gas chromatography-flame ionization detection
(GC-FID), or liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the following drugs:
-Amphetamines -Barbiturates -Benzodiazepines -Cocaine -Ethanol -Opiates -Phencyclidine
-Tetrahydrocannabinol This assay represents the coupling of an immunoassay screen with an automatic
confirmation of all positive results by the definitive assay available and described in each individual
reflex test ID (eg, AMPHU / Amphetamines Confirmation, Urine). All positive screening results are
confirmed by GC-MS, GC-FID, or LC-MS/MS and quantitated before a positive result is reported.
Useful For: Detecting drug abuse involving amphetamines, barbiturates, benzodiazepines, cocaine,
ethanol, marijuana, opiates, and phencyclidine This test is intended to be used in a setting where the test
results can be used definitively to make a diagnosis.
https://www.mayocliniclabs.com/test-info/drug-book/index.html..
Reference Values:
Negative
Ethanol: 10 mg/dL
Opiates: 300 ng/mL
edition. Edited by LL Bruntman. New York, McGraw-Hill Book Company, 2006 3. Langman LJ,
Bechtel L, Holstege CP: Chapter 35. In Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, 2011, pp
1109-1188
PNRCH Drug Immunoassay Panel, Urine

65061 Clinical Information: This test uses the simple screening technique that involves immunologic
testing for drugs by class. All positive immunoassay screening results are confirmed by gas
chromatography-mass spectrometry (GC-MS) and quantitated before a positive result is reported. This
assay was designed to test for and confirm by GC-MS the following: -Barbiturates -Cocaine
-Tetrahydrocannabinol This test is intended to be used in a setting where the test results can be used to
make a definitive diagnosis.
Useful For: Detecting drug use involving barbiturates, cocaine, and tetrahydrocannabinol This test is
not intended for use in employment-related testing.
including estimated detection times, see Drugs of Abuse Testing.
Reference Values:
Only orderable as part of profile. For more information see CSMPU / Controlled Substance Monitoring
Panel, Random, Urine.
Negative
Clinical References: 1. Physicians' Desk Reference: 60th ed. Medical Economics Company; 2006 2.
Bruntman LL, Lazo JS, Parker KL, eds: Goodman and Gilman's: The Pharmacological Basis of
Therapeutics. 11th ed. McGraw-Hill; 2006 3. Langman LJ, Bechtel L, Meier BM, Holstege CP: Clinical
toxicology In: Rifai N, Horwath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and
Molecular Diagnostics. 6th ed.Â Elsevier; 2018:832-887 4. Jannetto PJ, Bratanow NC, Clark WA, et al:
Guideline-Using clinical laboratory tests to monitor drug therapy in pain management patients. J Appl
Lab Med. 2018 Jan 1;2(4):489-526
PDSUX Drug Screen, Prescription/Over the Counter, Chain of Custody,

62741 Random, Urine
Clinical Information: This test looks for a broad spectrum of prescription and over-the-counter
(OTC) drugs. It is designed to detect drugs that have toxic effects, as well as known antidotes or active
therapies that a clinician can initiate to treat the toxic effect. The test is intended to help physicians
manage an apparent overdose or intoxicated patient, to determine if a specific set of symptoms might be
due to the presence of drugs, or to evaluate a patient who might be abusing these drugs intermittently.
This test is not appropriate for drugs of abuse or illicit drug testing, including benzodiazepines, opioids,
barbiturates, cocaine, and amphetamine type stimulants. Drugs of toxic significance that are not detected
by this test are: digoxin, lithium, and many drugs of abuse or illicit drugs, some benzodiazepines, and
some opiates. For these drugs, see Mayo Clinic Laboratories' drug abuse surveys, drug screens, or
individual tests. Chain of custody is a record of the disposition of a specimen to document the personnel
who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this
manner, analysis will be performed in such a way that it will withstand regular court scrutiny. See
Prescription and Over-the-Counter (OTC) Drug Screens in Special Instructions for detection limits for
drugs detected in this test.
Useful For: The qualitative detection and identification of prescription or over-the-counter drugs
frequently found in drug overdose or used with a suicidal intent Providing, when possible, the
identification of all drugs present This test is not useful for drugs of abuse or illicit drug testing, including
benzodiazepines, opioids, barbiturates, cocaine, and amphetamine type stimulants. This test is not useful
for the assessment of therapeutic compliance. This test is not intended for use in employment-related
testing. Chain of custody is required whenever the results of testing could be used in a court of law. Its
opportunity for specimen tampering would be limited.
Interpretation: The drugs that can be detected by this test are listed in Prescription and
Over-the-Counter (OTC) Drug Screens in Special Instructions. A detailed discussion of each drug
detected is beyond the scope of this text. Each report will indicate the drugs identified. If a clinical
interpretation is required, request a Clinical and Forensic Toxicology Lab consult (Mayo Clinic patients)
or contact Mayo Laboratory Inquiry (Mayo Clinic Laboratories clients).
Reference Values:
Drugs detected are presumptive. Additional testing may be required to confirm the presence of any
drugs detected.
Clinical References: 1. Langman LJ, Bechtel LK, Meier BM, Holstege C: Clinical toxicology. In:
Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics. 6th ed. Elsevier; 2018:1294 2. Baselty RC: Disposition of Toxic Drugs and Chemicals in
Man. 10th ed. Biomedical Publications, 2014
DSSX Drug Screen, Prescription/Over the Counter, Chain of

62723 Custody, Serum
Clinical Information: This test looks for a broad spectrum of prescription and over-the-counter
manage an apparent overdose or intoxicated patient, to determine if a specific set of symptoms might be
due to the presence of drugs, or to evaluate a patient who might be abusing these drugs intermittently.
This test is not appropriate for drugs of abuse or illicit drug testing, including benzodiazepines, opioids,
barbiturates, cocaine, and amphetamine type stimulants. Drugs of toxic significance that are not
detected by this test are: digoxin, lithium, and many drugs of abuse or illicit drugs, some
benzodiazepines, and most opiates. See Prescription and Over-the-Counter (OTC) Drug Screens Table 1
in Special Instructions for detection limits for drugs detected in this test.
Useful For: Detection and identification of prescription or over the counter drugs frequently found in
drug overdose or used with a suicidal intent Qualitatively identifying drugs present in the specimen;
quantification of identified drugs, when available, may be performed upon client request. This test is not
intended for therapeutic drug monitoring or compliance testing. This test is not intended for use in
employment-related testing. This test is not useful for drugs of abuse or illicit drug testing, including
benzodiazepines, opioids, barbiturates, cocaine, and amphetamine type stimulants. Chain of custody is
required whenever the results of testing could be used in a court of law. Its purpose is to protect the
rights of the individual contributing the specimen by demonstrating that it was under the control of
Interpretation: The drugs that are detected by this test are listed in Prescription and
Over-the-Counter (OTC) Drug Screens Table 1 in Special Instructions. The pharmacology of each drug
determines how the test should be interpreted. A detailed discussion of each drug is beyond the scope of
this text. If you wish to have a report interpreted, call 800-533-1710 and ask for a toxicology consultant.
Each report will indicate the drugs detected.
Reference Values:
Drugs detected are presumptive. Additional testing may be required to confirm the presence of any
drugs detected.
Man. 10th ed. Biomedical Publications, 2014
PDSU Drug Screen, Prescription/Over the Counter, Random, Urine

88760 Clinical Information: This test looks for a broad spectrum of prescription and over-the-counter
manage an apparent overdose or intoxicated patient, or to determine if a specific set of symptoms might
be due to the presence of drugs. This test is not appropriate for drugs of abuse or illicit drug testing,
including benzodiazepines, opioids, barbiturates, cocaine, and amphetamine type stimulants. Drugs of
toxic significance that are not detected by this test are: digoxin, lithium, salicylate and many drugs of
abuse or illicit drugs, some benzodiazepines, and some opioids. For these drugs, see Mayo Clinic
Laboratories' drug abuse surveys, drug screens, or individual tests. See Prescription and
Over-the-Counter (OTC) Drug Screens in Special Instructions for detection limits for drugs detected in
this test.
Useful For: Qualitative detection and identification of prescription or over-the-counter drugs

frequently found in drug overdose or used with a suicidal intent Providing, when possible, the
identification of all drugs present in the specimen This test is not intended for use in employment-related
testing. This test is not intended for therapeutic compliance testing. This test is not useful for drugs of
abuse or illicit drug testing, including benzodiazepines, opioids, barbiturates, cocaine, and amphetamine
type stimulants.
Interpretation: The drugs that can be detected by this test are listed in Prescription and
Over-the-Counter (OTC) Drug Screens in Special Instructions. A detailed discussion of each drug
detected is beyond the scope of this text. Each report will indicate the drugs identified. If a clinical
interpretation is required, request a Clinical and Forensic Toxicology Lab consult (Mayo Clinic patients)
or contact Mayo Laboratory Inquiry (Mayo Clinic Laboratories clients).
Reference Values:
Drugs detected are presumptive. Additional testing may be required to confirm the presence of any drugs
detected.
6th ed. Elsevier; 2018:1294 2. Baselty RC: Disposition of Toxic Drugs and Chemicals in Man. 10th ed.Â
Biomedical Publications, 2014
DSS Drug Screen, Prescription/Over the Counter, Serum

8421 Clinical Information: This test looks for a broad spectrum of prescription and over-the-counter
manage an apparent overdose or intoxicated patient, or to determine if a specific set of symptoms might
be due to the presence of drugs. This test is not appropriate for drugs of abuse or illicit drug testing,
including benzodiazepines, opioids, barbiturates, cocaine, and amphetamine type stimulants. Drugs of
toxic significance that are not detected by this test are: digoxin, lithium, and many drugs of abuse or illicit
drugs, some benzodiazepines, and some opioids. See Prescription and Over-the-Counter (OTC) Drug
Screens in Special Instructions for detection limits for drugs detected in this test.
Useful For: Detection and identification of prescription or over the counter drugs frequently found in
drug overdose or used with a suicidal intent Qualitatively identifying drugs present in the specimen;
quantification of identified drugs, when available, may be performed upon client request This test is not
intended for therapeutic drug monitoring or compliance testing. This test is not intended for use in
employment-related testing. This test is not useful for drugs of abuse or illicit drug testing, including
benzodiazepines, opioids, barbiturates, cocaine, amphetamine type stimulants.
Interpretation: The drugs that are detected by this test are listed in Prescription and Over-the-Counter
(OTC) Drug Screens in Special Instructions. The pharmacology of each drug determines how the test
should be interpreted. A detailed discussion of each drug is beyond the scope of this text. If you wish to
have a report interpreted, call 800-533-1710 and ask for a toxicology consultant. Each report will indicate
the drugs detected.
Reference Values:
Drugs detected are presumptive. Additional testing may be required to confirm the presence of any drugs
detected.
Man. 10th ed. Biomedical Publications; 2014
FDA1S Drugs of Abuse (10 panel) and Alcohol Screen, Serum

Test Result Units
Ethanol None Detected mg/dL
Opiates None Detected ng/mL
Cocaine/Metabolites None Detected ng/mL
Benzodiazepines None Detected ng/mL
Cannabinoids None Detected ng/mL

Amphetamines None Detected ng/mL
Barbiturates None Detected mcg/mL
Methadone/Metabolite None Detected ng/mL
Phencyclidine None Detected ng/mL
Methamphetamine/MDMA None Detected ng/mL
Oxycodone/Oxymorphone None Detected ng/mL
FD10S Drugs of Abuse Screen (10 panel), Serum

Test Result Units
Opiates None Detected ng/mL
Cocaine/Metabolites None Detected ng/mL
Benzodiazepines None Detected ng/mL
Cannabinoids None Detected ng/mL
Amphetamines None Detected ng/mL
Barbiturates None Detected ng/mL
Methadone/Metabolite None Detected ng/mL
Phencyclidine None Detected ng/mL
Methamphetamine/MDMA None Detected ng/mL
Oxycodone/Oxymorphone None Detected ng/mL
DSM4X Drugs of Abuse Screen 4, Chain of Custody, Meconium

62721 Clinical Information: Illicit drug use during pregnancy is a major social and medical issue. Drug
abuse during pregnancy is associated with significant perinatal complications, which include a high
incidence of stillbirths, meconium-stained fluid, premature rupture of the membranes, maternal
hemorrhage (abruption placenta or placenta praevia), and fetal distress.(1) In the neonate, the mortality
rate, as well as morbidity (eg, asphyxia, prematurity, low birthweight, hyaline membrane distress,
infections, aspiration pneumonia, cerebral infarction, abnormal heart rate and breathing problems, drug
withdrawal) are increased.(1) The disposition of drug in meconium is not well understood. The
proposed mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in
meconium either by direct deposit from bile or through swallowing of amniotic fluid.(2) The first
evidence of meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation,
and slowly moves into the colon by the 16th week of gestation.(3) Therefore, the presence of drugs in
meconium has been proposed to be indicative of in utero drug exposure up to 5 months before birth, a
longer historical measure than is possible by urinalysis.(2) Chain of custody is a record of the
disposition of a specimen to document who collected it, who handled it, and who performed the
analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it
will withstand regular court scrutiny.
Useful For: Identifying amphetamines (and methamphetamines), opiates, as well as metabolites of

cocaine and marijuana in meconium specimen Chain of custody is required whenever the results of testing
could be used in a court of law. Its purpose is to protect the rights of the individual contributing the
specimen by demonstrating that it was under the control of personnel involved with testing the specimen
at all times; this control implies that the opportunity for specimen tampering would be limited. Since the
evidence of illicit drug use during pregnancy can be cause for separating the baby from the mother, a
complete chain of custody ensures that the test results are appropriate for legal proceedings.
Interpretation: The limit of quantitation varies for each of these drug groups. -Amphetamines: >100
ng/g -Methamphetamines: >100 ng/g -Cocaine and metabolite: >100 ng/g -Opiates: >100 ng/g
-Tetrahydrocannabinol carboxylic acid: >20 ng/g
Reference Values:
Negative
Positives are reported with a quantitative LC-MS/MS result.
Amphetamines by ELISA: 100 ng/g
Methamphetamine by ELISA: 100 ng/g
Benzoylecgonine (cocaine metabolite) by ELISA: 100 ng/g
Opiates by ELISA: 100 ng/g
Tetrahydrocannabinol carboxylic acid (marijuana metabolite) by ELISA: 20 ng/g
Clinical References: 1. Ostrea EM Jr: Understanding drug testing in the neonate and the role of
meconium analysis. J Perinat Neonatal Nurs 2001 Mar;14(4):61-82; quiz 105-106 2. Ostrea EM Jr, Brady
MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers: an alternative to
urine testing. J Pediatr 1989 Sep;115(3):474-477 3. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG:
Meconium passage in utero mechanisms, consequences, and management. Obstet Gynecol Surv 2005
Jan;60(1):45-56; quiz 73-74
DSM5X Drugs of Abuse Screen 5, Chain of Custody, Meconium

rate, as well as morbidity (eg, asphyxia, prematurity, low birthweight, hyaline membrane disease,
infections, aspirations pneumonia, cerebral infarction, abnormal heart rate and breathing patterns, drug
withdrawal) are increased.(1) The disposition of drug in meconium is not well understood. The proposed
meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation, and slowly
moves into the colon by the 16th week of gestation.(3) Therefore, the presence of drugs in meconium has
been proposed to be indicative of in utero drug exposure during the final 4 to 5 months of pregnancy, a
longer historical measure than is possible by urinalysis.(2) Chain of custody is a record of the disposition
of a specimen to document who collected it, who handled it, and who performed the analysis. When a
specimen is submitted in this manner, analysis will be performed in such a way that it will withstand
regular court scrutiny.

cocaine and marijuana in meconium specimens Chain of custody is required whenever the results of
testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing
the specimen by demonstrating that it was under the control of personnel involved with testing the
specimen at all times; this control implies that the opportunity for specimen tampering would be limited.
Since the evidence of illicit drug use during pregnancy can be cause for separating the baby from the
mother, a complete chain of custody ensures that the test results are appropriate for legal proceedings.
Interpretation: The limit of quantitation varies for each of these drug groups. -Amphetamines: >100
ng/g -Methamphetamines: >100 ng/g -Cocaine and metabolite: >100 ng/g -Opiates: >100 ng/g
-Tetrahydrocannabinol carboxylic acid: >20 ng/g -Phencyclidine (PCP): >20 ng/g
Reference Values:
Negative
Phencyclidine by ELISA: 20 ng/g
meconium analysis. J Perinat Neonatal Nurs 2001 Mar;14(4):61-82; quiz 105-106 2. Ostrea EM Jr,
Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers; an
alternative to urine testing. J Pediatr 1989 Sep;115(3):474-477 3. Ahanya SN, Lakshmanan J, Morgan
BL, Ross MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet
Gynecol Surv 2005 Jan;60(1):45-56; quiz 73-74
DASM4 Drugs of Abuse Screen, Meconium 4

rate, as well as morbidity (eg, asphyxia, prematurity, low birthweight, hyaline membrane distress,
infections, aspiration pneumonia, cerebral infarction, abnormal heart rate and breathing problems, drug
withdrawal) are increased.(1) The disposition of drug in meconium is not well understood. The
proposed mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in
meconium either by direct deposit from bile or through swallowing of amniotic fluid.(2) The first
evidence of meconium in the fetal intestine appears at approximately the tenth to twelfth week of
gestation, and slowly moves into the colon by the sixteenth week of gestation.(3) Therefore, the
final 4 to 5 months of pregnancy, a longer historical measure than is possible by urinalysis.(2)

cocaine and marijuana in meconium specimens
Interpretation: A positive result indicates that the baby was exposed to the drugs indicated.
Reference Values:
Negative
MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers: an alternative to
Meconium passage in utero mechanisms, consequences, and management. Obstet Gynecol Surv 2005
Jan;60(1):45-56; quiz 73-74
DASM5 Drugs of Abuse Screen, Meconium 5

rate, as well as morbidity (eg, asphyxia, prematurity, low birthweight, hyaline membrane disease,
infections, aspirations pneumonia, cerebral infarction, abnormal heart rate and breathing patterns, drug
withdrawal) are increased.(1) The disposition of drug in meconium is not well understood. The proposed
meconium in the fetal intestine appears at approximately the tenth to twelfth week of gestation, and
slowly moves into the colon by the sixteenth week of gestation.(3) Therefore, the presence of drugs in
meconium has been proposed to be indicative of in utero drug exposure during the final 4 to 5 months of
pregnancy, a longer historical measure than is possible by urinalysis.(2)
Useful For: Identifying amphetamines (and methamphetamines), opiates, phencyclidine (PCP), as well
as metabolites of cocaine and marijuana in meconium specimens
Interpretation: A positive result indicates that the baby was exposed to the drugs indicated.
Reference Values:
Negative
Phencyclidine by ELISA: 20 ng/g
MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers; an alternative to
Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv 2005
Jan;60(1):45-56; quiz 73-74
DBMD Duchenne/Becker Muscular Dystrophy, DMD Gene, Large

58125 Deletion/Duplication Analysis, Varies
Clinical Information: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder
characterized initially by proximal muscle weakness beginning before age 5 years. Affected individuals
typically have pseudohypertrophy of the calf muscles and exhibit toe-walking, waddling gait, and the
Gower sign (climbing up the legs when rising from a seated position on the floor). Not only is skeletal
muscle affected in DMD but also the smooth muscle of the gastrointestinal tract, and possibly bladder,
as well as cardiac muscle. Initial symptoms are followed by dramatic progression of weakness leading
to loss of ambulation by age 11 or 12. Death is often caused by cardiac failure or by respiratory failure
before age 30 years unless ventilator support is provided. The allelic Becker muscular dystrophy (BMD)
has a similar presentation, although age of onset is later, and the clinical course is much milder. Cardiac
involvement can be the only sign and patients are often ambulatory into their thirties. DMD and BMD
are caused by variants in the DMD gene, which encodes for dystrophin. Approximately 50% to 65% of
patients have intragenic deletions and approximately 5% to 10% have intragenic duplications. Less
frequently, DMD and BMD result from nondeletion and nonduplication variants, which are not detected
by this assay. Approximately one-third of sporadic cases of DMD/BMD occur due to new variants. In
sporadic cases, it is possible for the mother of an affected individual to have germline mosaicism. This
means that the germ cells may contain a variant even if the variant is not detected in peripheral blood. In
cases of germline mosaicism, which occurs with a frequency of up to 15%, further offspring are at risk
for inheriting a dystrophin variant.
Useful For: Confirmation of a clinical diagnosis of Duchenne muscular dystrophy (DMD) or Becker
muscular dystrophy (BMD) Distinguishing DMD from BMD in some cases, based on the type of
deletion detected (allows for better prediction of prognosis) Determination of carrier status in family
member at risk for DMD or BMD Prenatal diagnosis of DMD or BMD in at-risk pregnancies

Reference Values:
Clinical References: 1. Thompson MW, McInnes RR, Willard HF: Genetics in Medicine. 5th ed.
WB Saunders Company; 1991:367-372 2. Desquerre I, Christov C, Mayer M, et al: Clinical
heterogeneity of duchenne muscular dystrophy (DMD): definition of sub-phenotypes and predictive
criteria by long-term follow-up. PLoS One. 2009;4(2):e4347. doi: 10.1371/journal.pone.0004347 3.
Verma S, Anziska Y, Cracco J: Review of Duchenne muscular dystrophy (DMD) for the pediatricians
in the community. Clin Pediatr (Phila). 2010;49(11):1011-1017. doi: 10.1177/0009922810378738
DUCK Duck Feathers, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to duck feathers Defining the allergen responsible

Reference Values:
0 Negative

apply to all ages.
FDME Duck Meat IgE

Reference Values:
<0.35 kU/L
DULOX Duloxetine, Serum

89305 Clinical Information: Duloxetine is an antidepressant of the serotonin-norepinephrine reuptake
inhibitor class. It is effective in treating symptoms of depression, including physical pain associated with
depression; other uses include therapy of neuropathic pain, fibromyalgia, and urinary stress incontinence.
Duloxetine also inhibits serotonin uptake in human platelets and may be associated with potentiation of
bleeding. Duloxetine undergoes extensive hepatic biotransformation to numerous inactive metabolites.
The drug is metabolized by cytochrome P450 (CYP) 1A2 and CYP2D6, with moderate potential for drug
interactions (duloxetine is both a substrate and a moderate inhibitor of CYP2D6). The mean elimination
half-life is 12.5 hours with steady-state concentrations occurring in about 3 days. Specimens for
therapeutic monitoring should be collected immediately before the next scheduled dose (ie, trough).
Duloxetine is not recommended for patients with hepatic impairment, substantial alcohol use, or chronic
liver disease. Use in patients with kidney disease significantly increases exposure to duloxetine due to
decreased elimination. Patients with mild-to-moderate kidney dysfunction should be monitored closely;
use of duloxetine is not recommended in end-stage kidney disease.
Useful For: Monitoring serum concentration during therapy Evaluating potential toxicity Evaluating
patient compliance
Interpretation: Therapeutic ranges are not well-established, but literature suggests that patients
receiving duloxetine monotherapy for depression responded well when trough concentrations were 30 to
120 ng/mL. Higher levels may be tolerated by individual patients. The therapeutic relevance of this
concentration range to other uses of duloxetine therapy is currently unknown.
Reference Values:
30-120 ng/mL
Clinical References: 1. Hiemke C, Bergemann N, Clement HW, et al: Consensus Guidelines for
Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018
Jan;51(1-02):9-62 2. Westanmo AD, Gayken J, Haight R: Duloxetine: a balanced and selective
norepinephrine- and serotonin-reuptake inhibitor. Am J Health-Syst Pharm. 2005
Dec;62(23):2481-2490 3. Waldschmitt C, Vogel F, Pfuhlmann B, Hiemke C: Duloxetine serum
concentrations and clinical effects. Data from a therapeutic drug monitoring (TDM) survey.
Pharmacopsychiatry. 2009 Sep;42(5):189-193 4. Feighner JP, Cohn JB: Double-blind comparative trials
of fluoxetine and doxepin in geriatric patients with major depressive disorder. J Clin Psychiatry. 1985
Mar;46(3 Pt 2):20-25 5. Kelly MW, Perry PJ, Holstad SG, Garvey MJ: Serum fluoxetine and
norfluoxetine concentrations and antidepressant response. Ther Drug Monit. 1989;11:165-170 6.
Benfield P, Heel RC, Lewis SP: Fluoxetine: a review of its pharmacodynamic and pharmacokinetic
properties, and therapeutic efficacy in depressive illness. Drugs. 1986 Dec;32(6):481-508 7. Wille SM,
Cooreman SG, Neels, et al: Relevant issues in the monitoring and toxicology of antidepressants. Crit
Rev Clin Lab Sci. 2008;45(1):25-89
DYS2 Dysautonomia, Autoimmune/Paraneoplastic Evaluation,

92121 Serum
Clinical Information: Autoimmune dysautonomia encompasses disorders of peripheral autonomic
synapses, ganglionic neurons, autonomic nerve fibers, and central autonomic pathways mediated by
neural-specific IgG or effector T cells. These disorders may be idiopathic or paraneoplastic, subacute or
insidious in onset, and may present as a limited disorder or generalized pandysautonomia.
Pandysautonomia is usually subacute in onset and severity and includes impaired pupillary light reflex,
anhidrosis, orthostatic hypotension, cardiac arrhythmias, gastrointestinal dysmotility, sicca
manifestations, and bladder dysfunction. Limited dysautonomia is confined to one or just a few
domains, is often mild, and may include sicca manifestations, postural orthostatism and cardiac
arrhythmias, bladder dysfunction, or gastrointestinal dysmotilities. Diagnosis of limited dysautonomia
requires documentation of objective abnormalities by autonomic reflex testing, thermoregulatory sweat
test, or gastrointestinal motility studies. The most commonly encountered autoantibody marker of
autoimmune dysautonomia is the neuronal ganglionic alpha-3-acetylcholine receptor (AChR)
autoantibody. This autoantibody to date is the only proven effector of autoimmune dysautonomia. A
direct relationship has been demonstrated between antibody titer and severity of dysautonomia in both
alpha-3-AChR-immunized animals and patients with autoimmune dysautonomia. Patients with high
alpha-3-AChR autoantibody values (>1.0 nmol/L) generally have profound pandysautonomia.
Dysautonomic patients with lower alpha-3-AChR autoantibody values (0.03-0.99 nmol/L) have limited
dysautonomia. Importantly, cancer is detected in 30% of patients with alpha-3-AChR autoantibody.
Cancers recognized include small-cell lung carcinomas, thymoma, lymphoma, and adenocarcinomas of
breast, lung, prostate, and gastrointestinal tract. Cancer risk factors include a past or family history of
cancer, history of smoking, or social or environmental exposure to carcinogens. Early diagnosis and
treatment of the neoplasm favors neurologic improvement and lessens morbidity. Autoantibodies to
other onconeural proteins shared by neurons, glia or muscle (eg, antineuronal nuclear antibody-type 1
[ANNA-1], collapsin response-mediator protein-5 neuronal [CRMP-5-IgG]) serve as additional markers
of paraneoplastic or idiopathic dysautonomia. A specific neoplasm is often predictable by the individual
patient's autoantibody profile.
Useful For: Investigating idiopathic dysautonomic symptoms Directing a focused search for cancer
in patients with idiopathic dysautonomia Investigating autonomic symptoms that appear in the course or
wake of cancer therapy and are not explainable by recurrent cancer or metastasis (detection of
autoantibodies in this profile helps differentiate autoimmune dysautonomia from the effects of
chemotherapy)
Interpretation: Antibodies directed at onconeural proteins shared by neurons, muscle, and glia are
valuable serological markers of a patient's immune response to cancer. These autoantibodies are not
found in healthy subjects and are usually accompanied by subacute neurological symptoms and signs. It
is not uncommon for more than one autoantibody to be detected in patients with autoimmune
dysautonomia. These include: -Plasma membrane cation channel antibodies (neuronal ganglionic
[alpha-3]). All of these autoantibodies are potential effectors of autonomic dysfunction. -Antineuronal
nuclear autoantibody-type 1 -Neuronal and muscle cytoplasmic antibodies (CRMP-5 IgG) A rising
autoantibody titer in previously seropositive patients suggests cancer recurrence.
Reference Values:
ADEI Dysautonomia, Interpretation, S Medical interpretation NA
GANG AChR Ganglionic Neuronal Ab, S RIA < or =0.02 nmol/L
ANN1S Anti-Neuronal Nuclear Ab, Type 1 IFA
PCAB2 Purkinje Cell Cytoplasmic Ab Type 2 IFA Reflex Information:

AMPIS AMPA-R Ab IF Titer Assay,IFA

S

S

S

Assay, S

Assay, S
PCTBS PCA-Tr Immunoblot, S IB Negative
PCABP Purkinje Cell Cytoplasmic IFA

Ab Type 1
PCATR Purkinje Cell Cytoplasmic IFA *Methodology abbreviations:
Ab Type Tr Immunofluorescence assay (IFA)
for ANNA-1, CRMP-5-IgG,
PCA-1, PCA-2, or PCA-Tr may be
reported as "unclassified
anti-neuronal IgG." Complex
patterns that include nonneuronal
elements may be reported as
"uninterpretable." Note: CRMP-5
titers lower than 1:240 are
weeks). This supplemental testing
is recommended in cases of chorea,
myelopathy. Call 800-533-1710 to
request CRMP-5 Western blot.
Clinical References: 1. Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA:
Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J
Med. 2000 Sep 21;343(12):847-855 2. O'Suilleabhain PO, Low PA, Lennon VA: Autonomic dysfunction
in the Lambert-Eaton myasthenic syndrome: serologic and clinical correlates. Neurology. 1998
Jan;50(1):88-93 3. Dhamija R, Tan KM, Pittock SJ, Foxx-Orenstein A, Benarroch E, Lennon VA:
Serological profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin Gastroenterol
Hepatol. 2008 Sep;6(9):988-992 4. McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ:
Ganglionic acetylcholine receptor autoantibody: oncological, neurological and serological
accompaniments. Arch Neurol. 2009 Jun;66(6):735-741 5. McKeon A, Lennon VA, LaChance DH, Klein
CJ, Pittock SJ: Striational antibodies in a paraneoplastic context. Muscle Nerve. 2013 Apr;47(4):585-587
ECADB E-Cadherin Immunostain, Bone Marrow, Technical Component

603211 Only
Clinical Information: Membrane protein expressed on normal breast epithelial cells. Expression
can be lost on lobular neoplasms of the breast, in contrast to ductal neoplasms of the breast.
Useful For: Differentiation between lobular and ductal neoplasms of the breast
Clinical References: 1. Engstrom MJ, Opdahl S, Vatten LJ, et. al: Invasive lobular breast cancer:
The prognostic impact of histopathological grade, E-cadherin and molecular subtypes. Histopathol.
2015;66(3):409-419 2. Dabbs DJ, Schnitt SJ, Geyer FC, et al: Lobular neoplasia of the breast revisited
with emphasis on the role of e-cadherin immunohistochemistry. Am J Surg Pathol. 2013;37;e1-e11 3.
Liu J, Feng C, Deng M, et al: E-cadherin expression phenotypes associated with molecular subtypes in
invasive non-lobular breast cancer: evidence from a retrospective study and meta-analysis. World J Surg
Onc. 2017;15:139
ECAD E-Cadherin Immunostain, Technical Component Only
70423 Clinical Information: Membrane protein expressed on normal breast epithelial cells. Expression can
be lost on lobular neoplasms of the breast, in contrast to ductal neoplasms of the breast.
Useful For: Differentiation between lobular and ductal neoplasms of the breast
Clinical References: 1. Engstrom MJ, Opdahl S, Vatten LJ, et al: Invasive Lobular Breast Cancer:
The Prognostic Impact of Histopathological Grade, E-cadherin and Molecular Subtypes. Histopathol.
2015;66(3):409-419 2. Dabbs DJ, Schnitt SJ, Geyer FC et al. Lobular neoplasia of the breast revisited
with emphasis on the role of e-cadherin immunohistochemistry. Am J Surg Pathol. 2013;37:e1-e11 3. Liu
J, Feng C, Deng M, et al: E-cadherin expression phenotypes associated with molecular subtypes in
invasive non-lobular breast cancer: evidence from a retrospective study and meta-analysis. World J Surg
Onc. 2017;15:139
EEPC Eastern Equine Encephalitis Antibody Panel, IgG and IgM,

83917 Spinal Fluid
Clinical Information: Eastern equine encephalitis (EEE) is within the alphavirus group. It is a
low-prevalence cause of human disease in the Eastern and Gulf Coast states. EEE is maintained by a cycle
of mosquito/wild bird transmission, peaking in the summer and early fall, when man may become an
adventitious host. The most common clinically apparent manifestation is a mild undifferentiated febrile
illness, usually with headache. Central nervous system involvement is demonstrated in only a minority of
infected individuals and is more abrupt and more severe than with other arboviruses, with children being
more susceptible to severe disease. Fatality rates are approximately 70% EEE. Infections with arboviruses
can occur at any age. The age distribution depends on the degree of exposure to the particular transmitting
arthropod, relating to age, sex, and occupational, vocational, and recreational habits of the individuals.
Once humans have been infected, the severity of the host response may be influenced by age.
Useful For: Aiding in the diagnosis of Eastern equine encephalitis

Interpretation: Detection of organism-specific antibodies in the cerebrospinal fluid (CSF) may
suggest central nervous system (CNS) infection. However, these results are unable to distinguish between
intrathecal antibodies and serum antibodies introduced into the CSF at the time of lumbar puncture or
from a breakdown in the blood-brain barrier. The results should be interpreted with other laboratory and
clinical data prior to a diagnosis of CNS infection.
Reference Values:
IgG: <1:1
IgM: <1:1
Clinical References: 1. Gonzalez-Scarano F, Nathanson N: Bunyaviruses. In: Fields BM, Knipe

DM, eds. Fields Virology. Vol 1. 2nd ed. . Raven Press; 1990:1195-1228 2. Donat JF, Rhodes KH,
meningoencephalitis. Mayo Clin Proc. 1980:55:156-160 3. Tsai TF: Arboviruses. In: Murray PR, Baron
EF, Pfaller MA, eds. Manual of Clinical Microbiology. 7th ed. ASM Press; 1999:1107-1124 4. Calisher
CH: Medically important arboviruses of the United States and Canada. Clin Microbiol Rev.
1994;7:89-116 5. Beckham JD, Tyler KL: Arbovirus Infections. Continuum (Minneap Minn). 2015
Dec;21(6 Neuroinfectious Disease):1599-1611. doi: 10.1212/CON.0000000000000240
EEEP Eastern Equine Encephalitis Antibody, IgG and IgM, Serum

83155 Clinical Information: Eastern equine encephalitis (EEE) is within the alphavirus group. It is a low
prevalence cause of human disease in the Eastern and Gulf Coast states. EEE is maintained by a cycle
of mosquito/wild bird transmission, peaking in the summer and early fall, when man may become an
adventitious host. The most common clinically apparent manifestation is a mild undifferentiated febrile
illness, usually with headache. Central nervous system involvement is demonstrated in only a minority
of infected individuals; it is more abrupt and more severe with EEE than other arboviruses, with
children being more susceptible to severe disease. Fatality rates are approximately 70% for EEE.
Useful For: Aiding in the diagnosis of Eastern equine encephalitis

Interpretation: In patients infected with this virus, IgG antibody is generally detectable within 1 to 3
weeks of onset, peaking within 1 to 2 months, and declining slowly thereafter. IgM class antibody is
also reliably detected within 1 to 3 weeks of onset, peaking and rapidly declining within 3 months.
Single serum specimen IgG greater than or equal to 1:10 indicates exposure to the virus. Results from a
single serum specimen can differentiate early (acute) infection from past infection with immunity if IgM
is positive (suggests acute infection). A 4-fold or greater rise in IgG antibody titer in acute and
convalescent sera indicate recent infection. In the United States it is unusual for any patient to show
positive reactions to more than 1 of the arboviral antigens, although Western equine encephalitis and
Eastern equine encephalitis antigens will show a noticeable cross-reactivity. Infections can occur at any
age. The age distribution depends on the degree of exposure to the particular transmitting arthropod
relating to age and sex, as well as the occupational, vocational, and recreational habits of the
individuals. Once humans have been infected, the severity of the host response may be influenced by
age.
Reference Values:
IgG: <1:10
IgM: <1:10

DM, eds. Fields Virology. Vol 1. 2nd ed. Raven Press, 1990; 1195-1228 2. Donat JF, Hable-Rhodes
KH, Groover RV, Smith TF: Etiology and outcome in 42 children with acute nonbacterial
meningoencephalitis. Mayo Clin Proc. 1980;55:156-160 3. Tsai TF: Arboviruses. In: Murray PR, Baron
EJ, Pfaller MA, et al, eds. Manual of Clinical Microbiology. 7th ed. American Society for
Microbiology, 1999; 1107-1124 4. Calisher CH: Medically important arboviruses of the United States
and Canada. Clin Microbiol Rev. 1994;7:89-116 5. Markoff L: Alphaviruses (Chikungunya, Eastern
equine encephalitis). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's
ESYC Eastern Sycamore, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Eastern Sycamore Defining the allergen

Reference Values:
0 Negative

apply to all ages.
ECHNO Echinococcus Antibody, IgG, Serum

64985 Clinical Information: Echinococcosis, also referred to as hydatidosis or hydatid disease, is 1 of the
17 neglected tropical diseases recognized by the World Health Organization and affects over 1 million
people worldwide. Echinococcus species are tapeworms or cestodes, and 2 main species infect humans:
Echinococcus granulosus and Echinococcus multilocularis. With respect to geographic distribution, E
granulosus can be found worldwide but, more frequently, is found in rural grazing areas where dogs may
feed on infected sheep or cattle carcasses. E multilocularis is largely localized to the northern hemisphere.
The definitive hosts for E granulosus are dogs or other canids, while the definitive host for E
multilocularis are foxes and, to a much lesser extent, canids. Echinococcus tapeworms reside in the small
intestine of definitive hosts and release eggs that are passed in the feces and ingested by an intermediate
host, typically sheep or cattle in the case of E granulosus or small rodents for E multilocularis. The eggs
hatch in the small bowel, releasing an oncosphere that penetrates the intestinal wall and migrates through
the circulatory system to various organs where it develops into a cyst that gradually enlarges producing
protoscolicies and daughter cysts, which fill the interior. The definitive host becomes infected following
ingestion of these infectious cysts. Humans become accidentally infected following ingestion of
Echinococcus eggs. In humans, E granulosus (cystic echinococcal disease) cysts typically develop in the
lungs and liver, and the infection may remain silent or latent for years (5-20 years) prior to cyst
enlargement and symptom manifestation. Symptomatic manifestations include chest pain, hemoptysis,
and cough for pulmonary involvement and abdominal pain and biliary duct obstruction for liver infection.
E multilocularis (alveolar echinococcal disease) infections manifest more rapidly than those of E
granulosus and similarly to a rapidly growing, destructive tumor, resulting in abdominal pain and biliary
obstruction. Rupture of cysts can produce fever, urticaria, and anaphylactic shock. Diagnosis of
echinococcal infections relies on characteristic finding by ultrasound or other imaging techniques and
serologic findings. Fine-needle aspirates of cystic fluid may be performed; however, they carry the risk of
cyst puncture and fluid leakage, which may potentially lead to severe allergic reactions. Importantly,
infected individuals do not shed eggs in stool.
Useful For: Detection of antibodies to Echinococcus species, including Echinococcus multilocularis
and Echinococcus granulosus
Interpretation: Negative: The absence of antibodies to Echinococcus species suggests that the
individual has not been exposed to this cestode. A single negative result should not be used to rule-out
infection (see Cautions). Equivocal: Consider repeat testing on a new serum sample in 1 to 2 weeks.
Positive: Results suggest infection with Echinococcus. False-positive results may occur in settings of
infection with other helminths, or in patients with chronic immune disorders. Results should be
considered alongside other clinical findings (eg, characteristic findings on imaging) and exposure
history.
Reference Values:
Negative
Clinical References: 1. Higuita NIA, Brunetti E, McCloskey C: Cystic echinococcosis. J Clin

Microbiol. 2016 Mar;54(3):518-523 2. Sarkari B, Rezaei Z: Immunodiagnosis of human hydatid
disease: Where do we stand? World J Methodol. 2015 Dec 26;5(4):185-195
ECUMP Eculizumab Monitoring Panel, Serum

64722 Clinical Information: Eculizumab (Soliris, Alexion Pharmaceuticals) is a humanized hybrid
monoclonal antibody (IgG2/IgG4) that blocks complement C5 cleavage, thereby preventing the
activation of the proinflammatory effects of C5a and the cytolytic effects of the membrane attack
complex (MAC) formed by C5b-C9. It is US Food and Drug Administration approved for atypical
hemolytic uremic syndrome(1) and paroxysmal nocturnal hemoglobinuria,(2) and it is also prescribed
for other conditions such as C3 glomerulopathies.(3) The dosing regimen for an average adult may vary
from 300 to 1200 mg intravenously every 2 weeks during the maintenance stages, according to the
condition for which the drug is prescribed. Therapy efficacy may be monitored by measuring efficiency
of complement blockade.(4) Eculizumab will affect complement function assays that rely on the
formation of the MAC to generate cell lysis. Although total complement and soluble MAC have been
recommended for eculizumab monitoring, the measurement of C5 function and C5 antigen more
specifically indicate the impact of eculizumab on the complement system blockage and may help guide
the next dose of the drug. This panel measures the pharmacodynamics effects of eculizumab on the
complement system.
Useful For: Therapeutic drug monitoring of eculizumab

Interpretation: The panel will measure the pharmacodynamic effects of eculizumab on the
complement system. Total complement function, alternative pathway function, and C5 function assays
will be decreased to a similar extent in the presence of eculizumab. The function of C5 may be
completely absent when eculizumab is present at therapeutic concentrations. C5 antigen, on the other
hand, will be normal or elevated. C5 complement function drops on average 30% with 25 mcg/mL of
eculizumab, and 70% with 50 mcg/mL. In the presence of 100 mcg/mL of eculizumab in serum, there is
on average 20% residual C5 function. Decreased C5 function in the presence of normal or elevated C5
antigen concentrations suggests eculizumab is partially blocking C5 activity. Absent C5 function in the
presence of normal or elevated C5 antigen concentrations suggests eculizumab is completely blocking
C5 activity. Normal C5 function in the presence of normal or elevated C5 antigen concentrations
suggests eculizumab concentration is not sufficient to block C5 activity. If C5 function and C5 antigen
concentrations are all decreased, it may be due to a secondary consumption process, poor hepatic
synthesis of complement proteins or C5 deficiency. Clinical correlation recommended. If indicated,
resubmit samples to confirm results.
Reference Values:
C5 COMPLEMENT ANTIGEN
10.6-26.3 mg/dL
C5 COMPLEMENT FUNCTIONAL
29-53 U/mL
Clinical References: 1. Wong EK, Goodship TH, Kavanagh D: Complement therapy in atypical
haemolytic uraemic syndrome (aHUS). Mol Immunol. 2013;56:199-212 2. Rother RP, Rollins SA,
Mojcik CF, Brodsky RA, Bell L: Discovery and development of the complement inhibitor eculizumab for
the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25:1256-1264 3. Zuber J,
Le Quintrec M, Krid S, et al: Eculizumab for atypical hemolytic uremic syndrome recurrence in renal
transplantation. Am J Transplant. 2012;12:3337-3354 4. Volokhina EB, van de Kar NC, Bergseth G, et al:
Sensitive, reliable and easy-performed laboratory monitoring of eculizumab therapy in atypical hemolytic
uremic syndrome. Clin Immunol. 2015;160(2):237-243 5. Andreguetto B, Murray D, Snyder M, et al: The
impact of eculizumab in complement assays. Mol Immunol. 2015;67:119-120 6. Willrich MAV, Braun
KMP, Moyer AM, Jeffrey DH, Frazer-Abel A. Complement testing in the clinical laboratory. Crit Rev
Clin Lab Sci. 2021 Nov;58(7):447-478. doi: 10.1080/10408363.2021.1907297
ECULI Eculizumab, Serum

65676 Clinical Information: Eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal
IgG2/4 kappa antibody therapeutic directed against complement component C5, has been heralded as a
breakthrough treatment for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic
syndrome (aHUS). By association with C5, eculizumab inhibits the terminal complement pathway
through simultaneous blockade of the generation of the potent prothrombotic and proinflammatory
molecule, C5a, and the formation of membrane attack complex initiator, C5b. Since all 3 arms of the
complement cascade converge at the point of C5 activation, targeted by eculizumab, this drug may have
broad potential application and is being clinically evaluated in other disorders with complement
overactivation. In PNH, eculizumab has become the standard of care, proving to be a safe and effective
therapy with long-lasting effects, potentially enabling patients to become transfusion-independent and
extending their survival. Eculizumab is administered as an IV infusion, and the dosing regimen prescribed
for an average adult diagnosed with PNH is 600 mg weekly for the first 4 weeks, followed by 900 mg for
the fifth dose 1 week later; then, 900 mg every 2 weeks thereafter. Eculizumab has been evaluated in
aHUS patients through 2 prospective, open-label, single-arm studies (C08-002 and C08-003) as well as a
single-arm retrospective study. In aHUS, it is prescribed for an average adult at 900 mg weekly for the
first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter.
Eculizumab was generally well tolerated and no significant adverse effects were attributed to drug
treatment; some adverse reactions included upper respiratory tract infections and diarrhea in prospective
and retrospective studies, hypertension, headache, and leucopenia (C08-002/C08-003), and fever
(C09-001R). Additional case reports suggest that eculizumab may prevent posttransplantation recurrence
of aHUS, even in those patients harboring CFH/CFHR1 hybrid gene variants, who are at very high risk of
recurrence. Further research is needed to determine the duration of eculizumab therapy in the context of
the genetic background of aHUS cases and risk of disease relapse. The drawbacks of eculizumab therapy
are associated with its potentially life-threatening side-effects, variations in response profiles, and the cost
of treatment. Patients treated with eculizumab are at an increased risk of susceptibility towards
life-threatening infections such as Neisseria meningitides; to prevent such infections, vaccinations and, in
some cases, prophylactic antibiotic treatment is recommended. A number of serious and potentially
treatment-related adverse effects were observed including pyrexia, headache, abdominal distension, viral
infection, renal impairment, and anxiety. It is important to note that there is variability among individuals
towards eculizumab response, and some patients may not benefit from this therapy. This is potentially a
life-long therapy with a high cost of administration. The cost of eculizumab may limit its use in routine
clinical practice worldwide. Therapeutic drug monitoring of eculizumab is typically not performed during
treatment regimens due to the low toxicity of biologics. Measurement of therapy efficacy is usually based
on clinical presentation and improvement of symptoms, although this landscape is changing, as it is
recognized that patients undergoing life-long therapy with eculizumab who are in complete remission
without significant evidence or pathogenic genetic variants leading to increased risk of relapse may
benefit from dose de-escalation or discontinuing therapy. Pharmacodynamic studies of complement
blockage may also be recommended, see ECUMP / Eculizumab Monitoring Panel, Serum for more
information.
Useful For: Assessing the response to eculizumab therapy Assessing the need for dose escalation
Evaluating the potential for dose de-escalation or discontinuation of therapy in remission states
Monitoring patients who need to be above a certain eculizumab concentration in order to improve the
odds of a clinical response for therapy optimization
Interpretation: Minimum trough therapeutic concentrations (immediately before next infusion) of

eculizumab are expected to be above 35 mcg/mL for paroxysmal nocturnal hemoglobinuria (PNH) and
above 50 mcg/mL for aHUS.
Reference Values:
Lower limit of quantitation =5.0 mcg/mL
>35 Therapeutic concentration for paroxysmal nocturnal hemoglobinuria (PNH)
>50 Therapeutic concentration for atypical hemolytic uremic syndrome (aHUS)
Clinical References: 1. Ladwig PM, Barnidge DR, Willrich MA: Quantification of the IgG2/4
kappa Monoclonal Therapeutic Eculizumab from Serum Using Isotype Specific Affinity Purification
and Microflow LC-ESI-Q-TOF Mass Spectrometry. J Am Soc Mass Spectrom 2017 May;28(5):811-817
2. Willrich MA, Murray DL, Barnidge DR, et al: Quantitation of infliximab using clonotypic peptides
and selective reaction monitoring by LC-MS/MS. International immunopharmacology 2015
Sep;28(1):513-520 3. Ladwig PM, Barnidge DR, Willrich MA: Mass Spectrometry Approaches for
Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory. Clin
Vaccine Immunol 2017 May 5;24(5)
EGFRS EGFR Gene, Targeted Mutation Analysis, 51 Mutation Panel,

614665 Tumor
Clinical Information: Targeted cancer therapies are defined as antibody or small molecule drugs
that block the growth and spread of cancer by interfering with specific cell molecules involved in tumor
growth and progression. Multiple targeted therapies have been approved by the FDA for treatment of
specific cancers. Molecular genetic profiling is often needed to identify targets amenable to targeted
therapies and to minimize treatment costs and therapy-associated risks. Epidermal growth factor
receptor (EGFR) protein is activated by the binding of specific ligands, resulting in activation of the
RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately leading to cell
proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression for many
solid tumors. Targeted therapies directed to tumors harboring activating mutations within the EGFR
tyrosine kinase domain (exons 18-21) have demonstrated some success in treating a subset of patients
with non-small cell lung cancer. As a result, the mutation status of EGFR can be a useful marker by
which patients are selected for EGFR-targeted therapy.
Useful For: Identifying non-small cell lung cancers that may respond to epidermal growth factor
receptor-targeted therapies

Reference Values:
Clinical References: 1. Sharma SV, Bell DW, Settleman J, Haber DA: Epidermal growth factor
receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-181. doi: 10.1038/nrc2088 2.
Gao G, Ren S, Li A, et al: Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is
effective as first- line treatment of advanced non-small-cell lung cancer with mutated EGFR: a
meta-analysis from six phase III randomized controlled trials. Int J Cancer. 2012 Sep
1;131(5):E822-829. doi: 10.1002/ijc.27396 3. Mok TS: Personalized medicine in lung cancer: what we
need to know. Nat Rev Clin Oncol. 2011 Aug 23;8(11):661-668. doi: 10.1038/nrclinonc.2011.126 4.
Lee CS, Sharma S, Miao E, Mensah C, Sullivan K, Seetharamu N: A comprehensive review of
contemporary literature for epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell
lung cancer and their toxicity. Lung Cancer (Auckl) 2020 Oct 7;11:73-103. doi:
10.2147/LCTT.S258444
EGFRW EGFR Targeted Mutation Analysis with ALK Reflex, Tumor
614666 Clinical Information: Targeted cancer therapies are defined as antibody or small molecule drugs that
block the growth and spread of cancer by interfering with specific cell molecules involved in tumor
growth and progression. Multiple targeted therapies have been approved by the FDA for treatment of
specific cancers. Molecular genetic profiling is often needed to identify targets amenable to targeted
therapies and to minimize treatment costs and therapy-associated risks. Epidermal growth factor receptor
(EGFR) protein is activated by the binding of specific ligands, resulting in activation of the RAS/MAPK
pathway. Activation of this pathway induces a signaling cascade, ultimately leading to cell proliferation.
Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression for many solid tumors.
Targeted therapies directed to tumors harboring activating mutations within the EGFR tyrosine kinase
domain (exons 18-21) have demonstrated some success in treating a subset of patients with non-small cell
lung cancer (NSCLC). As a result, the mutation status of EGFR can be a useful marker by which patients
are selected for EGFR-targeted therapy. Rearrangements of the anaplastic lymphoma kinase (ALK) locus
are found in a subset of lung carcinomas (generally EGFR wildtype tumors) and their identification by
fluorescence in situ hybridization (FISH) may guide important therapeutic decisions for the management
of these tumors. The fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with
the ALK gene results from an inversion of chromosome band 2p23. The ALK-EML4 rearrangement has
been identified in 3% to 5% of NSCLC with the majority occurring in adenocarcinoma and younger male
patients who were light or nonsmokers. Recent studies have demonstrated that lung cancers harboring
ALK rearrangements are resistant to EGFR tyrosine kinase inhibitors but may be highly sensitive to ALK
inhibitors, like crizotinib (Xalkori). The drug crizotinib works by blocking certain kinases, including those
produced by the abnormal ALK gene. Clinical studies have demonstrated that crizotinib treatment of
patients with tumors exhibiting ALK rearrangements can halt tumor progression or result in tumor
regression. The ALK/EML4 FISH assay is an FDA-approved companion diagnostic test for crizotinib,
which was recently approved by the FDA to treat certain patients with late-stage (locally advanced or
metastatic), non-small cell lung cancers that harbor ALK gene rearrangements. It is useful for the
identification of patients with lung cancer who will benefit from crizotinib therapy.
Useful For: Identifying non-small cell lung cancers that may benefit from treatment with epidermal
growth factor receptor -targeted therapies or anaplastic lymphoma kinase inhibitors

Reference Values:
Clinical References: 1. Sharma SV, Bell DW, Settleman J, Haber DA: Epidermal growth factor
receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-181. doi: 10.1038/nrc2088 2. Gao
G, Ren S, Li A, et al: Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as
first- line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six
phase III randomized controlled trials. Int J Cancer. 2012 Sep 1;131(5):E822-829. doi: 10.1002/ijc.27396
3. Mok TS: Personalized medicine in lung cancer: what we need to know. Nat Rev Clin Oncol. 2011 Aug
23;8(11):661-668. doi: 10.1038/nrclinonc.2011.126 4. Cheng L, Alexander RE, Maclennan GT, et al:
Molecular pathology of lung cancer: key to personalized medicine. Mod Path 2012 Mar;25(3):346-369.
doi: 10.1038/modpathol.2011.215
EGGPF Egg Comprehensive Profile, Serum

IgE-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with
allergen. Allergy to egg represents one of the most common causes of food allergy, especially in children.
The evaluation for egg-related IgE antibodies can identify up to 95% of individuals at risk for clinical
allergic reactions. The most clinically prevalent allergens in egg are found in the egg white, but egg yolk
also contains clinically significant specific IgE-binding allergens. The allergenic egg proteins found in
egg white include ovomucoid (Gal d 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3) and lysozyme (Gal
d 4). Ovomucoid has been demonstrated to be the most clinically significant egg allergen, in part due to
its heat and digestion resistance. In the yolk, the protein alpha-livetin (Gal d 5) is the major allergen and is
involved in bird-egg syndrome. Foods that may contain egg include salad dressings, breads, breaded
foods, muffins, cakes, marshmallows, prepared soups and beverages, frostings, ice cream and sherbets,
pie fillings, sausages, prepared meats, mayonnaise, coatings and breading for fried foods, and other
sauces. Sensitization to allergic reaction to inhaled egg-white allergens has been reported in
egg-processing workers and bakers. Certain vaccines grown on chick embryos may cause severe allergic
reactions in patients when injected. Further development of vaccines, most of which are no longer grown
on egg protein, seems to have decreased or even eliminated the risk. There is cross-reactivity between
chicken egg white and turkey, duck, goose, and gull egg whites. In vitro serum testing for IgE antibodies
provides an indication of the immune response to allergen(s) that may be associated with allergic disease.
Useful For: Identifying egg allergens: -Responsible for allergic disease and/or anaphylactic episode
-To confirm sensitization prior to beginning immunotherapy This test is not useful for patients
previously treated with immunotherapy to determine if residual clinical sensitivity exists, or for patients
in whom the medical management does not depend upon identification of allergen specificity.
Interpretation: Whole egg includes proteins and potential allergens from both egg white and egg
yolk. Egg white is generally more allergenic than egg yolk. Clinical reactions to egg are predominantly
IgE-mediated immediate reactions characterized by atopic dermatitis, urticarial (hives), angioedema,
vomiting, diarrhea, rhinoconjunctivitis, and asthma. Children with atopic dermatitis may have an
immediate exacerbation of symptoms or a delayed reaction causing a worsening of their dermatitis 1-2
days after exposure to egg. Eosinophilic esophagitis as a result of allergy to egg has been described. Egg
white is often responsible for the early development of urticaria and eczema during infancy. In egg yolk,
alpha-livetin (Gal d 5) is the major allergen and allegenicity to Gal d 5 is involved in bird-egg syndrome
characterized egg intolerance in adults is due to sensitization by inhalation of bird dander. In these
cases, there is secondary sensitization or cross-reactivity with serum albumin in egg yolk (Gal d 5)
resulting in potential respiratory symptoms including asthma or rhinitis with bird exposure and
additional allergic symptoms to egg. Table of Major Egg Allergens Egg white allergen Common name
Heat-and digestion stability Allergenic activity Gal d 1 Ovomucoid Stable +++ (major allergen) Gal d 2
Ovalbumin Unstable ++ Gal d 3 Ovotransferrin/conalbumin Unstable + Gal d 4 Lysozyme Unstable ++
Egg yolk allergen Gal d 5 Alpha-livetin, serum albumin Partially stable ++ Gal d 6 YGP42, a
lipoprotein Stable + Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased
Reference Values:
0 Negative
0/1 0.10-0.34 Borderline/Equivocal
6 > or =100 Strongly positive For EGG,

YOLK, OVAL, OVMU:
0 Negative

apply to all ages.
Clinical References: 1. Homburger HA, Hamilton RG: Allergic diseases. In: McPherson RA,
Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed.
Elsevier; 2017:1057-1070 2. Caubet JC, Wang J: Current understanding of egg allergy. Pediatr Clin
North Am. 2011;58(2):427-xi. doi:10.1016/j.pcl.2011.02.014 3. Shin M, Han Y, Ahn K: The influence
of the time and temperature of heat treatment on the allergenicity of egg white proteins. Allergy Asthma
Immunol Res. 2013 Mar;5(2):96-101. doi: 10.4168/aair.2013.5.2.96 4. Allergen Encyclopedia.
ThermoFisher Scientific; 2021. Available at
www.thermofisher.com/diagnostic-education/hcp/us/en/resource-center/allergen-encyclopedia.html
EGWTP Egg White Component Profile, Serum

IgE-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with
allergen. Allergy to egg represents one of the most common causes of food allergy, especially in children.
The evaluation for egg-related IgE antibodies can identify up to 95% of individuals at risk for clinical
allergic reactions. The most clinically prevalent allergens in egg are found in the egg white, but egg yolk
also contains clinically significant specific IgE-binding allergens. The allergenic egg proteins found in
egg white include ovomucoid (Gal d 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3), and lysozyme (Gal
d 4). Ovomucoid has been demonstrated to be the most clinically significant egg allergen, in part due to
its heat and digestion resistance. In the yolk, the protein alpha-livetin (Gal d 5) is the major allergen and is
involved in bird-egg syndrome. Foods that may contain egg include salad dressings, breads, breaded
foods, muffins, cakes, marshmallows, prepared soups and beverages, frostings, ice cream and sherbets,
pie fillings, sausages, prepared meats, mayonnaise, coatings and breading for fried foods, and other
sauces. Sensitization to allergic reaction to inhaled egg-white allergens has been reported in
egg-processing workers and bakers. Certain vaccines grown on chick embryos may cause severe allergic
reactions in patients when injected. Further development of vaccines, most of which are no longer grown
on egg protein, seems to have decreased or even eliminated the risk. There is cross-reactivity between
chicken egg white and turkey, duck, goose, and gull egg whites. In vitro serum testing for IgE antibodies
provides an indication of the immune response to allergen(s) that may be associated with allergic disease.
Useful For: Identifying egg white allergens: -Responsible for allergic disease and/or anaphylactic
episode -To confirm sensitization prior to beginning immunotherapy This test is not useful for patients
previously treated with immunotherapy to determine if residual clinical sensitivity exists, or for patients in
whom the medical management does not depend upon identification of allergen specificity.
Interpretation: Whole egg includes proteins and potential allergens from both egg white and egg yolk.
Egg white is generally more allergenic than egg yolk. Clinical reactions to egg are predominantly
IgE-mediated immediate reactions characterized by atopic dermatitis, urticarial (hives), angioedema,
vomiting, diarrhea, rhinoconjunctivitis, and asthma. Children with atopic dermatitis may have an
immediate exacerbation of symptoms or a delayed reaction causing a worsening of their dermatitis 1-2
days after exposure to egg. Eosinophilic esophagitis as a result of allergy to egg has been described. Egg
white is often responsible for the early development of urticaria and eczema during infancy. In egg yolk,
alpha-livetin (Gal d 5) is the major allergen and allegenicity to Gal d 5 is involved in bird-egg syndrome
characterized egg intolerance in adults is due to sensitization by inhalation of bird dander. In these cases,
there is secondary sensitization or cross-reactivity with serum albumin in egg yolk (Gal d 5) resulting in
potential respiratory symptoms including asthma or rhinitis with bird exposure and additional allergic
symptoms to egg. Table of Major Egg Allergens Egg white allergen Common name Heat-and digestion
stability Allergenic activity Gal d 1 Ovomucoid Stable +++ (major allergen) Gal d 2 Ovalbumin Unstable
++ Gal d 3 Ovotransferrin/conalbumin Unstable + Gal d 4 Lysozyme Unstable ++ Egg yolk allergen Gal
d 5 Alpha-livetin, serum albumin Partially stable ++ Gal d 6 YGP42, a lipoprotein Stable + Detection of
IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as
opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and
symptoms. The level of IgE antibodies in serum varies directly with the concentration of IgE antibodies
expressed as a class score or kU/L.
Reference Values:
0 Negative


apply to all ages.
Clinical References: 1. Homburger HA, Hamilton RG: Allergic diseases. In: McPherson RA,
Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed.
Elsevier; 2017:1057-1070 2. Caubet JC, Wang J: Current understanding of egg allergy. Pediatr Clin
North Am. 2011;58(2):427-xi. doi:10.1016/j.pcl.2011.02.014 3. Shin M, Han Y, Ahn K: The influence
of the time and temperature of heat treatment on the allergenicity of egg white proteins. Allergy Asthma
Immunol Res. 2013 Mar;5(2):96-101. doi: 10.4168/aair.2013.5.2.96 4. Allergen Encyclopedia.
ThermoFisher Scientific; 2021. Available at
www.thermofisher.com/diagnostic-education/hcp/us/en/resource-center/allergen-encyclopedia.html
FEGWH Egg White IgG

Reference Values:
FEWG4 Egg White IgG4

Reference Values:
Reference ranges have not been established for food-specific IgG4 tests. The clinical utility of
food-specific IgG4 tests has not been clearly established. These tests can be used in special clinical
situations to select foods for evaluation by diet elimination and challenge in patients who have
food-related complaints, and to evaluate food allergic patients prior to food challenges. The presence of
food-specific IgG4 has been studied in response to various oral food immunotherapy treatments but
cutoffs have not been established
EGG Egg White, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to egg white Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
FEWHG Egg Whole IgG

FEGYK Egg Yolk IgG
Reference Values:
YOLK Egg Yolk, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to egg yolk Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
EGGP Eggplant, IgE, Serum
Useful For: Establishing the diagnosis of an allergy to eggplant Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
EDSGP Ehlers-Danlos Syndrome Panel (12 Genes), Next-Generation

65749 Sequencing and Deletion/Duplication Analysis, Varies
Clinical Information: The Ehlers Danlos syndromes (EDS) are a clinically and genetically diverse
group of heritable connective tissue disorders. An EDS classification system proposed by the International
EDS Consortium identifies 13 subtypes of EDS, with an overall estimated prevalence of EDS between
1:5000 and 1:25,000. Over 90% of cases are either classic or hypermobile EDS (cEDS or hEDS), while
less than 5% of cases are vascular EDS (vEDS). Other, rarer, subtypes of EDS also exist and are listed in
the table below. The clinical hallmarks of EDS are joint hypermobility, skin hyperextensibility, and tissue
fragility. However, a variety of skin, ligament, joint, and cardiovascular features are seen across the
spectrum of EDS. A clinical diagnosis of a specific subtype of EDS may be suspected based on a
combination of major (a symptom present in the majority of affected individuals) and minor (a symptom
of lesser diagnostic specificity that supports the diagnosis) clinical criteria. However, due to the clinical
overlap between EDS subtypes and other heritable connective tissue disorders (eg, Marfan syndrome and
Loeys-Dietz syndrome), a definitive diagnosis of all EDS subtypes (except EDS hypermobility type)
relies on the identification of a causative variant in the appropriate gene. Genetic variants in
collagen-encoding or collagen-modifying genes have been identified as the cause of EDS in the majority
of subtypes. These variants result in defects in collagen structure, processing, folding, and cross-linking.
One notable exception to this is hypermobile EDS (hEDS). Hypermobile EDS is inherited in an autosomal
dominant inheritance pattern, similar to cEDS and vEDS, however, the molecular basis of this condition is
unknown, and a diagnosis is based on clinical criteria. This panel also tests for variants in the ATP7A and
FLNA genes, which result in X-linked conditions. Some patients with these conditions have clinical
overlap with EDS. Table1. Genes included in this gene panel Gene symbol Protein Inheritance* EDS
Cclassification ADAMTS2 Procollagen I N-proteinase (NPI) AR Dermatosparaxis EDS (dEDS) / human
dermatosparaxis EDS VIIC ATP7A Copper-transporting ATPase 1 XL Occipital horn syndrome CHST14
Dermatan-4-sulfotransferase-1 (D4ST1) AR Musculocontractural EDS (mcEDS-CHST14) COL1A1
Collagen alpha-1(I) chain AD AD AD Classical EDS (cEDS) Vascular EDS (vEDS) Arthrochalasia EDS
(aEDS) COL1A2 Collagen alpha-2(I) chain AD AR Arthrochalasia EDS (aEDS) Cardiac valvular EDS
(cvEDS) COL3A1 Collagen alpha-1(III) chain AD Vascular EDS (vEDS) COL5A1 Collagen alpha-1(V)
chain AD Classical EDS (cEDS) COL5A2 Collagen alpha-2(V) chain AD Classical EDS (cEDS)
FKBP14 Peptidyl-prolyl cis-trans isomerase FKBP14 (FK506 binding protein 14) AR Kyphoscoliotic
EDS (kEDS-FKBP14) FLNA Filamin A XL Filamin A related EDS with periventricular nodular
heterotopia PLOD1 Procollagen-lysine 5-dioxygenase AR Kyphoscoliotic EDS (kEDS â€“ PLOD1)
SLC39A13 Zinc transporter ZIP13 AR Spondylodysplastic EDS (spEDS-SLC39A13) *Abbreviations:
Autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), Ehlers-Danlos syndrome (EDS)
Useful For: Confirmation of a clinical diagnosis of Ehlers-Danlos Syndrome (EDS) Differentiating

between the different subtypes of EDS for diagnosis and management purposes Ascertaining carrier
status of family members of individuals diagnosed with EDS for genetic counseling purposes
Reference Values:
May;17(5):405-424 2. Malfait F, Francomano C, Byers P, et al: The 2017 international classification of
the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. doi:
10.1002/ajmg.c.31552 3. Meester JAN, Verstraeten A, Schepers D, et al: Differences in manifestations
of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann Cardiothorac Surg.
2017;6(6):582-594. doi: 10.21037/acs.2017.11.03 4. Brady AF, Demirdas S, Fournel-Gigleux S, et al:
The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet. 2017;175(1):70-115.
doi: 10.1002/ajmg.c.31550 5. Bowen JM, Sobey GJ, Burrows NP, et al: Ehlers-Danlos syndrome,
classical type. Am J Med Genet C Semin Med Genet. 2017;175(1):27-39. doi: 10.1002/ajmg.c.31548 6.
Bursztejn AC, Baumann M, Lipsker D: Ehlers-Danlos syndrome related to FKBP14 mutations: detailed
cutaneous phenotype. Clin Exp Dermatol 2017;42(1):64-67. doi: 10.1111/ced.12983
EHRCP Ehrlichia Antibody Panel, Serum

81480
Clinical Information: Anaplasma phagocytophilum, an intracellular rickettsia-like bacterium,
preferentially infects granulocytes and forms inclusion bodies, referred to as morulae. A phagocytophilum
is transmitted by Ixodes species ticks, which also transmit Borrelia burgdorferi and Babesia species.
Infection with A phagocytophilum is also referred to as human granulocytic anaplasmosis (HGA) and
symptoms in otherwise healthy individuals are often mild and nonspecific, including fever, myalgia,
arthralgia, and nausea. Clues to the diagnosis of anaplasmosis in a patient with an acute febrile illness
after tick exposure include laboratory findings of leukopenia or thrombocytopenia and elevated liver
enzymes. HGA is most prevalent in the upper Midwest and in other areas of the United States that are
endemic for Lyme disease. Ehrlichia chaffeensis is an intracellular rickettsia-like bacterium that
preferentially infects monocytes and is sequestered in parasitophorous vacuoles referred to as morulae.
Infections with E chaffeensis are also referred to as human monocytotropic ehrlichiosis (HME). E
chaffeensis is transmitted by Amblyomma species ticks, which are found throughout the southeastern and
south-central United States. Many cases of HME are subclinical or mild, however, the infection can be
severe and life-threatening, particularly in immunosuppressed individuals. Reported mortality rates range
from 2% to 3%. Fever, fatigue, malaise, headache, and other "flu-like" symptoms occur most commonly.
Leukopenia, thrombocytopenia, and elevated hepatic transaminases are frequent laboratory findings.
Useful For: An adjunct in the diagnosis of infection with Anaplasma phagocytophilum or Ehrlichia
chaffeensis Seroepidemiological surveys of the prevalence of the infection in certain populations
Interpretation: A positive immunofluorescence assay (titer > or =1:64) suggests current or previous
infection. In general, the higher the titer, the more likely the patient has an active infection. Four-fold rises
in titer also indicate active infection. Previous episodes of ehrlichiosis may produce a positive serology
although antibody levels decline significantly during the year following infection.
Reference Values:
ANAPLASMA PHAGOCYTOPHILUM
<1:64
EHRLICHIA CHAFFEENSIS
<1:64
Clinical References: Centers for Disease Control and Prevention (CDC), Division of Vector-Borne
Diseases: Tickborne diseases of the United States: A Reference Manual for Health Care Providers. 4th ed.
CDC; 2017
EHRC Ehrlichia chaffeensis (HME) Antibody, IgG, Serum

81478 Clinical Information: Ehrlichia chaffeensis is an intracellular rickettsia-like bacterium that
preferentially infects monocytes and is sequestered in parasitophorous vacuoles referred to as morulae.
Infections with E chaffeensis are also referred to as human monocytotropic ehrlichiosis (HME). E
chaffeensis is transmitted by Amblyomma species ticks, which are found throughout the southeastern and
south-central United States. Many cases of HME are subclinical or mild, however, the infection can be
severe and life-threatening, particularly in immunosuppressed individuals. Reported mortality rates range
from 2% to 3%. Fever, fatigue, malaise, headache, and other "flu-like" symptoms occur most commonly.
Leukopenia, thrombocytopenia, and elevated hepatic transaminases are frequent laboratory findings.
Useful For: An adjunct in the diagnosis of ehrlichiosis Seroepidemiological surveys of the prevalence
of the infection in certain populations
Interpretation: A positive immunofluorescence assay (titer > or =1:64) suggests current or previous
although antibody levels decline significantly during the year following infection.
Reference Values:
<1:64
Clinical References: Centers for Disease Control and Prevention (CDC), Division of
Vector-Borne Diseases: Tickborne diseases of the United States: A Reference manual for health care
providers. 4th ed. CDC; 2017
EHRL Ehrlichia/Anaplasma, Molecular Detection, PCR, Blood

84319 Clinical Information: Ehrlichiosis and anaplasmosis are a group of emerging zoonotic tick-borne
infections caused by Ehrlichia and Anaplasma species, respectively. These obligate intracellular,
gram-negative rickettsial organisms infect leukocytes and cause a potentially serious febrile illness in
humans. Human granulocytic anaplasmosis (HA) is caused by Anaplasma phagocytophilum, which is
transmitted through the bite of an infected Ixodes species tick. The epidemiology of this infection in the
United States is very much like that of Lyme disease (caused by Borrelia burgdorferi) and babesiosis
(caused primarily by Babesia microti), which all have the same tick vector. HA is most prevalent in the
upper Midwest and in other areas of the United States that are endemic for Lyme disease. Human
monocytic ehrlichiosis (HE) is caused by Ehrlichia chaffeensis, which is transmitted by the Lone Star
tick, Amblyomma americanum. Most cases of HE have been reported from the southeastern and
south-central regions of the United States. E ewingii, the known cause of canine granulocytic
ehrlichiosis, can occasionally cause an HE-like illness in humans. Clinical features and laboratory
abnormalities are similar to those of E chaffeensis infection, and antibodies to E ewingii cross-react
with current serologic assays for detection of antibodies to E chaffeensis. Most recently, Mayo Clinic
Laboratories detected a new species of Ehrlichia in patients with exposure to ticks in Wisconsin and
Minnesota. This organism is most closely related to E muris and has therefore been referred to as the E
muris-like agent or EMLA. The name E muris eauclairensis has recently been proposed after the city in
which the first case was described. E muris eauclairensis causes a similar disease to ehrlichiosis due to
E chaffeensis and E ewingii, and may cause more severe disease in immunocompromised hosts. Most
cases of anaplasmosis and ehrlichiosis are subclinical or mild, but infection can be severe and
life-threatening in some individuals. Fever, fatigue, malaise, headache, and other "flu-like" symptoms,
including myalgias, arthralgias, and nausea, occur most commonly. Central nervous system
involvement can result in seizures and coma. Diagnosis may be difficult since the patient's clinical
course is often mild and nonspecific. This symptom complex is easily confused with other illnesses such
as influenza, or other tick-borne zoonoses such as Lyme disease, babesiosis, and Rocky Mountain
spotted fever. Clues to the diagnosis of ehrlichiosis in an acutely febrile patient after tick exposure
include laboratory findings of leukopenia or thrombocytopenia and elevated serum aminotransferase
levels. However, while these abnormal laboratory findings are frequently seen, they are not specific.
Rarely, intra-granulocytic or monocytic morulae may be observed on peripheral blood smear, but this is
not a reliable means of diagnosing cases of human ehrlichiosis or anaplasmosis. Definitive diagnosis is
usually accomplished through PCR and serologic methods. Serologic testing is done primarily for
confirmatory purposes, by demonstrating a 4-fold rise or fall in specific antibody titers to Ehrlichia
species or Anaplasma antigens. There is not currently a commercially available specific serologic test
for E muris eauclairensis, but cross-reactivity with the other Ehrlichia species by serology may be
detected. PCR techniques allow direct detection of pathogen-specific DNA from patients' whole blood
and is the preferred method for detection during the acute phase of illness. The Mayo PCR assay is
capable of detecting and differentiating A phagocytophilum, E chaffeensis, E ewingii, and E muris
eauclairensis. It is important to note that concurrent infection with A phagocytophilum, Borrelia
burgdorferi, and Babesia microti is not uncommon as these organisms share the same Ixodes tick vector,
and additional testing for these pathogens may be indicated.
Useful For: Evaluating patients suspected of acute anaplasmosis or ehrlichiosis

Interpretation: Positive results indicate presence of specific DNA from Ehrlichia chaffeensis, E
ewingii, E muris eauclairensis organism, or Anaplasma phagocytophilum and support the diagnosis of
ehrlichiosis or anaplasmosis. Negative results indicate absence of detectable DNA from any of these 4
pathogens in specimens, but do not exclude the presence of these organisms or active or recent disease.
Since DNA of E ewingii is indistinguishable from that of E canis by this rapid PCR assay, a positive
result for E ewingii/canis indicates the presence of DNA from either of these 2 organisms.
Reference Values:
Negative
Clinical References: 1. Bakken JS, Dunler JS: Human granulocytic ehrlichiosis. Clin Infect Dis
2000 Aug;31(2):554-560 2. Dunler JS, Bakken JS: Human ehrlichioses: newly recognized infections
transmitted by ticks. Ann Rev Med 1998;49:201-213 3. Krause PJ, McKay K, Thompson CA, et al:
Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis,
and Lyme disease. Clin Infect Dis 1999 May 1;34(9):1184-1191 4. McQuiston JH, Paddock CD, Holman
RC, Childs JE: The human ehrlichioses in the United States. Emerging Infect Dis 1999
Sept-Oct;5(5):635-642 5. Pritt BS, Sloan LM, Johnson DK, et al: Emergence of a new pathogenic
Ehrlichia species, Wisconsin and Minnesota, 2009. N Engl J Med 2011 Aug 4;365(5):422-429 6. Johnson
DK, Schiffman E, Davis JP, et al. Human infection with Ehrlichia muris-like Pathogen, United States,
2007-2013. Emerging Infect Dis 2015; 21(10):1794-99
EHBAP Ehrlichia/Babesia Antibody Panel, Immunofluorescence, Serum

608396 Clinical Information: Anaplasma phagocytophilum: Anaplasma phagocytophilum, an intracellular
rickettsia-like bacterium, preferentially infects granulocytes and forms inclusion bodies, referred to as
morulae. A phagocytophilum is transmitted by Ixodes species ticks, which also transmit Borrelia
burgdorferi and Babesia species. Infection with A phagocytophilum is also referred to as human
granulocytic anaplasmosis (HGA) and symptoms in otherwise healthy individuals are often mild and
nonspecific, including fever, myalgia, arthralgia, and nausea. Clues to the diagnosis of anaplasmosis in a
patient with an acute febrile illness after tick exposure include laboratory findings of leukopenia or
thrombocytopenia and elevated liver enzymes. HGA is most prevalent in the upper Midwest and in other
areas of the United States that are endemic for Lyme disease. Ehrlichia chaffeensis: Ehrlichia chaffeensis
is an intracellular rickettsia-like bacterium that preferentially infects monocytes and is sequestered in
parasitophorous vacuoles referred to as morulae. Infections with E chaffeensis are also referred to as
human monocytotropic ehrlichiosis (HME). E chaffeensis is transmitted by Amblyomma species ticks,
which are found throughout the southeastern and south central United States. Babesia microti: Many cases
of HME are subclinical or mild; however, the infection can be severe and life-threatening, particularly in
immunosuppressed individuals. Reported mortality rates range from 2% to 3%. Fever, fatigue, malaise,
headache, and other "flu-like" symptoms occur most commonly. Leukopenia, thrombocytopenia, and
elevated hepatic transaminases are frequent laboratory findings. Babesiosis is a zoonotic infection caused
by the protozoan parasite Babesia microti. The infection is acquired by contact with Ixodes ticks carrying
the parasite. The deer mouse is the animal reservoir, and overall, the epidemiology of this infection is
much like that of Lyme disease. Babesiosis is most prevalent in the Northeast, upper Midwest, and Pacific
coast of the United States. Infectious forms (sporozoites) are injected during tick bites and the organism
enters the vascular system where it infects red blood cells (RBC). In this intraerythrocytic stage it
becomes disseminated throughout the reticuloendothelial system. Asexual reproduction occurs in RBC,
and daughter cells (merozoites) are formed, which are liberated on rupture (hemolysis) of the RBC. Most
cases of babesiosis are probably subclinical or mild, but the infection can be severe and life threatening,
especially in older or asplenic patients. Fever, fatigue, malaise, headache, and other flu-like symptoms
occur most commonly. In the most severe cases, hemolysis, acute respiratory distress syndrome, and
shock may develop. Patients may have hepatomegaly and splenomegaly. A serologic test can be used as
an adjunct in the diagnosis and follow-up of babesiosis, when infection is chronic or persistent, or in
seroepidemiologic surveys of the prevalence of the infection in certain populations. Babesiosis is usually
diagnosed by observing the organisms in infected RBC on Giemsa-stained thin blood films of smeared
peripheral blood. Serology may also be useful if the parasitemia is too low to detect or if the infection has
cleared naturally or following treatment.
Useful For: As an adjunct in the diagnosis of infection with Anaplasma phagocytophilum, Ehrlichia
chaffeensis or Babesia microti Seroepidemiological surveys of the prevalence of the infection in certain
populations
Interpretation: Anaplasma phagocytophilum: A positive result of an immunofluorescence assay (IFA)

test (titer > or =1:64) suggests current or previous infection with human granulocytic ehrlichiosis. In
general, the higher the titer, the more likely it is that the patient has an active infection. Seroconversion
may also be demonstrated by a significant increase in IFA titers. During the acute phase of the infection,
serologic tests are often nonreactive, polymerase chain reaction (PCR) testing is available to aid in the
diagnosis of these cases (see EHRL / Ehrlichia/Anaplasma, Molecular Detection, PCR, Blood). Ehrlichia
chaffeensis: A positive immunofluorescence assay (titer > or =1:64) suggests current or previous
although antibody levels decline significantly during the year following infection. Babesia microti: A
positive result of an indirect fluorescent antibody test (titer > or =1:64) suggests current or previous
infection with Babesia microti. In general, the higher the titer, the more likely it is that the patient has an
active infection. Patients with documented infections have usually had titers ranging from 1:320 to
1:2,560.
Reference Values:
ANAPLASMA PHAGOCYTOPHILUM
<1:64
EHRLICHIA CHAFFEENSIS
<1:64
BABESIA MICROTI
<1:64
Clinical References: Centers for Disease Control and Prevention: Tickborne Diseases of the
United States: A Reference Manual for Health Care Providers. 4th ed. Department of Health and
Human Services; 2017
FELAS Elastase, Pancreatic, Serum

90158 Clinical Information: Serum Elastase, also called Pancreatopeptidase, is a protease present in
pancreatic secretion with the unique ability to rapidly hydrolyze elastin. Elastin is a fibrillar protein
found in connective tissue. Elastin forms the elastic fibers found mostly in lungs and skin. Elastase is
able to hydrolyze denatured hemoglobin, casein, fibrin, albumin and denatured but not native collagen.
Elastase has been implicated in the pathogenesis of pulmonary emphysema, atherosclerosis and in the
vascular injury of acute pancreatic necrosis. Elastase activity is inhibited by protease inhibitors
including a1-Anti-Trypsin, a1-anti-Chymotrypsin, anti-Thrombin III, a2-Macroglobulin and
b1-anti-Collagenase. Patients with thyroid dysfunction have decreased Elastase activity. Serum
pancreatic levels quantify EL 1 for the diagnosis or exclusion of an acute pancreatitis or an
inflammatory episode of chronic pancreatitis or gallstone induced pancreatitis.
Reference Values:
Adult Reference Ranges:
Normal pancreatic exocrine function:
Less than 3.5 ng/mL
No pediatric reference ranges available for this test.
ELDR Elder, IgE, Serum

Useful For: Establishing the diagnosis of an allergy to elder Defining the allergen responsible for
specificity.

Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
EFPO Electrolyte and Osmolality Panel, Feces

35091 Clinical Information: The concentration of electrolytes in fecal water and their rate of excretion are
dependent upon 3 factors: -Normal daily dietary intake of electrolytes -Passive transport from serum and
other vascular spaces to equilibrate fecal osmotic pressure with vascular osmotic pressure -Electrolyte
transport into fecal water due to exogenous substances and rare toxins (eg, cholera toxin) Fecal osmolality
is normally in equilibrium with vascular osmolality, and sodium is the major effector of this equilibrium.
Fecal osmolality is normally 2 x (sodium + potassium) unless there are exogenous factors inducing a
change in composition, such as the presence of other osmotic agents (magnesium sulfate, saccharides) or
drugs inducing secretions, such as phenolphthalein or bisacodyl. Osmotic diarrhea is caused by ingestion
of poorly absorbed ions or sugars.(1) There are multiple potential causes of osmotic diarrhea.
Measurement of phosphate and/or magnesium in liquid stool can assist in identifying intentional or
inadvertent use of magnesium and/or phosphate containing laxatives as the cause.(2-4) The other causes
of osmotic diarrhea include ingestion of osmotic agents such as sorbitol or polyethylene glycol laxatives,
or carbohydrate malabsorption due most commonly to lactose intolerance. Carbohydrate malabsorption
can be differentiated from other osmotic causes by a low stool pH (<6).(5,6) Non-osmotic causes of
diarrhea include bile acid malabsorption, inflammatory bowel disease, endocrine tumors, and
neoplasia.(1) Secretory diarrhea is classified as non-osmotic and is caused by disruption of epithelial
electrolyte transport when secretory agents such as anthraquinones, phenolphthalein, bisacodyl, or cholera
toxin are present. The fecal fluid usually has elevated electrolytes (primarily sodium and chloride) and a
low osmotic gap (<50 mOsm/kg). Infection is a common secretory process; however, it does not typically
cause chronic diarrhea (defined as symptoms >4 weeks). Differentiating osmotic from non-osmotic causes
of diarrhea is the goal of liquid stool testing.(1,7) The primary way this is accomplished is through the
measurement of sodium and chloride and calculation of the osmotic gap, which uses an assumed normal
osmolality of 290 mOsm/kg rather than direct measurement of the osmolality. Measurement of osmolality
can be useful in the evaluation of chronic diarrhea to help identify whether a specimen has been diluted
with hypotonic fluid to simulate diarrhea.(1,8) Chronic diarrhea with elevations in fecal chloride
concentrations are caused by congenital chloridorrhea. This is a rare condition associated with a genetic
defect in a protein responsible for transport of chloride ions across the mucosal membranes in the lower
intestinal tract in exchange for bicarbonate ions. It plays an essential part in intestinal chloride absorption,
therefore mutations in this gene have been associated with congenital chloride diarrhea.(9) Acquired
chloridorrhea is a rare condition which has been described as causing profuse, chloride-rich diarrhea and a
surprising contraction metabolic alkalosis rather than metabolic acidosis often associated with typical
diarrhea. Contributors to acquired chloridorrhea include chronic intestinal inflammation and reduction of
chloride/bicarbonate transporter expression in genetically susceptible persons post-bowel resection and
ostomy placement. Acquired chloridorrhea is rare but may be an under-recognized condition in
post-bowel resection patients.(10)
Useful For: Workup of cases of chronic diarrhea Diagnosis of factitious diarrhea (where patient adds
water to stool to simulate diarrhea)
Interpretation: Osmotic Gap: Osmotic gap is calculated as 290 mOsm/kg-(2[Na]+2[K]). Typically,

stool osmolality is similar that seen in serum since the gastrointestinal (GI) tract does not secrete
water.(1) An osmotic gap above 50 mOsm/kg is suggestive of an osmotic component contributing to the
symptoms of diarrhea.(1,5,7) Magnesium-induced diarrhea should be considered if the osmotic gap is
above 75 mOsm/kg and is likely if the magnesium concentration is above110 mg/dL.(1) An osmotic gap
of50 mOsm/kg or less is suggestive of secretory causes of diarrhea.(1,5,7) A highly negative osmotic
gap or a fecal sodium concentration greater than plasma or serum suggests the possibility of either
sodium phosphate or sodium sulfate ingestion by the patient.(4) Phosphorus: Phosphorus elevation
above 102 mg/dL is suggestive of phosphate-induced diarrhea.(4) Osmolality: Osmolality below 220
mOsm/kg indicates dilution with a hypotonic fluid.(1) Sodium and Potassium: High sodium and
potassium in the absence of an osmotic gap indicate active electrolyte transport in the GI tract that
might be induced by agents such as cholera toxin or hypersecretion of vasointestinal peptide.(1)
Sodium: Sodium is typically found at lower concentrations (mean 30 +/- 5 mmol/L) in patients with
osmotic diarrhea caused by magnesium-containing laxatives, while typically at higher concentrations
(mean 104 +/- 5 mmol/L) in patients known to be taking secretory laxatives.(8) Chloride: Chloride may
be low (<20 mmol/L) in sodium sulfate-induced diarrhea.(5) Markedly elevated fecal chloride
concentration in infants (>60 mmol/L) and adults (>100 mmol/L) is associated with congenital and
secondary chloridorrhea.(6)
Reference Values:
Clinical References: 1. Steffer KJ, Santa Ana CA, Cole JA, Fordtran JS: The practical value of
comprehensive stool analysis in detecting the cause of idiopathic chronic diarrhea. Gastroenterol Clin
North Am. 2012;41:539-560 2. Ho J, Moyer TP, Phillips SF: Chronic diarrhea: the role of magnesium.
Mayo Clin Proc. 1995;70:1091-1092 3. Fine KD, Santa Ana CA, Fordtran JS: Diagnosis of
magnesium-induced diarrhea. N Engl J Med. 1991;324:1012-1017 4. Fine KD, Ogunji F, Florio R,
Porter J, Ana CS: Investigation and diagnosis of diarrhea caused by sodium phosphate. Dig Dis Sci.
1998;43(12):2708-2714 5. Eherer AJ, Fordtran JS: Fecal osmotic gap and pH in experimental diarrhea
of various causes. Gastroenterology. 1992;103:545-551 6. Casprary WF: Diarrhea associated with
carbohydrate malabsorption. Clin Gastroenterol. 1986;15:631-655 7. Sweetser S: Evaluating the patient
with diarrhea: A case-based approach. Mayo Clin Proc. 2012;87:596-602 8. Phillips S, Donaldson L,
Geisler K, Pera A, Kochar R: Stool composition in factitial diarrhea: a 6-year experience with stool
analysis. Ann Intern Med. 1995;123:97-100 9. Makela S, Kere J, Holmberg C, Hoglund P: SLC26A3
mutations in congenital chloride diarrhea. Hum Mutat. 2002 Dec;20(6):425-438. doi:
10.1002/humu.10139 10. Ali OM, Shealy C, Saklayen M: Acute pre-renal failure: acquired chloride
diarrhea after bowel resection. Clin Kidney J. 2012;5(4):356-358. doi: 10.1093/ckj/sfs082
ELPSR Electrolyte Panel, Serum

113632 Clinical Information: The electrolyte panel is ordered to identify electrolyte, fluid, or pH imbalance.
Electrolyte concentrations are evaluated to assist in investigating conditions that cause electrolyte
imbalances such as dehydration, kidney disease, lung diseases, or heart conditions. Repeat testing of the
electrolyte or its components may be used to monitor the patientÃ¢â‚¬â„¢s response to treatment of any
condition that may be causing the electrolyte, fluid or pH imbalance. Electrolyte and acid-base imbalances
can often be indicative of many acute and chronic illnesses. For this reason, the electrolyte panel is often
used in the hospital and emergency settings to evaluate patients.
Useful For: Identifying a suspected imbalance in electrolytes or acid/base imbalance

Interpretation: With an imbalance of a single electrolyte, such as sodium or potassium, repeat testing
may be ordered of that particular electrolyte, can be used to monitor the imbalance until remedied. With
an acid-base imbalance, blood gases may be ordered, which will measure the oxygen, carbon dioxide, and
pH levels in the arterial blood. These tests assist in evaluating the acuteness of the imbalance and
monitoring the response to treatment.
Reference Values:
SODIUM
> or =1 year: 135-145 mmol/L
POTASSIUM
> or =1 year: 3.6-5.2 mmol/L
CHLORIDE
1-17 years: 102-112 mmol/L
BICARBONATE
Males
Females
ANION GAP
> or =7 years: 7-15
Clinical References: 1. Oh MS: Evaluation of renal function, water, electrolytes, and acid-base
balance. In Henry's Clinical Diagnosis and Management by Laboratory Methods. 22nd edition. Edited by
RA McPherson, MR Pincus. Philadelphia, PA: Elsevier Saunders; 2011:chap 14 2. AACC: Lab Tests
Online: Access 03/22/2017. Available at https://labtestsonline.org/understanding/analytes/electrolyes
EM Electron Microscopy, Varies

70316 Clinical Information: Transmission electron microscopy is an important diagnostic tool used in the
comprehensive assessment of human disease and is most often used in conjunction with other methods
such as light microscopy and immunohistopathological techniques. This fundamental technology can
provide both confirmatory and diagnostic value to the pathologist and clinician.
Useful For: Providing information to aid in the diagnosis of medical disorders such as storage
diseases, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy), and primary ciliary dyskinesia
Interpretation: The images and case histories are correlated and interpreted by a pathologist who is
an expert in the field of the suspected diagnoses. Results will be provided by telephone. If requested,
representative images showing diagnostic features will be sent.
Reference Values:
Clinical References: Schroder JA: Diagnostic transmission electron microscopy. Imaging and
Microscopy. 2012. Accessed January 20, 2022. Available at
www.imaging-git.com/science/electron-and-ion-microscopy/diagnostic-transmission-electron-microsco
py
EPU Electrophoresis, Protein, 24 Hour, Urine

82441 Clinical Information: Urine proteins can be grouped into 5 fractions by protein electrophoresis:
-Albumin -Alpha-1 -Alpha-2 -Beta-globulin -Gamma-globulin The urine total protein concentration, the
electrophoretic pattern, and the presence of a monoclonal immunoglobulin light chain may be
characteristic of monoclonal gammopathies such as multiple myeloma, primary systemic amyloidosis,
and light chain deposition disease. The following algorithms are available: -Amyloidosis: Laboratory
Approach to Diagnosis -Multiple Myeloma: Laboratory Screening
Useful For: Monitoring patients with monoclonal gammopathies

Interpretation: A characteristic monoclonal band (M-spike) is often found in the urine of patients
with monoclonal gammopathies. The initial identification of an M-spike or an area of restricted
migration should be followed by immunofixation to identify the immunoglobulin heavy chain and/or
light chain. Immunoglobulin heavy chain fragments as well as free light chains may be seen in the urine
of patients with monoclonal gammopathies. The presence of a monoclonal light chain M-spike of
greater than 1 g/24 hours is consistent with a diagnosis of multiple myeloma or macroglobulinemia. The
presence of a small amount of monoclonal light chain and proteinuria (total protein >3 g/24 hours) that
is predominantly albumin is consistent with amyloidosis (AL) or light chain deposition disease (LCDD).
Because patients with AL and LCDD may have elevated urinary protein without an identifiable
M-spike, urine protein electrophoresis is not considered an adequate screen for these disorders and
immunofixation is also recommended.
Reference Values:
PROTEIN, TOTAL
<229 mg/24 hours
Reference values have not been established for patients <18 years of age.
Reference value applies to 24-hour collection.
ELECTROPHORESIS, PROTEIN
The following fractions, if present, will be reported as mg/24 hours:
Albumin
Alpha-1-globulin
Alpha-2-globulin
Beta-globulin
Gamma-globulin
Clinical References: 1. Abraham RS, Barnidge DR: Protein analysis in the clinical immunology
laboratory. In: Detrick BD, Hamilton RG, Schmitz JL eds. Manual of Molecular and Clinical Laboratory
Immunology. 8th ed. 2016:chap 4 2. Sykes E, Posey Y: Immunochemical characterization of
immunoglobulins in serum, urine, and cerebrospinal fluid. In: Detrick B, Hamilton RG, Schmitz JL, eds.
Molecular and Clinical Laboratory Immunology. 8th ed. Wiley; 2016:chap 9
REPU Electrophoresis, Protein, Random, Urine

60068 Clinical Information: Urine proteins can be grouped into 5 fractions by protein electrophoresis:
-Albumin -Alpha-1-globulin -Alpha-2-globulin -Beta-globulin -Gamma-globulin The urine total protein
concentration, the electrophoretic pattern, and the presence of a monoclonal immunoglobulin light chain
may be characteristic of monoclonal gammopathies such as multiple myeloma, primary systemic
amyloidosis, and light-chain deposition disease. The following algorithms are available: -Amyloidosis:
Laboratory Approach to Diagnosis -Multiple Myeloma: Laboratory Screening
Useful For: Identifying monoclonal gammopathies using random urine specimens

Interpretation: A characteristic monoclonal band (M-spike) is often found in the urine of patients with
monoclonal gammopathies. The initial identification of an M-spike or an area of restricted migration
should be followed by immunofixation to identify the immunoglobulin heavy chains and light chains.
Immunoglobulin heavy chain fragments as well as free light chains may be seen in the urine of patients
with monoclonal gammopathies. The presence of a monoclonal light chain M-spike of greater than 1 g/24
hours is consistent with a diagnosis of multiple myeloma or macroglobulinemia. The presence of a small
amount of monoclonal light chain and proteinuria (total protein >3 g/24 hours) that is predominantly
albumin is consistent with primary systemic amyloidosis (AL) and light-chain deposition disease
(LCDD). Because patients with AL and LCDD may have elevated urinary protein without an identifiable
M-spike, urine protein electrophoresis is not considered an adequate screen for these disorders and
immunofixation is also recommended.
Reference Values:
PROTEIN, TOTAL
No reference values apply to random urine.
ELECTROPHORESIS, PROTEIN
The following fractions, if present, will be reported as mg/dL:
-Albumin
-Alpha-1-globulin
-Alpha-2-globulin
-Beta-globulin
-Gamma-globulin
No reference values apply to random urines.
Clinical References: 1. Abraham RS, Barnidge DR: Protein analysis in the clinical immunology
laboratory. In: Detrick B, Hamilton RG, Schmitz JL, eds. Molecular and Clinical Laboratory
Immunology. 8th ed Wiley; 2016:chap 4 2. Keren DF, Humphrey RL: Clinical indications and
applications for serum and urine protein electrophoresis and immunofixation. In: Detrick B, Hamilton
RG, Schmitz JL, eds. Molecular and Clinical Laboratory Immunology. 8th ed. Wiley; 2016:chap 8
SPEP Electrophoresis, Protein, Serum

97408 Clinical Information: This profile includes both total protein and protein electrophoresis. The serum
proteins can be grouped into 5 fractions by protein electrophoresis: -Albumin, which represents almost
two-thirds of the total serum protein -Alpha-1, composed primarily of alpha-1-antitrypsin (A1AT), an
alpha-1-acid glycoprotein -Alpha-2, composed primarily of alpha-2-macroglobulin and haptoglobin -Beta,
composed primarily of transferrin and C3 -Gamma, composed primarily of immunoglobulins The
concentration of these fractions and the electrophoretic pattern may be characteristic of diseases such as
monoclonal gammopathies, A1AT deficiency disease, nephrotic syndrome, and inflammatory processes
associated with infection, liver disease, and autoimmune diseases.
Useful For: Screening patients with suspected monoclonal gammopathies Diagnosis of monoclonal
gammopathies, when used in conjunction with matrix-assisted laser desorption/ionization-time of flight
mass spectrometry (MALDI-TOF MS) and free light chain analysis
Interpretation: Monoclonal Gammopathies: A characteristic monoclonal band (M-spike) is often

found on serum protein electrophoresis (SPE) in the gamma-globulin region and, more rarely, in the
beta or alpha-2 regions. The finding of a M-spike, restricted migration, or hypogammaglobulinemic
SPE pattern is suggestive of a possible monoclonal protein and should be confirmed by
immunoaffinity-purification matrix-assisted laser desorption/ionization-time of flight mass spectrometry
(MALDI-TOF MS) to identify any immunoglobulin heavy or light chains. A MPSU / Monoclonal
Protein Study, 24 Hour, Urine is suggested for first-time M-spike patients to assess for renal disease that
can be associated with an M-spike. -A monoclonal IgG or IgA greater than 3 g/dL is consistent with
multiple myeloma (MM). -A monoclonal IgG or IgA less than 3 g/dL may be consistent with
monoclonal gammopathy of undetermined significance (MGUS), primary systemic amyloidosis, early
or treated myeloma, as well as a number of other monoclonal gammopathies. -A monoclonal IgM
greater than 3 g/dL is consistent with macroglobulinemia. -The initial identification of a serum M-spike
greater than 1.5 g/dL on SPE should be followed by MPSU / Monoclonal Protein Study, 24 Hour,
Urine. -The initial identification of an IgM, IgA, or IgG M-spike greater than 4 g/dL, greater than 5
g/dL, and greater than 6 g/dL, respectively, should be followed by VISCS / Viscosity, Serum. After the
initial identification of an M-spike, quantitation of the M-spike on follow-up SPE can be used to
monitor the monoclonal gammopathy. However, if the monoclonal protein falls within the beta region
(most commonly an IgA or an IgM) quantitative immunoglobulin levels may be more a useful tool to
follow the monoclonal protein level than SPE. A decrease or increase of the M-spike that is greater than
0.5 g/dL is considered a significant change. Patients suspected of having a monoclonal gammopathy
may have normal serum SPE patterns. Approximately 11% of patients with MM have a completely
normal serum SPE, with the monoclonal protein only identified by MALDI-TOF MS. Approximately
8% of MM patients have hypogammaglobulinemia without a quantifiable M-spike on SPE but
identified by MALDI-TOF MS. Accordingly, a normal serum SPE does not rule out the disease and
should not be used to screen for the disorder. The DMOGA / Monoclonal Gammopathy, Diagnostic,
Serum, which includes MALDI-TOF MS, and serum free light chains, conforms to the International
Myeloma Working Group (IMWG) guidelines for screening and should be performed if there is clinical
suspicion. Other Abnormal SPE Findings: -A qualitatively normal but elevated gamma fraction
(polyclonal hypergammaglobulinemia) is consistent with infection, liver disease, or autoimmune
disease. -A depressed gamma fraction (hypogammaglobulinemia) is consistent with immune deficiency
and can also be associated with primary amyloidosis or nephrotic syndrome. -A decreased albumin (<2
g/dL), increased alpha-2 fraction (>1.1 g/dL), and decreased gamma fraction (<1 g/dL) is consistent
with nephrotic syndrome, and when seen in an adult older than 40 years, should be followed by MPSU /
Monoclonal Protein Study, 24 Hour, Urine. -In the hereditary deficiency of a protein (eg,
agammaglobulinemia, alpha-1-antitrypsin [A1AT] deficiency, hypoalbuminemia), the affected fraction
is faint or absent. -An absent alpha-1 fraction is consistent with A1AT deficiency disease and should be
followed by a quantitative A1AT assay (AAT / Alpha-1- Antitrypsin, Serum).
Reference Values:
TOTAL PROTEIN
> or =1 year: 6.3-7.9 g/dL
PROTEIN ELECTROPHORESIS
Albumin: 3.4-4.7 g/dL
Alpha-1-globulin: 0.1-0.3 g/dL
Beta-globulin: 0.7-1.2 g/dL
Gamma-globulin: 0.6-1.6 g/dL
An interpretive comment is provided with the report.
Reference values have not been established for patients that are <16 years of age.
Clinical References: 1. Kyle RA, Katzmann JA, Lust JA, Dispenzieri A: Clinical indications and
applications of electrophoresis and immunofixation. In: Rose NR, Hamilton RG, Detrick B, eds. Manual
of Clinical Laboratory Immunology. 6th ed. ASM Press. 2002:66-70 2. Mills JR, Kohlhagen MC, Dasari
S, et al: Comprehensive assessment of M-Proteins using nanobody enrichment coupled to MALDI-TOF
mass spectrometry. Clin Chem. 2016 Oct;62(10):1334-1344 3. Milani P, Murray DL, Barnidge DR, et al:
The utility of MASS-FIX to detect and monitor monoclonal proteins in the clinic, Am J Hematol. 2017
Aug;92(8):772-779. doi: 10.1002/ajh.24772
PEL Electrophoresis, Protein, Serum

800301 Clinical Information: Serum proteins can be grouped into 5 fractions by protein electrophoresis:
-Albumin, which represents almost two-thirds of the total serum protein -Alpha-1, composed primarily of
alpha-1-antitrypsin (A1AT), an alpha-1-acid glycoprotein -Alpha-2, composed primarily of
alpha-2-macroglobulin and haptoglobin -Beta, composed primarily of transferrin and C3 -Gamma,
composed primarily of immunoglobulins The concentration of these fractions and the electrophoretic
pattern may be characteristic of diseases such as monoclonal gammopathies, A1AT deficiency disease,
nephrotic syndrome, and inflammatory processes associated with infection, liver disease, and autoimmune
diseases.
Useful For: Monitoring patients with monoclonal gammopathies Diagnosis of monoclonal

gammopathies
Interpretation: Monoclonal Gammopathies: -A characteristic monoclonal band (M-spike) is often

found on protein electrophoresis (PEL) in the gamma-globulin region and more rarely in the beta or
alpha-2 regions. The finding of a M-spike, restricted migration, or hypogammaglobulinemic PEL pattern
is suggestive of a possible monoclonal protein and should be followed by MPSU / Monoclonal Protein
Study, 24 Hour, Urine, which includes immunofixation (IF), to identify the immunoglobulin heavy chain
and/or light chain. -A monoclonal IgG or IgA greater than 3 g/dL is consistent with multiple myeloma
(MM). -A monoclonal IgG or IgA less than 3 g/dL may be consistent with monoclonal gammopathy of
undetermined significance (MGUS), primary systemic amyloidosis, early or treated myeloma, as well as a
number of other monoclonal gammopathies. -A monoclonal IgM greater than 3 g/dL is consistent with
macroglobulinemia. -The initial identification of a serum M-spike greater than 1.5 g/dL on PEL should be
followed by MPSU / Monoclonal Protein Study, 24 Hour, Urine. -The initial identification of an IgM,
IgA, or IgG M-spike greater than 4 g/dL, greater than 5 g/dL, and greater than 6 g/dL, respectively, should
be followed by VISCS / Viscosity, Serum. -After the initial identification of an M-spike, quantitation of
the M-spike on follow-up PEL can be used to monitor the monoclonal gammopathy. However, if the
monoclonal protein falls within the beta region (most commonly an IgA or an IgM) quantitative
immunoglobulin levels may be more a useful tool to follow the monoclonal protein level than PEL. A
decrease or increase of the M-spike that is greater than 0.5 g/dL is considered a significant change.
-Patients suspected of having a monoclonal gammopathy may have normal serum PEL patterns.
Approximately 11% of patients with MM have a completely normal serum PEL, with the monoclonal
protein only identified by IF. Approximately 8% of MM patients have hypogammaglobulinemia without a
quantifiable M-spike on PEL but identified by IF. Accordingly, a normal serum PEL does not rule out the
disease and should not be used to screen for the disorder. The MPSS / Monoclonal Protein Study, Serum,
which includes immunofixation, and FLCP / Immunoglobulin Free Light Chains, Serum should be done
to screen if the clinical suspicion is high. Other Abnormal PEL Findings: -A qualitatively normal but
elevated gamma fraction (polyclonal hypergammaglobulinemia) is consistent with infection, liver disease,
or autoimmune disease. -A depressed gamma fraction (hypogammaglobulinemia) is consistent with
immune deficiency and can also be associated with primary amyloidosis or nephrotic syndrome. -A
decreased albumin (<2 g/dL), increased alpha-2 fraction (>1.1 g/dL), and decreased gamma fraction (<1
g/dL) is consistent with nephrotic syndrome, and when seen in an adult older than 40 years, should be
followed by MPSU / Monoclonal Protein Study, 24 Hour, Urine. -In the hereditary deficiency of a protein
(eg, agammaglobulinemia, alpha-1-antitrypsin [A1AT] deficiency, hypoalbuminemia), the affected
fraction is faint or absent. -An absent alpha-1 fraction is consistent with A1AT deficiency disease and
should be followed by a quantitative A1AT assay (AAT / Alpha-1- Antitrypsin, Serum).
Reference Values:
PROTEIN, TOTAL
> or =1 year: 6.3-7.9 g/dL
PROTEIN ELECTROPHORESIS
Albumin: 3.4-4.7 g/dL
Beta-globulin: 0.7-1.2 g/dL
Gamma-globulin: 0.6-1.6 g/dL
An interpretive comment is provided with the report.
Reference values have not been established for patients that are less than 16 years of age.
Clinical References: 1. Sykes E, Posey Y: Immunochemical characterization of immunoglobulins

in serum, urine, and cerebrospinal fluid. In: Detrick B, Schmitz JL, Hamilton RG, eds. Manual of
Molecular and Clinical Laboratory Immunology. 8th ed. ASM Press; 2016:89-100 2. Katzmann JA,
Keren DF: Strategy for detecting and following monoclonal gammopathies. In: Detrick B, Schmitz JL,
Hamilton RG, eds. Manual of Molecular and Clinical Laboratory Immunology. 8th ed. ASM Press;
2016:112-124 3. Kyle RA, Katzmann JA, Lust JA, Dispenzieri A: Clinical indications and applications
of electrophoresis and immunofixation. In: Rose NR, Hamilton RG, Detrick B, eds. Manual of Clinical
Laboratory Immunology. 6th ed. ASM Press; 2002:66-70
ELM Elm, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to elm Defining the allergen responsible for

Reference Values:
0 Negative

apply to all ages.
EMR EM, Renal Biopsy (Bill Only)

EMICZ Emicizumab, Modified One Stage Assay Factor VIII, Plasma

610074 Clinical Information: Emicizumab (Hemlibra) is a bi-specific antibody directed toward factor IXa
and factor X, bridging in close enough proximity to mimic and replace factor VIII. Emicizumab has been
approved by the Food and Drug Administration for prevention of bleeding in hemophilia A patients, both
with and without inhibitors to factor VIII. In clinical trials, clinical outcomes were achieved without the
measurement of plasma emicizumab levels to inform and make management decisions. However, in
selected clinical situations, measurement of drug level would be useful. (eg, For patients experiencing
break through bleeding episodes, if levels are not detectable or below the published [observed] ranges,
this may imply noncompliance or development of an antidrug antibody.)
Useful For: Monitoring compliance or potential development of an antidrug antibody This assay is not
indicated for monitoring factor VIII infusions or for making a diagnosis of hemophilia.
Interpretation: Therapeutic ranges for plasma emicizumab concentrations have not been established.
Trough plasma concentrations observed during clinical trials ranged between 35 and 55 micrograms/mL.
Reference Values:
<1 mcg/mL
Clinical References: 1. Knight T, Callaghan MU: The role of emicizumab, a bispecific factor IXa-
and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A.
Ther Adv Hematol. 2018; 9:319-334. doi: 10.1177/2040620718799997 2. Jenkins PV, Bowyer A,
Burgess C, et al: Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia
Centre Doctors' Organisation guideline. Haemophilia. 2020;26:151-155. doi: 10.1111/hae.13903 3.
Jonsson F, Schmitt C, Petry C, Mercier F, Frey N, Retout S: Exposure-response Modeling of Emicizumab
for the Prophylaxis of Bleeding in Hemophilia A Patients with and without Inhibitors against Factor VIII.
Poster PB0325 presented at: The XXVII Congress of the International Society on Thrombosis and
Haemostasis. July 6-10, 2019; Melbourne, Australia 4. Pipie SW, Shima M, Lehle M, et al: Efficacy,
safety and pharmacokinetics emicizumab prophylaxis given every 4 weeks in people with haemophilia
(HAVEN 4): a multicenter, open-label, non-randomized phase 3 study. Lancet Haematol.
2019;6(6):e295-e305. doi: 10.1016/S2352-3026(19)30054-7
FENC Encainide (Enkaid), ODE and MODE

Encainide:
O-Demethylencainide (ODE):
3-Methoxy-ODE (MODE):
10% of patients do not form therapeutic concentrations of the active metabolites, ODE and MODE. In
these patients the recommended range for the encainide concentration is 300 - 1200 ng/mL.
ENS2 Encephalopathy, Autoimmune/Paraneoplastic Evaluation,

92116 Serum
Clinical Information: Autoimmune encephalopathies extend beyond the classically recognized
clinical and radiological spectrum of "limbic encephalitis." They encompass a diversity of neurological
presentations with subacute or insidious onset, including confusional states, psychosis, delirium,
memory loss, hallucinations, movement disorders, sensory or motor complaints, seizures, dyssomnias,
ataxias, eye movement problems, nausea, vomiting, inappropriate antidiuresis, coma, dysautonomias, or
hypoventilation. A diagnosis of autoimmune encephalopathy should be suspected on the basis of
clinical course, coexisting autoimmune disorder (eg, thyroiditis, diabetes), serological evidence of
autoimmunity, spinal fluid evidence of intrathecal inflammation, neuroimaging or
electroencephalographic abnormalities, and favorable response to trial of immunotherapy. Detection of
one or more neural autoantibodies aids the diagnosis of autoimmune encephalopathy and may guide a
search for cancer. Pertinent autoantibody specificities include: -Neurotransmitter receptors and ion
channels such as neuronal voltage-gated potassium channels (and interacting synaptic and axonal
proteins, leucine-rich glioma inactivated 1 [LGI1] protein and contactin associated protein 2
[CASPR2]), ionotropic glutamate receptors (N-methyl-D-aspartate receptor [NMDA] and
2-amino-3-[5-methyl-3-oxo-1,2- oxazol-4-yl] propanoic acid [AMPA]), metabotropic
gamma-aminobutyric acid (GABA)-B receptors -Enzymes, signaling molecules, and RNA-regulatory
proteins in the cytoplasm and nucleus of neurons (glutamic acid decarboxylase 65 [GAD65], collapsin
response-mediator protein-5 neuronal [CRMP-5], antineuronal nuclear antibody-type 1 [ANNA-1], and
ANNA-2) Importantly, autoimmune encephalopathies are reversible. Misdiagnosis as a progressive
(currently irreversible) neurodegenerative condition is not uncommon and has devastating consequences
for the patient. Clinicians must consider the possibility of an autoimmune etiology in the differential
diagnoses of encephalopathy. For example, a potentially reversible disorder justifies a trial of
immunotherapy for the detection of neural autoantibodies in patients presenting with symptoms of
personality change, executive dysfunction, and psychiatric manifestations. A triad of clues helps to
identify patients with an autoimmune encephalopathy: 1) Clinical presentation (subacute symptoms,
onset rapidly progressive course, and fluctuating symptoms) and radiological findings consistent with
inflammation 2) Detection of neural autoantibodies in serum or cerebrospinal fluid (CSF) 3) Favorable
response to a trial of immunotherapy Detection of neural autoantibodies in serum or CSF informs the
physician of a likely autoimmune etiology, and may heighten suspicion for a paraneoplastic basis and
guide the search for cancer. Neurological accompaniments of neural autoantibodies are generally not
syndromic, but diverse and multifocal. For example, LGI1 antibody was initially considered to be
specific for autoimmune limbic encephalitis, but over time other presentations have been reported,
including rapidly progressive course of cognitive decline mimicking neurodegenerative dementia.
Comprehensive antibody testing is more informative than selective testing for 1 or 2 neural antibodies.
Some antibodies strongly predict an underlying cancer. For example, small-cell lung carcinoma
(ANNA-1, CRMP-5-IgG), ovarian teratoma (NMDA-R), and thymoma (CRMP-5 IgG). An individual
patient's profile autoantibody may be informative for a specific cancer type. For example, in a patient
presenting with encephalitis who has CRMP 5 IgG, and subsequent reflex reveals muscle acetylcholine
receptor (AChR) binding antibody, the findings should raise a high suspicion for thymoma. Testing of
CSF for autoantibodies is particularly helpful when serum testing is negative, though in some
circumstances testing both serum and CSF simultaneously is pertinent. Testing of CSF is recommended
for some antibodies in particular (such as NMDA-R antibody and glial fibrillary acidic protein
[GFAP]-IgG) because CSF testing is both more sensitive and specific. In contrast, serum testing for
LGI1 antibody is more sensitive than CSF testing.
Useful For: Evaluating new onset encephalopathy (noninfectious or metabolic) comprising confusional
states, psychosis, delirium, memory loss, hallucinations, movement disorders, sensory or motor
complaints, seizures, dyssomnias, ataxias, nausea, vomiting, inappropriate antidiuresis, coma,
dysautonomias, or hypoventilation in serum specimens The following accompaniments should increase of
suspicion for autoimmune encephalopathy: -Headache -Autoimmune stigmata (personal or family history
or signs of diabetes mellitus, thyroid disorder, vitiligo, poliosis [premature graying], myasthenia gravis,
rheumatoid arthritis, systemic lupus erythematosus) -History of cancer -Smoking history (over 20
pack-years) or other cancer risk factors -Inflammatory cerebral spinal fluid (or isolated protein elevation)
-Neuroimaging signs suggesting inflammation Evaluating limbic encephalitis (noninfectious) Directing a
focused search for cancer Investigating encephalopathy appearing in the course or wake of cancer therapy
and not explainable by metastasis or drug effect
Interpretation: Neuronal, glial, and muscle autoantibodies are valuable serological markers of
autoimmune encephalopathy and of a patient's immune response to cancer. These autoantibodies are
usually accompanied by subacute neurological symptoms and signs are not found in healthy subjects. It is
not uncommon for more than 1 of the following autoantibody specificities to be detected in patients with
an autoimmune encephalopathy: -Plasma membrane autoantibodies: N-methyl-D-aspartate (NMDA)
receptor; 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid (AMPA) receptor; gamma-amino
butyric acid (GABA-B) receptor; neuronal ACh receptor. These are all potential effectors of neurological
dysfunction. -Neuronal nuclear autoantibodies, type 1 (ANNA-1), type 2 (ANNA-2), or type 3 (ANNA-3)
-Neuronal or muscle cytoplasmic antibodies: amphiphysin, Purkinje cell antibodies (PCA-1) and PCA-2,
CRMP-5, GAD65, or striational
Reference Values:
AEESI Encephalopathy, Interpretation, Medical interpretation NA

S
ANN1S Anti-Neuronal Nuclear Ab, Type IFA

1
2

3

IG5IS IgLON5 IFA, S IFA Negative
NIFIS NIF IFA, S IFA Negative
PCABP Purkinje Cell Cytoplasmic Ab IFA

Type 1

Type 2

Type Tr

Binding Ab
AINCS Alpha Internexin CBA, S CBA Negative
AMPIS AMPA-R Ab IF Titer Assay,IFA

S
S

S

Assay, S
IG5CS IgLON5 CBA, S CBA Negative
IG5TS IgLON5 IFA Titer, S IFA
NFHCS NIF Heavy Chain CBA, S CBA Negative
NIFTS NIF IFA Titer, S IFA
NFLCS NIF Light Chain CBA, S CBA Negative

Assay, S
abbreviations: Immunofluorescence
assay (IFA) Cell-binding assay
(CBA) Western blot (WB)
Radioimmunoassay (RIA)
Immunoblot (IB) Neuron-restricted
patterns of IgG staining that do not
fulfill criteria for ANNA-1,
ANNA-2, CRMP-5-IgG, PCA-1,
PCA-2, or PCA-Tr may be reported
as "unclassified anti-neuronal IgG."
weeks). This supplemental testing
is recommended in cases of chorea,
Western blot.
Clinical References: 1. McKeon A, Lennon, VA, Pittock, SJ: Immunotherapy responsive dementias
and encephalopathies. Continuum (Minneap Minn). 2010 Apr;16(2 Dementia):80-101 2. Lucchinetti CF,
Kimmel DW, Lennon VA: Paraneoplastic and oncological profiles of patients seropositive for type 1
anti-neuronal nuclear autoantibodies. Neurology. 1998;50:652-657 3. Pittock SJ, Yoshikawa H, Ahlskog
JE, et al: Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal and spinal cord
dysfunction. Mayo Clin Proc. 2006 Sep;81(9):1207-1214 4. Lancaster E, Martinez-Hernandez E, Dalmau
J: Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011 Jul
12;77(2):179-189 5. Klein CJ, Lennon VA, Aston PA, et al: Insights from LGI1 and CASPR2 potassium
channel complex autoantibody subtyping. JAMA Neurol. 2013 Feb;70(2):229-234
ENC2 Encephalopathy, Autoimmune/Paraneoplastic Evaluation,

92117 Spinal Fluid
Clinical Information: Autoimmune encephalopathies extend beyond the classically recognized
clinical and radiological spectrum of "limbic encephalitis." They encompass a diversity of neurological
presentations with subacute or insidious onset, including confusional states, psychosis, delirium, memory
loss, hallucinations, movement disorders, sensory or motor complaints, seizures, dyssomnias, ataxias, eye
movement problems, nausea, vomiting, inappropriate antidiuresis, coma, dysautonomias, or
hypoventilation. A diagnosis of autoimmune encephalopathy should be suspected on the basis of clinical
course, coexisting autoimmune disorder (eg, thyroiditis, diabetes), serological evidence of autoimmunity,
spinal fluid evidence of intrathecal inflammation, neuroimaging or electroencephalographic abnormalities,
and favorable response to trial of immunotherapy. Detection of one or more neural autoantibodies aids the
diagnosis of autoimmune encephalopathy and may guide a search for cancer. Pertinent autoantibody
specificities include: -Neurotransmitter receptors and ion channels such as neuronal voltage-gated
potassium channels (and interacting synaptic and axonal proteins, leucine-rich glioma inactivated 1
[LGI1] protein and contactin associated protein 2 [CASPR2]), ionotropic glutamate receptors
(N-methyl-D-aspartate receptor [NMDA] and 2-amino-3-[5-methyl-3-oxo-1,2- oxazol-4-yl] propanoic
acid [AMPA]), metabotropic gamma-aminobutyric acid (GABA)-B receptors -Enzymes, signaling
molecules, and RNA-regulatory proteins in the cytoplasm and nucleus of neurons (glutamic acid
decarboxylase 65 [GAD65], collapsin response-mediator protein-5 neuronal [CRMP-5], antineuronal
nuclear antibody-type 1 [ANNA-1], and ANNA-2) Importantly, autoimmune encephalopathies are
reversible. Misdiagnosis as a progressive (currently irreversible) neurodegenerative condition is not
uncommon and has devastating consequences for the patient. Clinicians must consider the possibility of
an autoimmune etiology in the differential diagnoses of encephalopathy. For example, a potentially
reversible disorder justifies a trial of immunotherapy for the detection of neural autoantibodies in patients
presenting with symptoms of personality change, executive dysfunction, and psychiatric manifestations. A
triad of clues helps to identify patients with an autoimmune encephalopathy: 1) Clinical presentation
(subacute symptoms, onset rapidly progressive course, and fluctuating symptoms) and radiological
findings consistent with inflammation 2) Detection of neural autoantibodies in serum or cerebrospinal
fluid (CSF) 3) Favorable response to a trial of immunotherapy Detection of neural autoantibodies in
serum or CSF informs the physician of a likely autoimmune etiology and may heighten suspicion for a
paraneoplastic basis and guide the search for cancer. Neurological accompaniments of neural
autoantibodies are generally not syndromic, but diverse and multifocal. For example, LGI1 antibody was
initially considered to be specific for autoimmune limbic encephalitis, but over time other presentations
have been reported, including rapidly progressive course of cognitive decline mimicking
neurodegenerative dementia. Comprehensive antibody testing is more informative than selective testing
for 1 or 2 neural antibodies. Some antibodies strongly predict an underlying cancer. For example,
small-cell lung carcinoma (ANNA-1; CRMP-5-IgG), ovarian teratoma (NMDA-R), and thymoma
(CRMP-5-IgG). An individual patient's profile autoantibody may be informative for a specific cancer
type. For example, in a patient presenting with encephalitis who has CRMP-5-IgG, and subsequent reflex
reveals muscle acetylcholine receptor (AChR) binding antibody, the findings should raise a high suspicion
for thymoma. Testing of CSF for autoantibodies is particularly helpful when serum testing is negative,
though in some circumstances testing both serum and CSF simultaneously is pertinent. Testing of CSF is
recommended for some antibodies in particular (such as NMDA-R antibody and glial fibrillary acidic
protein [GFAP]-IgG) because CSF testing is both more sensitive and specific. In contrast, serum testing
for LGI1 antibody is more sensitive than CSF testing.
Useful For: Evaluating new onset encephalopathy (noninfectious or metabolic) comprising

confusional states, psychosis, delirium, memory loss, hallucinations, movement disorders, sensory or
motor complaints, seizures, dyssomnias, ataxias, nausea, vomiting, inappropriate antidiuresis, coma,
dysautonomias, or hypoventilation in spinal fluid specimens The following accompaniments should
increase of suspicion for autoimmune encephalopathy: -Headache -Autoimmune stigmata (personal or
family history or signs of diabetes mellitus, thyroid disorder, vitiligo, poliosis [premature graying],
myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus) -History of cancer -Smoking
history (over 20 pack-years) or other cancer risk factors -Inflammatory cerebrospinal fluid (or isolated
protein elevation) -Neuroimaging signs suggesting inflammation Evaluating limbic encephalitis
(noninfectious) Directing a focused search for cancer Investigating encephalopathy appearing in the
course or wake of cancer therapy and not explainable by metastasis or drug effect
Interpretation: Neuronal, glial, and muscle autoantibodies are valuable serological markers of
autoimmune encephalopathy and of a patient's immune response to cancer. These autoantibodies are
usually accompanied by subacute neurological symptoms and signs are not found in healthy subjects. It
is not uncommon for more than 1 of the following autoantibody specificities to be detected in patients
with an autoimmune encephalopathy: -Plasma membrane autoantibodies: These are all potential
effectors of neurological dysfunction: N-methyl-D-aspartate (NMDA) receptor;
2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid (AMPA) receptor; gamma-amino butyric
acid (GABA-B) receptor; neuronal ACh receptor. -Neuronal nuclear autoantibodies: type 1 (ANNA-1),
type 2 (ANNA-2), or type 3 (ANNA-3) -Neuronal or muscle cytoplasmic antibodies: amphiphysin,
Purkinje cell antibodies (PCA-1 and PCA-2), CRMP-5, GAD65, or striational.
Reference Values:
AEECI Encephalopathy, Interpretation, Medical interpretation NA

CSF
ANN1C Anti-Neuronal Nuclear Ab, TypeIFA

1

2

3
GD65C GAD65 Ab Assay, CSF RIA < or =0.02 nmol/L

Reference values apply to
all ages.

IG5IC IgLON5 IFA, CSF IFA Negative
NIFIC NIF IFA, CSF IFA Negative
PCTRC Purkinje Cell Cytoplasmc Ab IFA

Type Tr
PCA1C Purkinje Cell Cytoplasmic Ab IFA

Type 1

Type 2
AINCC Alpha Internexin CBA, CSFCBA Negative

Assay, CSF

CSF

CSF

Assay, CSF
IG5CC IgLON5 CBA, CSF CBA Negative
IG5TC IgLON5 IFA Titer, CSF IFA
NFLCC NIF Light Chain CBA, CSF CBA Negative
NMDIC NMDA-R Ab IF Titer IFA Negative at

Assay, CSF
PCTBC PCA-Tr Immunoblot, CSF IB Negative *Methodology

abbreviations:
Immunofluorescence assay (IFA)
for ANNA-1, ANNA-2, ANNA-3,
detectable by recombinant
CRMP-5 Western blot analysis will
be done on request on stored spinal
fluid (held 4 weeks). This
Western blot.
Clinical References: 1. McKeon A, Lennon, VA, Pittock, SJ: Immunotherapy responsive

dementias and encephalopathies. Continuum (Minneap Minn). 2010 Apr;16(2 Dementia)::80-101 2.
Lucchinetti CF, Kimmel DW, Lennon VA: Paraneoplastic and oncological profiles of patients
seropositive for type 1 anti-neuronal nuclear autoantibodies. Neurology. 1998 Mar;50(3):652-657 3.
Pittock SJ, Yoshikawa H, Ahlskog JE, et al: Glutamic acid decarboxylase autoimmunity with brainstem,
extrapyramidal and spinal cord dysfunction. Mayo Clin Proc. 2006 Sep;81(9):1207-1214 4. Lancaster E,
Martinez-Hernandez E, Dalmau J: Encephalitis and antibodies to synaptic and neuronal cell surface
proteins. Neurology. 2011 Jul;77(2):179-189 5. Klein CJ, Lennon VA, Aston PA, et al: Insights from
LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol. 2013
Feb;70(2):229-234
ESTUF Endometrial Stromal Tumors (EST), 7p15 (JAZF1), 6p21.32

35851 (PHF1), 17p13.3 (YWHAE) Rearrangement, FISH, Tissue
Clinical Information: Endometrial stromal tumors (EST) arise from the uterus and include the
benign endometrial stromal nodule (ESN) and infiltrative endometrial stromal sarcoma (ESS). These
tumors are characterized by a translocation that fuses JAZF1 at 7p15 to JJAZ1 at 17q21 or a variant 6;7
translocation involving JAZF1 and PHF1. Published literature employing FISH and reverse
transcriptase PCR (RT-PCR) suggests rearrangement of JAZF1 occurs in approximately 76% of ESN
and approximately 58% of ESS. JAZF1 is not generally considered to be involved in the genetic
mechanism of the high-grade undifferentiated endometrial sarcoma (UES), although rarely some cases
of UES are positive for JAZF1, which may reflect the presence of an ESS component. For PHF1
disruption, a study of 94 EST demonstrated the following: -PHF1/JAZF1 fusion in 4 primary ESS
-PHF1/EPC1 fusion in 2 primary ESS and 1 extrauterine ESS -PHF1 rearrangement without a known
partner in 6 primary or metastatic ESS and 1 extrauterine ESS JAZF1/JJAZ1, PHF1/JAZF1 and
PHF1/EPC1 fusions were mutually exclusive in individual patients.(4) No rearrangement of PHF1 was
found in ESN, UES, or non-EST tumors in the differential diagnosis. These results indicate that PHF1
can rearrange with both known and unknown partners in addition to JAZF1 and is potentially specific
for ESS. In high-grade ESS, a recurrent t(10;17)(q22;p13) resulting in fusion of YWHAE (also called
14-3-3epsilon at 17p13.3 with either FAM22A or FAM22B was identified. In contrast, JAZF1
rearrangements are typically observed in low-grade ESS. JAZF1 and YWHAE rearrangements are
mutually exclusive and have distinct gene expression profiles. YWHAE rearrangement is potentially
specific for high-grade ESS as no YWHAE disruption has been reported in other uterine or nonuterine
mesenchymal tumors. The clinical utility of identifying JAZF1 rearrangement is mainly to address the
differential diagnostic dilemma that occurs when ESS are present as metastatic lesions or exhibit variant
morphology. In JAZF1-negative EST cases, reflex genetic analysis to identify PHF1 or YWHAE
rearrangement increases the diagnostic sensitivity for EST. In addition, confirmation of YWHAE
rearrangement may have prognostic implications as YWHAE defines a distinct, clinically more
aggressive and histologically higher grade subgroup of ESS compared to those with JAZF1
rearrangements.
Useful For: Supporting the diagnosis of endometrial stromal tumors when used in conjunction with an
anatomic pathology consultation
the normal cutoff for any given probe. Detection of an abnormal clone likely indicates a diagnosis of an
endometrial stromal tumor of various subtypes. The absence of an abnormal clone does not rule out the
Reference Values:
Clinical References: 1. Koontz J, Soreng AL, Nucci M, et al: Frequent fusion of the JAZF1 and
JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci USA 2001;98(11):6348-6353 2. Nucci R,
Harburger D, Koontz J, et al: Molecular analysis of the JAZF1-JJAZ1 gene fusion by RT-PCR and
fluorescence in situ hybridization in endometrial stromal neoplasms. Am J Surg Pathol 2007;31(1):65-70
3. Huang HY, Ladanyi M, Soslow RA: Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial
stromal neoplasms with classic and variant histology-evidence for genetic heterogeneity. Am J Surg
Pathol 2004;28(2):224-232 4. Chiang S, Ali R, Melnyk N, et al: Frequency of known gene
rearrangements in endometrial stromal tumors. Am J Surg Pathol 2011;35(9):1364-1372 5. Lee CH,
Marino-Enriquez A, Ou W, et al: The clinicopathologic features of YWHAE-FAM22 endometrial stromal
sarcomas: A histologically high-grade and clinically aggressive tumor. Am J Surg Pathol
2012;36(5):641-653 6. Panagopoulos I, Mertens F, Griffin CA, et al: An endometrial stromal sarcoma cell
line with the JAZF1/PHF1 chimera. Cancer Genet Cytogenet 2008 Sep;185(2):74-77 7. Lee CH, Ou WB,
Marino-Enriquez A, et al: 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma. Proc Natl
Acad Sci U S A 2012;109(3):929-934 8. Micci F, Panagopoulos I, Bjerkehagen B, et al: Consistent
rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1
in endometrial stromal sarcoma. Cancer Res 2006;66(1):107-112 9. Gebre-Medhin S, Nord KH, Moller E,
et al: Recurrent rearrangement of the PHF1 gene in ossifying fibromyxoid tumors. Am J Pathol
2012;181(3):1069-1077
EMA Endomysial Antibodies, IgA, Serum

9360 Clinical Information: Circulating IgA endomysial antibodies are present in 70% to 80% of patients
with dermatitis herpetiformis or celiac disease, and in nearly all such patients who have high grade
gluten-sensitive enteropathy and are not adhering to a gluten-free diet. Because of the high specificity of
endomysial antibodies for celiac disease, this test may obviate the need for multiple small bowel biopsies
to verify the diagnosis. This may be particularly advantageous in the pediatric population, including the
evaluation of children with failure to thrive.
Useful For: Analysis of IgA-endomysial antibodies for the diagnosis of dermatitis herpetiformis and
celiac disease Monitoring adherence to gluten-free diet in patients with dermatitis herpetiformis and
celiac disease
Interpretation: The finding of IgA-endomysial antibodies (EMA) is highly specific for dermatitis
herpetiformis or celiac disease. The titer of IgA-EMA generally correlates with the severity of
gluten-sensitive enteropathy. If patients strictly adhere to a gluten-free diet, the titer of IgA-EMA should
begin to decrease within 6 to 12 months of onset of dietary therapy. Occasionally, the staining results
cannot be reliably interpreted as positive or negative because of strong smooth muscle staining, weak
EMA staining or other factors.Â In these cases, the results will be reported as "indeterminate" and
additional testing is recommended. For more informationÂ see TTGA / Tissue Transglutaminase
Antibody, IgA, Serum and IGA / Immunoglobulin A (IgA), Serum.
Reference Values:
Negative in normal individuals; also negative in dermatitis herpetiformis or celiac disease patients
adhering to gluten-free diet.
Clinical References: 1. Peters MS, McEvoy MT: IgA antiendomysial antibodies in dermatitis
herpetiformis. J Am Acad Dermatol. 1989 Dec;21(6):1225-1231 2. Chorzelski TP, Buetner EH, Sulej J,
et al: IgA anti-endomysium antibody. A new immunological marker of dermatitis herpetiformis and
coeliac disease. Br J Dermatol. 1984 Oct;111(4):395-402 3. Kapuscinska A, Zalewski T, Chorzelski TP,
et al: Disease specificity and dynamics of changes in IgA class anti-endomysial antibodies in celiac
disease. J Pediatr Gastroenterol Nutr. 1987 Jul-Aug;6(4):529-534. doi:
10.1097/00005176-198707000-00006 4. Elwenspoek MMC, Jackson J, Dawson S, et al: Accuracy of
potential diagnostic indicators for coeliac disease: a systematic review protocol. BMJ Open. 2020 Oct
5;10(10):e038994. doi: 10.1136/bmjopen-2020-038994
EMAT Endomysial Antibodies, IgA, Titer, Serum

65091 Clinical Information: Circulating IgA endomysial antibodies are present in 70% to 80% of patients
endomysial antibodies for celiac disease, the test may obviate the need for multiple small bowel
biopsies to verify the diagnosis. This may be particularly advantageous in the pediatric population,
including the evaluation of children with failure to thrive.
Useful For: Confirmation of a positive IgA-endomysial antibodies result

Interpretation: The finding of IgA-endomysial antibodies (EMA) is highly specific for dermatitis
herpetiformis or celiac disease. The titer of IgA-EMA generally correlates with the severity of
gluten-sensitive enteropathy. If patients strictly adhere to a gluten-free diet, the titer of IgA-EMA should
EMA staining, or other factors. In these cases, the results will be reported as "indeterminate," and
additional testing is recommended; see TTGA / Tissue Transglutaminase Antibody, IgA, Serum and
IGA / Immunoglobulin A (IgA), Serum.
Reference Values:
Only orderable as a reflex. For more information see EMA / Endomysial Antibodies, IgA, Serum.
Negative
Clinical References: 1. Peters MS, McEvoy MT: IgA antiendomysial antibodies in dermatitis
herpetiformis. J Am Acad Dermatol. 1989 Dec;21(6):1225-1231. doi: 10.1016/s0190-9622(89)70335-2
2. Chorzelski TP, Buetner EH, Sulej J, et al: IgA anti-endomysium antibody: a new immunological
marker of dermatitis herpetiformis and coeliac disease. Br J Dermatol. 1984 Oct;111(4):395-402. doi:
10.1111/j.1365-2133.1984.tb06601.x 3. Kapuscinska A, Zalewski T, Chorzelski TP, et al: Disease
specificity and dynamics of changes in IgA class anti-endomysial antibodies in celiac disease. J Pediatr
Gastroenterol Nutr. 1987;6(4):529-534. doi: 10.1097/00005176-198707000-00006 4. Elwenspoek
MMC, Jackson J, Dawson S, et al: Accuracy of potential diagnostic indicators for coeliac disease: a
systematic review protocol. BMJ Open. 2020 Oct 5;10(10):e038994. doi:
10.1136/bmjopen-2020-038994
EMAIG Endomysial Antibodies, IgG, Serum

608880 Clinical Information: Circulating IgG endomysial antibodies are present in 70% to 80% of patients
endomysial antibodies for celiac disease, the test may obviate the need for multiple small bowel biopsies
to verify the diagnosis. This may be particularly advantageous in the pediatric population, including the
evaluation of children with failure to thrive.
Useful For: Analysis of IgG-endomysial antibodies for the diagnosis of dermatitis herpetiformis and
celiac disease Monitoring adherence to gluten-free diet in patients with dermatitis herpetiformis and celiac
disease
Interpretation: The finding of IgG-endomysial antibodies (EMA) is highly specific for dermatitis
herpetiformis or celiac disease. The titer of IgG-EMA generally correlates with the severity of
gluten-sensitive enteropathy. If patients strictly adhere to a gluten-free diet, the titer of IgG-EMA should
EMA staining or other factors; in this case, the results will be recorded as "indeterminate." In this setting,
further testing with measurement of TTGA / Tissue Transglutaminase Antibody, IgA, Serum and IGG /
Immunoglobulin G (IgG), Serum levels are recommended.
Reference Values:
Negative in normal individuals; also negative in patients with either dermatitis herpetiformis or celiac
disease while adhering to gluten-free diet.
Clinical References: 1. Dahlbom I, Olsson M, Forooz NK, Sjoholm AG, Truedsson L, Hannson T:
Immunoglobulin G (IgG) anti-tissue transglutaminase antibodies used as markers for IgA-deficient celiac
disease patients. Clin Diagn Lab Immunol. 2005 Feb;12(2): 254-258. doi:
10.1128/CDLI.12.2.254-258.2005 2. Korponay-Szabo IR, Dahlbom I, Laurila K, et al: Elevation of IgG
antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA
deficiency. Gut. 2003 Nov 52(11):1567-1571. doi: 10.1136/gut.52.11.1567 3. Kumar V,
Jarzabek-Chorzelska M, Sulej J, Karnewska K, Farrell T, Jablonska S: Celiac disease and
immunoglobulin A deficiency: How effective are the serological methods of diagnosis? Clin Diagn Lab
Immunol. 2002 Nov;9(6):1295-1300. doi: 10.1128/CDLI.9.6.1295-1300.2002 4. Elwenspoek MMC,
Jackson J, Dawson S, et al: Accuracy of potential diagnostic indicators for coeliac disease: a systematic
review protocol. BMJ Open. 2020 Oct 5;10(10):e038994. doi: 10.1136/bmjopen-2020-038994
EGPL English Plantain, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to English plantain Defining the allergen

Reference Values:
0 Negative

apply to all ages.
SAM Entamoeba histolytica Antibody, Serum

9049 Clinical Information: Amebiasis is an infection by the protozoan parasite, Entamoeba histolytica.
The infection is acquired by ingestion of cysts in fecally contaminated food or water; excystation and
infection occur in the large intestine. After excystation, trophozoites attach to the intestinal wall and
liberate extracellular enzymes that enable invasion of the mucosa and spread to other organs, especially
the liver and lung where abscesses develop. Amebiasis (or amebic dysentery) can cause bloody diarrhea
accompanied by fever and prostration. White and red blood cells are found in the stool. Liver abscess
can develop several weeks to months later producing hepatomegaly and fever. Pathogenic (E
histolytica) and nonpathogenic (Entamoeba dispar) species of Entamoeba occur. Additionally, some of
those infected with pathogenic strains are asymptomatic cyst carriers. Serology may be particularly
useful in supporting the diagnosis of amebic liver abscess in patients without a definite history of
intestinal amebiasis and who have not spent substantial periods of time in endemic areas.
Useful For: As an adjunct in the diagnosis of extraintestinal amebiasis, especially liver abscess
Interpretation: A positive result suggests current or previous infection with Entamoeba histolytica.
Since pathogenic and nonpathogenic species of Entamoeba cannot be differentiated microscopically,
some authorities believe a positive serology indicates the presence of the pathogenic species (ie, E
histolytica).
Reference Values:
Negative
Clinical References: 1. Bruckner DA: Amebiasis. Clin Microbiol Rev. 1992 Oct;5(4):356-369.
doi: 10.1128/CMR.5.4.356 2. Petri WA, Haque R, Moonah SN: Entamoeba species, including amebic
colitis and liver abscess. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's
FEHAG Entamoeba histolytica Antigen, EIA

75350 Clinical Information: Entamoeba histolytica are intestinal parasites that infect a half billion people
worldwide annually. Of those infected, most are infected with the non-pathogenic E. dispar, which has not
been associated with disease.Â It is estimated that approximately 10 % of the half billion people infected
each year are infected with the pathogenic E. histolytica. These individuals become symptomatic and
develop colitis and liver abscesses. Limitations: Extraintestinal amebiasis is frequently found without
trophozoites or cysts in stool: patients may have a negative stool antigen result.
Reference Values:
Entamoeba histolytica Antigen: Not Detected
The Entamoeba histolytica Antigen EIA test detects only the antigen of the pathogenic E. histolytica; the
non-pathogenic E. dispar is not detected.
STL Enteric Pathogens Culture, Feces

8098 Clinical Information: Diarrhea may be caused by a number of agents (eg, bacteria, viruses, parasites,
and chemicals) and these agents may result in similar symptoms. A thorough patient history covering
symptoms, severity, duration of illness, age, travel history, food consumption, history of recent antibiotic
use, and illnesses in the family or other contacts will help the physician categorize the disease and ensure
that any special requests are communicated to the laboratory.
Useful For: Determining whether a bacterial enteric pathogen is the cause of diarrhea May be helpful
in identifying the source of the infectious agent (eg, dairy products, poultry, water, or meat) This test is
previously.
Interpretation: The growth of an enteric pathogen identifies the cause of diarrhea.

Reference Values:
No growth of pathogens
Clinical References: 1. York MK, Rodrigues-Wong P, Church L: Fecal culture for aerobic
pathogens of gastroenteritis. In Clinical Microbiology Procedures Handbook, Third edition. Washington,
DC, ASM Press, 2010, Section 3.8.1 2. Jerris RC, Fields PI, Nicholson MA: Fecal culture for
Campylobacter and related organisms. In Clinical Microbiology Procedures Handbook, Third edition.
Washington, DC, ASM Press, 2010, Section 3.8.2 3. DuPont HL: Persistent diarrhea: A clinical review.
JAMA June 28, 2016;315(24):2712-2723 doi:10.1001/jama.2016.7833
ENTP Enterovirus, Molecular Detection, PCR, Plasma

89893 Clinical Information: Enteroviruses are positive-sense RNA viruses in the Picornaviridae family.
These viruses were initially classified by serotype as polioviruses (3 types), echoviruses (31 types,
including types 22 and 23, which are now classified as parechoviruses), coxsackievirus A (23 types), and
coxsackievirus B (6 types). However, genomic studies have demonstrated that there is significant overlap
in the biological characteristics of different serotypes and, more recently, isolated enteroviruses are now
named with consecutive numbers (eg, EV68, EV69). The normal site of enterovirus replication is the
gastrointestinal tract where the infection is typically subclinical. However, in a proportion of cases, the
virus spreads to other organs, causing systemic manifestations, including mild respiratory disease (eg,
common cold); conjunctivitis; hand, foot, and mouth disease; aseptic meningitis; myocarditis; and acute
flaccid paralysis. Collectively, enteroviruses are the most common cause of upper respiratory tract disease
in children. In addition, the enteroviruses are the most common cause of central nervous system (CNS)
disease; they account for almost all viruses recovered in culture from spinal fluid. Differentiation of
enteroviruses from other viruses and bacteria that cause CNS disease is important for the appropriate
medical management of these patients. Traditional cell culture methods require 6 days, on average, for
enterovirus detection. In comparison, real-time PCR allows same-day detection. Detection of enterovirus
nucleic acid by PCR is also the most sensitive diagnostic method for the diagnosis of CNS infection
caused by these viruses.
Useful For: Aids in diagnosing enterovirus infections

Interpretation: A positive result indicates the presence of enterovirus RNA in the specimen.
Reference Values:
Negative
Clinical References: 1. Enterovirus surveillance-United States, 1970-2005. MMWR Morb Mortal

Wkly Rep Sept 15 2006;55(SS08):1-20 2. Foray S, Pailloud F, Thouvenot D, et al: Evaluation of
combining upper respiratory tract swab samples with cerebrospinal fluid examination for the diagnosis
of enteroviral meningitis in children. J Med Virology 1999;57(2):193-197 3. Furione M, Zavattoni M,
Gatti M, et al: Rapid detection of enteroviral RNA in cerebrospinal fluid (CSF) from patients with
aseptic meningitis by reverse transcription-nested polymerase chain reaction. New Microbiol
1998;21(4):343-351
LENT Enterovirus, Molecular Detection, PCR, Varies

80066 Clinical Information: Enteroviruses are positive-sense RNA viruses in the Picornaviridae family.
These viruses were initially classified by serotype as polioviruses (3 types), echoviruses (31 types,
including types 22 and 23, which are now classified as parechoviruses), coxsackievirus A (23 types),
and coxsackievirus B (6 types). However, genomic studies have demonstrated that there is significant
overlap in the biological characteristics of different serotypes and more recently isolated enteroviruses
are now named with consecutive numbers (eg, EV68, EV69). The normal site of enterovirus replication
is the gastrointestinal tract where the infection is typically subclinical. However, in a proportion of
cases, the virus spreads to other organs, causing systemic manifestations, including mild respiratory
disease (eg, the common cold); conjunctivitis; hand, foot, and mouth disease; aseptic meningitis;
myocarditis; and acute flaccid paralysis. Collectively, enteroviruses are the most common cause of
upper respiratory tract disease in children. In addition, the enteroviruses are the most common cause of
central nervous system (CNS) disease; they account for almost all viruses recovered in culture from
spinal fluid. Differentiation of enteroviruses from other viruses and bacteria that cause CNS disease is
important for the appropriate medical management of these patients. Traditional cell culture methods
require 6 days, on average, for enterovirus detection. In comparison, real-time polymerase chain
reaction (PCR) allows same-day detection. Detection of enterovirus nucleic acid by PCR is also the
most sensitive diagnostic method for the diagnosis of CNS infection caused by these viruses.
Useful For: Aids in diagnosing enterovirus infections This test should not be used to screen
asymptomatic patients
Interpretation: A positive result indicates the presence of enterovirus RNA in the specimen.
Reference Values:
Negative
Clinical References: 1. Khetsuriani N: Enterovirus surveillance-United States, 1970-2005.

MMWR Morbidity Mortality Weekly Report. Sept 15 2006;55(SS08):1-20 2. Abedi GR, Watson JT,
Nix WA, Oberste MS et al: Enterovirus and Parechovirus Surveillance - United States, 2014-2016.
MMWR Morb Mortal Wkly Rep. 2018;67:515â€“518 3. Foray S, Pailloud F, Thouvenot D, et al:
Evaluation of combining upper respiratory tract swab samples with cerebrospinal fluid examination for
the diagnosis of enteroviral meningitis in children. J Med Virology. 1999;57(2):193-197 4. Furione M,
Zavattoni M, Gatti M, et al: Rapid detection of enteroviral RNA in cerebrospinal fluid (CSF) from
patients with aseptic meningitis by reverse transcription-nested polymerase chain reaction. New
Microbiol. 1998;21(4):343-351
FECP Eosinophil Cationic Protein (ECP)

2-10 mcg/L
EOSU1 Eosinophils, Random, Urine

610552 Clinical Information: Eosinophils are white blood cells that normally do not appear in urine. The
presence of eosinophils in the urine is seen in acute interstitial nephritis, which is caused by an allergic
reaction, typically to drugs.
Useful For: Investigation of possible acute interstitial nephritis

Interpretation: Results of greater than 5% eosinophils are indicative of acute interstitial nephritis;
results between 1% and 5% eosinophils are indeterminant.
Reference Values:
0%
Clinical References: 1.Hansel FK: In: Clinical Allergy. CV Mosby Company; 1953 2. Brunzel NA:
Microscopic examination of urine sediment. In:Â Fundamentals of Urine and Body Fluid Analysis. 4th
ed. Saunders; 2017:141 3. Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, Nasr SH.
Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 2014
Oct;64(4):558-566. doi: 10.1053/j.ajkd.2014.04.027
FEPHD Ephedrine, Serum

EPUR Epicoccum purpurascens, IgE, Serum

Useful For: Establishing a diagnosis of an allergy to Epicoccum purpurascens Defining the allergen

Reference Values:
0 Negative

apply to all ages.
SPBX Epidermal Nerve Fiber Density Consultation, Varies

70599 Clinical Information: Small fiber peripheral neuropathy is a common neurological complaint and a
frequent source of morbidity in many patient populations. Direct investigation of small fiber
involvement has been limited as most classical techniques (eg, electromyography, nerve conduction
studies, and nerve biopsy) focus on large diameter nerve fibers and may be normal in patients with
small fiber neuropathies. The advent of epidermal skin biopsies and PGP 9.5 immunohistochemistry
allows the direct visualization and morphologic assessment of small sensory fibers innervating the
skin.(1) Assessment of intraepidermal nerve fiber density has been used to reliably demonstrate
pathologic abnormalities in small fiber neuropathy of various etiologies including diabetes, HIV,
systemic lupus erythematosus, and neurosarcoidosis. Further, the technique has been validated, shown
to have acceptable sensitivity and specificity, and is minimally invasive. The publication of normative
data for commonly tested sites such as the distal and proximal legs and arms permits direct comparison
of patients to age- and sex-matched controls facilitating localization and diagnosis.(2-4) Based on class
1 evidence and American Medical Association CPT code review process acceptance, intraepidermal
nerve fiber density (IENFD) measurements are now an accepted investigational method in the workup
of polyneuropathy, including the characterization and diagnosis of varieties of length-dependent small
fiber polyneuropathies. IEFND measurements have been incorporated in recent practice guidelines
published by the American Academy of Neurology and the European Federation of Neurological
Science.(5,6)
Useful For: Investigation of polyneuropathies

Interpretation: The number of intraepidermally originating nerve fibers that cross the basement
membrane between the dermis and epidermis are counted in several sections.(2,5) The total linear
length of the epidermis is measured using standard morphometric techniques and a density of epidermal
nerve fibers (number of fibers/mm) is reported. This value is compared to previously published
normative data.
Reference Values:
A consultative report will be provided.
Clinical References: 1. Lauria G, Lombardi R, Camozzi F, Devigili G: Skin biopsy for the
diagnosis of peripheral neuropathy. Histopathology. 2009 Feb;54(3):273-285 2. McArthur JC, Stocks
EA, Hauer P, Cornblath DR, Griffin JW: Epidermal nerve fiber density: normative reference range and
diagnostic efficiency. Arch Neurol. 1998 Dec;55(12):1513-1520 3. Goransson LG, Mellgren SI, Lindal
S, Omdal R: The effect of age and gender on epidermal nerve fiber density. Neurology. 2004 Mar
9;62(5):774-777 4. Umapathi T, Tan WL, Tan NCK, Chan YH: Determinants of epidermal nerve fiber
density in normal individuals. Muscle Nerve. 2006 Jun;33(6):742-746 5. Lauria G, Cornblath DR,
Johansson O, et al: EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy.
Eur J Neurol. 2005 Oct;12(10):747-758 6. England JD, Gronseth GS, Franklin G, et al: Practice
parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and
skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American
Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical
Medicine and Rehabilitation. Neurology. 2009 Jan 13;72(2):177-184 7. Engelstad JK, Taylor SW, Witt
LV, et al: Epidermal nerve fibers: confidence intervals and continuous measures with nerve conduction.
Neurology. 2012 Nov 27;79(22):2187-2193 8. England JD, Gronseth GS, Franklin G, et al: Evaluation
of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an
evidence-based review). Muscle Nerve. 2009 Jan;39(1):106-115
FEPI Epidermophyton floccosum IgE

Reference Values:
<0.35 kU/L
EPS2 Epilepsy, Autoimmune/Paraneoplastic Evaluation, Serum

92118 Clinical Information: Antiepileptic drugs (AED) are the mainstay of treatment for epilepsy, but
seizures continue in one-third of patients despite appropriate AED therapeutic trials. The etiology of
epilepsy often remains unclear. Seizures are a common symptom in autoimmune neurological disorders,
including limbic encephalitis and multifocal paraneoplastic disorders. Seizures may be the exclusive
manifestation of an autoimmune encephalopathy without evidence of limbic encephalitis. Autoimmune
epilepsy is increasingly recognized in the spectrum of neurological disorders characterized by detection of
neural autoantibodies in serum or spinal fluid (CSF) and responsiveness to immunotherapy. The advent of
more sensitive and specific serological detection methods is increasingly revealing previously
underappreciated autoimmune epilepsies. Neural autoantibodies specific for intracellular and plasma
membrane antigens aid the diagnosis of autoimmune epilepsy, but no single antibody is specific for this
diagnosis. Autoantibody specificities currently most informative for autoimmune epilepsies include
leucine-rich glioma inactivated protein-1 (LGI1), glutamic acid decarboxylase-65 (GAD65),
N-methyl-D-aspartate receptor (NMDA-R), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptors (AMPA-R), and gamma-aminobutyric acid type B receptor (GABA-B-R) antibodies.
Autoantibodies recognizing onconeural proteins shared by neurons, glia, or muscle (eg, antineuronal
nuclear antibody, type 1 [ANNA 1]; collapsin response-mediator protein-5 neuronal [CRMP-5-IgG];
N-type calcium channel antibody), also serve as markers of paraneoplastic or idiopathic autoimmune
epilepsies. A specific neoplasm is often predictable by the individual patient's autoantibody profile.
Suspicion for autoimmune epilepsy on clinical grounds justifies comprehensive evaluation of CSF and
serum for neural autoantibodies. Selective testing for individual autoantibodies is not advised because
each is individually rare, and a timely diagnosis is critical. Collectively, the antibodies tested for in the
autoimmune epilepsy evaluations represent a broad spectrum of treatable disorders, some of which are
associated with occult cancer. Testing of CSF for autoantibodies is particularly helpful when serum
testing is negative, though in some circumstances testing both serum and CSF simultaneously is pertinent.
Testing of CSF is recommended for some antibodies in particular (such as NMDA-R antibody and glial
fibrillary acidic protein [GFAP]-IgG) because CSF testing is both more sensitive and specific. In contrast,
serum testing for LGI1 antibody is more sensitive than CSF testing. Failure to detect a neural antibody
does not exclude the diagnosis of autoimmune epilepsy when other clinical clues exist. A trial of
immunotherapy is justifiable in those cases.
Useful For: Investigating new onset cryptogenic epilepsy with incomplete seizure control and duration
of less than 2 years using serum specimens Investigating new onset cryptogenic epilepsy plus 1 or more of
the following accompaniments: -Psychiatric accompaniments (psychosis, hallucinations) -Movement
disorder (myoclonus, tremor, dyskinesias) -Headache -Cognitive impairment/encephalopathy
-Autoimmune stigmata (personal history or family history or signs of diabetes mellitus, thyroid disorder,
vitiligo, premature graying of hair, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus,
idiopathic adrenocortical insufficiency), or multiple sclerosis -History of cancer -Smoking history (over
20 pack-years) or other cancer risk factors -Investigating seizures occurring within the context of a
subacute multifocal neurological disorder without obvious cause, especially in a patient with a past or
family history of cancer -A rising autoantibody titer in a previously seropositive patient suggests cancer
recurrence
autoimmune dementia. -Plasma membrane antibodies (N-methyl-D-aspartate [NMDA] receptor;
2-amino-3-[5-methyl-3-oxo-1,2-oxazol-4-yl] propanoic acid [AMPA] receptor; gamma-amino butyric
acid [GABA-B] receptor). These autoantibodies are all potential effectors of dysfunction. -Antineuronal
nuclear antibody, type 1 (ANNA-1) or type 3 (ANNA-3). -Neuronal or muscle cytoplasmic antibodies
(amphiphysin, Purkinje cell antibody-type 2 [PCA-2], collapsin response-mediator protein-5 neuronal
[CRMP-5-IgG], or glutamic acid decarboxylase [GAD65] antibody).
Reference Values:
Test ID Reporting Name Methodology* Reference Value
AEPSI Epilepsy, Interpretation, S Medical interpretation NA

Type 1

Type 2

Type 3

values apply to all ages

Type 2

Type Tr

Binding Ab
AMPIS AMPA-R Ab IF Titer IFA

Assay, S

S

S

Assay, S

Assay, S
PCTBS PCA-Tr Immunoblot, S IB Negative
PCABP Purkinje Cell Cytoplasmic IFA *Methodology abbreviations:

for ANNA-1, ANNA-2, PCA-1,
PCA-2, or PCA-Tr may be
anti-neuronal IgG." Complex
patterns that include nonneuronal
titers lower than 1:240 are
detectable by recombinant
CRMP-5 Western blot analysis
will be done on request on stored
serum (held 4 weeks). This
Western blot.
Clinical References: 1. Quek AM, Britton JW, McKeon A, et al: Autoimmune epilepsy: clinical
characteristics and response to immunotherapy. Arch Neurol. 2012 May;69(5):582-593 2. Yu Z, Kryzer
TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA: CRMP-5 neuronal autoantibody: marker of
lung cancer and thymoma-related autoimmunity. Ann Neurol. 2001 Feb;49(2):146-154 3. Pittock SJ,
Yoshikawa H, Ahlskog JE, et al: Glutamic acid decarboxylase autoimmunity with brainstem,
extrapyramidal and spinal cord dysfunction. Mayo Clin Proc. 2006 Sep;81:1207-1214 4. Klein CJ,
Lennon VA, Aston PA, et al: Insights from LGI1 and CASPR2 potassium channel complex
autoantibody subtyping. JAMA Neurol. 2013 Feb;70(2):229-234 5. Lancaster E, Martinez-Hernandez
E, Dalmau J: Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology.
2011 Jul;77(2):179-189
EPC2 Epilepsy, Autoimmune/Paraneoplastic Evaluation, Spinal Fluid

92119 Clinical Information: Antiepileptic drugs (AED) are the mainstay of treatment for epilepsy, but
seizures continue in one-third of patients despite appropriate AED therapeutic trials. The etiology of
epilepsy often remains unclear. Seizures are a common symptom in autoimmune neurological disorders,
including limbic encephalitis and multifocal paraneoplastic disorders. Seizures may be the exclusive
manifestation of an autoimmune encephalopathy without evidence of limbic encephalitis. Autoimmune
epilepsy is increasingly recognized in the spectrum of neurological disorders characterized by detection
of neural autoantibodies in serum or spinal fluid (CSF) and responsiveness to immunotherapy. The
advent of more sensitive and specific serological detection methods is increasingly revealing previously
underappreciated autoimmune epilepsies. Neural autoantibodies specific for intracellular and plasma
membrane antigens aid the diagnosis of autoimmune epilepsy, but no single antibody is specific for this
diagnosis. Autoantibody specificities currently most informative for autoimmune epilepsies include
leucine-rich glioma inactivated protein-1 (LGI1), glutamic acid decarboxylase-65 (GAD65),
N-methyl-D-aspartate receptor (NMDA-R), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid receptors (AMPA-R), and gamma-aminobutyric acid type B receptor (GABA-B-R) antibodies.
Autoantibodies recognizing onconeural proteins shared by neurons, glia, or muscle (eg, antineuronal
nuclear antibody, type 1 [ANNA 1]; collapsin response-mediator protein-5 neuronal [CRMP-5-IgG];
N-type calcium channel antibody), also serve as markers of paraneoplastic or idiopathic autoimmune
epilepsies. A specific neoplasm is often predictable by the individual patient's autoantibody profile.
Suspicion for autoimmune epilepsy on clinical grounds justifies comprehensive evaluation of CSF and
serum for neural autoantibodies. Selective testing for individual autoantibodies is not advised because
each is individually rare, and a timely diagnosis is critical. Collectively, the antibodies tested for in the
autoimmune epilepsy evaluations represent a broad spectrum of treatable disorders, some of which are
associated with occult cancer. Testing of CSF for autoantibodies is particularly helpful when serum
testing is negative, though in some circumstances testing both serum and CSF simultaneously is
pertinent. Testing of CSF is recommended for some antibodies in particular (such as NMDA-R antibody
and glial fibrillary acidic protein [GFAP]-IgG) because CSF testing is both more sensitive and specific.
In contrast, serum testing for LGI1 antibody is more sensitive than CSF testing. Failure to detect a
neural antibody does not exclude the diagnosis of autoimmune epilepsy when other clinical clues exist.
A trial of immunotherapy is justifiable in those cases.
Useful For: Investigating new onset cryptogenic epilepsy with incomplete seizure control and
duration of fewer than 2 years using spinal fluid specimens Investigating new onset cryptogenic
epilepsy plus 1 or more of the following accompaniments: -Psychiatric accompaniments (psychosis,
hallucinations) -Movement disorder (myoclonus, tremor, dyskinesias) -Headache -Cognitive
impairment/encephalopathy -Autoimmune stigmata (personal history or family history or signs of
diabetes mellitus, thyroid disorder, vitiligo, premature graying of hair, myasthenia gravis, rheumatoid
arthritis, systemic lupus erythematosus, idiopathic adrenocortical insufficiency) or "multiple sclerosis"
-History of cancer -Smoking history (over 20 pack-years) or other cancer risk factors -Investigating
seizures occurring within the context of a subacute multifocal neurological disorder without an obvious
cause, especially in a patient with a past or family history of cancer
markers of autoimmune epilepsy and a patient's immune response to cancer. These autoantibodies are
autoimmune epilepsy: -Plasma membrane antibodies (N-methyl-D-aspartate [NMDA] receptor;
2-amino-3-[5-methyl-3-oxo-1,2-oxazol-4-yl] propanoic acid [AMPA] receptor; gamma-aminobutyric
acid [GABA-B] receptor). These autoantibodies are all potential effectors of dysfunction. -Neuronal
nuclear autoantibody, type 1 (ANNA-1) or type 3 (ANNA-3). -Neuronal or muscle cytoplasmic
antibodies (amphiphysin, Purkinje cell antibody-type 2 [PCA-2], collapsin response-mediator protein-5
neuronal [CRMP-5-IgG], or glutamic acid decarboxylase [GAD65] antibody). A rising autoantibody
titer in a previously seropositive patient suggests cancer recurrence.
Reference Values:
AEPCI Epilepsy, Interpretation, CSF Medical interpretation NA

ANN1C Anti-Neuronal Nuclear Ab, IFA Negative at
Type 1

Type 2

Type 3
GD65C GAD65 Ab Assay, CSF RIA < or =0.02 nmol/L Reference

PCTRC Purkinje Cell Cytoplasmic Ab IFA

Type Tr

Type 2

Assay, CSF

CSF
CSF

Assay, CSF
NMDIC NMDA-R Ab IF Titer IFA Negative at

Assay, CSF
PCTBC PCA-Tr Immunoblot, CSF IB Negative

PCA1C Purkinje Cell Cytoplasmic IFA *Methodology abbreviations:
for ANNA-1, ANNA-2, ANN3C,
PCA-1, PCA-2, or PCA-Tr may be
antineuronal IgG." Complex
patterns that include non-neuronal
titers lower than 1:2 are detectable
by recombinant CRMP-5 Western
blot analysis. CRMP-5 Western
blot analysis will be done on
request on stored spinal fluid (held
for 4 weeks). This supplemental
testing is recommended in cases of
chorea, vision loss, cranial
neuropathy, and myelopathy. Call
the Neuroimmunology Laboratory
at 800-533-1710 to request
CRMP-5 Western blot.
Clinical References: 1. Quek AL, Britton JW, McKeon A, et al: Autoimmune epilepsy: clinical
characteristics and response to immunotherapy. Arch Neurol. 2012 May;69(5):582-593. doi:
10.1001/archneurol.2011.2985 2. Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA:
CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol.
2001 Feb;49(2):146-154 3. Pittock SJ, Yoshikawa H, Ahlskog JE, et al: Glutamic acid decarboxylase
autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc. 2006
Sep;81(9):1207-1214. doi: 10.4065/81.9.1207 4. Klein CJ, Lennon VA, Aston PA, et al: Insights from
LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol. 2013
Feb;70(2):229-234. doi: 10.1001/jamaneurol.2013.592 5. Lancaster E, Martinez-Hernandez E, Dalmau J:
Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011
Jul;77(2):179-189. doi: 10.1212/WNL.0b013e318224afde
EPIP1 Epithelia Panel # 1, Serum
Useful For: Establishing a diagnosis of an allergy to cat, cow, dog, or horse Defining the allergen
Interpretation: Positive results indicate the possibility of allergic disease induced by one or more
allergens present in the multi-allergen cap. Negative results may rule out allergy, except in rare cases of
allergic disease induced by exposure to a single allergen. Detection of IgE antibodies in serum (Class 1 or
greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the
allergens that may be responsible for eliciting signs and symptoms. The level of IgE antibodies in serum
varies directly with the concentration of IgE antibodies expressed as a class score or kU/L.
Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
EPIP2 Epithelia Panel # 2, Serum

Useful For: Establishing a diagnosis of an allergy to guinea pig, hamster, mouse, rabbit, or rat
Defining the allergen responsible for eliciting signs and symptoms Identifying allergens: -Responsible
for allergic disease and/or anaphylactic episode -To confirm sensitization prior to beginning
immunotherapy -To investigate the specificity of allergic reactions to insect venom allergens, drugs, or
chemical allergens Testing for IgE antibodies is not useful in patients previously treated with
immunotherapy to determine if residual clinical sensitivity exists, or in patients in whom the medical
management does not depend upon identification of allergen specificity.
Interpretation: Positive results indicate the possibility of allergic disease induced by one or more
allergens present in the multi-allergen cap. Negative results may rule out allergy, except in rare cases of
allergic disease induced by exposure to a single allergen. Detection of IgE antibodies in serum (Class 1
or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and
defines the allergens that may be responsible for eliciting signs and symptoms. The level of IgE
antibodies in serum varies directly with the concentration of IgE antibodies expressed as a class score or
kU/L.
Reference Values:
0 Negative

apply to all ages.
2017:1057-1070
EMAI Epithelial Membrane Antigen (EMA) Immunostain, Technical

Clinical Information: Epithelial membrane antigen (EMA), also known as mucin 1 (MUC1), is
expressed by epithelial cells of all types, mesothelial cells, perineural cells, and a subset of plasma cells.
EMA is expressed by meningiomas, synovial sarcoma, epithelioid sarcoma, a subset of peripheral nerve
sheath tumors, the lymphocyte-predominant cells of lymphocyte-predominant Hodgkin lymphoma, and
anaplastic large cell lymphoma. Diagnostically, EMA is useful in recognizing epithelial derivation of
poorly differentiated malignant tumors and, in conjunction with a panel of mucin markers (MUC2,
MUC5AC, and MUC6), may be used in subtyping intraductal papillary mucinous neoplasms.
Useful For: Recognizing epithelial derivation of poorly differentiated malignant tumors Subtyping
intraductal papillary mucinous neoplasms when used in conjunction with mucin (MUC) 2, MUC5AC
and MUC6
upon request, .call 855-516-8404. Interpretation of this test should be performed in the context of the
Clinical References: 1. Kwak H, Liu X, Allende D, et al: Interobserver variability in intraductal

papillary mucinous neoplasm subtypes and application of their mucin immunoprofiles. Modern Pathol.
2016; 29:977-984 2. Ramezani M, Mohamadzaheri E, Khazaei S, et al: Comparison of EMA,CEA, CD10
and Bcl-2 Biomarkers by immunohistochemistry in squamous cell carcinoma and basal cell carcinoma of
the skin. Asian Pac J Cancer Prev. 2016;17(3):1379-83. doi: 10.7314/apjcp.2016.17.3.1379 3. Song W,
Flucke U, Suurmeijer AJH. Myoepithelial tumors of bone. Surg Pathol Clin. 2017 Sep;10(3):657-674.
doi: 10.1016/j.path.2017.04.010
EBNA2 Epstein Barr Nuclear Antigen 2 (EBNA2) Immunostain,

Clinical Information: Epstein Barr virus (EBV) nuclear antigen 2 (EBNA2) is an EBV-encoded
nuclear protein of 82 kD. EBNA2 is necessary for transformation of EBV-infected B lymphocytes and has
been shown to modulate the activity of several viral and cellular promoters. This immunostain may be
useful in the diagnosis of reactive and neoplastic lymphoproliferative and plasma cell proliferative
disorders.
Useful For: Identification of Epstein Barr virus infection in normal, inflammatory, and neoplastic
tissues
Clinical References: 1. Wood CD, Carvell T, Gunnell A, et al: Enhancer control of microRNA
miR-155 expression in Epstein-Barr virus-infected B cells. J Virol. 2019 Jan 17;93(3):e01893-18. doi:
10.1128/JVI.01893-18 2. Anastasiadou E, Stroopinsky D, Alimperti S, et al: Epstein-Barr virus-encoded
EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas.
Leukemia. 2019;33:132â€“147 3. Hudnall SD, Ge Y, Wei L, et al: Distribution and phenotype of
Epstein-Barr virus-infected cells in human pharyngeal tonsils. Mod Pathol. 2005;18:519-527
LMP1I Epstein Barr Virus Latency Membrane Protein 1 Immunostain,

Clinical Information: The latent membrane protein 1 (LMP-1) oncogene of Epstein-Barr virus
(EBV) is believed to contribute to the development of many EBV-associated tumors. This antibody may
be useful in the diagnosis of reactive and neoplastic lymphoproliferative and plasma cell proliferative
disorders.
Useful For: Identification of Epstein Barr virus infection in normal, inflammatory, and neoplastic
tissues
Clinical References: 1. Qi ZL, Han XQ, Hu J, Wang GH, Gao JW, Wang X, Liang DY:
Comparison of three methods for the detection of Epstein-Barr virus in Hodgkin's lymphoma in
paraffin-embedded tissues. Mol Med Rep. 2013 Jan;7(1):89-92 2. Zhao Y, Wang Y, Zeng S, Hu X:
LMP1 expression is positively associated with metastasis of nasopharyngeal carcinoma: evidence from
a meta-analysis. J Clin Pathol. 2012;65(1):41-45. doi: 10.1136/jclinpath-2011-200198 3. Ayee R, Ofori
MEO, Wright E, Quaye O: Epstein Barr virus associated lymphomas and epithelia cancers in humans. J
Cancer. 2020;11(7):1737-1750. doi: 10.7150/jca.37282
SEBV Epstein-Barr Virus (EBV) Antibody Profile, Serum

84421 Clinical Information: Epstein-Barr virus (EBV), a member of the herpesvirus group, is the
etiologic agent of infectious mononucleosis. EBV infections are difficult to diagnose in the laboratory
since the virus does not grow in standard cell cultures. The majority of infections can be recognized,
however, by testing the patient's serum for heterophile antibodies (rapid latex slide agglutination test;
eg, MONOS / Infectious Mononucleosis, Rapid Test, Serum), which usually appear within the first 3
weeks of illness but then decline rapidly within a few weeks. The heterophile antibody, however, fails
to develop in about 10% of adults, more frequently in children, and almost uniformly in infants with
primary EBV infections. Most of these heterophile antibody-negative cases of infectious
mononucleosis-like infections are due to cytomegalovirus, but in a series of 43 cases, EBV was the
cause in 7. In cases where EBV is suspected but the heterophile antibody is not detected, an evaluation
of the EBV-specific antibody profile (eg, EBV viral capsid antigen: VCA IgM, EBV VCA IgG, and
EBV nuclear antigen: EBNA) may be useful. Infection with EBV usually occurs early in life. For
several weeks to months after acute onset of the infection, it is spread by upper respiratory secretions
that contain the virus. Among the clinical disorders due to EBV infection, infectious mononucleosis is
the most common. Other disorders due to EBV infection have been recognized for several years,
including African-type Burkitt lymphoma and nasopharyngeal carcinoma. EBV infection may also
cause lymphoproliferative syndromes, especially in patients who have undergone renal or bone marrow
transplantation and in those who have AIDS.
Useful For: Diagnosing infectious mononucleosis when a mononucleosis screening procedure is

negative and infectious mononucleosis or a complication of Epstein-Barr virus infection is suspected
This assay is not intended for viral isolation or identification.
Interpretation: The test has 3 components: viral capsid antigen (VCA) IgG, VCA IgM, and
Epstein-Barr nuclear antigen (EBNA). Presence of VCA IgM antibodies indicates recent primary
infection with Epstein-Barr virus (EBV). The presence of VCA IgG antibodies indicates infection
sometime in the past. Antibodies to EBNA develop 6 to 8 weeks after primary infection and are
detectable for life. Over 90% of the normal adult population has IgG class antibodies to VCA and
EBNA. Few patients who have been infected with EBV will fail to develop antibodies to the EBNA
(approximately 5%-10%). Possible results VCA IgG VCA IgM EBNA IgG Interpretation - - - No
previous exposure + + - Recent infection + - + Past infection + - - See note* + + + Past infection
*Results indicate infection with EBV at some time (VCA IgG positive). However, the time of the
infection cannot be predicted (ie, recent or past) since antibodies to EBNA usually develop after
primary infection (recent) or, alternatively, approximately 5% to 10% of patients with EBV never
develop antibodies to EBNA (past).
Reference Values:
Epstein-Barr Virus (EBV) VIRAL CAPSID ANTIGEN (VCA) IgM ANTIBODY
Negative
Epstein-Barr Virus (EBV) VIRAL CAPSID ANTIGEN (VCA) IgG ANTIBODY

Negative
EPSTEIN-BARR NUCLEAR ANTIGEN (EBNA) ANTIBODIES

Negative
Clinical References: 1. Knipe DM, Howley PM, Griffin DE, eds: Fields Virology. 5th ed.
Lippincott Williams and Wilkins; 2007 2. Linde A, Falk KI: Epstein-Barr virus. In: Barron EJ, Jorgensen
JH, Landry ML, et al, eds. Manual of Clinical Microbiology. 9th ed. ASM Press. 2007;1564-1573 3.
Johannsen EC, Kaye KM: Epstein-Barr virus (infectious mononucleosis, Epstein-Barr virus-associated
malignant diseases, and other diseases). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and
Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020:1872-1890
EBV Epstein-Barr Virus (EBV) In Situ Hybridization, Technical

Clinical Information: Epstein-Barr virus (EBV) plays a pathogenic role in a variety of disease states,
including infectious mononucleosis, nasopharyngeal carcinoma, Burkitt lymphoma, B-cell lymphomas in
patients with congenital or acquired immunodeficiency, and some cases of classical Hodgkin lymphoma.
Useful For: Detection of Epstein-Barr virus (EBV)-encoded RNA (EBER) in the diagnosis of
EBV-associated conditions
pathologist.
Clinical References: 1. Yu F, Lu Y, Petersson F, Wang DY, Loh KS. Presence of lytic Epstein-Barr
virus infection in nasopharyngeal carcinoma. Head Neck. 2018 Jul;40(7):1515-1523. doi:
10.1002/hed.25131 2. Randhawa PS, Jaffe R, Demetris AJ, et al: The systemic distribution of
Epstein-Barr virus genomes in fatal post-transplantation lymphoproliferative disorders. An in situ
hybridization study. Am J Pathol. 1991;138:1027-1033 3. Chang KL, Chen YY, Shibata D, Weiss LM:
Description of an in situ hybridization methodology for detection of Epstein-Barr Virus RNA in
paraffin-embedded tissues, with a survey of normal and neoplastic tissues. Diagn Mol Pathol.
1992;1:246-255
EBVE Epstein-Barr Virus (EBV), IgG Antibody to Early Antigen, Serum

56104 Clinical Information: Epstein-Barr virus (EBV), a member of the herpesvirus group, is the etiologic
agent of infectious mononucleosis. EBV infections are difficult to diagnose in the laboratory since the
virus does not grow in standard cell cultures. The majority of infections can be recognized, however, by
testing the patient's serum for heterophile antibodies (rapid latex slide agglutination test; eg, MONOS /
Infectious Mononucleosis Rapid Test, Serum). Heterophile antibodies usually appear within the first 3
weeks of illness but decline rapidly within a few weeks. However, this heterophile antibody fails to
develop in about 10% of adults, more frequently in children, and almost uniformly in infants with primary
EBV infections. Most of these heterophile antibody negative cases of infectious mononucleosis-like
infections are due to cytomegalovirus, but in one series of 43 cases, EBV was the cause in 7. In cases
where EBV is suspected but the heterophile antibody is not detected, an evaluation of EBV-specific
antibodies (eg, IgM and IgG antibodies to EBV viral capsid antigen: VCA) and antibodies to EBV nuclear
antigen (EBNA) may be useful. The EBV EIA tests that detect antibodies to the EBV VCA and early
antigen (EA) are more sensitive than heterophile antibody tests. Infection with EBV usually occurs early
in life. For several weeks to months after acute onset of the infection, it is spread by upper respiratory
secretions that contain the virus. Among the clinical disorders due to EBV infection, infectious
mononucleosis is the most common. Other disorders due to EBV infection include African-type Burkitt
lymphoma and nasopharyngeal carcinoma (NPC). EBV infection may also cause lymphoproliferative
syndromes, especially in patients with AIDS and in patients who have undergone renal or bone marrow
transplantation. Using immunofluorescent staining techniques, 2 patterns of EA are seen, 1) diffuse
staining of both cytoplasm and nucleus (early antigen-diffuse: EA-D) and 2) cytoplasmic or early antigen
restricted (EA-R). Antibodies responsible for the diffuse staining pattern (EA-D) are seen in infectious
mononucleosis and NPC, and are measured in this assay.
Useful For: A third-order test in the diagnosis of infectious mononucleosis, especially in situations
when initial testing results (heterophile antibody test) are negative and follow-up testing (viral capsid
antigen: VCA IgG, VCA IgM, and Epstein-Barr nuclear antigen) yields inconclusive results aiding in
the diagnosis of type 2 or type 3 nasopharyngeal carcinoma
Interpretation: Generally, this antibody can only be detected during active Epstein-Barr virus
(EBV) infection, such as in patients with infectious mononucleosis. Clinical studies have indicated that
patients who have chronic active or reactivated EBV infection commonly have elevated levels of
IgG-class antibodies to the EA of EBV. IgG antibody specific for the diffuse early antigen of EBV is
often found in patients with nasopharyngeal carcinoma (NPC). Of patients with type 2 or 3 NPC (World
Health Organization classification), 94% and 83% respectively, have positive-antibody responses to EA.
Only 35% of patients with type 1 NPC have a positive response. The specificity of the test is such that
82% to 91% of healthy blood donor controls and patients who do not have NPC have negative
responses (9%-18% false-positives). Although this level of specificity is useful for diagnostic purposes,
the false-positive rate indicates that the test is not useful for NPC screening.
Reference Values:
Negative
Clinical References: 1. Fields BN, Knipe DM: Epstein-Barr virus. In: Fields BN, Knipe DM,
Howley PM, eds. Fields Virology. 4th ed. Lippincott Williams and Wilkins; 2001 2. Lennette ET:
Epstein-Barr virus. In: Murray PR, Baron EJ, Pfaller MA, et al, eds. Manual of Clinical Microbiology.
6th ed. ASM Press; 1995:905-910
LEBV Epstein-Barr Virus (EBV), Molecular Detection, PCR, Varies

81239 Clinical Information: Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis,
Burkitt lymphoma, and in Southern China, nasopharyngeal carcinoma. EBV-associated central nervous
system (CNS) disease is most commonly associated with primary CNS lymphoma in patients with
AIDS. In addition, CNS infection associated with the detection of EBV DNA can be seen in
immunocompetent patients.
Useful For: Rapid qualitative detection of Epstein-Barr virus (EBV) DNA in specimens Diagnosis of
disease due to EBV This test should not be used to screen asymptomatic patients.
Interpretation: Detection of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid (CSF) supports
the clinical diagnosis of central nervous system (CNS) disease due to the virus. EBV DNA is not
detected in CSF from patients without CNS disease caused by this virus.
Reference Values:
Negative
Clinical References: 1. Tachikawa N, Goto M, Hoshino Y, et al: Detection of Toxoplasma gondii,

Epstein-Barr virus, and JC virus DNAs in the cerebrospinal fluid in acquired immunodeficiency
syndrome patients with focal central nervous system complications. Intern Med. 1999;38(7):556-562.
doi: 10.2169/internalmedicine.38.556 2. Antinori A, Cingolani A, De Luca A, et al: Epstein-Barr virus
in monitoring the response to therapy of acquired immunodeficiency syndrome-related primary central
nervous system lymphoma. Ann Neurol. 1999;45(2):259-261 3. Cingolani A, De Luca A, Larocca LM,
et al: Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central
nervous system lymphoma. J Natl Cancer Inst. 1998;90(8):364-369. doi: 10.1093/jnci/90.5.364 4. Niller
HH, Wolf H, Minarovits J: Regulation and dysregulation of Epstein-Barr virus latency: implications for
the development of autoimmune disease. Autoimmunity. 2008:41(4):298-328. doi:
10.1080/08916930802024772 5. Studahl M, Hagberg L, Rekvdar E, Bergstrom T: Herpesvirus DNA
detection in cerebrospinal fluid: difference in clinical presentation between alph-, beta-, and
gamma-herpes viruses. Scand J Infect Dis. 2000;32(3):237-248. doi: 10.1080/00365540050165857 6.
Lau AH, Soltys K, Sindhi RK, Bond G, Mazariegos GV, Green M: Chronic high Epstein-Barr viral load
carriage in pediatric small bowel transplant recipients. Pediatr Transplant. 2010;14(4):549-553. doi:
10.1111/j.1399-3046.2009.01283.x
EBVQN Epstein-Barr Virus DNA Detection and Quantification, Plasma

615297 Clinical Information: Primary infection with Epstein-Barr virus (EBV), a DNA virus in the
Herpesviridae family, may cause infectious mononucleosis resulting in a benign lymphoproliferative
condition characterized by fever, fatigue, sore throat, and lymphadenopathy. Infection occurs early in life,
and, by 10 years of age, 70% to 90% of children have been infected with this virus. Usually, infection in
children is asymptomatic or mild and may be associated with minor illnesses such as upper respiratory
tract infection, pharyngitis, tonsillitis, bronchitis, and otitis media. The target cell for EBV infection is the
B lymphocyte. Immunocompromised individuals lacking antibody to EBV are at risk for acute EBV
infection that may cause lymphoproliferative disorders in organ transplant recipients (posttransplant
lymphoproliferative disorders: PTLD) and AIDS-related lymphoma. The incidence of PTLD ranges from
1% for kidney transplant recipients to as high as 9% for heart/lung transplants and 12% for pancreas
transplant patients. EBV DNA can be detected in the blood of patients with this viral infection, and
increasing serial levels of EBV DNA in plasma have been shown to correlate highly with subsequent (in
3-4 months) development of PTLD in susceptible patients. Organ transplant recipients who are
seronegative (at risk for primary EBV infection) for EBV (most often children) who receive
antilymphocyte globulin for induction immunosuppression and OKT-3 treatment for early organ rejection
are at highest risk for developing PTLD when compared to immunologically normal individuals with
prior EBV infection.
Useful For: Diagnosis of Epstein-Barr virus (EBV)-associated infectious mononucleosis in individuals

with equivocal or discordant EBV serologic marker test results Diagnosis of posttransplant
lymphoproliferative disorders (PTLD), especially in EBV-seronegative organ transplant recipients
receiving antilymphocyte globulin for induction immunosuppression and OKT-3 treatment for early organ
rejection Monitoring progression of EBV-associated PTLD in organ transplant recipients This test should
not be used to screen asymptomatic patients.
Interpretation: The quantification range of this assay is 35 to 100,000,000 IU/mL (1.54 log to 8.00 log
IU/mL), with a limit of detection (95% detection rate) at 19 IU/mL. Increasing levels of Epstein-Barr
virus (EBV) DNA in serial plasma specimens of a given organ transplant recipient may indicate possible
development of posttransplant lymphoproliferative disorder (PTLD). An "Undetected" result indicates
that EBV DNA is not detected in the plasma specimen (see Cautions). If clinically indicated, repeat
testing in 1 to 2 months is recommended. A result of "<35 IU/mL" indicates that the EBV DNA level
present in the plasma specimen is below 35 IU/mL (1.54 log IU/mL), and the assay cannot accurately
quantify the EBV DNA present below this level. A quantitative value (reported in IU/mL and log IU/mL)
indicates the EBV DNA level (ie, viral load) present in the plasma specimen. A result of ">100,000,000
IU/mL" indicates that the EBV DNA level present in the plasma specimen is above 100,000,000 IU/mL
(8.00 log IU/mL), and this assay cannot accurately quantify the EBV DNA present above this level. An
"Inconclusive" result indicates that the presence or absence of EBV DNA in the plasma specimen could
not be determined with certainty after repeat testing in the laboratory, possibly due to polymerase chain
reaction inhibition or presence of interfering substance. Submission of a new specimen for testing is
recommended if clinically indicated.
Reference Values:
Undetected
Clinical References: 1. San-Juan R, Comoli P, Caillard S, et al: Epstein-Barr virus-related

post-transplant lymphoproliferative disorder in solid organ transplant recipients. Clin Microbiol Infect.
2014 Sep;20(Suppl 7):109-118. doi: 10.1111/1469-0691.12534 2. Jiang SY, Yang JW, Shao JB, Liao XL,
Lu ZH, Jiang H: Real-time polymerase chain reaction for diagnosing infectious mononucleosis in
pediatric patients: A systematic review and meta-analysis. J Med Virol. 2016 May;88(5):871-876. doi:
10.1002/jmv.24402 3. Allen UD, Preiksaitis JK, AST Infectious Diseases Community of Practice:
Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ
transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community
of Practice. Clin Transplant. 2019 Sep;33(9):e13652. doi: 10.1111/ctr.13652 4. Kimura H, Kwong YL:
EBV Viral Loads in Diagnosis, Monitoring, and Response Assessment. Front Oncol. 2019 Feb 12;9:62.
doi: 10.3389/fonc.2019.00062
EBVQU Epstein-Barr Virus DNA Detection and Quantification, Plasma

601922 Clinical Information: Primary infection with Epstein-Barr virus (EBV), a DNA virus in the
Herpesviridae family, may cause infectious mononucleosis resulting in a benign lymphoproliferative
condition characterized by fever, fatigue, sore throat, and lymphadenopathy. Infection occurs early in
life, and by 10 years of age, 70% to 90% of children have been infected with this virus. Usually,
infection in children is asymptomatic or mild and may be associated with minor illnesses such as upper
respiratory tract infection, pharyngitis, tonsillitis, bronchitis, and otitis media. The target cell for EBV
infection is the B-lymphocyte. Immunocompromised individuals lacking antibody to EBV are at risk for
acute EBV infection that may cause lymphoproliferative disorders in organ transplant recipients
(posttransplant lymphoproliferative disorders [PTLD]) and AIDS-related lymphoma. The incidence of
PTLD ranges from 1% for renal transplant recipients to as high as 9% for heart/lung transplants and
12% for pancreas transplant patients. EBV DNA can be detected in the blood of patients with this viral
infection, and increasing serial levels of EBV DNA in plasma have been shown to correlate highly with
subsequent (in 3-4 months) development of PTLD in susceptible patients. Organ transplant recipients
who are sero-negative (at risk for primary EBV infection) for EBV (most often children) who receive
antilymphocyte globulin for induction immunosuppression and OKT-3 treatment for early organ
rejection are at highest risk for developing PTLD when compared to immunologically normal
individuals with prior EBV infection.Â
Useful For: Diagnosis of EBV-associated infectious mononucleosis in individuals with equivocal or

discordant Epstein-Barr virus (EBV) serologic marker test results Diagnosis of posttransplant
lymphoproliferative disorders (PTLD), especially in EBV-seronegative organ transplant recipients
receiving antilymphocyte globulin for induction immunosuppression and OKT-3 treatment for early
organ rejection Monitoring progression of EBV-associated PTLD in organ transplant recipients
Interpretation: The quantification range of this assay is 100 to 5,000,000 IU/mL (or 2.00-6.70 log
IU/mL), with a limit of detection (based on a 95% detection rate) at 45 IU/mL (1.65 log IU/mL).
Increasing levels of Epstein-Barr virus (EBV) DNA in serial plasma specimens of a given organ
transplant recipient may indicate possible development of posttransplant lymphoproliferative disorder
(PTLD). An "Undetected" result indicates that EBV DNA is not detected in the plasma specimen (see
Cautions). If clinically indicated, repeat testing in 1 to 2 months is recommended. A result of "<100
IU/mL" indicates that the EBV DNA level present in the plasma specimen is below 100 IU/mL (or 2.00
log IU/mL), and the assay cannot accurately quantify the EBV DNA present below this level. A
quantitative value (reported in IU/mL and log IU/mL) indicates the EBV DNA level (ie, viral load)
present in the plasma specimen. A result of ">5,000,000 IU/mL" indicates that the EBV DNA level
present in the plasma specimen is above 5,000,000 IU/mL (6.70 log IU/mL), and this assay cannot
accurately quantify the EBV DNA present above this level. An "Inconclusive" result indicates that the
presence or absence of EBV DNA in the plasma specimen could not be determined with certainty after
repeat testing in the laboratory, possibly due to PCR inhibition or presence of interfering substance.
Submission of a new specimen for testing is recommended if clinically indicated.
Reference Values:
Undetected
Clinical References: 1. Kimura H, Ito Y, Suzuki R, et al: Measuring Epstein-Barr virus (EBV)
load: the significance and application for each EBV-associated disease. Rev Med Virol
2008;18(5):305-319 2. Gulley ML, Tang W: Using Epstein-Barr viral load assays to diagnose, monitor,
and prevent post-transplant lymphoproliferative disorder. Clin Microbiol Rev 2010;23(2):350-366 3.
Ruf S, Wagner HJ: Determining EBV load: current best practice and future requirements. Expert Rev
Clin Immunol 2013;9(2):139-151 4. San-Juan R, Comoli P, Caillard S, et al: Epstein-Barr virus-related
post-transplant lymphoproliferative disorder in solid organ transplant recipients. Clin Microbiol Infect
2014;20(Suppl 7):109-118 5. Jiang SY, Yang JW, Shao JB, et al: Real-time polymerase chain reaction
for diagnosing infectious mononucleosis in pediatric patients: a systematic review and meta-analysis. J
Med Virol 2016;88(5):871-876.Â Â
ERG ERG Immunostain, Technical Component Only

70426 Clinical Information: ETS-related gene (ERG) is a member of the erythroblast transformation
specific (ETS) family of transcription factors. Expression of ERG is observed in prostate cancers where
the TMPRSS2-ERG gene rearrangement has occurred.
Useful For: Identification of erythroblast transformation specific (ETS)-related gene (ERG) protein
expression
stain. If an interpretation is required, order PATHC / Pathology Consultation for a full diagnostic
request, call 855-516-8404. Interpretation of this test should be performed in the context of the patient's
Clinical References: 1. He H, Magi-Galluzzi C, Li J, et al: The diagnostic utility of novel

immunohistochemical marker ERG in the workup of prostate biopsies with "atypical glands suspicious for
cancer". Am J Surg Pathol. 2011 Apr;35(4):608-614 2. Park K, Tomlins SA, Mudaliar KM, et al:
Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia. 2010
Jul;12(7):590-598 3. Karnes RJ, Cheville JC, Ida CM, et al: The ability of biomarkers to predict systemic
progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. Cancer
Res. 2010 Nov 15;70(22):8994-9002
REVE1 Erythrocytosis Evaluation, Whole Blood

608093 Clinical Information: Erythrocytosis (polycythemia) is identified by a sustained increase in
hemoglobin or hematocrit. An isolated increase in red blood cell count (in the absence of chronic
phlebotomy or coincident iron deficiency) may occur in thalassemia or other causes and does not indicate
erythrocytosis. Erythrocytosis may occur as a primary disorder, due to an intrinsic defect of bone marrow
stem cells, or secondary, in response to increased serum erythropoietin (EPO) levels. Secondary
erythrocytosis is associated with a number of disorders including chronic lung disease, chronic increase in
carbon monoxide, cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other
EPO-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable
cause involving hemoglobin or erythrocyte regulatory mechanisms may be present. It is important to
differentiate polycythemia vera (PV) from heritable causes of erythrocytosis, the latter of which can be
passed to progeny but do not carry the risks of clonal evolution or marrow fibrosis associated with PV.
The most common cause of hereditary erythrocytosis is the presence of high-oxygen-affinity (HOA)
hemoglobin. A subset of hemoglobins with increased oxygen (O2) affinity result in clinically evident
erythrocytosis caused by decreased O2 unloading at the tissue level. Many are asymptomatic; however,
some patients have recurrent headaches, dizziness, fatigue, and restless legs. A minor subset of patients
has thrombotic episodes. Affected individuals can be plethoric and many are misclassified as
polycythemia vera. The oxygen dissociation curve is left-shifted (p50 values are decreased). Changes to
the amino acid sequence of the hemoglobin molecule may distort the protein structure, affecting O2
transport or unloading and the binding of 2,3-bisphosphoglyceric acid (2,3-BPG). 2,3-BPG stabilizes the
deoxygenated state of hemoglobin. Therefore, a decrease in the 2,3-BPG concentration results in greater
O2 affinity of the normal hemoglobin molecule. A few cases of erythrocytosis have been associated with
a reduction in 2,3-BPG formation. This is most commonly due to variants in the converting enzyme,
bisphosphoglycerate mutase. Truncating variants in the erythropoietin receptor gene, EPOR, have been
shown to be a cause of the autosomal dominant primary familial and congenital polycythemia (OMIM
133100). In addition, oxygen sensing pathway variants, EPAS1(HIF2A) (OMIM 611783);
EGLN1(PHD2) (OMIM 609820), and VHL (OMIM 263400) cause hereditary erythrocytosis and a subset
are associated with pheochromocytoma and paragangliomas. All have shown an autosomal dominant
pattern of inheritance, except VHL-associated erythrocytosis, which is an autosomal recessive disorder.
Homozygous VHL R200W alterations have been shown to be causative of Chuvash polycythemia, an
endemic heritable erythrocytic disorder first described in Russia but subsequently found in other ethnic
groups. The prevalence of causative variants in EPOR and the oxygen sensing pathway genes is unknown,
but in our experience, they are less prevalent than genetic variants that cause HOA hemoglobin variants
and are much less prevalent than polycythemia vera. Because there are many causes of erythrocytosis, an
algorithmic and reflexive testing strategy is useful for evaluating these disorders. Initial JAK2 V617F
alteration testing and serum EPO levels are important with p50 results further stratifying JAK2-negative
cases. Importantly, a significant subset of HOA hemoglobin variants can be electrophoretically silent on
multiple routine screening platforms; however, most, if not all, of HOA hemoglobin variants can be
identified with addition of the mass spectrometry method. Our extensive experience with these disorders
allows an economical, comprehensive evaluation with high sensitivity.
Useful For: Definitive, comprehensive, and economical evaluation of an individual with

JAK2-negative erythrocytosis associated with lifelong sustained increased hemoglobin or hematocrit
Interpretation: The evaluation includes testing for a hemoglobinopathy and oxygen (O2) affinity of
the hemoglobin molecule. An increase in O2 affinity is demonstrated by a shift to the left in the O2
dissociation curve (decreased p50 result). Reflex testing for EPOR, EGLN1 (PHD2), EPAS1 (HIF2a),
VHL, and BPGM will be performed as needed. A hematopathologist expert in these disorders will
evaluate the case, appropriate tests are performed, and an interpretive report is issued.
Reference Values:
Definitive results and an interpretive report will be provided.
Clinical References: 1. Patnaik MM, Tefferi A: The complete evaluation of erythrocytosis:

congenital and acquired. Leukemia. 2009 May;23(5):834-844 2. McMullin MF: The classification and
diagnosis of erythrocytosis. Int J Lab Hematol. 2008;30:447-459 3. Percy MJ, Lee FS: Familial
erythrocytosis: molecular links to red blood cell control. Haematologica. 2008 Jul;93(7):963-967 4.
Huang LJ, Shen YM, Bulut GB: Advances in understanding the pathogenesis of primary familial and
congenital polycythaemia. Br J Haematol. 2010 Mar;148(6):844-852 5. Maran J, Prchal J: Polycythemia
and oxygen sensing. Pathol Biol. 2004;52:280-284 6. Lee F: Genetic causes of erythrocytosis and the
oxygen-sensing pathway. Blood Rev. 2008;22:321-332 7. Merchant SH, Oliveira JL, Hoyer JD,
Viswanatha DS: Erythrocytosis. In: His ED, ed. Hematopathology. 2nd ed. Elsevier Saunders;
2012:722-723 8. Zhuang Z, Yang C, Lorenzo F, et al: Somatic HIF2A gain-of-function mutations in
paraganglioma with polycythemia. N Engl J Med. 2012 Sep 6;367(10):922-930 9. Oliveira JL, Coon
LM, Frederick LA, et al: Genotype-phenotype correlation of hereditary erythrocytosis mutations, a
single center experience. Am J Hematol. 2018 May 23. doi: 10.1002/ajh.25150
REVEI Erythrocytosis Interpretation

608426 Clinical Information: Erythrocytosis (polycythemia) is identified by a sustained increase in
hemoglobin or hematocrit. An isolated increase in red blood cell (RBC) count (in the absence of chronic
phlebotomy or coincident iron deficiency) may occur in thalassemia or other causes and does not
indicate erythrocytosis. Erythrocytosis may occur as a primary disorder, due to an intrinsic defect of
bone marrow stem cells, or secondary, in response to increased serum erythropoietin (EPO) levels.
Secondary erythrocytosis is associated with a number of disorders including chronic lung disease,
chronic increase in carbon monoxide, cyanotic heart disease, high-altitude living, renal cysts and
tumors, hepatoma, and other EPO-secreting tumors. When these common causes of secondary
erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory
mechanisms may be present. It is important to differentiate polycythemia vera (PV) from heritable
causes of erythrocytosis, the latter of which can be passed to progeny but do not carry the risks of clonal
evolution or marrow fibrosis associated with PV. The most common cause of hereditary erythrocytosis
is the presence of high-oxygen-affinity (HOA) hemoglobin. A subset of hemoglobins with increased
oxygen (O2) affinity result in clinically evident erythrocytosis caused by decreased O2 unloading at the
tissue level. Many are asymptomatic; however some patients have recurrent headaches, dizziness,
fatigue and restless legs. A minor subset of patients has thrombotic episodes. Affected individuals can
be plethoric and many are misclassified as polycythemia vera. The oxygen dissociation curve is
left-shifted (p50 values are decreased). Changes to the amino acid sequence of the hemoglobin molecule
may distort the protein structure, affecting O2 transport or unloading and the binding of
2,3-bisphosphoglyceric acid (2,3-BPG). 2,3-BPG stabilizes the deoxygenated state of hemoglobin.
Therefore a decrease in the 2,3-BPG concentration results in greater O2 affinity of the normal
hemoglobin molecule. A few cases of erythrocytosis have been associated with a reduction in 2,3-BPG
formation. This is most commonly due to variants in the converting enzyme, bisphosphoglycerate
mutase (BPGM). Truncating variants in the erythropoietin receptor gene, EPOR, have been shown to be
a cause of the autosomal dominant primary familial and congenital polycythemia (PFCP)(OMIM
133100). In addition, oxygen sensing pathway variants, EPAS1(HIF2A)(OMIM 611783);
EGLN1(PHD2)(OMIM 609820), and VHL (OMIM 263400) cause hereditary erythrocytosis and a
subset are associated with pheochromocytoma and paragangliomas. All have shown an autosomal
dominant pattern of inheritance, except VHL-associated erythrocytosis, which is an autosomal recessive
disorder. Homozygous VHL R200W alterations have been shown to be causative of Chuvash
polycythemia, an endemic heritable erythrocytic disorder first described in Russia but subsequently
found in other ethnic groups. The prevalence of causative variants in EPOR and the oxygen sensing
pathway genes is unknown, but in our experience they are less prevalent than genetic variants that cause
HOA hemoglobin variants, and much less prevalent than polycythemia vera. Because there are many
causes of erythrocytosis, an algorithmic and reflexive testing strategy is useful for evaluating these
disorders. Initial JAK2 V617F alteration testing and serum EPO levels are important with p50 results
further stratifying JAK2-negative cases. Importantly, a significant subset of HOA hemoglobin variants
can be electrophoretically silent on multiple routine screening platforms; however, most if not all of
HOAs can be identified with addition of the mass spectrometry method. Our extensive experience with
these disorders allows an economical, comprehensive evaluation with high sensitivity.
Useful For: Interpretation of results for the evaluation of erythrocytosis Definitive, comprehensive, and
economical evaluation of an individual with JAK2-negative erythrocytosis associated with lifelong
sustained increased hemoglobin or hematocrit
Interpretation: The evaluation includes testing for a hemoglobinopathy and oxygen (O2) affinity of
the hemoglobin molecule. An increase in O2 affinity is demonstrated by a shift to the left in the O2
dissociation curve (decreased p50 result). Reflex testing for EPOR, EGLN1 (PHD2), EPAS1 (HIF2a),
VHL, and BPGM will be performed as needed. A hematopathologist expert in these disorders will
evaluate the case, appropriate tests are performed, and an interpretive report is issued.
Reference Values:
Only orderable as part of a profile. For more information see REVE1 / Erythrocytosis Evaluation, Whole
Blood.
Definitive results and an interpretative report will be provided.

and oxygen sensing. Pathol Biol. 2004;52:280-284 6. Lee F: Genetic causes of erythrocytosis and the
oxygen-sensing pathway. Blood Rev. 2008;22:321-332 7. Merchant SH, Oliveira JL, Hoyer JD,
Viswanatha DS: Erythrocytosis. In: His ED, ed. Hematopathology. 2nd ed. Elsevier Saunders; 2012:
722-723 8. Zhuang Z, Yang C, Lorenzo F, et al: Somatic HIF2A gain-of-function mutations in
paraganglioma with polycythemia. N Engl J Med. 2012 Sep 6;367(10):922-930 9. Oliveira JL, Coon LM,
Frederick LA, et al: Genotype-Phenotype Correlation of Hereditary Erythrocytosis Mutations, a single
center experience. Am J Hematol. 2018 May 23 PMID: 29790589
REVE0 Erythrocytosis Summary Interpretation

608094 Clinical Information: The etiology of congenital (inherited) erythrocytosis can be due to one of
several abnormalities. This includes high oxygen affinity hemoglobin variants, genetic variants in the
erythropoietin receptor gene, genetic variants in the genes involved in the oxygen-sensing pathway
(PHD2/EGLN1, HIF2A/EPAS1, VHL) or BPGM variants causing 2,3-BPG (2,3-bisphosphoglycerate)
deficiency. To determine the underlying abnormality frequently requires molecular testing. A summary
interpretation that incorporates all of the testing performed is beneficial to the ordering clinician.
Useful For: Incorporating and summarizing subsequent results into an overall evaluation if 1 or more
molecular tests are reflexed on the REVE1 / Erythrocytosis Evaluation, Blood

Reference Values:
Only orderable as a reflex. For more information see REVE1 / Erythrocytosis Evaluation, Blood.

congenital and acquired. Leukemia. 2009 May;23(5):834-844 2. Percy MJ, Lee FS: Familial
Maran J, Prchal J: Polycythemia and oxygen sensing. Pathol Biol. 2004;52:280-284 4. Merchant SH,
Oliveira JL, Hoyer JD, Viswanatha DS: Erythrocytosis. In: His ED, ed. Hematopathology. 2nd ed.
Elsevier Saunders; 2012:722-723 5. Harteveld CL, Higgs DR: Alpha-thalassemia. Orphanet J Rare Dis.
2010;5:13 6. Thein SL: The Molecular basis of beta-thalassemia. Cold Spring Harb Persepct Med.
2013;1;3(5):a011700 7. Crowley MA, Mollan TL, Abdulmalik OY, et al: A hemoglobin variant
associated with neonatal cyanosis and anemia. N Engl J Med. 2011;364:1837-1843 8. Kipp BR,
Roellinger SE, Lundquist PA, et al: Development and clinical implementation of a combination deletion
PCR and multiplex ligation-dependent probe amplification assay for detecting deletions involving the
human alpha-globin gene cluster. J Mol Diagn. 2011 Sep;13(5):549-557. doi:
10.1016/j.jmoldx.2011.04.001 9. Hein MS, Oliveira JL, Swanson KC, et al: Large deletions involving
the beta globin gene complex: genotype-phenotype correlation of 119 cases. Blood. 2015;126:3374
EPOR Erythropoietin Receptor (EPOR) Gene, Exon 8 Sequencing,

61679 Whole Blood
Clinical Information: Erythrocytosis (ie, increased RBC mass or polycythemia) may be primary,
due to an intrinsic defect of bone marrow stem cells (ie, polycythemia vera: PV), or secondary, in
response to increased serum erythropoietin (EPO) levels. Secondary erythrocytosis is associated with a
number of disorders including chronic lung disease, chronic increase in carbon monoxide (due to
smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other
EPO-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a
heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be suspected. Unlike
polycythemia vera, hereditary erythrocytosis is not associated with the risk of clonal evolution and
should present with isolated erythrocytosis that has been present since birth. A small subset of cases is
associated with pheochromocytoma and/or paraganglioma formation. It is caused by variants in several
genes and may be inherited in either an autosomal dominant or autosomal recessive manner. A family
history of erythrocytosis would be expected in these cases, although it is possible for new alterations to
arise in an individual. The genes coding for hemoglobin, beta globin and alpha globin
(high-oxygen-affinity hemoglobin variants), hemoglobin-stabilization proteins (2,3 bisphosphoglycerate
mutase: BPGM), and the erythropoietin receptor, EPOR, and oxygen-sensing pathway enzymes
(hypoxia-inducible factor: HIF/EPAS1, prolyl hydroxylase domain: PHD2/EGLN1, and von Hippel
Lindau: VHL) can result in hereditary erythrocytosis (see Table). High-oxygen-affinity hemoglobin
variants and BPGM abnormalities result in a decreased p50 result, whereas those affecting EPOR, HIF,
PHD, and VHL have normal p50 results. The true prevalence of hereditary erythrocytosis-causing
alterations is unknown. The hemoglobin genes, HBA1/HBA2 and HBB are not assayed in this profile.
Genes Associated with Hereditary Erythrocytosis Gene Inheritance Serum EPO p50 JAK2 V617F
Acquired Decreased Normal JAK2 exon 12 Acquired Decreased Normal EPOR Dominant Decreased
Normal PHD2/EGLN1 Dominant Normal level Normal BPGM Recessive Normal level Decreased Beta
Globin Dominant Normal level to increased Decreased Alpha Globin Dominant Normal level to
increased Decreased HIF2A/EPAS1 Dominant Normal level to increased Normal VHL Recessive
Normal level to increased Normal The oxygen-sensing pathway functions through an enzyme,
hypoxia-inducible factor (HIF), which regulates RBC mass. A heterodimer protein comprised of alpha
and beta subunits, HIF functions as a marker of depleted oxygen concentration. When present, oxygen
becomes a substrate mediating HIF-alpha subunit degradation. In the absence of oxygen, degradation
does not take place and the alpha protein component is available to dimerize with a HIF-beta subunit.
The heterodimer then induces transcription of many hypoxia response genes including EPO, VEGF, and
GLUT1. HIF-alpha is regulated by von Hippel-Lindau (VHL) protein-mediated ubiquitination and
proteosomal degradation, which requires prolyl hydroxylation of HIF proline residues. The HIF-alpha
subunit is encoded by the HIF2A (EPAS1) gene. Enzymes important in the hydroxylation of HIF-alpha
are the prolyl hydroxylase domain proteins, of which the most significant isoform is PHD2, which is
encoded by the PHD2 (EGLN1) gene. Genetic variants resulting in altered HIF-alpha, PHD2, and VHL
proteins can lead to clinical erythrocytosis. A small subset of variants, in PHD2/EGLN1 and
HIF2A/EPAS1, has also been detected in erythrocytic patients presenting with paragangliomas or
pheochromocytomas. Truncating variants in the EPOR gene coding for the erythropoietin receptor can
result in erythrocytosis through loss of the negative regulatory cytoplasmic SHP-1 binding domain
leading to EPO hypersensitivity. All currently known alterations have been localized to exon 8 and are
heterozygous truncating variants. EPOR variants are associated with decreased EPO levels and normal
p50 values (see Table).
Useful For: Assessing EPOR in the evaluation of an individual with JAK2-negative erythrocytosis
associated with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit
Interpretation: An interpretive report will be provided as a part of the HEMP / Hereditary

Erythrocytosis Mutations, Whole Blood, and will include specimen information, assay information, and
whether the specimen was positive for any mutations in the gene. If positive, the mutation will be
correlated with clinical significance, if known.
Reference Values:
Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis
Mutations, Whole Blood.

and oxygen sensing. Pathologie Biologie. 2004;52:280-284 6. Lee F: Genetic causes of erythrocytosis and
the oxygen-sensing pathway. Blood Rev. 2008;22:321-332 7. Merchant SH, Oliveira JL, Hoyer JD,
Viswanatha DS: Erythrocytosis. In: His ED, ed. Hematopathology. 2nd ed. Elsevier Saunders;
2012:22-723 8. Zhuang Z, Yang C, Lorenzo F, et al: Somatic HIF2A gain-of-function mutations in
paraganglioma with polycythemia. N Engl J Med. 2012 Sep 6;367(10):922-930 9. Ladroue C, Carcenac
R, Leporrier M, et al: PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med.
2008 Dec 18;359(25):2685-2692 10. Lorenzo FR, Yang C, Ng Tang Fui M, et al: A novel EPAS1/HIF2A
germline mutation in congenital polycythemia with paraganglioma. J Mol Med. 2013 Apr;91(4):507-512
11. Tarade D, Robinson CM, Lee JE, Ohh M: HIF-2alpha-pVHL complex reveals broad
genotype-phenotype correlations in HIF-2aalpha-driven disease. Nat Commun. 2018;9(1):3359 12.
Oliveira JL: Algorithmic evaluation of hereditary erythrocytosis: Pathways and caveats. Int J Lab
Hematol. 2019 May;41 Suppl 1:89-94
EPO Erythropoietin, Serum

80173 Clinical Information: Erythropoietin (EPO), a large (193 amino acid residue) glycoprotein hormone
secreted by the kidney, regulates red blood cell (RBC) production. Normally, EPO levels vary inversely
with hematocrit. Hypoxia stimulates EPO release, which, in turn, stimulates bone marrow erythrocyte
production. High blood levels of RBC, hemoglobin, hematocrit, or oxygen suppress the release of EPO.
Primary polycythemia (polycythemia vera) is a neoplastic (clonal) blood disorder characterized by
autonomous production of hematopoietic cells. Increased RBCs result in compensatory suppression of
EPO levels. Findings consistent with polycythemia vera include hemoglobin greater than 18.5 g/dL,
persistent leukocytosis, persistent thrombocytosis, unusual thrombosis, splenomegaly, and
erythromelalgia (dysesthesia and erythema involving the distal extremities). Secondary polycythemias
may either be due to an appropriate or an inappropriate increase in red cell mass. Appropriate secondary
polycythemias (eg, high-altitude living and pulmonary disease) are characterized by hypoxia and a
compensatory increase in red cell mass. EPO production is increased in an attempt to increase the delivery
of oxygen by increasing the number of oxygen-carrying RBCs. Some tumors secrete EPO or EPO-like
proteins; examples include tumors of the kidney, liver, lung, and brain. Such increases result in
inappropriate secondary polycythemias. Abnormal EPO levels also may be seen in renal failure. The
majority of EPO production is in the kidneys. Therefore, chronic kidney failure may result in decreased
EPO production and, subsequently, anemia. In addition to the kidneys, the liver also produces a small
amount of EPO. Thus, patients who are anephric have a residual amount of EPO produced by the liver.
Patients in chronic kidney failure, as well as patients with anemia due to a variety of other causes
including chemotherapy, HIV/AIDS, and some hematologic disorders, may be candidates for treatment
with recombinant human EPO. Recombinant EPO compounds used to treat anemia include epoetin alpha
and darbepoetin. Epoetin alpha is a 165 amino acid glycoprotein produced in mammalian cells and has an
identical amino acid sequence to natural human EPO. It has 3 oligosaccharide chains and a molecular
mass of 30.4 kDa. Darbepoetin alpha is a 165 amino acid glycoprotein that is also produced in
mammalian cells. It has 2 additional N-linked oligosaccharide chains and a molecular mass of 37 kDa.
There are no specific assays for measuring recombinant EPO compounds. Drug levels can only be
roughly estimated from the cross reactivity of the compounds in EPO assays. According to in-house
studies, epoetin and darbepoetin show approximately 58% and 36% cross-reactivity, respectively, in the
EPO assay.
Useful For: An aid in distinguishing between primary and secondary polycythemia Differentiating
between appropriate secondary polycythemia (eg, high-altitude living, pulmonary disease, tobacco use)
and inappropriate secondary polycythemia (eg, tumors) Identifying candidates for erythropoietin (EPO)
replacement therapy (eg, those with chronic renal failure) Evaluating patients undergoing EPO
replacement therapy who demonstrate an inadequate hematopoietic response
Interpretation: In the appropriate clinical setting (eg, confirmed elevation of hemoglobin >18.5
g/dL, persistent leukocytosis, persistent thrombocytosis, unusual thrombosis, splenomegaly, and
erythromelalgia), polycythemia vera is unlikely when erythropoietin (EPO) levels are elevated but is
likely when EPO levels are suppressed. EPO levels are also increased in patients with anemia of bone
marrow failure, iron deficiency, or thalassemia. Patients, who have either a poor or no erythropoietic
response to EPO therapy, but high-normal or high EPO levels, may have additional, unrecognized
causes for their anemia. If no contributing factors can be identified after adequate further study, the
possibility that the patient may have developed EPO-antibodies should be considered. This can be a
serious clinical situation that can result in red cell aplasia and should prompt expeditious referral to
hematologists or immunologists skilled in diagnosing and treating this disorder.
Reference Values:
2.6-18.5 mIU/mL
Clinical References: 1. Tefferi A: Diagnosing polycythemia vera: a paradigm shift. Mayo Clin
Proc. 1999;74:159-162 2. Hoagland HC: Myelodysplastic (preleukemia) syndromes: the bone marrow
factory failure problem. Mayo Clin Proc. 1995;70:673-677 3. Casadeval N: Pure red cell aplasia and
anti-erythropoietin antibodies in patients treated with epoetin. Nephrol Dial Transplant. 2003;18 (Suppl.
8):viii37-viii41 4. Fisher JW: Erythropoietin: physiology and pharmacology update. Exp Biol Med.
2003;228:1-14 5. Strippoli GFM, Manno C, Schena FP, Craig JC: Haemoglobin and haematocrit targets
for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003967 6.
Tefferi A: Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk
stratification, and management. Am J Hematol. 2012 Mar;87:285-293. doi: 10.1002/ajh.23135 7. Moore
E, Bellomo R: Erythropoietin (EPO) in acute kidney injury. Ann Intensive Care. 2011 March;1(3). doi:
10.1186/2110-5820-1-3 8. Macdougall I: Anaemia and chronic renal failure. Medicine.
2011;39(7):425-428. doi: 10.1016/j.mpmed.2011.04.009
E157C Escherichia coli O157:H7 Culture, Feces

determine the appropriate testing to be performed. Shiga toxin-producing Escherichia coli (STEC) are E
coli strains capable of producing Shiga toxin, which can result in diarrhea that can be bloody. The
incubation period between exposure and symptom onset is 1 to 9 days. Hemolytic-uremic syndrome
(HUS) is a systemic complication of STEC infection and is characterized by renal failure,
microangiopathic hemolytic anemia, and nonimmune thrombocytopenia. HUS complicates approximately
15% of STEC infections in children younger than 10 years and 6% to 9% overall. Â Treatment of STEC
infection consists of supportive care. Antibiotic therapy is generally not beneficial in patients with STEC
infection and has been associated with development of HUS in some studies. Thus, when STEC is
clinically suspected, antibiotics should be withheld. Antiperistaltic agents also increase the risk of
systemic complications and should be avoided.
Useful For: Determining whether Escherichia coli O157:H7 may be the cause of diarrhea Reflexive
testing for Shiga toxin and/or E coli O157:H7 nucleic acid amplification test-positive feces This test is
previously.
Interpretation: The growth of Escherichia coli O157:H7 identifies a potential cause of diarrhea.
Reference Values:
Clinical References: 1. Pillai DR: Fecal culture for Campylobacter and related organisms. In
Clinical Microbiology Procedures Handbook, Fourth edition. Washington, DC, ASM Press, 2016, Section
3.8.2 2. DuPont HL: Persistent diarrhea: A clinical review. JAMA, 2016;315(24):2712-2723
doi:10.1001/jama.2016.7833 3. Page AV, Liles WC: Enterohemorrhagic Escherichia coli infections and
the hemolytic-uremic syndrome. Med Clin North Am 2013;97:681 4. Nelson JM, Griffin PM, Jones TF,
et al: Antimicrobial and antimotility agent use in persons with shiga toxin-producing Escherichia coli
O157 infection in FoodNet Sites. Clin Infect Dis 2011;52:1130
FFES Estradiol Free, Serum (includes Estradiol and SHBG)

Estradiol, Serum MS
Units: pg/mL
Age Range
Newborn
Levels are markedly elevated at birth and fall rapidly during the first week to prepubertal values of <15.
Males <6 m
Levels increase to 10 - 32 between 30 and 60 days, then decline to prepubertal levels of <15 by six
months.
Females <1 y
Levels increase to 5.0 - 50 between 30 and 60 days, then decline to prepubertal levels of <15 during the
first year.
Prepubertal <15
Adult Males 8.0 - 35
Adult Females
Follicular 30 - 100
Luteal 70 - 300
Postmenopausal <15
Free Estradiol, Percent

Units: %
Age Range
Adult Males 1.7 - 5.4
Adult Females 1.6 - 3.6
Free Estradiol, Serum

Units: pg/mL
Age Range
Adult Males 0.2 - 1.5
Adult Females 0.6 - 7.1
Sex Hormone Binding Globulin

Units: nmol/L
Age Range
Infants (1 - 23m) 60.0 - 252.0
Prepubertal 72.0 - 220.0
Pubertal
Males 16.0 - 100.0
Females 36.0 - 125.0
Adult Males
20 - 49 y 16.5 - 55.9
>49y 19.3 - 76.4
Adult Females
20 Ã¢â‚¬â€œ 49y 24.6 - 122.0
>49y 17.3 - 125.0
ESTS Estradiol, Rapid, Immunoassay, Serum

8575 Clinical Information: Estrogens are responsible for the development and maintenance of female
sex organs and female secondary sex characteristics. In conjunction with progesterone, they participate
in regulation of the menstrual cycle, breast and uterine growth, and in the maintenance of pregnancy.
Estrogens affect calcium homeostasis and have a beneficial effect on bone mass. They decrease bone
resorption and, in prepubertal girls, estrogen accelerates linear bone growth. Long-term estrogen
depletion is associated with loss of bone mineral content, an increase in stress fractures, and
postmenopausal osteoporosis. The 3 most biologically active estrogens in order of potency are estrone
(E1), estradiol (E2), and estriol (E3). Estrogens are produced primarily in the ovary (follicle, corpus
luteum), but small quantities are also formed in the testes and in the adrenal cortex. During pregnancy,
estrogens are mainly formed in the placenta. About 98% of estradiol is bound to transport proteins (sex
hormone-binding globulin) and albumin. Estrogen secretion is biphasic during the menstrual cycle. The
determination of E2 is utilized clinically in the elucidation of fertility disorders in the
hypothalamus-pituitary-gonad axis, gynecomastia, estrogen-producing ovarian and testicular tumors,
and in hyperplasia of the adrenal cortex. Additional clinical indications are the monitoring of fertility
therapy and determining the time of ovulation within the framework of in vitro fertilization. The
laboratory plays an important role in the process of ovulation induction. The principle involves
administration of gonadotropins to stimulate follicular growth, followed by human chorionic
gonadotropin (hCG) to stimulate ovulation follicular maturation. Clinical, laboratory, and ultrasound
monitoring of the treatment cycle is necessary to identify the dose and length of therapy, determine
when or whether to administer hCG, and obtain an adequate ovulatory response while avoiding
hyperstimulation.
Useful For: Rapid assessment of ovarian status, including follicle development, for assisted
reproduction protocols (eg, in vitro fertilization) Establishing time of ovulation and optimal time for
conception
Interpretation: Optimal time for conception is within 48 to 72 hours following the midcycle estradiol
peak. Serial specimens must be drawn over several days to evaluate baseline and peak estradiol levels.
Low baseline levels and a lack of rise, as well as persistent high levels without midcycle rise, are
indicative of anovulatory cycles. For determining the timing of initiation of ovarian stimulation in in vitro
fertilization (IVF) studies, low levels before stimulation are critical, as higher values often are associated
with poor stimulation cycles. Before final human chorionic gonadotropin (hCG) stimulation at mid-IVF
cycle, estradiol concentrations above 2000 to 3000 pg/mL are considered by some IVF specialists to be
indicative of an increased likelihood of ovarian hyperstimulation and it may be advisable to consider
withholding further hCG stimulation. Estradiol (E2) concentrations below 200 pg/mL following midcycle
stimulation (hCG or follicle-stimulating hormone [FSH]) are associated with very low pregnancy success
rates. E2 concentrations change during the menstrual cycle, as follows: -less than 50 pg/mL before
midfollicular phase -250 to 500 pg/mL midcycle peak as the follicle matures -Abrupt decrease after
ovulation -125 pg/mL peak during the luteal phase Estrogen replacement in reproductive-age women
should aim to mimic natural estrogen levels as closely as possible. E2 levels should be within the
reference range for premenopausal women and luteinizing hormone and FSH should be within the normal
range.
Reference Values:
Males: 10-40 pg/mL
Females
Premenopausal: 15-350 pg/mL*
Postmenopausal: <10 pg/mL
*Estradiol concentrations vary widely throughout the menstrual cycle
Clinical References: 1. Rifai N, Chiu RWK, Young I, Burnham CAD, Wittwer CT, eds. Tietz
Textbook of Laboratory Medicine. 7th ed. Elsevier; 2023 2. Practice Committee of the American Society
for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril. 2008 Nov;90(5
Suppl):S188-S193
EEST Estradiol, Serum

81816 Clinical Information: Estrogens are involved in development and maintenance of the female
phenotype, germ cell maturation, and pregnancy. They also are important for many other,
nongender-specific processes, including growth, nervous system maturation, bone
metabolism/remodeling, and endothelial responsiveness. The 2 major biologically active estrogens in
nonpregnant humans are estrone (E1) and estradiol (E2). A third bioactive estrogen, estriol (E3), is the
main pregnancy estrogen, but plays no significant role in nonpregnant women or men. E2 is produced
primarily in ovaries and testes by aromatization of testosterone. Small amounts are produced in the
adrenal glands and some peripheral tissues, most notably fat. By contrast, most of the circulating E1 is
derived from peripheral aromatization of androstenedione (mainly adrenal). E2 and E1 can be converted
into each other, and both can be inactivated via hydroxylation and conjugation. E2 demonstrates 1.25 to 5
times the biological potency of E1. E2 circulates at 1.5 to 4 times the concentration of E1 in
premenopausal, nonpregnant women. E2 levels in men and postmenopausal women are much lower than
in nonpregnant women, while E1 levels differ less, resulting in a reversal of the premenopausal E2:E1
ratio. E2 levels in premenopausal women fluctuate during the menstrual cycle. They are lowest during the
early follicular phase. E2 levels then rise gradually until 2 to 3 days before ovulation, at which stage they
start to increase much more rapidly and peak just before the ovulation-inducing luteinizing hormone
(LH)/follicle stimulating hormone (FSH) surge at 5 to 10 times the early follicular levels. This is followed
by a modest decline during the ovulatory phase. E2 levels then increase again gradually until the midpoint
of the luteal phase and, thereafter, decline to trough, early follicular levels. Measurement of serum E2
forms an integral part of the assessment of reproductive function in females, including assessment of
infertility, oligo-amenorrhea, and menopausal status. In addition, it is widely used for monitoring
ovulation induction, as well as during preparation for in vitro fertilization. For these applications E2
measurements with modestly sensitive assays suffice. However, extra sensitive E2 assays, simultaneous
measurement of E1, or both are needed in a number of other clinical situations. These include inborn
errors of sex steroid metabolism, disorders of puberty, estrogen deficiency in men, fracture risk
assessment in menopausal women, and increasingly, therapeutic drug monitoring, either in the context of
low-dose female hormone replacement therapy or antiestrogen treatment. See Steroid Pathways in Special
Instructions.
Useful For: All applications that require moderately sensitive measurement of estradiol: -Evaluation
of hypogonadism and oligo-amenorrhea in females -Assessing ovarian status, including follicle
development, for assisted reproduction protocols (eg, in vitro fertilization) -In conjunction with
luteinizing hormone measurements, monitoring of estrogen replacement therapy in hypogonadal
premenopausal women -Evaluation of feminization, including gynecomastia, in males -Diagnosis of
estrogen-producing neoplasms in males and, to a lesser degree, females -As part of the diagnosis and
workup of precocious and delayed puberty in females, and, to a lesser degree, males -As part of the
diagnosis and workup of suspected disorders of sex steroid metabolism (eg, aromatase deficiency and
17 alpha-hydroxylase deficiency) -As an adjunct to clinical assessment, imaging studies and bone
mineral density measurement in the fracture risk assessment of postmenopausal women, and, to a lesser
degree, older men -Monitoring low-dose female hormone replacement therapy in postmenopausal
women -Monitoring antiestrogen therapy (eg, aromatase inhibitor therapy)
Interpretation: Estradiol (E2) levels below the premenopausal reference range in young females
indicate hypogonadism. If luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels are
elevated, primary gonadal failure is diagnosed. The main causes are genetic (eg, Turner syndrome,
familial premature ovarian failure), autoimmune (eg, autoimmune ovarian failure, possibly as part of
autoimmune polyglandular endocrine failure syndrome type II), and toxic (eg, related to chemotherapy
or radiation therapy for malignant disease). If LH/FSH levels are low or inappropriately "normal," a
diagnosis of hypogonadotrophic hypogonadism is made. This can have functional causes, such as
starvation, overexercise, severe physical or emotional stress, and heavy drug and/or alcohol use. It also
can be caused by organic disease of the hypothalamus or pituitary. Further workup is usually necessary,
typically including measurement of pituitary hormones (particularly prolactin), and possibly imaging.
Irregular or absent menstrual periods with normal or high E2 levels (and often high estrone: E1 levels)
are indicative of possible polycystic ovarian syndrome, androgen producing tumors, or estrogen
producing tumors. Further workup is required and usually includes measurement of total and
bioavailable testosterone, androstenedione, dehydroepiandrosterone (sulfate), sex hormone-binding
globulin, and possibly imaging. E2 levels change during the menstrual cycle, as follows: -Post-menses,
levels may be as low as 15 pg/mL -Levels then rise during the follicular phase to a preovulatory peak,
typically in the 300+ pg/mL range -Levels fall in the luteal phase -Menses typically occur when E2
levels are in the 50 to 100 pg/mL range E2 analysis may be helpful in establishing time of ovulation and
optimal time for conception. Optimal time for conception is within 48 to 72 hours following the
midcycle E2 peak. Serial specimens must be drawn over several days to evaluate baseline and peak total
estrogen (E1 + E2) levels. Low baseline levels and a lack of rise, as well as persistent high levels
without midcycle rise, are indicative of anovulatory cycles. For determining the timing of initiation of
ovarian stimulation in in vitro fertilization studies, low levels (around 30 pg/mL) before stimulation, are
critical, as higher values often are associated with poor stimulation cycles. Estrogen replacement in
reproductive-age women should aim to mimic natural estrogen levels as closely as possible. E2 levels
should be within the reference range for premenopausal women, LH/FSH should be within the normal
range, and E2 levels should ideally be higher than E1 levels. The current recommendations for
postmenopausal female hormone replacement are to administer therapy in the smallest beneficial doses
for as briefly as possible. Ideally, E2 and E1 levels should be held below, or near, the lower limit of the
premenopausal female reference range. Postmenopausal women and older men in the lowest quartile of
E2 levels are at increased risk of osteoporotic fractures. E2 levels are typically less than 5 pg/mL in
these patients. Antiestrogen therapy with central or peripheral acting agents that are not pure receptor
antagonists usually aims for complete suppression of E2 production, and in the case of aromatase
inhibitors, complete E1 and E2 suppression. Gynecomastia or other signs of feminization in males may
be due to an absolute or relative (in relation to androgens) surplus of estrogens. Gynecomastia is
common during puberty in boys. Unless E1, E2, or testosterone levels exceed the adult male reference
range, the condition is usually not due to hormonal disease (though it sometimes may still result in
persistent breast tissue, which later needs to be surgically removed). For adults with gynecomastia, the
workup should include testosterone and adrenal androgen measurements, in addition to E2 and E1
measurements. Causes for increased E1 or E2 levels include: -High androgen levels caused by tumors or
androgen therapy (medical or sport performance enhancing), with secondary elevations in E1 and E2
due to aromatization -Obesity with increased tissue production of E1 -Decreased E1 and E2 clearance in
liver disease -Estrogen producing tumors -Estrogen ingestion Normal male E1 and E2 levels also may
be associated with feminization or gynecomastia, if bioavailable testosterone levels are low due to
primary/secondary testicular failure. This may occur, for example, when patients are receiving
antiandrogen therapy or other drugs with antiandrogenic effects (eg, spironolactone, digitalis
preparations). The gonadotrophin-releasing hormone stimulation test remains the central part of the
workup for precocious puberty. However, baseline sex steroid and gonadotrophin measurements also
are important. Prepubertal girls have E2 levels below 10 pg/mL (most <5 pg/mL). Levels in prepubertal
boys are less than half the levels seen in girls. LH/FSH are very low or undetectable. E1 levels also are
low, but may rise slightly in obese children after onset of adrenarche. E2, which is produced in the
gonads, should remain low in these children. In true precocious puberty, both E2 and LH/FSH levels are
elevated above the prepubertal range. Elevation of E2 or E1 alone suggests pseudo-precocious puberty,
possibly due to a sex steroid-producing tumor. In delayed puberty, estrogens and gonadotrophins are in
the prepubertal range. A rise over time predicts the spontaneous onset of puberty. Persistently low
estrogens and elevated gonadotrophins suggest primary ovarian failure, while low gonadotrophins
suggest hypogonadotrophic hypogonadism. In this latter case, Kallmann syndrome (or related disorders)
or hypothalamic/pituitary tumors should be excluded in well-nourished children. Inherited disorders of
sex steroid metabolism are usually associated with production abnormalities of other steroids, most
notably a lack of cortisol. Aromatase deficiency is not associated with cortisol abnormalities and usually
results in some degree of masculinization in affected females, as well as primary failure of puberty.
Males may show delayed puberty and delayed epiphyseal closure, as well as low bone-density. E2 and
E1 levels are very low or undetectable. Various forms of testicular feminization are due to problems in
androgen signaling pathways and are associated with female (or feminized) phenotypes in genetic
males. E2 and E1 levels are above the male reference range, usually within the female reference range,
and testosterone levels are very high. See Steroid Pathways in Special Instructions.
Reference Values:
Tanner Stages# Mean Age Reference Range
Stage I (>14 days and prepubertal) 7.1 years Undetectable-13 pg/mL
Stage II 12.1 years Undetectable-16 pg/mL
Stage III 13.6 years Undetectable-26 pg/mL
Stage IV 15.1 years Undetectable-38 pg/mL
Stage V 18 years 10-40 pg/mL #Puberty onset (transition

from Tanner stage I to Tanner stage II)
occurs for boys at a median age of 11.5 (+/-
2) years. For boys, there is no proven
relationship between puberty onset and
body weight or ethnic origin. Progression
stage V (adult) should be reached by age 18.
Females
Tanner Stages# Mean Age Reference Range
Stage I (>14 days and 7.1 years Undetectable-20 pg/mL

prepubertal)
Stage IV 12.3 years 15-85 pg/mL
Stage V 14.5 years 15-350 pg/mL** #Puberty onset (transition from Tanner stage I to Tanner
stage II) occurs for girls at a median age of 10.5 (+/- 2) years. There is
evidence that it may occur up to 1 year earlier in obese girls and in African
American girls. Progression through Tanner stages is variable. Tanner stage V
(adult) should be reached by age 18. *The reference ranges for children are
based on the published literature(1,2), cross-correlation of our assay with
assays used to generate the literature data, and on our data for young adults.
ADULTS Males: 10-40 pg/mL Females Premenopausal: 15-350 pg/mL**
Postmenopausal: **E2 levels vary widely through the menstrual cycle.
Conversion factor E2: pg/mL x 3.676=pmol/L (molecular weight=272) For SI
unit Reference Values, see
Clinical References: 1. Bidlingmaier F, Wagner-Barnack M, Butenandt O, Knorr D: Plasma

estrogens in childhood and puberty under physiologic and pathologic conditions. Pediatr Res
1973;7(11):901-907 2. Elmlinger MW, Kuhnel W, Ranke MB: Reference ranges for serum concentrations
of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin
(SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young
adults. Clin Chem Lab Med 2002;40(11):1151-1160 3. Cummings SR, Browner WS, Bauer D, et al:
Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med
1998;339:733-738 4. Iughetti L, Predieri B, Ferrari M, et al: Diagnosis of central precocious puberty:
endocrine assessment. J Pediatr Endocrinol Metab 2000;13 Suppl 1:709-715 5. Ismail AA, Barth JH:
Endocrinology of gynaecomastia. Ann Clin Biochem 2001;38:596-607 6. Kligman I, Rosenwaks Z:
Differentiating clinical profiles: predicting good responders, poor responders, and hyperresponders. Fertil
Steril 2001;76:1185-1190 7. Traggiai C, Stanhope R: Delayed puberty. Best Pract Res Clin Endocrinol
Metab 2002;16:139-151
UE3 Estriol, Unconjugated, Serum

phenotype, germ cell maturation, and pregnancy. There are 3 major biologically active estrogens in
humans: estrone (E1), estradiol (E2), and estriol (E3). Like all members of the steroid hormone family,
they diffuse into cells and bind to specific nuclear receptors, which in turn alter gene transcription in a
tissue specific manner. E2 is the most potent natural human estrogen, closely followed by E1, while E3
possess only 20% of the E2 affinity for the estrogen receptor. In men and nonpregnant women, E1 and
E2 are formed from the androgenic steroids androstenedione and testosterone, respectively. E3 is
derived largely through conversion of E2, and to a lesser degree from 16a-metabolites of E1. E2 and E1
can also be converted into each other, and both can be inactivated via hydroxylation and conjugation.
During pregnancy E3 becomes the dominant estrogen. The fetal adrenal gland secretes
dehydroepiandrosterone-sulfate (DHEAS), which is converted to E3 in the placenta and diffuses into the
maternal circulation. The half-life of unconjugated E3 (uE3) in the maternal blood system is 20 to 30
minutes since the maternal liver quickly conjugates E3 to make it more water soluble for urinary
excretion. E3 levels increase throughout the course of pregnancy, peaking at term. Decreased second
trimester uE3 has been shown to be a marker for Down and trisomy-18 syndromes. uE3 is a part of
multiple marker prenatal biochemical screening, together with alpha-fetoprotein (AFP), human
chorionic gonadotropin (hCG), and inhibin-A measurements. Low levels of uE3 also have been
associated with pregnancy loss, Smith-Lemli-Opitz syndrome (defect in cholesterol biosynthesis),
X-linked ichthyosis and contiguous gene syndrome (placental sulfatase deficiency disorders), aromatase
deficiency, and primary or secondary fetal adrenal insufficiency.
Useful For: A part of second trimester or cross-trimester biochemical screening for Down syndrome
and trisomy 18 syndrome A marker of fetal demise An adjunct biomarker in the prenatal diagnosis of
disorders of fetal steroid metabolism, including Smith-Lemli-Opitz syndrome (SLO)(3-4), and X-linked
ichthyosis (placental sulfatase deficiency disorders) Evaluating primary or secondary fetal adrenal
insufficiency after excluding other rare single gene defects, including aromatase deficiency, 17
alpha-hydroxylase deficiency and/or various forms of congenital adrenal hyperplasia
Interpretation: In second trimester maternal serum screening (QUAD), , unconjugated E3 (uE3) forms
part of a complex, multivariate risk calculation formula, using maternal age, gestational stage, and other
demographic information, in addition to the results of the biochemical markers, for Down syndrome and
trisomy 18 risk calculation. A serum uE3 <0.15 multiples of the gestational age median in women, who
otherwise screen negative in the quad test, can indicate Smith-Lemli-Opitz syndrome and X-linked
ichthyosis. A low uE3 level can indicate the possibility of aromatase deficiency, congenital adrenal
hyperplasia, primary or secondary (including maternal corticosteroid therapy) fetal adrenal insufficiency
and/or fetal demise.
Reference Values:
Males: <0.07 ng/mL
Females: <0.08 ng/mL
Clinical References: 1. Thaniyaporn S, Chanane W, Supatra S, et al: Association between isolated

abnormal levels of maternal serum unconjugated estriol in the second trimester and adverse pregnancy
outcomes. J Matern Fetal Neonatal Med. 2016;29:13, 2093-2097 2. Minsart AF, Van Onderbergen A,
Jacques F, et al: Indication of prenatal diagnosis in pregnancies complicated by undetectable
second-trimester maternal serum estriol levels. J Prenat Med. 2008;2(3):27-30 3. Bradley LA, Palomaki
GE, Knight GJ, et al: Levels of unconjugated estriol and other maternal serum markers in pregnancies
with Smith Lemli Opitz (RSH) syndrome fetuses [letter]. Am J Med Genet 1999;82:355-358 4. Reisch N,
Idkowiak J, Hughes B,Prenatal Diagnosis of Congenital Adrenal Hyperplasia Caused by P450
Oxidoreductase Deficiency. J Clin Endocrinol Metab. 2013 Mar;98(3):E528-E536. doi:
10.1210/jc.2012-3449 5. Yarbrough ML, Stout M, Gronowski AM: Ch 69 Pregnancy and Its Disorders. In
Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Sixth edition. Edited by N Rafai, AR
Horvath, CT Wittwer. Elsevier, 2018, pp 1655-1696
ESR1 Estrogen Receptor 1 (ESR1) Mutation Analysis, Tumor

65414 Clinical Information: The estrogen receptor 1 (ESR1) gene encodes an estrogen receptor that
regulates cell growth through activation of downstream signaling pathways upon binding of estrogen.
Tumors demonstrating estrogen receptor expression (ER-positive) are candidates for endocrine therapy
such as selective estrogen receptor modulators (SERM) and aromatase inhibitors. ESR1 mutations are
rarely observed in primary tumors; however, mutations in the ligand-binding domain of ESR1 have been
reported at a higher frequency in ER-positive metastatic breast tumors. Preclinical data suggests that
ESR1 mutations mitigate resistance to aromatase inhibitors and decrease sensitivity to SERMs and
estrogen-receptor downregulators. Studies also suggest that ESR1 mutations are an independent indicator
of poor prognosis. This test assesses for somatic mutations in the ligand-binding domain of the ESR1
gene associated with acquired resistance to endocrine therapy (ie, aromatase inhibitors) in patients with
ER-positive metastatic breast cancer.
Useful For: Assisting in the clinical management of patients with metastatic breast cancer by
identifying tumors with evolving resistance to endocrine therapy Stratifying prognosis of metastatic breast
cancer This test is not useful for hematological malignancies.

Reference Values:
Clinical References: 1. Arenedos M, Vicier C, Loi S, et al: Precision medicine for metastatic breast
cancer-limitations and solutions. Nat Rev Clin Oncol. 2015 Dec;12(12):693-704 2. Angus L, Beije N,
Jager A, et al: ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast
cancer patients. Cancer Treat Rev. 2017 Jan;52:33-40 3. Gradishar WJ, Anderson BO, Balassanian R, et
al: NCCN Guidelines Insights: Breast Cancer, Version 1.2017. J Natl Compr Canc Netw. 2017
Apr;15(4):433-451 4. Toy W, Shen Y, Won H, et al: ESR1 ligand-binding domain mutations in
hormone-resistant breast cancer. Nat Genet. 2013 Dec;45(12):1439-1445 5. Robinson DR, Wu YM, Vats
P, et al: Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013
Dec;45(12):1446-1451 6. Toy W, Weir H, Razavi P, et al: Activating ESR1 Mutations Differentially
Affect the Efficacy of ER Antagonists. Cancer Discov. 2017 Mar;7(3):277-287
ERBE1 Estrogen Receptor Beta-1 Immunostain, Technical Component

71485 Only
Clinical Information: This test is intended to identify the presence of estrogen receptor beta 1
(ER-beta 1) protein. ER-beta 1 is a member of the nuclear receptor superfamily of transcription factors
and is the product of the ESR2 gene on chromosome 14q22-24. Unlike ER-alpha, ER-beta 1 is highly
expressed in normal breast epithelium but expression is reduced in many precancerous and cancerous
breast tumors. ER-beta 1 is expressed in 30% to 40% of triple negative breast cancers and is associated
with improved outcomes in ER-alpha positive tamoxifen treated patients.
Useful For: Detection of estrogen receptor-beta 1 protein levels in cancer, including triple-negative
breast cancer
Clinical References: 1. Kim TJ, Lee A, Choi YJ, Song BJ, et al: Prognostic significance of high
expression of ER-beta in surgically treated ER-positive breast cancer following endocrine therapy. J
Breast Cancer. 2012 Mar;15(1):79-86. doi: 10.4048/jbc.2012.15.1.79 2. Reese JM, Suman VJ,
Subramaniam M, et al: ER beta1: Characterization, prognosis, and evaluation of treatment strategies in
ER alpha-positive and-negative breast cancer. BMC Cancer. 2014;14:749-764 3. Wu X, Subramaniam
M, Negron V, et al: Development, characterization, and applications of a novel estrogen receptor beta
monoclonal antibody. J Cell Biochem. 2012;113:711-723 4. Marotti J, Collins L, Hu R: Estrogen
receptor-beta expression in invasive breast cancer in relation to molecular phenotype: Results from the
Nurses' Health Study. Mod Pathol. 2010; 23,197-204
ESTR Estrogen Receptor Immunostain, Technical Component Only

70427 Clinical Information: Estrogen receptor alpha protein expression is limited to normal and
neoplastic tissues related to the reproductive system (breast, cervix, endometrium, uterus, ovary, and
prostate).
Useful For: Qualitative detection of estrogen receptor alpha protein in a diagnostic setting
Clinical References: 1. Peng Y, Butt YM, Chen B, Zhang X, Tang P: Update on

Immunohistochemical Analysis in Breast Lesions. Arch Pathol Lab Med. 2017;141(8):1033-1051. doi:
10.5858/arpa.2016-0482-RA 2. Gibert-Ramos A, Lopez C, Bosch R, et al: Immune response profile of
primary tumour, sentinel and non-sentinel axillary lymph nodes related to metastasis in breast cancer:
an immunohistochemical point of view. Histochem Cell Biol. 2019;152(3):177-193. doi:
10.1007/s00418-019-01802-7 3. McCullough AE, Dell'orto P, Reinholz MM, et al: Central pathology
laboratory review of HER2 and ER in early breast cancer: an ALTTO trial (BIG 2-06/NCCTG N063D
[Alliance]) ring study. Breast Cancer Res Treat. 2014;143(3):485-492. doi: 10.1007/s10549-013-2827-0
ERPR Estrogen/Progesterone Receptor, Semi-Quantitative

70589 Immunohistochemistry, Manual
Clinical Information: The steroid hormone receptors, estrogen receptor (ER) and progesterone
receptor (PR), are commonly used in the management of women with breast cancer. ER and PR status
provide an indication of prognosis and of the potential benefit from hormonal therapy. Generally,
ER/PR-positive tumors are more likely to respond to endocrine therapy and have a better prognosis,
stage-for-stage, than receptor-negative tumors. While the test can be performed on any formalin-fixed,
paraffin-embedded tissue, it is infrequently used for non-breast cancer specimens.
Useful For: Guiding decisions on hormonal therapy in patients with breast carcinomas This test is not
useful for cases of lobular carcinoma in situ.
Interpretation: Immunoperoxidase-stained slides are examined microscopically by the consulting

anatomic pathologist and interpreted as negative (<1% reactive cells), or positive. The percent of reactive
cells is provided in the report.
Reference Values:
Negative: <1% reactive cells
Positive: > or =1% reactive cells
Clinical References: 1. Hammond ME, Hayes DF, Dowsett M, et al: American Society of Clinical
Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing
of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med. 2010 Jun;134(6):907-22.
doi: 10.1043/1543-2165-134.6.907. Erratum in: Arch Pathol Lab Med. 2010 Aug;134(8):1101 2. Allison
KH, Hammond MEH, Dowsett M, et al: Estrogen and progesterone receptor testing in breast cancer:
ASCO/CAP Guideline Update. J Clin Oncol. 2020 Apr 20;38(12):1346-1366. doi: 10.1200/JCO.19.02309
ESTF Estrogens, Estrone (E1) and Estradiol (E2), Fractionated, Serum

non-gender-specific processes, including growth, nervous system maturation, bone
into each other, and both can be inactivated via hydroxylation and conjugation. E2 demonstrates 1.25 to 5
times the biological potency of E1. E2 circulates at 1.5 to 4 times the concentration of E1 in
premenopausal, nonpregnant women. E2 levels in men and postmenopausal women are much lower than
in nonpregnant women, while E1 levels differ less, resulting in a reversal of the premenopausal E2:E1
ratio. E2 levels in premenopausal women fluctuate during the menstrual cycle. They are lowest during the
early follicular phase. E2 levels then rise gradually until 2 to 3 days before ovulation, at which stage they
start to increase much more rapidly and peak just before the ovulation-inducing luteinizing
hormone/follicle stimulating hormone surge at 5 to 10 times the early follicular levels. This is followed by
a modest decline during the ovulatory phase. E2 levels then gradually increase again until the midpoint of
the luteal phase and thereafter decline to trough, early follicular levels. Measurement of serum E2 forms
an integral part of the assessment of reproductive function in females, including assessment of infertility,
oligo-amenorrhea, and menopausal status. In addition, it is widely used for monitoring ovulation
induction, as well as during preparation for in vitro fertilization. For these applications E2 measurements
with modestly sensitive assays suffice. However, extra sensitive E2 assays, simultaneous measurement of
E1, or both are needed in a number of other clinical situations. These include inborn errors of sex steroid
metabolism, disorders of puberty, estrogen deficiency in men, fracture risk assessment in menopausal
women, and increasingly, therapeutic drug monitoring, either in the context of low-dose female hormone
replacement therapy or antiestrogen treatment.
Useful For: Simultaneous high-sensitivity determination of serum estrone and estradiol levels
Situations requiring either higher sensitivity estradiol measurement, estrone measurement, or both,
including -As part of the diagnosis and workup of precocious and delayed puberty in females and, to a
lesser degree, males -As part of the diagnosis and workup of suspected disorders of sex steroid
metabolism, eg, aromatase deficiency and 17 alpha-hydroxylase deficiency -As an adjunct to clinical
assessment, imaging studies, and bone mineral density measurement in the fracture risk assessment of
postmenopausal women and, to a lesser degree, older men -Monitoring low-dose female hormone
replacement therapy in postmenopausal women -Monitoring antiestrogen therapy (eg, aromatase
inhibitor therapy) Applications that require moderately sensitive measurement of estradiol including:
-Evaluation of hypogonadism and oligo-amenorrhea in females -Assessing ovarian status, including
follicle development, for assisted reproduction protocols (eg, in vitro fertilization) In conjunction with
luteinizing hormone measurements, monitoring of estrogen replacement therapy in hypogonadal
premenopausal women Evaluation of feminization, including gynecomastia, in males Diagnosis of
estrogen-producing neoplasms in males, and, to a lesser degree, females
Interpretation: Estradiol (E2) levels below the premenopausal reference range in young females
indicate hypogonadism. If luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are
elevated, primary gonadal failure is diagnosed. The main causes are genetic (eg, Turner syndrome,
familial premature ovarian failure), autoimmune (eg, autoimmune ovarian failure, possibly as part of
autoimmune polyglandular endocrine failure syndrome type II), and toxic (eg, related to chemotherapy
or radiation therapy for malignant disease). If LH/FSH levels are low or inappropriately "normal," a
diagnosis of hypogonadotrophic hypogonadism is made. This can have functional causes, such as
starvation, overexercise, severe physical or emotional stress, and heavy drug and/or alcohol use. It also
can be caused by organic disease of the hypothalamus or pituitary. Further work-up is usually
necessary, typically including measurement of pituitary hormones (particularly prolactin), and possibly
imaging. Irregular or absent menstrual periods with normal or high E2 levels (and often high estrone:
E1 levels) are indicative of possible polycystic ovarian syndrome, androgen producing tumors, or
estrogen producing tumors. Further work-up is required and usually includes measurement of total and
bioavailable testosterone, androstenedione, dehydroepiandrosterone (sulfate), sex hormone-binding
globulin, and possibly imaging. E2 analysis may be helpful in establishing time of ovulation and
optimal time for conception. Optimal time for conception is within 48 to 72 hours following the
midcycle E2 peak. Serial specimens must be drawn over several days to evaluate baseline and peak total
estrogen (E1 + E2) levels. Low baseline levels and a lack of rise, as well as persistent high levels
without midcycle rise are indicative of anovulatory cycles. For determining the timing of initiation of
ovarian stimulation in in vitro fertilization studies, low levels (around 30 pg/mL) before stimulation are
critical, as higher values often are associated with poor stimulation cycles. Estrogen replacement in
reproductive age women should aim to mimic natural estrogen levels as closely as possible. E2 levels
should be within the reference range for premenopausal women, LH/FSH should be within the normal
range, and E2 levels should ideally be higher than E1 levels. The current recommendations for
postmenopausal female hormone replacement are to administer therapy in the smallest beneficial doses
for as briefly as possible. Ideally, E2 and E1 levels should be held below, or near, the lower limit of the
premenopausal female reference range. Postmenopausal women and older men in the lowest quartile of
E2 levels are at increased risk of osteoporotic fractures. E2 levels are typically less than 5 pg/mL.
Antiestrogen therapy with central or peripheral acting agents that are not pure receptor antagonists
usually aims for complete suppression of E2 production, and in the case of aromatase inhibitors,
complete E1 and E2 suppression. Gynecomastia or other signs of feminization in males may be due to
an absolute or relative (in relation to androgens) surplus of estrogens. Gynecomastia is common during
puberty in boys. Unless E1, E2, or testosterone levels exceed the adult male reference range, the
condition is usually not due to hormonal disease (though it sometimes may still result in persistent
breast tissue, which later needs to be surgically removed). For adults with gynecomastia, the workup
should include testosterone and adrenal androgen measurements, in addition to E2 and E1
measurements. Causes for increased E1 or E2 levels include: -High androgen levels caused by tumors or
androgen therapy (medical or sport performance enhancing), with secondary elevations in E1 and E2
due to aromatization -Obesity with increased tissue production of E1 -Decreased E1 and E2 clearance in
liver disease -Estrogen producing tumors -Estrogen ingestion Normal male E1 and E2 levels also may
be associated with feminization or gynecomastia, if bioavailable testosterone levels are low due to
primary/secondary testicular failure. This may occur, for example, when patients are receiving
antiandrogen therapy or other drugs with antiandrogenic effects (eg, spironolactone, digitalis
preparations). The gonadotrophin-releasing hormone (GnRH) stimulation test remains the central part of
the workup for precocious puberty. However, baseline sex steroid and gonadotrophin measurements
also are important. Prepubertal girls have E2 levels less than 10 pg/mL (most <5 pg/mL). Levels in
prepubertal boys are less than half the levels seen in girls. LH/FSH are very low or undetectable. E1
levels also are low, but may rise slightly, in obese children after onset of adrenarche. E2, which is
produced in the gonads, should remain low in these children. In true precocious puberty, both E2 and
LH/FSH levels are elevated above the prepubertal range. Elevation of E2 or E1 alone suggests pseudo
precocious puberty, possibly due to a sex steroid-producing tumor. In delayed puberty, estrogens and
gonadotrophins are in the prepubertal range. A rise over time predicts the spontaneous onset of puberty.
Persistently low estrogens and elevated gonadotrophins suggest primary ovarian failure, while low
gonadotrophins suggest hypogonadotrophic hypogonadism. In this latter case, Kallman syndrome (or
related disorders) or hypothalamic/pituitary tumors should be excluded in well-nourished children.
Inherited disorders of sex steroid metabolism are usually associated with production abnormalities of
other steroids, most notably a lack of cortisol. Aromatase deficiency is not associated with cortisol
abnormalities and usually results in some degree of masculinization in affected females, as well as
primary failure of puberty. Males may show delayed puberty and delayed epiphyseal closure, as well as
low bone-density. E2 and E1 levels are very low or undetectable. Various forms of testicular
feminization are due to problems in androgen signaling pathways and are associated with female (or
feminized) phenotypes in genetic males. E2 and E1 levels are above the male reference range, usually
within the female reference range, and testosterone levels are very high.
Reference Values:
Tanner stages# Mean age Reference range
Stage III 13.6 years 10-25 pg/mL

2) years. For boys there is no proven
Females
Stage II 10.5 years 10-33 pg/mL
Stage III 11.6 years 15-43 pg/mL
Stage V 14.5 years 17-200 pg/mL #Puberty onset (transition
occurs for girls at a median age of 10.5 (+/-
2) years. There is evidence that it may occur
up to 1 year earlier in obese girls and in
African American girls. Progression through
Tanner stages is variable. Tanner stage V
(adult) should be reached by age 18. *The
reference ranges for children are based on
the published literature,(1,2)
cross-correlation of our assay with assays
used to generate the literature data and on
our data for young adults. ADULTS Males:
10-60 pg/mL Females Premenopausal:
17-200 pg/mL Postmenopausal: 7-40 pg/mL
Conversion factor E1: pg/mL x
3.704=pmol/L (molecular weight=270)
ESTRADIOL (E2) CHILDREN* 1-14 days:
Estradiol levels in newborns are very
elevated at birth but will fall to prepubertal
levels within a few days. Males
Stage IV 15.1 years Undetectable-38 pg/mL

2) years. For boys there is no proven
Females
Stage I (>14 days and 7.1 years Undetectable-20 pg/mL

prepubertal)
Stage V 14.5 years 15-350 pg/mL** #Puberty onset (transition from Tanner stage I to Tanner
stage II) occurs for girls at a median age of 10.5 (+/- 2) years. There is
evidence that it may occur up to 1 year earlier in obese girls and in African
American girls. Progression through Tanner stages is variable. Tanner stage V
(adult) should be reached by age 18. *The reference ranges for children are
based on the published literature,(1,2) cross-correlation of our assay with
assays used to generate the literature data and on our data for young adults.
ADULTS Males: 10-40 pg/mL Females Premenopausal: 15-350 pg/mL**
Postmenopausal: **E2 levels vary widely through the menstrual cycle.
Conversion factor E2: pg/mL x 3.676=pmol/L (molecular weight=272) For SI
unit Reference Values, see
Clinical References: 1. Elmlinger MW, Kuhnel W, Ranke MB: Reference ranges for serum
concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex
hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in
neonates, children and young adults. Clin Chem Lab Med. 2002;40(11):1151-1160 2. Cummings SR,
Browner WS, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B: Endogenous hormones and the risk of
hip and vertebral fractures among older women. N Engl J Med. 1998;339:733-738 3. Lughetti L, Predieri
B, Ferrari M, et al: Diagnosis of central precocious puberty: endocrine assessment. J Pediatr Endocrinol
Metab. 2000;13 Suppl 1:709-715 4. Ismail AA, Barth JH: Endocrinology of gynaecomastia. Ann Clin
Biochem. 2001;38:596-607 5. Kligman I, Rosenwaks Z: Differentiating clinical profiles: predicting good
responders, poor responders, and hyperresponders. Fertil Steril. 2001;76:1185-1190 6. Traggiai C,
Stanhope R: Delayed puberty. Best Pract Res Clin Endocrinol Metab. 2002;16:139-151 7. Mauras N,
Ross JL, Gagliardi P, et al: Randomized trial of aromatase inhibitors, growth hormone, or combination in
pubertal boys with idiopathic short stature. J Clin Endocrinol Metab. 2016 Dec;101(12):4984-4993. doi:
10.1210/jc.2016-2891 8. Ketha H, Girtman A, Singh RJ: Estradiol assays-The path ahead. Steroids. 2015
Jul;99(Pt A):39-44. doi: 10.1016/j.steroids.2014.08.009 9. Ingle JN, Cairns J, Suman VJ, et al:
Anastrozole has an assocaition between degree of estrogen suppression and outcomes in early breast
cancer and is a ligamd for estrogen receptor alpha. Clin Cancer Res. 2020 Jun 15;26(12):2986-2996 doi:
10.1158/1078-0432.CCR-19-3091 10. Richardson H, Ho V, Pasquet R, et al: Baseline estrogen levels in
postmenopausal women participating in the MAP.3 breast cancer chemoprevention trial. Menopause.
2020 Jun;27(6):693-700 doi: 10.1097/GME.0000000000001568.
E1 Estrone, Serum
nongender-specific processes, including growth, nervous system maturation, bone
into each other, and both can be inactivated via hydroxylation and conjugation. E2 demonstrates 1.25-5
times the biological potency of E1. E2 circulates at 1.5-4 times the concentration of E1 in premenopausal,
nonpregnant women. E2 levels in men and postmenopausal women are much lower than in nonpregnant
women, while E1 levels differ less, resulting in a reversal of the premenopausal E2:E1 ratio. E2 levels in
premenopausal women fluctuate during the menstrual cycle. They are lowest during the early follicular
phase. E2 levels then rise gradually until 2 to 3 days before ovulation, at which stage they start to increase
much more rapidly and peak just before the ovulation-inducing luteinizing hormone/follicle stimulating
hormone surge at 5 to 10 times the early follicular levels. This is followed by a modest decline during the
ovulatory phase. E2 levels then increase again gradually until the midpoint of the luteal phase and
thereafter decline to trough, early follicular levels. Measurement of serum E2 forms an integral part of the
assessment of reproductive function in females, including assessment of infertility, oligo-amenorrhea and
menopausal status. In addition, it is widely used for monitoring ovulation induction, as well as during
preparation for in vitro fertilization. For these applications E2 measurements with modestly sensitive
assays suffice. However, extra sensitive E2 assays or simultaneous measurement of E1, or both are
needed in a number of other clinical situations. These include inborn errors of sex steroid metabolism,
disorders of puberty, estrogen deficiency in men, fracture risk assessment in menopausal women, and
increasingly, therapeutic drug monitoring, either in the context of low-dose female hormone replacement
therapy or antiestrogen treatment. See Steroid Pathways in Special Instructions.
Useful For: As part of the diagnosis and workup of precocious and delayed puberty in females and, to
a lesser degree, males As part of the diagnosis and workup of suspected disorders of sex steroid
metabolism (eg, aromatase deficiency and 17 alpha-hydroxylase deficiency) As an adjunct to clinical
assessment, imaging studies and bone mineral density measurement in the fracture risk assessment of
postmenopausal women, and, to a lesser degree, older men Monitoring low-dose female hormone
replacement therapy in postmenopausal women Monitoring antiestrogen therapy (eg, aromatase inhibitor
therapy)
Interpretation: Irregular or absent menstrual periods with normal or high estradiol (E2) levels (and
often high estrone: E1 levels) are indicative of possible polycystic ovarian syndrome, androgen
producing tumors, or estrogen producing tumors. Further work-up is required and usually includes
measurement of total and bioavailable testosterone, androstenedione, dehydroepiandrosterone (sulfate),
sex hormone-binding globulin, and possibly imaging. Estrogen replacement in reproductive age women
should aim to mimic natural estrogen levels as closely as possible. E2 levels should be within the
reference range for premenopausal women, luteinizing hormone/follicle-stimulating hormone (LH/FSH)
should be within the normal range, and E2 levels should ideally be higher than E1 levels.
Postmenopausal women and older men in the lowest quartile of E2 levels are at increased risk of
osteoporotic fractures. E2 levels are typically less than 5 pg/mL in these patients. The current
recommendations for postmenopausal female hormone replacement are to administer therapy in the
smallest beneficial doses for as briefly as possible. Ideally, E2 and E1 levels should be held below, or
near, the lower limit of the premenopausal female reference range. Antiestrogen therapy with central or
peripheral acting agents that are not pure receptor antagonists usually aims for complete suppression of
E2 production, and in the case of aromatase inhibitors, complete E1 and E2 suppression. Gynecomastia
or other signs of feminization in males may be due to an absolute or relative (in relation to androgens)
surplus of estrogens. Gynecomastia is common during puberty in boys. Unless E1, E2, or testosterone
levels exceed the adult male reference range, the condition is usually not due to hormonal disease
(though it sometimes may still result in persistent breast tissue, which later needs to be surgically
removed). For adults with gynecomastia, the work-up should include testosterone and adrenal androgen
measurements, in addition to E2 and E1 measurements. Causes for increased E1 or E2 levels include:
-High androgen levels caused by tumors or androgen therapy (medical or sport performance enhancing),
with secondary elevations in E1 and E2 due to aromatization -Obesity with increased tissue production
of E1 -Decreased E1 and E2 clearance in liver disease -Estrogen producing tumors -Estrogen ingestion
Normal male E1 and E2 levels also may be associated with feminization or gynecomastia if bioavailable
testosterone levels are low due to primary/secondary testicular failure. This may occur, for example,
when patients are receiving antiandrogen therapy or other drugs with antiandrogenic effects (eg,
spironolactone, digitalis preparations). The gonadotrophin-releasing hormone stimulation test remains
the central part of the work-up for precocious puberty. However, baseline sex steroid and gonadotrophin
measurements also are important. Prepubertal girls have E2 levels less than 10 pg/mL (most <5 pg/mL).
Levels in prepubertal boys are less than half the levels seen in girls. LH/FSH are very low or
undetectable. E1 levels also are low, but may rise slightly in obese children after onset of adrenarche.
E2, which is produced in the gonads, should remain low in these children. In true precocious puberty,
both E2 and LH/FSH levels are elevated above the prepubertal range. Elevation of E2 or E1 alone
suggests pseudo precocious puberty, possibly due to a sex steroid-producing tumor. In delayed puberty,
estrogens and gonadotrophins are in the prepubertal range. A rise over time predicts the spontaneou

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Rochester

2022 Interpretive Handbook

Sorted By Test Name

Current as of July 20, 2022 12:05 pm CDT

Complete Terms of Use is available at http://www.mayocliniclabs.com/customer-service/terms.html

Definition of Specimen "Minimum Volume"

Business Continuity and Contingency Planning

Phone Inquiry Policy—One of the following unique identifiers will be required:

Framework for Quality

*Measured using Six Sigma defects per million (dpm) method.

Informed Consent Certification

Patient Safety Goals

Referral of Tests to Another Laboratory

Request for Physician Name and Number

There is a nominal charge associated with any special handling.

Specimen Identification Policy

Test Development Process

Test Result Call-Backs

Turnaround Time (TAT)

Interpretation: 1,25-Dihydroxyvitamin D (DVHD) concentrations are low in chronic renal failure

For SI unit Reference Values, see https://www.mayocliniclabs.com/order-tests/si-unit-conversion.html

SFUNG 1,3-Beta-D-Glucan (Fungitell), Serum

FUNGITELL QUALITATIVE RESULT:

Reference values apply to all ages.

DOCS 11-Deoxycorticosterone, Serum

Interpretation: In 11 beta-hydroxylase 1 (CYP11B1) deficiency, serum concentrations of cortisol will

Clinical References: 1. Von Schnakenburg K, Bidlingmaier F, Knorr D: 17-hydroxyprogesterone,

DCORT 11-Deoxycortisol, Serum

For SI unit Reference Values, see https://www.mayocliniclabs.com/order-tests/si-unit-conversion.html

Age Range (ng/dL)

Premature (31 - 35 weeks) Day 4 48-579

Newborn Day 3 13-147

Prepubertal Children and Adults 8 AM 12-158

THCMX 11-nor-Delta-9-Tetrahydrocannabinol-9-Carboxylic Acid

Interpretation: The presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid > or =5 ng/g is

THCM 11-nor-Delta-9-Tetrahydrocannabinol-9-Carboxylic Acid

Useful For: Detection of in utero drug exposure to marijuana (tetrahydrocannabinol) up to 5 months

F143P 14-3-3 eta Protein

17OHP 17-Hydroxypregnenolone, Serum

Clinical References: 1. Wudy SA, Hartmann M, Svoboda M: Determination of

OHPG 17-Hydroxyprogesterone, Serum

FHC18 18-Hydroxycorticosterone, Serum

Premature (26 - 28 weeks) Day 4 10 - 670

Premature (31 - 35 weeks) Day 4 57 - 410

Full-term Day 3 31 - 546

31 days to 11 months 5 - 220

Adults 8:00 AM Supine 4 - 21

Adults 8:00 AM Upright 5 - 46

GLIOF 1p/19q Deletion in Gliomas, FISH, Tissue

BPGMM 2,3-Bisphosphoglycerate Mutase, Full Gene Sequencing

Useful For: Diagnosis of 2,3-bisphosphoglycerate mutase deficiency in individuals with lifelong,

23BPT 2,3-Dinor 11 Beta-Prostaglandin F2 Alpha, 24 Hour, Urine

Interpretation: Elevated urine 2,3-dinor-11beta-prostaglandin F2 alpha is consistent with systemic

Clinical References: 1. Gotlib J, Pardanani A, Akin C, et al: International Working

23BPR 2,3-Dinor 11 Beta-Prostaglandin F2 Alpha, Random, Urine

Interpretation: Elevated urine 2,3-dinor-11beta-prostaglandin F2 alpha is consistent with systemic

Clinical References: 1. Gotlib J, Pardanani A, Akin C, et al: International Working

Useful For: Determining type of 2-hydroxyglutaric aciduria by chiral analysis of urine

Age D-2-hydroxyglutaric acid (mmol/mol creatinine) L-2-hydroxyglutaric acid (mmol/mol creatinine)

0-11 months < or =14.11 < or =17.38