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c Health Sciences

HIGH-YIELD PRINCIPLES IN

Public Health Sciences

[' ll is a mathematical fact that fifty percent of all doctors graduate in the
bottom half of their class."
Author Unknown
There are two kinds of statistics : the kind you look

Epidemiology/
Biostatistics

246

Ethics

253

The Well Patient

258

Social Sciences

259

up and the kind you

make up."

Rex Stout
On a long enough time line, the survival rate for everyone drops to zero.
Chuck Palahniuk
There are three kinds ol lies: lies, damned lies, and statistics ."

Mark Twain

I
A heterogenous mix of epidemiology, biostatistics, ethics, law, healthcare
delivery, patient safety , quality improvement, and more falls under the
heading of public health sciences. Biostatistics and epidemiology are the
foundations of evidence-based medicine and arc verv high-yield. Make
sure vou can apply biostatistical concepts such as sensitivity , specificity ,
and predictive values in a problem-solving format.

Medical ethics questions mav seem less concrete than questions from
other disciplines. For example, if a patient does or savs something.
what should you do or sav in response? Many medical students do not
diligently study these topics because the material is felt to be easy or a
matter of common sense. In our opinion, this is a missed opportunity.
In addition, the key aspects of the doctor-patient relationship ( eg,
communication skills ) are high-vield. Last, the exam has also recently
added an emphasis on patient safety and quality improvement topics.
which arc discussed in this chapter.

245

246
1

SECTION II

PUBLIC HEALTH SCIENCES

PUBLIC HEALTH SCIENCES EPIDEMIOLOGY / BIOSTATISTICS

PUBLIC HEALTH SCIENCES EPIDEMIOLOGY / BIOSTATISTICS

Observational studies
STUDY TYPE

DESIGN

Cross- sectional study

Collects data from a group of people to assess


Disease prevalence.
frequency of disease (and related risk factors) at Can show risk factor association w ith disease, but
does not establish causality.
a particular point in time.
Asks, "What is happening?

Case-control study

Compares a group of people with disease to a


group without disease.

Looks for prior exposure or risk factor.


Asks, What happened? '
Cohort study

Compares a group with a given exposure or risk


factor to a group without such exposure.
Looks to see if exposure affects the likelihood of
disease.
Can be prospective (asks, Who will develop
disease?) or historical (asks, Who developed
the disease [exposed vs nonexposed] ?).

MEASURES /EXAMPLE

Odds ratio (OR ).


Patients w ith COPD had higher odds of a
history of smoking than those without COPD.

Relative risk ( RR).


had a higher risk of developing COPD

Smokers

than nonsmokers.

Twin concordance
study

Compares the frequency with which both


monozygotic twins or both dizygotic twins
develop the same disease.

Measures hcritability and influence of


environmental factors ( nature vs nurture ).

Adoption study

Compares siblings raised by biological vs


adoptive parents.

Measures heritability and influence of

Clinical trial

environmental factors.

Experimental study involving humans. Compares therapeutic benefits of 2 or more treatments,


or of treatment and placebo. Study quality improves when study is randomized, controlled, and
double-blinded ( ie, neither patient nor doctor knows whether the patient is in the treatment or
control group). Triple-blind refers to the additional blinding of the researchers analyzing the data.
Four phases ( Does the drug swim?!

DRUG TRIALS

TYPICAL STUDY SAMPLE

PURPOSE

Phase 1

Small number of healthy volunteers.

Is it safe? Assesses safety, toxicity,

Phase II

Small number of patients with disease of

Does it work? Assesses treatment efficacy,


optimal dosing, and adverse effects.

pharmacokinetics, and pharmacodynamics.


interest.
Phase III

Phase IV

large number of patients randomly assigned


either to the treatment under investigation or
to the best available treatment ( or placebo).

Is it as good or better?" Compares the new

Postmarketing surveillance of patients after


treatment is approved.

Can it stay? " Detects rare or long-term


adverse effects. Can result in treatment being
withdrawn from market.

treatment to the current standard of care tanv


improvement ?!

PUBLIC HEALTH SCIENCES

EPIDEMI 0 L06 Y / BI0 STATISTICS

Uses 2 x 2 table comparing test results with the


actual presence of disease. TP = true positive;
FP = false positive; TN = true negative; FN =
false negative.
Sensitivity and specificity are fixed properties
of a test. PPV and NPV vary depending on
disease prevalence.

Evaluation of
diagnostic tests

Sensitivity (true
positive rate )

PUBLIC HEALTH SCIENCES

Positive predictive
value

Negative predictive
value

Disease

TP

FP

FN

TN

PPV
= TP/ITP + FP)

Sensitivity Specificity
= TP/ fTP + FN) = TN/TTN + FPL

..

Prevalence
(T?

TP TN
FN * fP 4 TNl

= TN / (TN + FP)
= 1 - false-positive rate
SP-P-IN = highly SPecific test, when Positive,
rules IN disease
If specificity 100%. all positives must be Tl'4

Proportion of positive test results that are true


positive.
Probability that a person who has a positive test
result actually has the disease.
Proportion of negative test results that are true
negative.
Probability that a person with a negative test
result actually does not have the disease.

PPV = TP / (TP + FP )
PPV varies directly with pretest probability
( baseline risk, such as prevalence of disease):
high pretest probability high PPV'

Disease

lease

absent

present

TP

TN
FP

B
Test results

NPV = TN / ( TN + FN)
NPV7 varies inversely with prevalence or pretest
probability: high pretest probability low NPV'

POSSIBLE CUTOFF VALUES


A = 100% sensitivity cutoff value
B - practical compromise between specificity anti sensitivity
C = 100% specificity cutoff value

lowenna the cutoff point


B - A ( T FP 4 FN)

T Sensitivity t NPV
T Specificity X PPV

Raising the cutoff point


B
C ( tFNXFP)

T Specificity T PPV
i Sensitivity 1NPV

. T specificity. T PPV.

For example, in diabetes screening, raising the blood glucose level at which a patient is diagnosed will X sensitivity
and X NPV. The opposite changes occur with decreasing the blood glucose level at which a patient is diagnosed.

Ifssil

| Figure |

Proportion of all people without disease who


test negative, or the probability that when the
disease is absent, the test is negative.
Value approaching 100% is desirable for
ruling in disease and indicates a loss falsepositive rate. High specificity test used for
confirmation after a positive screening test.

I New I

iRevisedl

NPV
= TN/ON + FN)

= TP / ( TP + FN)
= 1 - false-negative rate
SN N-OUT = highly SeNsitive test, when
Negative, rules OUT disease
If sensitivity is 100%, all negatives must be TNj

.t

Likelihood ratio

247

Proportion of all people with disease who lest


positive, or the probability that when the
disease is present, the test is positive.
Value approaching 100% is desirable for ruling
out disease and indicates a low false negative
rate. High sensitivity test used for screening in
diseases with low prevalence.

Specificity (true
negative rate)

SECTION II

A measure indicating how likely a given test


result would occur in a patient with the
condition vs a patient without the condition.

I.Ri in

sensitivity

1 - specificity

_ I - sensitivity
specificity

13

248

SECTION II

Quantifying risk

PUBLIC HEALTH SCIENCES

PUBLIC HEALTH SCIENCES

EPIDEMIOLOGY / BIOSTATISTICS

Definitions and formulas are based on the classic


2 x 2 or contingency tabic.

Disease

si

II

II
Odds ratio

Typically used in case-control studies. OR


depicts the odds of an event ( eg. disease!
occurring giving a certain exposure ( a / b) vs
the odds of an event occurring in the absence
of that exposure ( c/d1

Relative risk

Typically used in cohort studies. Risk of


developing disease in the exposed group

OR

a /bj ad

RR =

be

a /( a + b )
c/(c + d )

divided by risk in the unexposed group ( eg. if


2\7c of smokers develop lung cancer vs 17c of
nonsmokers, RR = 21/1 = 21 ). If prevalence is
low, OR = RR .
RR = 1 no association between exposure and
disease.
RR > 1 e x p o s u r e associated with t disease

occurrence.

RR < 1

exposure associated

with t disease

occurrence.

Attributable risk

Relative risk reduction

Absolute risk
reduction

Number needed to
treat

Number needed to
harm

The difference in risk between exposed and


unexposed groups, or the proportion of
disease occurrences that are attributable to
the exposure (eg, if risk of lung cancer in
smokers is 21'/? and risk in nonsmokers is 1%,
then 20% of the lung cancer risk in smokers is
attributable to smoking).
T he proportion of risk reduction attributable to
the intervention as compared to a control (eg,
if 2% of patients who receiv e a flu shot develop
the flu, while 8% of unvaccinated patients
develop the flu , then RR = 2 /8 = 0.25, and
RRR = 0.75 ).

T he difference in risk (not the proportion )


attributable to the intervention as compared
to a control (eg, if 87c of people who receive
a placebo vaccine develop the flu vs 27c
of people who receive a flu vaccine, then
ARR = 8% - 17c = 6% = .06 ).
Number of patients who need to be treated for 1
patient to benefit .
Number of patients who need to be exposed to a
risk factor for 1 Datient to be harmed.

AR

a+b c+d

RRR = 1 - RR

ARR

c
c+d

NNT = 1 /ARR
NNH = 1/AR

a+b

PUBLIC HEALTH SCIENCES EPIDEMIOLOGY / BIOSTATISTICS

PUBLIC HEALTH SCIENCES

Incidence vs

Incidence

prevalence

rate

Prevalence

Recurrence

Tril?fT
Mortality

Cure

H of new cases
# of people at risk

03

[ during a specified
time period )

SECTION II

249

Incidence looks at new cases ( incidents).


Prevalence looks at all current cases.

II of existing cases (at a point in


t otal It of people time)
ill a population

Prevalence
Incidence rate x average duration
1 - prevalence of disease
Prevalence - incidence for short duration diseaseleg, common cold ).
Prevalence > incidence for chronic diseases, due to

Prevalence - pretest probability.


t prevalence

t PPV and t NPV

large II of existing cases ( eg diabetes).

Precision vs accuracy

Precision (reliability )!

The consistency and reproducibility of a teslj


The absence of random variation in a test.

Random error 1 precision in a test,


t precision - i standard deviation
t precision t statistical power ( 1 pi.
,

Accuracy (validity)!

Tire trueness of test measurement


The absence of systematic error or bias in a test.

External validity

Applicability of obtained results bevond the


cohort that was studied.

X X
X

Accurate, not precise

Systematic error i accuracy in a test.

Precise, not accurate

Accurate and
precise

Not accurate,
not precise

250

SECTION II

PUBLIC HEALTH SCIENCES

PUBLIC HEALTH SCIENCES EPIDEMIOLOGY / BIOSTATISTICS

Bias and study errors


TYPE

DEFINITION

EXAMPLES

STRATEGY TO REDUCE BIAS

Error in assigning subjects to


a study group resulting in
an unrepresentative sample.
Most commonly a sampling
bias.

Berkson bias study population Randomization


selected from hospital is
Ensure the choice of the right
less healthy than general
comparison/reference group

Recruiting participants
Selection bias

population
1 lealthy worker effect study
population is healthier than
the general population
Non-response biasparticipating subjects differ
from nonrespondents in
meaningful ways

Performing study

Recall bias

Patients with disease recall


Awareness of disorder alters
recall by subjects; common in exposure after learning of
similar cases
retrospective studies.

Measurement bias

Information is gathered in a
Association between HPV and Use objective, standardized,
and previously tested methods
systemic ally distorted manner. cervical carreer not observed
when using non-standardized
of data collection that arc
classifications
planned ahead of tinre
I lawthorne effect participants Use Dlacebo grouD
change their behavior in
response to their awareness of

Decrease time frottt exposure


to follow-up

being observed

Procedure bias

Observer- expectancy

bias

Subjects in different groups arc


not treated the same.

Patients in treatment group


spend more time in highly
specialized hospital units

If observ er expects treatment


Researchers belief in the
efficacy of a treatment changes group to show signs of
the outcome of that treatment
recovery, then he is more
(aka Pygmalion effect; selflikely to document positive
fulfilling prophecy).
outcomes

Blinding and use of placebo


reduce influence of

participants artd researchers


on procedures and

interpretation of outcomes
as neither are aware of group
allocation

Interpreting results

Confounding bias

When a factor is related to both Pulmonary disease is more


the exposure and outcome,
common itt coal workers
but not on the causal
than the general population;
however, people who w ork in
pathway - factor distorts or
confuses effect of exposure on coal mines also smoke more
outcome.
frequently than the gerteral

population
Lead-time bias

Early detection is confused


with t survival.

Early detection makes it


seem as though survival has
increased, but the natural
history of the disease has trot
changed

Multiple/repeated studies
Crossover studies (subjects act
as their own controls)
Matching ( patients with
similar characteristics in both
treatment atrd control groups)
Restriction
Randomization
Measure back-end survival
(adjust survival according to
the severity of disease at the
time of diagnosis)

252

SECTION I I

PUBLIC HEALTH SCIENCES

PUBLIC HEALTH SCIENCES EPIDEMIOLOGY / BIOSTATISTICS

Outcomes of statistical hypothesis testing

Correct result

Stating that there is an effect or difference when


one exists (null hypothesis rejected in favor of
alternative hypothesis).
Stating that there is not an effect or difference
when none exists ( null hypothesis not
rejectedl.

Incorrect result
Type I error (a)

Type II error ((5)

Stating that there is an effect or difference


when none exists (null hypothesis incorrectly
rejected in favor of alternative hvpothcsis).
a is the probability of making a typeI error, p is
judged against a preset a level of significance
(usually 0.05 ). If p < 0.05, then there is less
than a 5% chance that the data will show
something that is not really there.

Also knorvn as false-positive error.


a = you accused an innocent maij
You can never prove" the alternate hypothesis,
but you can reject the null hypothesis as being

very unlikely

Also knorvn as false-negative error.


Stating that there is not an effect or difference
when one exists ( null lnpothesis is not rejected
when it is in fact false ).
P is the probability' of making a type II error. P P = y ou blindly let the guilty man go freet
is related to statistical power ( 1 - p), which is
If you t sample size, you t porver. T here is power
the probability' of rejecting the null hy pothesis
in numbers.
when it is false,
t poyver and l P by:
t sample size
t expected effect size
t precision of measurement

Confidence interval

For a given X% Cl rvc arc X% confident that


the true mean of the target population falls
within the calculated interval
Cl for population mean = x Z( SEM )
SI M = cr / yj( N ) |q = sample standard deviation.
N = sample size ]
Jl'he 95'/f Cl (corresponding to - .05 ) is often
used.
For the 95% CI Z = 1.96.
For the 99% Cl, Z = 2.58.

If the 95% Cl for a mean difference between 2


variables includes 0, then there is no significant
difference and H0 is not rejected.
If the 95% Cl for odds ratio or relative risk
includes 1, llu is not rejected.
If the Cls betyveen 2 groups do not overlap
statistically significant difference exists
If the Cls betyveen 2 groups overlap usually
no significant difference exists.

PUBLIC HEALTH SCIENCES

BEHAVIORAL SCIENCE ETHICS

SECTION I I

253

Common statistical tests

f-test

Checks differences between means of 2 groups.

Tea is meant for 2.

Example: comparing the mean blood pressure


between men and women.
ANOVA

Checks differences between means of > or more


groups

Chi-square (%2)

Checks differences between 2 or more


percentages or proportions of categorical

outcomes (not mean values).

Pearson correlation
|coefficientl

words: ANalysis Of YAriance.


Example: comparing the mean blood pressure
between members of different ethnic groups.
Pronounce Chi-tegorical.
Example: comparing the percentage of members
of s different ethnic groups who have essential
hypertension.
>

r is always between -1 and +1. The closer the absolute value of r is to 1, the stronger the linear

correlation between the 2 variables.


Positive r value positive correlation (as one variable t, the other variable t )
Negative r value negative correlation (as one variable t the other variable t ).
Coefficient of determination = r ~ lamount of variance in one variable that can be explained bv
variance in another variahltl).

re a 4

re 0 8

r!

r= 0

re 0.8

i
'V
FPQ aft td corfie "

i.
I

..

r* 0.4
m

Strong positive

Weak positive

correlation

correlation

No correlation

Weak negative
correlation

Strong negative

correlation

BEHAVIORAL SCIENCE ETHICS


Core ethical principles

Autonomy

Beneficence

Obligation to respect patients as individuals ( truth-telling, confidentiality), to create conditions


necessary for autonomous choice (informed consent), and to honor their preference in accepting
or not accepting medical care.
Physicians have a special ethical ( fiduciary ) duty to act in the patient s best interest. May conflict
with autonomy (an informed patient has the right to decide) or what is best for society ( eg,
mandatory TB treatment). T raditionally, patient interest supersedes.

Nonmaleficence

"Do no harm. Must be balanced against beneficence; if the benefits outw eigh the risks, a patient
may make an informed decision to proceed (most surgeries and medications fall into this
category).

Justice

To treat nersons fnirlv and eonitahlv. T his does not nhvavs imnlv eouallv ( ep

triapel.

254

SECTION I I

Informed consent

PUBLIC HEALTH SCIENCES

BEHAVIORAL SCIENCE ETHICS

A process (not just a document/signature) that

requires:
Disclosure: discussion of pertinent
information
Understanding: ability to comprehend
Capacity: ability to reason and make ones
own decisions ( distinct from competence, a
legal determination )
Voluntariness: freedom from coercion and

manipulation

Exceptions to informed consent:


Patient lacks decision-making capacity or is
legally incompetent
Implied consent in an emergency
Therapeutic privilege withholding
information when disclosure would severely
harm the patient or undermine informed
decision-making capacity
Waiver patient explicitly waives the right of
informed consent

Patients must have an intelligent understanding


of their diagnosis and the risks/benefits of
proposed treatment and alternative options,
including no treatment.
Patient must be informed that he or she can
revoke written consent at any time, even orally.

Consent for minors

A minor is generally am person < 18 s ears old.


Parental consent laws in relation to health
care vary b\ state. In general, parental consent

should be obtained, but exceptions exist for


emergency treatment ( eg, blood

transfusions )

or if minor is legally emancipated leg, married,


self supporting, or in the military1

Situations in which parental consent is usually


not required:
Sex (contraception, STIs, pregnancy)
Drugs (substance abuse)
Rock and roll (emergency/trauma)
Physicians should always encourage healthy

minor-guardian communication.

Physician

should seek

patient consent

Decision- making
capacity

is

patient assent even

il

not required.

Physician must determine w hether the patient is psychologically and legally capable of making
a particular health care decision. Note that decisions made with capacity cannot be revoked
simply if the patient later loses capacity
Components:
Patient is > 18 years old or otherwise legally emancipated
Patient makes and communicates a choice
Patient is informed (knows and understands)
Decision remains stable over time
Decision is consistent with patient s values and goals, not clouded by a mood disorder
Decision is not a result of altered mental status (eg, delirium, psychosis, intoxication )

r BCHAVIUKAL SuttfU

PUBLIC HEALTH SCIENIO

Advance directives

tifTTo

Instructions given by a patient in anticipation of the need for a medical decision. Details vary per

state law
Oral advance directive

Incapacitated patients prior oral statements commonly used as guide. Problems arise from variance
in interpretation. If patient was informed, directive was specific, patient made a choice, and
decision was repeated over time to multiple people, then the oral directive is more valid.

Living will ( written


advance directive)

Describes treatments the patient wishes to receive or not receive if he/she loses decision-making
capacity. Usually, patient directs physician to withhold or withdraw life-sustaining treatment if he/
she develops a terminal disease or enters a persistent vegetative state.

Medical power of

Patient designates an agent to make medical decisions in the event that he/she loses decision
making capacity. Patient may also specif)' decisions in clinical situations. Can be revoked by
patient if decision-making capacity is intact . More flexible than a living will.

attorney

Do not resuscitate
order

Surrogate decision-

maker

DNR order applies only to cardiopulmonary resuscitation.

If a patient loses decision-making capacity and has not prepared an advance directive, individuals
(surrogates) who know the patient must determine what the patient would have done. Priority of
Siblings
surrogates: The spouse ChiPS in spouse adult Children Parents
other

relative

Confidentiality

Confidentiality respects patient privacy and autonomy. If patient is not present or is incapacitated.
disclosing information to family and friends should be guided by professional judgment of
patient 's best interest. The patient may voluntarily waive the right to confidentiality (eg, insurance
company request ).
General principles for exceptions to confidentiality:
Potential physical harm to others is serious and imminent
Likelihood of harm to self is great
No alternative means exists to warn or to protect those at risk
Physicians can take steps to prevent harm
Examples of exceptions to patient confidentiality (many are state-specific ) include the following
( " The physician's good judgement SAVED the dav" f
Suieidal/homicidal patients
Abuse ( children, elderly, and /or prisoners)
Tarasoff decision California Supreme Court decision requiring physician to directly inform
and protect potential victim from harm.
Epileptic patients and other impaired automobile drivers.
Reportable diseases ( eg, STls, hepatitis, food poisoning ); physicians may have a duly to warn
public officials, who will then notify people at risk. Dangerous communicable diseases, such as
TB or Ebola, may require involuntary treatment ]

'

IFTBnitRH

256

SECTION II

BEHAVIORAL SCIENCE

ETHICS

Ethical situations
SITUATION

Patient is not adherent.

Attempt to identify the reason for nonadherence and determine his/her willingness to
change; do not coerce the patient into adhering or refer him / her to another physician.

Patient desires an unnecessary

Attempt to understand why the patient wants the procedure and address underlying
concerns. Do not refuse to see the patient or refer him / her to another physician . Avoid
performing unnecessary procedures.

procedure.

PUBLIC HEALTH SCIENCES

Patient has difficult)' taking


medications.

I:

i 1 J 'I

Provide written instructions; attempt to simplify treatment regimens; use teach-back


method (ask patient to repeat regimen back to physician ) to ensure comprehension .

Family members ask for information Avoid discussing issues with relatives without the patient s permission.
about patients prognosis.
A patient s family member asks you Attempt to identify why the family member believes such information would be
detrimental to the patients condition . Explain that as long as the patient has decision
not to disclose the results of a test
making capacity and does not indicate otherwise, communication of information
if the prognosis is poor because
concerning his/her care will not be withheld . 1 lowever, if vou believe the patient
the patient will be unable to
might harm himself or others if informed, then you may invoke therapeutic privilege
handle it.
and withhold the information!
A 17-year-old girl is pregnant and
Many states require parental notification or consent for minors for an abortion. Unless
there are specific medical risks associated with pregnancy, a physician should not
requests an abortion.
sway the patient s decision for an elective abortion ( regardless of maternal age or fetal
condition ).
The patient retains the right to make decisions regarding her child , even if her parents
A 15-vcar-old girl is pregnant and
wants to keep the child . I ler
disagree. Provide information to the teenager about the practical issues of caring for
a baby. Discuss the options, if requested . Encourage discussion between the teenager
parents want you to tell her to give
the child up for adoption.
and her parents to reach the best decision .
A terminally ill patient requests
In the overw helming majority of states, refuse involvement in any form of physicianassisted suicide. Physicians may, however, prescribe medically appropriate analgesics
physician assistance in ending
his/ her own life.
that coincidentally shorten the patient s life.
Assess the seriousness of the threat . If it is serious, suggest that the patient remain in the
Patient is suicidal.
hospital voluntarily; patient can be hospitalized involuntarily if hc/she refuses.
Patient states that he/she finds you
Ask direct , closed-ended questions and use a chaperone if necessary. Romantic
attractive.
relationships with patients are never appropriate.
A woman who had a mastectomy
Find out why the patient feels this way. Do not offer falsely reassuring statements (eg,
You still look good").
says she now feels ugly.
Patient is angry about the long time Acknowledge the patient 's anger, but do not take a patient s anger personally. Apologize
for any inconvenience. Stay away from efforts to explain the delay.
he /she spent in the waiting room .
Patient is upset with the way he /she Suggest that the patient speak directly to that physician regarding his/her concerns. If the
was treated by another doctor.
problem is with a member of the office staff, tell the patient you will speak to that person .
An invasive test is performed on the Regardless of the outcome, a physician is ethically obligated to inform a patient that a
mistake has been made.
wrong patient.

PUBLIC HEALTH SCIENCES

BEHAVIORAL SCIENCE ETHICS

257

SECTION II

Ethical situations ( continued )


SITUATION

APPROPRIATE RESPONSE

A patient requires a treatment not


covered by his/her insurance.

Never limit or deny care because of the expense in time or money. Discuss all
treatment options with patients, even if some arc not covered by their insurance

Patient is victim of intimate partner


violence.

companies.
At ages 5 -7, children begin to understand that death is permanent, that all life
functions end completely at death, and that everything that is alive eventually
dies. Provide a direct, concrete description of his sisters death. Avoid cliches and
euphemisms. Reassure that the boy is not responsible. Identify and normalize fears
and feelings. Kncourage play and healthy coping behaviors (eg, remembering her in
his own way).
Ask if patient is safe and has an emergency plan. Do not pressure patient to leave his or
her partner, or disclose the incident to the authorities.

Patient wants to trv alternative or


holistic medicine.

Find out win and allow patient to do so as long as there arc no contraindications.
medication interactions, or adverse effects to the new treatment .

Phvsician colleague presents to


work impaired.

If impaired, incompetent, or unethical colleague threatens patient safety, report the


situation to local superv isory personnel. Should the organization fail to take action
alert the state licensing board.

Patient is officiallv determined to


suffer brain death. Patient s family
insists on maintaining life support
indefinitely because patient is still
moving when touched.

Gently explain to family that there is no chance of recovers , and that brain death is

A pharmaceutical company offers


vou a sponsorship in exchange for
advertising its new drug

Reject this offer. Generally, decline gifts and sponsorships to avoid any appearance of
conflict of interest. The AMA Code of Ethics does make exceptions for gifts directly
benefitting patients; gifts of minimal value; special funding for medical education
of students, residents, fellows: grants where recipients arc chosen bv independent

An adult refuses care because it is


against his/her religious beliefs.

Work with the patient bv cither explaining the treatment or pursuing alternative
treatments with the patient . However, a phvsician should never attempt to force adults
to receive care if it is contrary to their religious beliefs.

Mother and 15-vear-old daughter

Transfuse daughter, but do not transfuse mother. Emergent care can be refused bv the
healthcare proxy for an adult, particularly where patient preferences are known or
reasonably inferred, but not for a minod

A 7 year-old boy loses a sister to


cancer and now feels responsible.

eauivalent to death Movement is due to spinal arc reflex and is not voluntary. Patient
should be withdrawn from life support

institutional criteria; and where funds are distributed without attribution to sponsors.

arc unresponsive following a car


accident and are bleeding internally.
Father says do not transfuse because
they are Jehovah s Witnesses

SECTION II

PUBLIC HEALTH SCIENCES

PUBLIC HEALTH SCIENCES THE WELL PATIENT

PUBLIC HEALTH SCIENCES THE WELL PATIENT

Early developmental
milestones

Milestone dates are ranges that have been approximated and vary by source. Children not meeting
milestones may need assessment for potential developmental delay.

AGE

MOTOR

SOCIAL

Infant

Parents

Start

0-12 mo

Toddler

12- 36 mo

Preschool
3-5 yr

Observing,

Social smile (by 2 mo)


Primitive reflexes disappear
Moro ( by 3 mo ), rooting ( by
Stranger anxiety ( by 6 mo)
4 mo), palmar (by 6 mo),
Separation anxiety ( by 9 mo)
Babinski ( by 12 mo)
Posture lifts head up prone ( by
1 mo), rolls and sits (by 6 mo),
crawls (by 8 mo), stands ( by
10 mo), walks (by 12-18 mo)
Picks passes toys hand to
hand (by 6 mo), Pincer grasp
(by 10 mo)
Points to objects (by 12 mo)

Orients first to voice ( by


4 mo), then to name and
gestures (by 9 mo)
Object permanence ( by 9 mo)
Oratory says mama and
" dada" (by 10 mo)

Child

Rearing

Cruises, takes first steps ( by


12 mo)
Climbs stairs ( by 18 mo)
Cubes stacked number
= age (yr) x 3
Cutler \( feeds self with fork
and spoon (by 20 mo)
Kicks ball ( by 24 mo)

Recreation parallel play ( by


24-36 mo)
Rapprochement moves away
from and returns to mother
( by 24 mo)
Realization core gender
identity - formed (by 36 mo)

W ords 200 ssords by age 2


(2 zeros), 2-word sentences

Don't

Forget, they're still

Learning!

Drive tricvcle ( > wheels at


3 yr)
Drawings copies line or
circle, stick figure ( by 4 yr)
Dexterity hops on one foot
(by 4 yr), uses buttons or
zippers, grooms self ( by 5 yr )

Freedom comfortably spends


part of das ass ay from mother

Language 1000 ssords by age

Car seats for children

VERBAL /C0GNIT1VE

Working,

(by 3

vri

Friends cooperatise play, has


imaginary friends ( by 4 yr)

3 ( 3 zeros), uses complete


sentences and prepositions
(by 4 yr)
Legends can tell detailed
stories ( by 4 vr|

Children should ride in rear-facing car seats until thev are 2 sears old and in car seats with a
harness until thev are 4 sears. Older children should use a booster seat until thev are 8 sears
old or until the seat belt fits pi operlv. Children < 12 sears old should not ride in a seat ss ith an

airhaa

PUBLIC HEALTH SCIENCES

Changes in the
elderly

PUBLIC HEALTH SCIENCES SOCIAL SCIENCES

SECTION II

Sexual changes:
Men slower ereetion/ejaculation, longer refractor) period
Women vaginal shortening, thinning, and dryness.
Sleep patterns: I REM and slow-wave sleep; t sleep onset latency] t early awakenings
^
t suicide rate.
hearing
1 vision and
.
I immune response.
I renal, pulmonary, and Cl function .
=

1 muscle mass, t fat .


Intelligence docs not decrease!

PUBLIC HEALTH SCIENCES SOCIAL SCIENCES


Disease prevention

Primary

Prevent disease before it occurs (eg, HPV


vaccination)

Secondary

Screen early for and manage existing but


asymptomatic disease (eg Pap smear for
cervical cancer)

Tertiary

Treatment to reduce complications from


disease that is ongoing or has long-term effects
(eg, chemotherapy)

Quaternary identifying patients at risk of


unnecessary treatment, protecting from the
harm of new interventions ( eg, electronic
sharing of patient records to avoid duplicating
recent laboratory and imaging studies!

Types of insurance plans

Health Maintenance
Organization

Patients are restricted ( except in emergencies! to a limited panel of providers w ho arc in the
network.
Payment is denied for any service that does not meet established, es idencc-hascd guidelines.
Requires referral from primary care provider to see a specialist.

Point of Service

Patients arc allowed to sec providers outside of the netw ork, hut have higher out-of-pocket costs,
including higher copays and deductibles, for out-of-netw ork services.
Requires referral from primary care provider to see a specialist .

Preferred Provider

Patients are allowed to see physicians who are within or outside of the network. All serv ices have
higher enpavs and deductibles.
Do not need a referral from primary care provider to see a specialist.

Organization

Exclusive Provider
Organization

Patients arc limited (except in emergencies) to a network of doctors, specialists, and hospitals.
Does not require a referral from primary care provider to sec a specialist.

PUBLIC HEALTH SCIENCES

PUBLIC HEALTH SCIENCES SOCIAL SCIENCES

Patient payment models


Capitation!

Patient pays a fixed, predetermined fee in advance to cover all medical serv ices. Used in HMO
insurance plans!

Discounted fee- forservice

Patient pays for eaeli individual service at a predetermined, discounted rate,

Global payment

Patient pays for all expenses associated with a single incident of care with a single payment . Most
commonly used during elective surgeries, as it covers tile cost of surgery as w ell as the necessary
pre - and postoperative visits.

Medicare and
Medicaid

Medicare and Medicaid federal social


health care programd that originated from
amendments to the Social Security Act.
Medicare is available to patients > 65 years old.
< 65 with certain disabilities, and those with
end-stage renal disease.
Medicaid is joint federal and state health
assistance for people with very low income.

MedicarE is for Elderly


MedicaiD is for Destitute.
The 4 parts of Medicare:
Part A: Hospital insurance, home hospice
care

Part B: Basic medical bills ( eg, doctors fees,

diagnostic testing!
Part C: ( Parts A + B = Combrj) delivered by

approved private companies


Part D: Prescription drugs

Hospice care

Medical care focused oil providing comfort and palliation instead of definitive cure. Available to
patients on Medicare or Medicaid and in most private insurance plans whose life expectancy is
< 6 months.
During end - of-life care, priority is given to improving the patient 's comfort and relieving pain, and
care often includes opioid medications. Facilitating comfort is prioritized over potential side
effects leg, respiratory depression). This prioritization of positive effects over negative effects is
known as the principle of double effect.

Common causes of death (US) by age

#1

< 1 YR

1-14 YR

Congenital
malformations

Unintentional
injury

#2

Preterm birth

Cancer

#3

Maternal

Congenital
malformations

pregnancy

complication!

15-34 YR
Unintentional
injury

35-44 YR

45-64 YR

65+ YR

Unintentional
injury

Cancer

Heart disease

Suicide
Homicide

Cancer

1 leart disease
Unintentional
injury

Chronic

Heart disease

Cancer

respiratory
disease

262

SECTION II

Swiss cheese model

PUBLIC HEALTH SCIENCES

PUBLIC HEALTH SCIENCES SOCIAL SCIENCES

In complex organizations, flaws in multiple


processes and systems may align to cause
patient harm. Focuses on systems and
conditions rather than an individual's error.

FaAtrts m defense strategy


Hazard

N 'i i

|"
II M

Swapped

Figure

Types of medical
errors

May involve patient identification, diagnosis, monitoring, nosocomial infection, medications,


procedures, devices, documentation, handoffs. Errors causing harmful outcomes must be disclosed
to patients.

Active error

Occurs at level of frontline operator (eg, wrong


IV pump dose programmed).

Immediate impact.

Latent error

Occurs in processes indirect from operator hut


impacts patient care ( eg, different types of IV
pumps used within same hospital ).

Accident waiting to happen.

Root cause analysis

Uses records and participant interviews to


identify all the underlying problems that led to
an error. Categories of causes include process,
people (providers or patients), environment,
equipment, materials, management.

Retrospective approach applied after failure


event to prevent recurrence.
Plotted on fishbone ( Ishikawa, cause-and-effect )
diagram. Fix causes with corrective action

Failure mode and

Uses inductive reasoning to identify all the ways


a process might fail and prioritize these by
their probability of occurrence and impact on
patients.

forward-looking approach applied before process


implementation to prevent failure occurrence.

Medical error analysis

effects analysis

plan.

32

SECTION II

BIOCHEMISTRY MOLECULAR

BIOCHEMISTRY

BIOCHEMISTRY MOLECULAR
Chromatin structure

DNA double- helix

HI histone
(linker)

DNA

Revised
Figure

Supercoiled
structure

ELK:h omatir

Nucleosome
(H2 A, H2B,
H3, H4) X 2

DNA exists in the condensed, chromatin form


in order to fit into the nucleus. Negatively
charged DNA loops tw ice around positively
charged histone octamer to form nucleosome
beads on a string. Histones are rich in the
amino acids lysine and arginine. HI binds to
the nucleosome and to linker DNA, thereby
stabilizing the chromatin fiber.
In mitosis, DNA condenses to form
chromosomes. DNA and histone synthesis
occur during S phase.

Heterochromatin

eta phase
chromosome

Heterochromatin_

Condensed, appears darker on EM (labeled H


in gj Transcriptionally inactive, stericallv
inaccessible t methvlation, 1 acetylation!

HeteroChromatin = Highly Condensed.


Barr bodies (inactive X chromosomes) are
heterochromatin.

Euchromatin

Less condensed, appears lighter on EM ( labeled


E in Hi Transcriptionally active, stericallv

Eu = true, truly transcribed.


Euchromatin is Expressed.

DNA methylation

Template strand cytosine and adenine are


methylated in DNA replication, which allows
mismatch repair enzymes to distinguish
between old and new strands in prokaryotes.
DNA methylation at CpG islands represses

accessible.

CpG Methylation Makes DNA Mute.

transcription.
Histone methylation

Usually reversibly represses DNA transcription,

Histone Methylation Mostly Makes DNA Mute.

but can activate it in some cases depending on

methylation location.
Histone acetylation

Relaxes DNA coiling, allowing for transcription.

Histone Acetylation makes DNA Active.

Transcriptionally active, sterically accessible.


Template strand cytosine and adenine are
methylated in DNA replication, which allows
mismatch repair enzymes to distinguish
between old and new strands in prokaryotes.
DNA methylation at CpG islands represses
transcription.
Usually reversibly represses DNA transcription,
but can activate it in some cases depending on
methylation location.
Relaxes DNA coiling, allowing for transcription.

DNA methylation

Histone methylation

Histone acetylation

CpG Methylation Makes DNA Mute.


Histone Methylation Mostly Makes DNA Mute.

Histone Acetylation makes DNA Active.

BIOCHEMISTRY MOLECULAR

BIOCHEMISTRY

NucIcoSidc = base + ( dcoxylribose ( Sugar ).


NucleoTide = base + (deoxy )ribose + phosphaTe;
linked by V-V phosphodiester bond.

Nucleotides

PURines (A G) 2 rings.
PYrimidines (C,U,T)-1 ring.

Deamination of cytosine makes uracil.


Deamination of adenine makes guanine.
Uracil found m KNA ; thvminc in DNA .
Methylation of uracil makes tliviuinc ]

Purine (A C)

Pyrimidine (C U, T)

CO,
Aspartate

Glycine

\
c

N10

Euchromatin is Expressed.

-Formvt -

C ^N10 -Formyl tetrahydrofolate


N

..\

Carbamoyl

-A

phosphate

Aspartate

\N

[i

s' end of incoming nucleotide bears the

triphosphate ( energy source for the bond ).


Triphosphate bond is target of the V hydroxyl
attack ]
IT Rc As Gold.

CUT the PY (pie).


Thymine has a methyl.
G-C bond ( t H bonds) stronger than A-T bond
( 2 11 bonds; "G - C bonds arc like Graze Glue ),
t G-C content
t melting temperature of
DNA.

GAG Amino acids necessary for purine

synthesis:
Glvcine
Aspartate
Glutamine

Genetic code features

Unambiguous

Each codon specifies only 1 amino acid.

Degenerate/
redundant

Most amino acids are coded by multiple codons.

Commaless,
nonoverlapping

Read from a fixed starting point as a continuous


sequence of bases.
Genetic code is conserved throughout
evolution .
Accurate base pairing is usually required only in
first 2 nucleotide positions of mRNA codon .

Universal
Wobble

Exceptions: methionine and try ptophan encoded


by only 1 codon (AUG and UGG, respectively).
Exceptions: some viruses.
Exception in humans: mitochondria .
Codons that differ in srd , "wobble position may
code for same tRN.Vamino acid .

BIOCHEMISTRY

BIOCHEMISTRY MOLECULAR

35

SECTION II

DNA replication

Eukaryotic DNA replication is more complex than the prokaryotic process but uses many
enzymes analogous to those listed below. In both prokaryotes and eukary otes, DNA replication is
semiconservative and involves both continuous and discontinuous ( Okazaki fragment ) synthesis,
V direction!
and occurs in the V

Prigin of
replication Q

Particular consensus sequence of base pairs


in genome where DNA replication begins.
May be single ( prokaryotes) or multiple
(eukaryotes).
Y-shaped region along DNA template where
leading and lagging strands are synthesized.

Peplication forkQ

pielicaseQ
pingle- stranded
binding proteinsjjj
pNA

topoisomerases

)
Al-rich sequences ( such as '1 VIA box regions!
are found in promoters and origins of

replication.

Unwinds DNA template at replication fork.


Prevent strands from reannealing.
Create a single- or double-stranded break in the
helix to add or remove supercoils.

Irinotecan /lopotecan inhibits eukaryotic


topoisomerase 1.
Etoposide/teniposidc inhibit eukaryotic
topoisomerase II.
Fluoroquinolones inhibit prokaryotic topoisomerase
11 ( DNAgvrase ) and topoisomerase IV|

Makes an RNA primer on which DNA

PrimaseJQ
pNAJpolymerase llljgj

polymerase III can initiate replication.


Prokary otic only. Elongates leading strand
by adding dcoxynuclcotidcs to the V end.
Elongates lagging strand until it reaches
primer of preceding fragment. V -* 5'
exonuclease activity proofreads" each added
nucleotide.

DNA polymerase 111 has 5' V synthesis and


proofreads with V 5' exonuclease.
Drugs blocking DNA replication otten base
modified V OH, pres enting addition of the next
nucleotide ("chain termination" ).

PNA polymerase IJJJ

Prokary otic only. Degrades RNA primer;


replaces it w ith DNA.

PNA ligasej]

Catalyzes the formation of a phosphodiestcr


loins Okazaki fragments.
bond within a strand of double-stranded DNAj
Often dysregulated in cancer cells, allowing
F.ukarvotes only An RNA -dependent DNA
unlimited replication.
polymerase that adds DNA to V ends of
chromosomes to avoid loss of genetic material
with every duplication.!

Telomerase

Sam functions as DNA polymerase lll;!ilso


excises RNA primer w ith 5' - V cxonucleasc.

,QTopoisomerase

DNA polymerase III

Ongmof replication

Helicase

Leading strand

Replication fork

Single - stranded
Origin of replication
binding protein
Lagging strand

Area o( interest
Leading strand

RNA primer

DNA tigase Revise

Primase

Fa

Lagging strand

Lagging strand
Okazaki fragment

Id

ovvnM

Leading strand

A polymerase III

III

DNA polymerase I

BIOCHEMISTRY MOLECULAR

BIOCHEMISTRY

DNA repair

Single strand

Nucleotide excision
repair

Base excision repair

Defective in xeroderma pigmentosum, which


Specific endonucleases release the
oligonucleotides containing damaged bases;
prevents repair of pyrimidine dimers because
DNA polymerase and ligase fill and reseat the
of ultraviolet light exposure.
gap, respectively. Repairs bulky helix-distorting
lesions. Occurs in G( phase of cell cycle.
Base-specific Glvcosylasdremoves altered base
and creates AP site (apurinic/apyrirnidinic).
One or more nucleotides are removed bv
AP-Endonucleas which cleaves the 5' end.
Lyase cleaves the V end. DNAIj)lymerase-P
fills the gap and DNA jjjgasc seals it. Occurs

Important in repair of spontaneous/toxic


deamination.^
GEL PLease= (Glvcosvlase Endonuclease,
Lvase, Polymerase b. Ligase)

throughout cell cycle.


Mismatch repair

Newly synthesized strand is recognized,


mismatched nucleotides are removed,
and the gap is filled and rescaled. Occurs
predominantly in G-, phase of cell cycle.

Defective in Lynch syndrome (hereditary


nonpolyposis colorectal cancer [HNPCC]).

Double strand
Nonhomologous end
joining

DNA /RNA / protein


synthesis direction

Brings together 2 ends of DNA fragments to


repair double-stranded breaks. No requirement
for homologv. Some DNA mav be lost.

DNA and RNA arc both synthesized 5' V.


The 5' end of the incoming nucleotide bears
the triphosphate (energy source for bond ).
Protein synthesis is N-terminus to C-terminus.

Mutated in ataxia telangiectasia and breast /


ovarian cancers with BRC AI mutation;
Fanconi anemia]

mRNA is read 5' to V.


The triphosphate bond is the target of the
V hydroxyl attack . Drugs blocking DNA
replication often have modified V OH,
preventing addition of the next nucleotide
(chain termination").

Start and stop codons

mRNA start codons

Eukaryotes

AUG ( or rarely GUG).

At 1C inAUGurates protein synthesis.

Codes for methionine, which may be removed

before translation is completed.


Prokaryotes
mRNA stop codons

Codes for N-formylmethionine ( fMet).

fMet stimulates neutrophil chemotaxis.

UGA, UAA, UAG.

UGA = U Go Away.
UAA = lT Are Away
UAG = U Are Gone

UJ 8

SECTION II

BIOCHEMISTRY MOLECULAR

BIOCHEMISTRY

Functional
organization of a
eukaryotic gene

Transcription start
(mRNA synthesized 5'

CAAT box

Coding strand 5'

CAAT

30
Polyadenylation

ATG = Start codon

TATA box

signal

"

TATAAT

Exonl

GT

5' UTR

Promoter

AG

Exon 2 GT

AG

Intron 1

Intron 2

Exon 3 AATAAA

}y

3' UTR

Regulation of gene expression

Promoter

Site where RNA polymerase II and multiple


other transcription factors bind to DNA
upstream from gene locus ( AT-rich upstream
sequence with TATA and CAAT boxes).

Promoter mutation commonly results in


dramatic 1 in level of gene transcription.

Enhancer

Stretch of DNA that alters gene expression by


binding transcription factors ( eg activator

Enhancers and silencers may be located close to,


far from, or even within (in an intron) the gene
whose expression it regulates.

Silencer

Site where negative regulators ( repressors) bind.

protcinsi

RNA polymerases

Eukaryotes

I, II, and III are numbered in the same order


RNA polymerase I makes rRNA imost
that their products are used in protein
numerous RNA, rampant).
sy nthesis: rRNA, mRNA, then tRN.U
RNA polymerase II makes mRNA ( largest RNA,
massive) mRNA is read 5' to V.
a-amanitin, found in Amanita phalloides (death
RNA polymerase III makes sS rRNA, tRNA
cap mushrooms ), inhibits RNA polymerase II.
Causes severe hepatotoxicity if ingested.
(smallest RNA, tiny).
No proofreading function, but can initiate
J\ctinomycin D inhibits RNA polymerase in
chains. RNA polymerase 11 opens DNA at
both prokary otes and eukaryotes.
promoter site.

Prokaryotes

1 RNA polymerase (multisubunit complex)


makes all s kinds of RNA.

Rifampin inhibits RNA polvmerase in


prokaryotes.

iRevised
Figure

40

SECTION II

BIOCHEMISTRY MOLECULAR

BIOCHEMISTRY

tRNA

Structure

75-90 nucleotides, 2 structure, doverleaf form, anticodon end is opposite 5' aniinoacy! end. All
tRNAs, both eukaryotic and prokaryotic, have CCA at 5' end along with a high percentage of
chemically modified bases. The amino acid is covalently bound to the 5' end of the tRNA. CCA
Can Carry Amino acids.
T-arm: contains the TH'C (ribothymidine, pseudouridine, cytidine) sequence necessary for tRNAribosome binding. T-ann Tethers tRNA molecule to ribosointj
D-arm: contains diliydrouridine residues necessary for tRNA recognition by the correct aminoacyTtRNA synthetase. D-arm Detects the tRNA bv aminoacvl-tRNA svnthctascj
Acceptor stem: the 5 CCA-5' is the amino acid acceptor site.

Charging

Aminoacyl-tRNA synthetase ( 1 per amino acid; matchmaker; uses ATP) scrutinizes amino acid
before and after it binds to tRNA If incorrect, bond is hydrolyzed. The amino acid-tRNA bond
has energy for formation of peptide bond. A mischarged tRNA reads usual codon but inserts

wrong amino acid.

Aminoacyl-tRNA synthetase and binding of charged tRNA to the codon are responsible for
accuracy of amino acid selection.
Charging

Pairing

(aminoacylation)

( codon- anticodon)

Structure

OH

- 0

l:

Acceptor stem Ti -arm

Arruno acid

-*-

Aminoacyl-tRNA
synthetase

D-arm

V 0 C 0 > * * *c
* * *

Variable armS

Anticodon
loop

Amino acid

^0

Ir
t

^ii.

. ..

position

.....,
a

ii
"

mRNA

: :

Anticodon 15 CAU 5 I-C*


'

^Wobble

IF2

*
" "

(Initiation factor )

ATP

, ..u

c cC cC a

S
1

'

r
Codon
(S AUG 5 )

Et

Protein synthesis

Initiation

Elongation

Initiated by CTP hydrolysis; initiation factors


( eukaryotic IP's ) help assemble the 40S
ribosomal subunit with the initiator tRNA
and are released when the mRNA and the
ribosomal 60S subunit assemble with the
complex.

1. Aminoacyl-tRNA binds to A site (except for

Kukaryotes: 40S + 60S -* 80S ( Even ).


PrOkaryotcs: 10S + 50S 70S lOdd ).
Suithesis occurs troin N - lermimis to
C-terminns

ATP tRNA Activation ( charging).


GTP tRNA Gripping and Going places
(translocation ).

initiator methionine)

2. rRNA ( ribozyme") catalyzes peptide bond


formation, transfers growing polypeptide to
amino acid in A site
A Ribosome advances 5 nucleotides toward 5'
end of mRNA, moving peptidvl tRNA to 1'
site (translocation)
Termination

Stop codon is recognized by release factor,


and completed polypeptide is released from
ribosome.

Think of going APE":


A site = incoming Aminoacyl-tRNA .
P site = accommodates growing Peptide.
E site = holds Empty tRNA as it Exits.

f < sl
ssr \
rO fc U
S'

sV
i

'

- -

*
Revised

Figure

40S
B

\42

SECTION II

BIOCHEMISTRY

BIOCHEMISTRY CELLULAR

BIOCHEMISTRY CELLULAR
Cell cycle phases

Checkpoints control transitions between phases of cell cycle. This process is regulated by cyclins,
cyclin-dependent kinases (CDKs), and tumor suppressors. M phase (shortest phase of cell cycle)
includes mitosis ( prophase, prometaphase, metaphase, anaphase, telophase) and cytokinesis
( cytoplasm splits in two). C| and G( arc of variable duration.

REGULATION OF CEIL CYCLE

Cydin- dependent

Constitutive and inactive.

kinasej

'

Regulator) proteins that control cell cycle


events; phase specific; activate CDKs.
Cydin- CDK complexes Phosphorylate other proteins to coordinate
cell cycle progression; must be actu ated and
inactivated at appropriate times for cell cycle
to progress.
Tumor suppressors
pot induces p2l, which inhibits CDKs
hypophosphorylation (activation) of Rb
H inhibition of G,-S progression. Mutations in
Cyclins

XX

X
XX

/i

tumor suppressor genes resuli in unrestrained


cell division (eg. Li-Fraumeni syndrome).

vs

*'. , .

Rb p53 modulate
G restriction point

10

CEUTYPES

Remain in G0, regenerate from stem cells.

Neurons, skeletal and cardiac muscle RBCs.

Stable (quiescent)

Enter G| from Gn when stimulated.

Hepatocytes, lymphocytes.

Labile

Never go to G(), divide rapidly w ith a short G( .


Most affected b\ chemotherapv.

Bone marrow, gut epithelium, skin, hair follicles,


germ cells.

Rough endoplasmic
reticulum

Site of synthesis of secretory (exported) proteins


and of N-linked oligosaccharide addition to
many proteins.
Nissl bodies ( RER in neurons) synthesize
peptide neurotransmitters for secretion.
Free ribosomes unattached to any membrane;
site of synthesis of cytosolic and organellar
proteins.

Mucus-secreting goblet cells of the small


intestine and antibody-secreting plasma cells
are rich in RER.

Smooth endoplasmic
reticulum

Site of steroid synthesis and detoxification of


drugs and poisons. Lacks surface ribosomes.

Laver hepatocytes and steroid hormoneproducing cells of the adrenal cortex and
gonads are rich in SER.

Permanent

BIOCHEMISTRY CELLULAR

BIOCHEMISTRY

43

SECTION II

Golgi is the distribution center for proteins and lipids from the ER to the vesicles and plasma
membrane. Modifies N-oligosaccharidcs on asparagine. Adds O-oligosaccharides on serine and
threonine. Adds mannose-6-phosphate to proteins for trafficking to lysosomes.
Endosomes are sorting centers for material from outside the cell or from the Golgi, sending it to
lysosomes for destruction or back to the membrane/Golgi for further use.

Cell trafficking

l-cell disease (inclusion cell disease/mucolipidosis type II) inherited lysosomal storage disorder;
defect in N-acetylglucosaminyl-l-phosphotransferase failure of the Golgi to phosphors late
mannose residues ( ic, i mannosc-6-phosphatc) on glycoproteins
proteins arc secreted
extraeellularly rather than delivered to lysosomes. Results in coarse facial features, clouded
corneas, restricted joint movement, and high plasma levels of lysosomal enzymes Often fatal in

childhood.

K>
10

Signal recognition particle (SRP)


Abundant, cytosolic ribonucleoprotein that

*****

Clathrin

y
Early
endo

COM
Late

traffics proteins from the ribosome to


the RER. Absent or dysfunctional SRP
-* proteins accumulate in the cytosol.

Vesicular trafficking proteins


COPI: Golgi Golgi ( retrograde); cis Golgi

endosome
COMI

Golgi
apparatus

'

reticu inn

cis-Golgi (anterograde).

c:*

Endoplasmic

1 vo (COP11 ) steps forward ( anterograde); one


(GOPI ) step back ( retrograde ).
Clathrin: trans-Golgi lysosomes; plasma
membrane endosomes (receptormediated endoeytosis [eg, LDL receptor

CIS

activity]).

Nuclear envelope

Peroxisome

FR.
COPI1: ER

aiK

Membrane-enclosed organelle involved in catabolism of vcry-long-chain fattv acids ( through


( - oxidation), branchcd-chain fatty acids, amino acids, and ethanol.
i
Diseases o| the iicroxisoine coiiiiimiiK K - nl to neurologic diseases due I deficits in ssnthesis
"
il plasmalogens, imporlant phospholipids in irnelin. PeroxiMiin il diseases include Zellweger
syndrome i hypotonia, seziures. hepatomegaly, earlv deathi and Refsum disease iscalv skin, ataxia.
cataracts/night blindness, shortening of 4th toe, cpiphvseal dvsplasia ).

BIOCHEMISTRY

Cytoskeletal elements

BIOCHEMISTRY CELLULAR

A netw ork of protein fibers within the cytopl:asm that supports cell structure, cell and organelle
movement, and cell division.

TYPE OF FILAMENT

PREDOMINANT FUNCTION

EXAMPLES

Microfilaments

Muscle contraction, cytokinesis

Actin, microvilli.

Intermediate
filaments

Maintain cell structure

Vimentin, desmin, cytokeratin, larnins, glial


fibrillary acid proteins (GFAP), neurofilaments.

Microtubules

Movement, cell division

Cilia, flagella, mitotic spindle, axonal trafficking,


centrioles.

Immunohistochemical stains for intermediate filaments


STAIN

CELL TYPE

IDENTIFIES

ViMEntinj

MEsenchvmal tissue leg. fibroblasts.


endothelial cells, macrophages!

MEsenchvmal tumors leg. sarcoma), but


also manv other tumors (eg. cndoMEtrial
carcinoma, renal cell carcinoma.
MEningiomai

DesMin

Muscle

Cytokeratin

Epithelial cells

GFAP

NeuroGlia

Muscle tumors (eg, rhabdomyosarcoma)

Epithelial tumors (eg, squamous cell carcinoma )

( eg, astrocytes, Schw ann cells,

Astrocytoma, glioblastoma

oligodendroglia)
Neurofilaments

Microtubule
Positive
end (+)
Heterodimer

Neuronal tumors (eg, neuroblastoma)

Neurons

Drugs that act on microtubules ( Microtubules


Cylindrical outer structure composed of a
helical array of polymerized heterodimers
Get Constructed Yerv Poorly ):
Mebendazole (antihclminthic)
of a- and [J- tubulin. Each dimer has 2 GTP
bound. Incorporated into flagella, cilia, mitotic
Griscofulvin (antifungal)
Colchicine (antigout)
spindles. Grows slowly, collapses quickly .
Also involved in slow axoplasmic transport in
VincristineA'inblastine (anticancer )
neurons.

Protofilament

Negative
end H

Paclitaxel (anticancer )

Molecular motor proteins transport cellular


cargo toward opposite ends of microtubule

Negative end Near Nucleus


Positive end Points to Periphery
tracks.
Dynein retrograde to microtubule (+ -* ).
Kinesin anterograde to microtubule ( +).

BIOCHEMISTRY CELLULAR

BIOCHEMISTRY

Cilia structure

Sodium-potassium
pump

9 doublet + 2 singlet arrangement ol

microtubules farrows in Q).


Basal bods ( base of cilium below cell
membrane) consists of 9 microtubule triplets
( arrow in Ehvitli no central niieroliihulei
Axonemal dynein ATPase that links peripheral
9 doublets and causes bending of cilium by
differential sliding of doublets.

SECTION II

45

Kartagener syndrome (1 ciliary dyskinesia)


immotile cilia due to a dynein arm defect.
Results in 1 male and female fertility due tet

immotile sperm and dysfunctional fallopian


lube cilia, respectively; t risk of ectopic
pregnancy. Can cause bronchiectasis,
recurrent sinusitis, chronic ear infections,
conductive hearing loss, and situs inversus ( eg,
dextrocardia on CXRll

Pl MPKIM - PI IMP K2 IN
Xa+-K+ ATPase is located in the plasma
membrane with ATP site on cytosolic side.
Ouabain inhibits by binding to K+ site.
Cardiac glycosides ( digoxin and digitoxin )
For each ATP consumed, sNV go out of the
cell ( pump phosphorylatcd ) and 2K* come into directly inhibit the Na -K+ ATPase, which
leads to indirect inhibition of Na+/Ca+
the cell (pump dephosphorylated ).
Plasma membrane is an asymmetric linid
exchange t [Ca*]j -* t cardiac contractility.
'

bilaver containing cholesterol, phospholipids.


sphingolipids, glvcolipids, and proteins.

Extracellular
space

3Na+ /*

V*nf
Membrane

Cytosol

j. i

* e)

V1

A
A

I I ) {Vjtf '- fs
cr ,
i

5Na+

'

P
ATP

ADP

2K*

*\

2K

BIOCHEMISTRY

Osteogenesis
imperfecta

BIOCHEMISTRY CELLULAR

Genetic bone disorder ( brittle bone


disease) caused by a variety of gene defects
(most commonly COLlAl and COL1 A2 ).
Most common form is autosomal dominant
with t production of otherwise normal type I
collagen. Manifestations can include:

Multiple fractures with minimal


trauma Q Q; may occur during the birth

SECTION II

May be confused with child abuse.

Patients can t BITI


B ( BONES = multiple fractures )
I ( LVL - blue sclerae)
I ( TFhTH = dental imperfections!
I ( PAR - hearing loss)

process
Blue sclerae Q due to the translucent
connective tissue over choroidal veins
(Some forms have tooth abnormalities,
including opalescent teeth that wear easily
due to lack of dentin ( dentinogenesis

imperfecta)

Hearing loss ( abnormal ossicles|

Upper

extremity

Ehiers-Danlos
syndrome

Menkes disease

Fault) collagen synthesis causing


hyperextensiblc skin, tendency to bleed ( easy
bruising), and hvpermobile joints Q.
Multiple tvpes. Inheritance and severity vary.
Can be autosomal dominant or recessive. May
be associated with joint dislocation, berry and
aortic aneurysms, organ rupture.

Hypermobility tvpc ( joint instability): most


common type.

Classical type ( joint and skin symptoms): caused


by a mutation (eg, COL5AI , COLSAZjin type
V collagen.
Vascular type (vascular and organ rupture l:
deficient type III collagen.

X-linked recessive connective tissue disease caused by impaired copper absorption and transport
due to defective Menkes protein (ATP7A). Leads to i activity oflysyl oxidase ( copper is a
necessary cofactor). Results in brittle, kinky" hair, growth retardation, and hypotonia.

47

50

SECTION II

Flow cytometry

BIOCHEMISTRY

BIOCHEMISTRY

LABORATORY TECHNIQUES

Laboratory technique to assess size, granularity,


and protein expression ( immunophenotype ) of
individual cells in a sample.

Cells arc tagged with antibodies specific to


surface or intracellular proteins. Antibodies
are then tagged with a unique fluorescent
dye. Sample is analyzed one cell at a time by
focusing a laser on the cell and measuring
light scatter and intensity of fluorescence.

Commonly used in workup of hematologic


abnormalities (eg, paroxysmal nocturnal
hemoglobinuria , fetal RBCs in mothers blood )
and immunodeficiencies ( eg, CD4 cell count
in HIV ).
Fluorescent
label
Antibody

y w>*

Anb -CD3 Ab 'J

Anti -CD8 Ab

Cell

/1

LT :CI

Huorescence
is detected .
labeled cells

re

z1

are counted

Data are plotted either as histogram (one


measure) or scatter plot (any two measures, as
shown ). In illustration:
Cells in left lower quadrant for both CDS
and CD3.
Cells in right lower quadrant for CDS and
for CDllt Right lower quadrant is empty
because all CDS-expressing cells also express
Cells in left upper quadrant for CDs and

0 for CPtt
Cells in right upper quadrant for CD8
and CDs ( red + blue purple).

Microarrays

10*

10 s

8 102
to1

life

10

10

CDx i

Laser makes
label fluoresce

10!

10

CM

10!

10*
63

Thousands of nucleic acid sequences are arranged in grids on glass or silicon . DNA or RNA probes
are hybridized to the chip, and a scanner detects the relative amounts of complementary binding.
Used to profile gene expression levels of thousands of genes simultaneously to study certain diseases
and treatments. Able to detect single nucleotide polymorphisms (SNPs) and copy number
variations (CNVs) for a variety of applications including genotyping, clinical genetic testing,
forensic analysis, cancer mutations, and genetic linkage analysis.

BIOCHEMISTRY

BIOCHEMISTRY

LABORATORY TECHNIQUES

51

SECTION II

Note that line art for Enzyme linked immunosorbent assay was deleted and text
rewritten in 8th pass pages for 2016 edition. Please clarify needed changes.

Enzyme -linked
immunosorbent assay

Immunologic test used to detect the presence of either a specific antigen (eg. HBsAg ) or antibody
(eg, anti- HBs) in a patient s blood sample. Detection involves the use of an antibody linked to an
enzyme. Added substrate reacts with cnzvtnc, producing a detectable signal ( eg, color change ).
Major ELISA variations include direct , sandwich , and competitive. Can have high sensitivity and
specificity.

Karyotyping

A process in which metaphase chromosomes arc stained , ordered, and numbcrcdJQ according to
morphology, size, arm-length ratio, and banding pattern. Can be performed on a sample of blood ,
bone marrow, amniotic fluid , or placental tissue. Used to diagnose chromosomal imbalances (eg,
autosomal tTisomies, sex chromosome disorders).

Al
19

Fluorescence in situ
hybridization

..

IQ

Fluorescent DNA or RNA probe binds to specific gene site of interest on chromosomes (arrows in
point to abnormalities!
)
Used for specific localization of genes and direct visualization of chromosomal anomalies at the
molecular level.
..
\ lu lodclctiiin l i e i : n
a hi
i t I to
n
al the same 1 ir
on the second copy of that chromosome
Translocation fluorescence outside the original chromosome
Duplication extra site of fluorescence on one hromosomc relative I " its lionn ilogous
i

chromosome

Cloning methods

Cloning is the production of a recombinant DNA molecule that is self- perpetuating.


Steps:
1. Isolate eukaryotic mRNA ( post-RNA processing stepsi of interest.
2. Expose mRNA to reverse transcriptase to produce cDNA ( lacks introns).
v Insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes.
4. Transform recombinant plasmid into bacteria.
5. Survis ing bacteria on antibiotic medium produce cloned DNA (copies of cDNA).

BIOCHEMISTRY

BIOCHEMISTRY GENETICS

'i ,

Genetic terms (continued )


TERM

DEFINITION

EXAMPLE

Mosaicism

Presence of genetically distinct cell lines in the

McCune- Albright syndrome due to mutation


affecting G-protcin signaling. Presents with
unilateral cafc-au-lait spots with ragged
edges, polyostotic fibrous dysplasia, at least
one endocrinopathv (eg. precocious pubertvi

same individual.

Somatic mosaicism mutation arises from


mitotic errors after fertilization and propagates
through multiple tissues or organs.
Gonadal mosaicism mutation onlv in egg or
sperm cells. If parents and relatives do not
have the disease, suspect gonadal (or germline )

Lethal if mutation occurs before fertilization


(affecting all cells), but survivablc in patients
with mosaicism.

mosaicisni
Locus heterogeneity

Mutations at different loci can produce a similar

Albinism.

Allelic heterogeneity

phenotype.
Different mutations in the same locus
produce the same phenotype.

ff-thalassemia.

Heteroplasmy

Presence of both normal and mutated


mlDNA, resulting in variable expression in
mitochondrially inherited disease.

Uniparental disomy

Offspring receives 2 copies of a chromosome from Uniparental is el ploid ( correct number of


chromosomes ), not aneuploid. Most occurrences
1 parent and no copies from the other parent.
of UPD normal phenotype. Consider UPD
1 Ictcrodlsomv (heterozygous) indicates a meiosis
1 error. Isodlsomv (homozygous) indicates a
in an individual manifesting a recessive disorder
meiosis II errodor postzygotic chromosomal
when only one parent is a carrier.
duplication of one of a pair of chromosomes,
and loss of the other of the original pair.

Hardy-Weinberg
population genetics

pA

qa

pA

qa

AA

Aa

'

P * P =P

pxq

Aa

aa

pxq

qxq = q>

If a population is in Hardy-Weinberg
equilibrium and if p and q arc the frequencies
of separate alleles, then: p" + 2pq + q
= 1 and
p + q = 1, which implies that:
p- = frequency of homozygosity for allele
q- = frequency of homozygosity for allele j
2pq = frequency of heterozygosity (carrier
frequency, if an autosomal recessive disease ).

Tlw * frpnupnrv of an YJSnl'prl wrfsivp rlunacp

Hardy-Weinberg law

assumptions include:

No mutation occurring at the locus


Natural selection is not occurring

Completely random mating


No net migration

Variable expressivity

Patients with the same genotype have varying


phenotypei

2 patients with neurofibromatosis type 1 ( NF1)


may have varying disease severity.

Incomplete
penetrance

Not all individuals with a mutant genotype


show the mutant phenotype.

BRCAl gene mutations do not always result in


breast or ovarian cancer.

Pleiotropy

One gene contributes to multiple phenotypic


effects.

Untreated phenylketonuria ( PKU ) manifests with


light skin, intellectual disability, and musty hods
odor.

Anticipation

Increased severity or earlier onset of disease in


succeeding generations.

Trinucleotide repeat diseases ( eg, Huntington


disease).

Loss of heterozygosity

If a patient inherits or develops a mutation in


a tumor suppressor gene, the complementary

Retinoblastoma and the two-hit hypothesis,


Lynch syndrome ( HNPCC), Li-Fraumeni
syndrome.

allele must be delctcd /mutated before cancer


develops. This is not true of oncogenes.
Dominant negative
mutation

Linkage
disequilibrium

Exerts a dominant effect. A heterozvgote


produces a nonfunctional altered protein that
also prevents the normal gene product from
functioning.
Tendency for certain alleles at 2 linked
loci to occur together more or less often
than expected by chance . Measured in a
population, not in a family, and often varies in
different populations.

Mutation of a transcription factor in its allosteric


site. Nonfunctioning mutant can still bind

DNA, preventing wild-type transcription factor


from binding.

BIOCHEMISTRY

BIOCHEMISTRY GENETICS

'i ,

Genetic terms (continued )


TERM

DEFINITION

EXAMPLE

Mosaicism

Presence of genetically distinct cell lines in the

McCune- Albright syndrome due to mutation


affecting G-protcin signaling. Presents with
unilateral cafc-au-lait spots with ragged
edges, polyostotic fibrous dysplasia, at least
one endocrinopathv (eg. precocious pubertvi

same individual.

Somatic mosaicism mutation arises from


mitotic errors after fertilization and propagates
through multiple tissues or organs.
Gonadal mosaicism mutation onlv in egg or
sperm cells. If parents and relatives do not
have the disease, suspect gonadal (or germline )

Lethal if mutation occurs before fertilization


(affecting all cells), but survivablc in patients
with mosaicism.

mosaicisni
Locus heterogeneity

Mutations at different loci can produce a similar

Albinism.

Allelic heterogeneity

phenotype.
Different mutations in the same locus
produce the same phenotype.

ff-thalassemia.

Heteroplasmy

Presence of both normal and mutated


mlDNA, resulting in variable expression in
mitochondrially inherited disease.

Uniparental disomy

Offspring receives 2 copies of a chromosome from Uniparental is el ploid ( correct number of


chromosomes ), not aneuploid. Most occurrences
1 parent and no copies from the other parent.
of UPD normal phenotype. Consider UPD
1 Ictcrodlsomv (heterozygous) indicates a meiosis
1 error. Isodlsomv (homozygous) indicates a
in an individual manifesting a recessive disorder
meiosis II errodor postzygotic chromosomal
when only one parent is a carrier.
duplication of one of a pair of chromosomes,
and loss of the other of the original pair.

Hardy-Weinberg
population genetics

pA

qa

pA

qa

AA

Aa

'

P * P =P

pxq

Aa

aa

pxq

qxq = q>

If a population is in Hardy-Weinberg
equilibrium and if p and q arc the frequencies
of separate alleles, then: p" + 2pq + q
= 1 and
p + q = 1, which implies that:
p- = frequency of homozygosity for allele
q- = frequency of homozygosity for allele j
2pq = frequency of heterozygosity (carrier
frequency, if an autosomal recessive disease ).

Tlw * frpnupnrv of an YJSnl'prl wrfsivp rlunacp

Hardy-Weinberg law

assumptions include:

No mutation occurring at the locus


Natural selection is not occurring

Completely random mating


No net migration

56

SECTION II

Autosomal dominant
diseases

BIOCHEMISTRY

BIOCHEMISTRY GENETICS

Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis,


familial hypercholesterolemia, hereditary hemorrhagic telangiectasia, hcrcditjrv spherocytosis,
Huntington disease, Li-Fraumeni syndrome, Marfan syndrome, multiple endocrine neoplasias,
neurofibromatosis type 1 (von Recklinghausen disease), neurofibromatosis type 2, luberous
sclerosis, von I lippel-Lindan disease.

Hereditary
hemorrhagic
telangiectasia

Inherited disorder ofblood vessels. Findings: blanchingskin lesions ( telangiectasias), recurrent


epistaxis, skin discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria. Also
known as Osler-VVeber-Rendu syndrome.

Li- Fraumeni
syndrome

Abnormalities in f P53 ichromosome 17 ) multiple malignancies at an early age. Also known as


SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland).

Marfan syndrome

FBN1 gene mutation on chromosome 15 defective fibrillin (scaffold for elastin) connective
tissue disorder affecting skeleton, heart, and eyes. Findings: tall with long extremities, pectus
carinatum I more specific ) or pectus excavatunj hvpermobile joints, and long, tapering fingers and
toes (arachnodactyly); cystic medial necrosis of aorta aortic incompetence and dissecting aortic
aneurysms; floppy mitral valve. Subluxation of lenses, typically upward and temporally.

Neurocutaneous disorder characterized by cafe-au-lait spots, cutaneous neurofibromas, optic


gliomas, pheochromocytomas, Lisch nodules ( pigmented iris hamartomas). 100% penetrance,
variable expression. Caused by mutations in the NFI gene on chromosome 17; 17 letters in "von
Recklinghausen.

Neurofibromatosis
type 1 (von

Recklinghausen
disease)

Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas.


NF2 gene on chromosome 22; type 2 = 22.

Neurofibromatosis
type 2

Albinism, autosomal recessive polycystic kidney disease ( ARPKD), cvstic fibrosis, glycogen
storage diseases, hemochromatosis, Kartagcncr syndrome, mucopolysaccharidoses (except
Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoscs (except Fabry disease!,
thalassemias, Wilson disease.

Autosomal recessive
diseases

offspring of affected females may show signs of

inheritance

1-0
Or#

disease.

LTO

i# (Soh
= unaffected male;H = affected male; O = unaffected female; #

within a family due to heteroplasmy.


Mitochondrial myopathies rare disorders;
often present with myopathy, lactic acidosis,
and CNS disease, eg, MELAS syndrome
(mitochondrial encephalopathy, lactic

acidosis, and stroke-like episodes ). 2 to


failure in oxidative phosphorylation. Muscle
bio [) s \ otten shows "ragged red fiheis" ( due to
)
accumulations of diseased mitochondria!

- affected female.

66

SECTION II

Autosomal dominant
diseases

BIOCHEMISTRY

BIOCHEMISTRY GENETICS

Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis,


familial hypercholesterolemia, hereditary hemorrhagic telangiectasia, hcrcditjrv spherocytosis,
Huntington disease, Li-Fraumcni syndrome, Marfan syndrome, multiple endocrine neoplasias,
neurofibromatosis type 1 (von Recklinghausen disease ), neurofibromatosis type 2, luberous
sclerosis, von Hippel-Lindau disease.

Hereditary
hemorrhagic
telangiectasia

Inherited disorder of blood vessels. Findings: blanehin skin lesions ( telangieetasias), recurrent
epistaxis, skin discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria. Also
known as Osler-VVeber-Rendu syndrome.

Li- Fraumeni
syndrome

Abnormalities in TP53 ichromosome 17 ) multiple malignancies at an early age. Also known as


SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland).

Marfan syndrome

FBN1 gene mutation on chromosome 15 defective fibrillin (scaffold for elastin) connective
tissue disorder affecting skeleton, heart, and eyes. Findings: tall with long extremities, pectus
carinatum imore specific ) or pectus exeavatunj hvpermobile joints, and long, tapering fingers and
toes (arachnodactvly); cystic medial necrosis of aorta aortic incompetence and dissecting aortic
aneurysms; floppy mitral valve. Subluxation of lenses, typically upward and temporally.

Neurofibromatosis
type 1 (von

Recklinghausen
disease)
Neurofibromatosis
type 2

Autosomal recessive
diseases

Neurocutaneous disorder characterized by cafe-au-lait spots, cutaneous neurofibromas, optic


gliomas, pheochromocytomas, Lisch nodules ( pigmented iris hamartomas). 100% penetrance,
variable expression. Caused by mutations in the IVF1 gene on chromosome 17; 17 letters in "von
Recklinghausen.

Findings: bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas.


NF2 gene on chromosome 22; type 2 = 22.

Albinism, autosomal recessive polycystic kidnev disease (ARPKD), cvstic fibrosis, glycogen
storage diseases, hemochromatosis, Kartagcncr syndrome, mucopolysaccharidoses ( except
Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoscs ( except Fabry disease),
thalassemias, Wilson disease.

$8

SECTION II

BIOCHEMISTRY

BIOCHEMISTRY

Muscular dystrophies

,
T

M HWI

V4Wk

X linkcd disorder typically due to framcshift

Duchenne

S' #?
.*

GENETICS

Becker

Myotonic type 1

Fragile X syndrome

or nonsense mutations truncated or


absent dystrophin proteirt progressive
mvofiber damagrj Weakness begins in pelvic
girdle muscles and progresses superiorly.
Pscudohypertrophy of calf muscles due to
fibrofattv replacement of muscle Q. Gower
maneuver patients use upper extremities
to help them stand up. Waddling gait. Onset
before 5 years of age. Dilated cardiomyopathy
is common cause of death.

Duchenne = deleted dystrophin .


Dystrophin gene ( DJWD) is the largest
protein-coding human gene t chance of
spontaneous mutation. Dystrophin helps
anchor muscle fibers, primarily in skeletal and
cardiac muscle. It connects the intracellular
cvtoskeleton (actin) to the transmembranc
proteins a- and P dystroglycan, which are
connected to the extracellular matrix ( ECM ).
Loss of dystrophin results in myonecrosis
t CK and aldolase are seen ; Western blot and

muscle biopsy confirm diagnosis.


Deletions can cause both Duchenne and
X-linked disorder typically due to non
frameshift insertions in dystrophin gene
Becker.
( partially functional instead of truncated ). Less
severe than Duchenne. Onset in adolescence
or early adulthood.
Autosomal dominant. CTG trinucleotide repeat My Tonia, My Testicles (testicular atrophy ),
My Toupee (frontal balding), My Ticker
expansion in the DMPK gene - abnormal
(arrhythmia).
expression of myotonin protein kinase
myotonia, muscle wasting, cataracts,
testicular atrophy, frontal balding, arrhythmia.

X-linked dominant inheritance. Trinucleotide


repeat in FAIR 1 gene mcthylation
1 expression. Most common cause of
inherited intellectual disability and autism
and 2 nd most common cause of genetically
associated mental deficiency ( after Down
syndrome!Findings:

post pubertal

Trinucleotide repeat disorder (CGG) n.


Fragile X = eXtra large testes, jaw, ears.

COMPLICATIONS

TREATMENT

X-linked recessive
disorders

aureus [ early infancy), t' aeruginosa i adolescence] ), chronic


bronchitis and bronchiectasis reticulonodular pattern on CXR, opacification of sinusei
Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D E,
K ), biliary cirrhosis, liver disease. Meconium ileus in newborns.
Infertility in men (absence of vas deferens, spermatogenesis may be unaffected ) and subfertility in
women (amenorrhea, abnormally thick cervical mucus ).
Nasal polyps, clubbing of nails.
Recurrent pulmonary infections ( eg, i

Multifactorial: chest physiotherapy, albuterol , aerosolized dornase alfa ( DNAse), and hypertonic
saline facilitate mucus clearance. Azithromycin used as anti-inflammaton agent . Ibnprofen slow s
disease progressing Pancreatic enzymes for insufficiency.
Ornithine transcarbamyla.se deficiency, Fabry
disease, Wiskott-Aldrich syndrome, Ocular
albinism, G6PD deficiency, Hunter syndrome,
Bruton agammaglobulinemia Hemophilia
A and B, Lcsch - Nyhan syndrome, Duchcnnc
(and Becker) muscular dystrophy.
Lyonization female carriers variabK affected
depending on the percentage inactivation of
the X chromosome earn ing the mutant vs
normal gentj

Oblivious Female \\ ill Often Give I ler Boys


1 ler x-Linked Disorders

$8

SECTION II

BIOCHEMISTRY

BIOCHEMISTRY

Muscular dystrophies

,
T

M HWI

V4Wk

X linkcd disorder typically due to framcshift

Duchenne

S' #?
.*

GENETICS

Becker

Myotonic type 1

Fragile X syndrome

or nonsense mutations truncated or


absent dystrophin proteirt progressive
mvofiber damagrj Weakness begins in pelvic
girdle muscles and progresses superiorly.
Pscudohypertrophy of calf muscles due to
fibrofattv replacement of muscle Q. Gower
maneuver patients use upper extremities
to help them stand up. Waddling gait. Onset
before 5 years of age. Dilated cardiomyopathy
is common cause of death.

Duchenne = deleted dystrophin .


Dystrophin gene ( DJWD) is the largest
protein-coding human gene t chance of
spontaneous mutation. Dystrophin helps
anchor muscle fibers, primarily in skeletal and
cardiac muscle. It connects the intracellular
cvtoskeleton (actin) to the transmembranc
proteins a- and P dystroglycan, which are
connected to the extracellular matrix ( ECM ).
Loss of dystrophin results in myonecrosis
t CK and aldolase are seen ; Western blot and

muscle biopsy confirm diagnosis.


Deletions can cause both Duchenne and
X-linked disorder typically due to non
frameshift insertions in dystrophin gene
Becker.
( partially functional instead of truncated ). Less
severe than Duchenne. Onset in adolescence
or early adulthood.
Autosomal dominant. CTG trinucleotide repeat My Tonia, My Testicles (testicular atrophy ),
My Toupee (frontal balding), My Ticker
expansion in the DMPK gene - abnormal
(arrhythmia).
expression of myotonin protein kinase
myotonia, muscle wasting, cataracts,
testicular atrophy, frontal balding, arrhythmia.

X-linked dominant inheritance. Trinucleotide


repeat in FAIR 1 gene mcthylation
1 expression. Most common cause of
inherited intellectual disability and autism
and 2 nd most common cause of genetically
associated mental deficiency ( after Down
syndrome!Findings:

post pubertal

Trinucleotide repeat disorder (CGG) n.


Fragile X = eXtra large testes, jaw, ears.

. M ifrcte fiber
.

X-linkcd disorder typically due to frameshift

Duchenne

or nonsense mutations truncated nr


absent dystrophin protend progressise
invofiber damagtj Weakness begins in pelvic
girdle muscles and progresses superiorly.
Pseudohypertrophy of calf muscles due to
fibrofattv replacement of muscle Q. Gower
maneuver patients use upper extremities
to help them stand up. W addling gait. Onset
before S years of age. Dilated cardiomyopathy
is common cause of death .

Becker

Duchenne = deleted dystrophin .


Dystrophin gene ( DMD) is the largest
protein-coding human gene -* t chance of
spontaneous mutation . Dystrophin helps
anchor muscle fibers, primarily in skeletal and
cardiac muscle. It connects the intracellular
cytoskeleton (actin ) to the transmembrane
proteins a- and JJ-dystroglycan , which are
connected to the extracellular matrix (ECM ).
Loss ofdvstrophin results in nrvonecrosis.
t CK and aldolase are seen; W'estcrn blot and
muscle biopsy confirm diagnosis.

Deletions can cause both Duchenne and


X-litrked disorder typically due to non frameshift insertions in dystrophin gene
Becker.
( partialh functional instead of truncated ). Less
scs'crc than Duchenne. Onset in adolescence
or early adulthood .
Autosomal dominant. CTG trinucleotide repeat My Ponia. My Testicles ( testicular atrophy),
My Toupee ( frontal balding ), My Ticker
expansion in the DMPK gene abnormal
(arrhythmia ).
expression ofmyotonin protein kinase
- myotonia, muscle wasting, cataracts,
testicular atrophy, frontal balding, arrhythmia .
'

Myotonic type 1

Fragile X syndrome

X-linked dominant inheritance. Trinucleotide


repeat in FAJR1 gene methvlation
1 expression . Most common cause of
inherited intellectual disability' and autism
aird 2 nd most common cause of genetically
associated mental deficiency ( after Down

svndromcl

Trinucleotide repeat disorder (CGG ) n.


Fragile \ = cXtra large testes, jasv, cars.

Findings; post pubcrtal

macroorchidism icnlarged testes ), long face


rvith a large jaw, large everted ears, autism ,
mitral valve prolapse.

Trinucleotide repeat
expansion diseases

Huntington disease, mvotonic dystrophy .


fragile \ syndrome, and Friedreich ataxia.
Mav shorv genetic anticipation ( disease severity
t and age of onset t in successive generations ).
Huntington disease (CAG ) n
Mvotonic dy strophy = ( CTG )

Fragile X syndrome = ( CGC )n


Friedreich ataxia ( GAA ) j

Trv ( trinucleotide) hunting for mv fragile cagefree eggs ( X ).

Caudate has i ACh and GABA


Cataracts, loupe ( carls balding in men ).

Gonadal atrophy
Chin ( protruding ) Giant Gonads

GAit Ataxi 4

BIOCHEMISTRY GENETICS

BIOCHEMISTRY

Autosomal trisomies

Down syndrome
(trisomy 21)

Edwards syndrome
(trisomy 18)

Findings: inlellcctuil disability Hat facies,


prominent epicanthal folds, single palmar
crease, gap between 1st 2 toes, duodenal
atresia, Hirschsprung disease, congenital heart
disease (eg, atrioventricular septal defect|,
Brushfield spots. Associated with earlv-onset
Alzheimer disease (chromosome 21 codes for
amyloid precursor protein) and t risk of ALL
and AML.
95% of cases due to meiotic nondisjunction
( t with advanced maternal age; from 1:1500 in
women < 20 to 1:25 in women > 45 years old).
4% of cases due to unbalanced Robertsonian
translocation, most typically between
chromosomes 14 and 21. \% of cases due
to mosaicism ( no association with maternal
nondisjunction; postfertilization mitotic errorj

Incidence 1:700.
Drinking age ( 21).
Most common viable chromosomal disorder and
most common cause of genetic intellectual
disability.
First-trimester ultrasound commonly shows
t nuchal translucency and hypoplastic nasal
bone; 1 serum PAPP-A, t free (3-hCG
Second-trimester quad screen shows
1 a-fctoprotcin, t (J-hCG i estriol,
t inhibit! A.

Findings: PR1XCF, Edward: Prominent


occiput Rockcr-bottom feet Intellectual
disability Nondisjunction Clenched fists
( with overlapping fingers ), low-set Lars
micrognathia ( small jaw ), congenital heart
disease. Death usually occurs within 1 year of

Incidence 1:8000.
Flection age ( 18).
2nd most common autosomal trisoimlresulting
in live birth (most common is Down syndrome).
PAPP-A and free P-hCG are i in first trimester.
Quad screen shows i a-fetoprotein, 1 P-hCG,
1 estriol, i or normal inhihin A.

birth1
Patau syndrome
(trisomy 13 )

59

SECTION II

Findings: severe intellectual disability, rockerbottom feet, microphthalmia, microcephaly,


deft liP/Palate, holoProsencephaly,
Polydactyly, congenital heart disease, cutis
aplasia. Death usually occurs within 1 year of
birth.

Incidence 1:15,000.
Puberty (13).
First-trimester pregnancy screen shows J free
P-hCG, i PAPP-A.

Nondisjunction in meiosis II

Nondisjunction in meiosis I

n
t

Nondisjunction

<

C 3
C 3

Meiosis I

C 3

n +1

lllXDCIn +1

Trisomy

C 3

C 3

A A

III

Meiosis II

n -1

n 1

Monosomy

Gametes

Nondisjunction

ll ll l III
,
_ -, ,
'n

Normal

n 1
n +1
.
J l
II
Monosomy Trisomy

60

SECTION II

BIOCHEMISTRY GENETICS

BIOCHEMISTRY

Genetic disorders by

CHROMOSOME

SELECTED EXAMPLES

chromosome

von Hippel-Lindau disease, renal cell carcinoma

ADPKD (PKD2), achondroplasia, Huntington disease

Cri-du-chat syndrome, familial adenomatous polyposis

Hemochromatosis ( HFE )
Williams syndrome, cystic fibrosis

Friedreich ataxia

11
1?

Patau syndrome, Wilson disease, retinoblastoma ( RBI ), BRCA2

Wilms tumor, Pglobin gene defects ( eg, sickle cell disease, P-thalassemia)

15

Prader-Willi syndrome, Angelman syndrome, Marfan syndrome

16

ADPKD iPKDl ), a-globin gene defects (eg, a-thalassemia)

17

Neurofibromatosis type 1 BRCA 1, p53l

18

Edwards syndrome

20

Maturitv-onset diabetes of the voung

21

Down syndrome

22

Neurofibromatosis type 2, DiC eorge syndrome ( 22ql 1)


Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter syndrome (XXY)

Robertsonian
translocation

Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.
One of the most common types of translocation. Occurs when the long arms of 2 acrocentric
chromosomes (chromosomes with centromeres near their ends ) fuse at the centromere and the
2 short arms are lost. Balanced translocations normally do not cause any abnormal phenotype.
Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance ( eg.
Down syndrome, Patau syndrome).

Cri- du- chat syndrome

Congenital microdeletion of short arm of


chromosome 5 (46 XX or XT', 5p ).
Findings: microcephaly, moderate to
severe intellectual disability, high-pitched
crying/mewing, epicanthal folds, cardiac
abnormalities (VSD),

Williams syndrome

Congenital microdclction of long arm of chromosome 7 (deleted region includes clastin gene).
Findings: distinctive elfin facies, intellectual disability, hypercalcemia ( t sensitivity to vitamin D),
well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.

Cri da chat = cry of the cat.

Ul HRHlVH

BIOCHEMISTRY

BIOCHEMISTRY

NUTRITION

Vitamin A ( retinol )
FUNCTION

Antioxidant; constituent of visual pigments


( retinal ); essential for normal differentiation
of epithelial cells into specialized tissue
( pancreatic cells, mucus secreting cells);
prevents squamous metaplasia. Used to treat
measles and APLj

DEFICIENCY

EXCESS

Night blindness ( nyctalopia ); dry, scaly


skin (xerosis cutis ); corneal degeneration
( keratomalacia ); Bitot spots on conjunctiva;
immunosuppression.
Acute toxicity nausea , vomiting, vertigo, and
blurred vision .
Chronic toxicity alopecia, dry skin (eg,
scaliness), hepatic toxicity and enlargement ,
arthralgias, and pseudotumor cerebri .
Teratogenic ( cleft palate, cardiac abnormalities),
therefore a 0 pregnancy test and two forms of
contraception are required before isotretinoin
( vitamin A derivative ) is prescribed .

Retinol is vitamin A, so think retin A ( used


topically for wrinkles and Acne ).
Found in liver and leaf) vegetables.
Use oral isotretinoin to treat severe cystic acne.
Use all-trails retinoic acid to treat acute
promyelocvtic leukemia .

Isotretinoin is teratogenic.

Vitamin B1 ( thiamine )
FUNCTION

Think ATP: a ketoglutarate dehydrogenase,


Transketolase, and Pyruvate dehydrogenase.
Spell beriberi as BerlBerl to remember
vitamin Bj .
Wernicke- Korsakoff syndrome confusion ,
ophthalmoplegia , ataxia (classic triad ) +
confabulation , personality change, memory

Impaired glucose breakdown ATP depletion


worsened by glucose infusion ; highly aerobic
tissues (eg, brain , heart ) are affected first.
In alcoholic or malnourished patients, give
thiamine before dextrose to avoid precipitating
Wernicke encephalopathy Diagnosis made
by t in RBC transketolase activity following
vitamin B| administration .

loss ( permanent ). Damage to medial dorsal


nucleus of thalamus, mammillary bodies.
Dry beriberi polyneuritis, symmetrical muscle
wasting.
Wet beriberi high -output cardiac failure
(dilated cardiomyopathy), edema.

DEFICIENCY

In thiamine pyrophosphate (TPP), a cofactor for


several dehydrogenase enzyme reactions:
Pyruvate dehydrogenase ( links glycolysis to
TCA cycle )
a-ketoglutarate dehydrogenase (TCA cycle )
Transketolase ( HMP shunt )
Branchcd chain ketoacid dehydrogenase

64

SECTION I I

BIOCHEMISTRY

BIOCHEMISTRY NUTRITION

Vitamin B7 (biotin)
FUNCTION

Cofactor for carboxylation enzymes (which add


a 1-carbon group):
Pyruvate carboxylase: pyruvate (3C)
-* oxaloacetate (4C )
Acetyl-CoA carboxylase: acetyl-CoA (2C i
malonyl-CoA ( 3C)
Propionyl-CoA carboxylase: propionvl-CoA
( 3C ) methylmalonyl-CoA (4C )

Avidin in egg whites avidly binds biotin.

DEFICIENCY

Relatively rare. Dermatitis, alopecia, enteritis.


Caused by antibiotic use or excessive ingestion
of raw egg whites.

Vitamin B9 (folate)
FUNCTION

Converted to tctrahydrofolic acid ( THF), a


coenzyme for 1-carbon transfcr/mcthylation
reactions.
Important for the synthesis of nitrogenous bases
in DNA and RNA.

Found in leaf) green vegetables. Absorbed in


jejunum. Folate from foliage.
Small reserve pool stored primarily in the liver.

DEFICIENCY

Macrocytic, megaloblastic anemia;


hypersegmented polymorphonuclear cells
( PMNs); glossitis; no neurologic symptoms
( as opposed to vitamin Bp deficiency). Labs:
t homocysteine, normal methylmalonic acid
levels. Most common vitamin deficiency in
the United States. Seen in alcoholism and

Deficiency can be caused by several drugs (eg,


phenytoin sulfonamides, methotrexate).
Supplemental maternal folic acid at least 1 month
prior to conception and during earlv pregnanevi
1 risk of neural tube defects.

pregnancy.

BIOCHEMISTRY

BIOCHEMISTRY NUTRITION

65

SECTION II

Vitamin B12 (cobalamin )


FUNCTION

Cofactor for methionine synthase (transfers


ClI, groups as methylcobalamin) and
methvhnalonvl-CoA mutase. Important for
DNA synthesis

DEFICIENCY

Macrocytic, megaloblastic anemia;


hypersegmented PMNs; paresthesias
and subacute combined degeneration
( degeneration of dorsal columns, lateral
corticospinal tracts, and spinocerebellar tracts)
due to abnormal myelin. Associated with
t serum homocysteine and methylmalonic
acid levels, along with 2 folate deficiency
Prolonged deficiency - irreversible nerve
damage.

Found in animal products.


Synthesized only by microorganisms. Very large
reserve pool (several sears) stored primarily in
the liver. Deficiency caused by malabsorption
(eg, sprue, enteritis. Diphyllobotlirium latum ),
lack of intrinsic factor (pernicious anemia,
gastric bypass surgery), absence of terminal
ileum ( surgical resection, eg, for Crohn
disease), or insufficient intake (eg, veganism).
Anti-intrinsic factor antibodies diagnostic for
pernicious anemia.

Fatty acids with odd number of


carbons, branched-chain ammo acids

Protein

I
Methionine

SAM

CH to anabolic
D III IN MS

B,,

Methylmalonyl- CoA

Methylmalonyl-CoA

5- adenosyl

Methionine synthase

mutase

Succinyt- CoA

Homocysteine
Heme

Adenosine

TCA

Cysteine

Vitamin C (ascorbic acid)


FUNCTION

Antioxidant; also facilitates iron absorption


by reducing it to Fc "+ state. Necessary
for hydroxylation of proline and lysine in
collagen synthesis. Necessary for dopamine
P-hvdroxylase, which converts dopamine to

Found in fruits and vegetables.


Pronounce absorbic acid.
Ancillary treatment for methemoglobinemia by
reducing Fe + to Fe- \

NE
DEFICIENCY

Scurvy swollen gums, bruising, petcchiae,


hemarthrosis, anemia, poor wound healing,

perifollicular and subperiosteal hemorrhages,


corkscrew" hair.
Weakened immune response.
EXCESS

Nausea, vomiting, diarrhea, fatigue, calcium


oxalate nephrolithiasis. Can t risk of
iron toxicity in predisposed individuals
(eg, those with transfusions, hereditary
hemochromatosis).

Vitamin C deficiency causes sCurvy due to a


Collagen synthesis defect.

DO

Vitamin D

SECTION II

BIOCHEMISTRY

D = ergocalciferol ingested from plants.


D, = cholecalciferol consumed in milk, formed in sun-exposed skin (stratum basale ).
25 - OH D, = storage form.
l,25 (OH),D (calcitriol) = active form,

FUNCTION

DEFICIENCY

EXCESS

BIOCHEMISTRY NUTRITION

t intestinal absorption of calcium and phosphate, t bone mineralization at low levels, t bone

resorption at higher levels.


Rickets in children (bone pain and deformity), osteomalacia in adults (bone pain and muscle
weakness), hypocalcemic tetany. Breastfed infants should receive oral vitamin D. Deficiency is
exacerbated by low sun exposure, pigmented skin, prematurity.

Hypercalcemia, hypcrcalciuria, loss of appetite, stupor. Seen in granulomatous disease (t activation


of vitamin D by epithelioid macrophages ).

Vitamin E ( tocopherol / tocotrienol )


FUNCTION

Antioxidant ( protects RBCs and membranes


from free radical damage).

Can lead to impaired absorption of vitamin K


enhanced anticoagulant effects of warfarin!

DEFICIENCY

Hemolytic anemia, acanthocytosis,


muscle weakness, posterior column and
spinocerebellar tract demyelination.

Neurologic presentation may appear similar


to vitamin Bp deficiency, but without
megaloblastic anemia, hypersegmenled
neutrophils, or t serum methylmalonic acid
levels.

Vitamin K ( phytomenadione, phylloquinone, phytonadione)


FUNCTION

Activated bv epoxide reductase to the


reduced form, which is a cofactor for the
y-carboxvl ition of glutamic acid residues on
various proteins required for blood clotting.

DEFICIENCY

K is for Koagulation. Necessary for the


maturation of clotting factors II, VII, IX, X,
and proteins C and S. Warfarin inhibits
vitamin K-dcpcndcnt synthesis of these factors

Synthesized bv intestinal floral


and protein
Neonatal hemorrhage with t PT and t aPTT
Not in breast milk; neonates are given vitamin
but normal bleeding time (neonates have
K injection at birth to prevent hemorrhagic
sterile intestines and are unable to synthesize
disease of the newborn.
vitamin K |. Can also occur after prolonged use
of broad-spectrum antibiotics.

BIOCHEMISTRY

BIOCHEMISTRY NUTRITION

SECTION I I

67

Zinc
FUNCTION

DEFICIENCY

Mineral essential for the activity of 100+ enzymes. Important in the formation of zinc fingers
( transcription factor motif ).

Delayed wound healing, hypogonadism, 1 adult hair (axillary; facial, pubic ), dysgeusia. anosmia,
acrodermatitis enteropathica Q. May predispose to alcoholic cirrhosis.

Malnutrition
Kwashiorkor

Marasmus

New I

maael

Protein malnutrition resulting in skin lesions,


edema due to 1 plasma oncotic pressure,
liver malfunction (fatty change due to
i apolipoprotein synthesis). Clinical picture is
small child with swollen abdomen Q.

Kwashiorkor results from a proteindeficient MEAL:


Malnutrition

Total calorie malnutrition resulting in


emaciation (tissue and muscle wasting, loss of
subcutaneous fat; note wrinkled skin in dj
+/- edema.

Marasmus results in Muscle wasting,

Edema
Anemia
Liver (fatty )

BIOCHEMISTRY

Enzyme terminology

BIOCHEMISTRY METABOLISM

69

SECTION II

An enzymes name often describes its function. For example, glucokinase is an enzyme that
catalyzes the phosphorylation of glucose using a molecule of ATP The following are commonly
used enzyme descriptors.

Phosphorylase

Catalyzes transfer of a phosphate group from a high-energy molecule (usually ATP) to a substrate
( eg phosphofructokinase).
Adds inorganic phosphate onto substrate w ithout using ATP (eg, glycogen phosphorylase).

Phosphatase

Removes phosphate group from substrate (eg, fructosc -l,6-bisphosphatasc).

Dehydrogenase

Catalyzes oxidation-reduction reactions (eg, pyruvate dehydrogenase).


Adds hydroxyl group i-OH) onto substrate (eg tyrosine hydroxylase).

Kinase

Hydroxylase
Carboxylase

Mutase

Transfers CO,groups with the help of biotin (eg, pyruvate carboxylase ).


Relocates a functional group w ithin a molecule ( eg, vitamin Bp-dependent methylmalonyT-CoA

mutase)
Synthase /synthetase

Combines 2 molecules into 1 { condensation reaction ) either using an energy source


not ( synthetase ) ( eg, glvcogen synthase ).

( synthase)

or

Rate - determining enzymes of metabolic processes


PROCESS

ENZYME

REGULATORS

Glycolysis

Phosphofructokinase-I (PFK-1)

AMP , fructose-2,6-bisphosphate
ATP , citrate

Gluconeogenesis

Fructose-1,6-bisphosphatase

Citrate
AMP , fructose-2,6-bisphosphate

TCA cycle

Isocitrate dehydrogenase

ADP
ATP , NADH

Glycogenesis

Glycogen synthase

Glucosc-6-phosphatc , insulin , cortisol


Epinephrine , glucagon

Glycogenolysis

Glycogen phosphorylase

Epinephrine , glucagon , AMP


Glucose-6-phosphate , insulin , ATP

HMP shunt

Glucose-6-phosphatc dehydrogenase ( G6PD)

NADP
NADPH

De novo pyrimidine
synthesis

Carbamoyl phosphate synthetase II

ATP , PRPP
UTP

De novo purine
synthesis

Glutamine-phosphoribosvlpvrophosphate
(PRPP) amidotransferase

AMP , inosinc monophosphate ( IMP) ,


GMP

Urea cycle

Carbamoyl phosphate synthetase I

X-acetylglutamate

Fatty acid synthesis

Acetyl-CoA carboxylase (ACC )

Insulin , citrate
Glucagon , palmitoyl-CoA

Fatty acid oxidation

Carnitine acyltransfcrasc 1

Malonyl-CoA

Ketogenesis

IIMG-CoA synthase

Cholesterol synthesis

HMG-CoA reductase

Insulin , thyroxine
Glucagon , cholesterol 0

BIOCHEMISTRY METABOLISM

BIOCHEMISTRY

ATP production

Activated carriers

Universal electron
acceptors

SECTION I I

Aerobic metabolism of glucose produces 52 net


ATP via malate-aspartate shuttle (heart and
liver), 50 net ATP via glyccrol- 5 -phosphate
shuttle (muscle).
Anaerobic glycolysis produces only 2 net ATP
per glucose molecule.
ATP hydrolysis can be coupled to energetically
unfavorable reactions.

Arsenic causes glycolysis to produce zero net


ATP.

CARRIER MOLECULE

CARRIED IN ACTIVATED FORM

ATP
NADII, NADPH, FADH2
CoA, lipoamide

Phosphors ! groups
Electrons

Biotin

co2

Tetrahydrofolates
S-adenosvbnethionine (SAM )

CH groups

TPP

Aldehydes

Acyl groups
1-carbon units

Nicotinamides (NAD* from vitamin B;,


NADPI 1 is a product of the 1 IMP shunt.
NADPII is used in:
NADP* ) and flavin nucleotides (FAD* from
Anabolic processes
vitamin IT ).
NAD* is gcncrallv used in catabolic processes
Respiratory burst
to carry reducing equivalents away as NADH.
Cytochrome P-450 system
NADPI 1 is used in anabolic processes ( steroid
* Glutathione reductase
and fatty acid synthesis) as a supple of reducing

equivalents.
Hexokinase vs
glucokinase

Phosphorylation of glucose to yield glucosc-6-phosphatc serves as the 1st committed step of


glycolysis (also serves as the 1st step of glycogen synthesis in the liver). Reaction is catalyzed
he either hexokinase or glucokinase, depending on the tissue. At low glucose concentrations,
hexokinase sequesters glucose in the tissue. At high glucose concentrations, excess glucose is
stored in the liver.
Hexokinase

Glucokinase

Location

Most tissues, except liver


and pancreatic P cells

Liver, P cells of pancreas

K,

Lower ( t affinity)

Higher ( 1 affinity)

Lower (1 capacity)

Higher ( t capacity)

Induced by insulin

No

Yes

Feedback-inhibited by

Yes

No

No

Yes

glucose- 6-phosphatc
Gene mutation on chromosome
20 associated with maturityonset diabetes of the vouna

71

72

SECTION II

Glycolysis regulation,
key enzymes

BIOCHEMISTRY

BIOCHEMISTRY

Net glycolysis (cytoplasm):


Glucose + 2 P, + 2 ADP + 2 NAD+

METABOLISM

2 pyruvate + 2 ATP + 2 NADH + 2 H + + 2 H,0.

Equation not balanced chemically, and exact balanced equation depends on ionization state of
reactants and products.
Glucose

REQUIRE ATP

Hexokinase / glucokinase3

Fructose-6-P

Glucose-6-P hexokinase.
Fructose-6-P glucokinase.

Glucose-6- P

Fructose-l,6-BP

Phosphofructokinase -1

( rate limiting step)

AMP , fructose-2,6 -bisphosphate .


ATP , citrate .

G!ucokirvase in liver and {J cells of pancreas, hexokinase


in all other tissues.

1, 5-BPG

PRODUCE ATP

<

5-PG
Phosphoglycerate kinase

Fructose-1 ,6-bisphosphate .
ATP , alanine .

Pyruvate

Phosphoenolpyruvate

Pyruvate kinase

Regulation by
fructose -2,6
bisphosphate

FBPase-1
Fmctose-6-P *

Gluconeogenesis <

FBPase -2

PFK -1

> Fructose-1, 6-BP

Glycolysis

PFK - 2

(active in

(active in
fasting state)

fed state)

Fructose-26-BP

FBPase - 2 (fructose bisphospliatase- 2 ' and PFK 2 ( phosphofructokinase-2 are the same bifunctional
enzyme whose function is reversed by phosphorylation by protein kinase A.
Fasting state: t glucagon t cAMP t protein kinase A * T FBPase 2, 1 PFK-2 , less glycolysis,
more gluconeogenesis.
Fed state: t insulin 1 cAMP l protein kinase A i FBPase-2, t PFK-2 , more glycolysis, less
gluconeogenesis.

Pyruvate

dehydrogenase
complex

Mitochondrial enzyme complex linking


glycolysis and TGA cycle. Differentially
regulated in fed/fasting states (active in fed
state).
Reaction: pyruvate + NAD* + CoA aectylCOA + C02 + NADH.
Tlie complex contains s enzymes that require 5

cofactors:
1 . Thiamine pvrophosphate ( Bj )
2. Lipoic acid
s. CoA ( B-, pantothenic acid )
4. FAD ( B7, riboflavin )
5. NAD; ( B , niacin)
Activated by:
T NAD*/ NADH ratio
t ADP

The complex is similar to the a-kctoglutarate


dehydrogenase complex (same cofactors
similar substrate and action ), which converts
a-kctoglutarate succinyl-CoA ( TGA cycle).

The Lovelv Co- enzymes For Ncrdi


Arsenic inhibits lipoic acid . Findings:
vomiting, rice-water stools, garlic breatlijOT
prolongation.

;I

HUNJIM I

Electron transport
:hain and oxidative
ihosphorylation

inIt

NADH electrons from glycolysis enter mitochondria via the malatc-aspartatc or glyccrol-5 phosphate shuttle. FAD11, electrons are transferred to complex II (at a lower energy level than
NADII). The passage of electrons results in the formation of a proton gradient that, coupled to
oxidative phosphorylation, drives the production of ATP.
NADH NAD-

FADH?

ADP + P,

7,0;+ 2H'

FAD

ATP

H;0

Mitochondrial
matrix

V VI

Complex I

2,4-Dinitrophenol
Aspirin overdose

H*

ATP PRODUCED VIA ATP SYNTHASE

1 NADll
OXIDATIVE PHOSPHORYLATION POISONS

Electron transport
inhibitors

Complex II
(succinate
dehydrogenase)

Rotenone

Inner mitochondrial
membrane
Complex III

(
H'

Cyanide

rn
co

Complex V

JJ

AntimycinA

2.5 ATP; 1 FADH,

Complex IV

H*

Oligomycin

Intermembrane
space

[Revi
H

1.5 ATP.

Directly inhibit electron transport, causing a


i proton gradient and block of ATP synthesis.

RotcnONE: complex ONE inhibitor.


An-5 -mycin (antimycin) A : complex 5

inhibitor.

CO/CN: complex -t inhibitors ( 4 letters).

ATP synthase
inhibitors

Directly inhibit mitochondrial ATP synthase,


causing an t proton gradient. No ATP is
produced because electron transport stops.

Oligomycin.

Uncoupling agents

t permeability of membrane, causing a i proton


gradient and t O-, consumption. ATP synthesis
stops, but electron transport continues.

2,4-Dinitrophenol (used illicitly for weight


loss), aspirin ( fevers often occur after aspirin
overdose), thernrogenin in brown fat .

Produces heat.

jluconeogenesis,
rreversible enzymes
Pyruvate carboxylase

In mitochondria. Pvruvatc

Phosphoenolpyruvate
carboxykinase

In cytosol. Oxaloacctatc

Fructose-1,6bisphosphatase
Glucose- 6-

Pathway Produces Fresh

oxaloacctatc.

Requires GTP

phosphoenolpyruvate.
In cytosol. Fructose- 1,6-bisphosphate
fructose-6-phosphate.
In ER. Glucose-6-phosphate glucose.

Glucose.

Requires biotin, ATP. Activated bv acetyl-CoA.

Citrate AMP fructose 2.6-bisDhosphate .

phosphatase

Occurs primarilv in liver; serves to maintain eugiveemia during fasting. Enzymes also found in
kidney, intestinal epithelium. Deficiency of the key gluconeogenic enzymes causes hypoglycemia.
( Muscle cannot participate in gluconeogenesis because it lacks glucose- 6-phosphatase).
Odd chain fatty acids yield I propionyl-CoA during metabolism, which can enter the TCA cycle
( as succinvl-CoA ), undergo gluconeogenesis, and serve as a glucose source. Even-chain fatty acids
cannot produce new glucose, since they yield only acctyl-CoA equivalents.

76

SECTION II

BIOCHEMISTRY

BIOCHEMISTRY METABOLISM

Disorders of fructose metabolism


Essential fructosuria

Fructose intolerance

Involves a defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition, since


fructose is not trapped in cells.
Symptoms: fructose appears in blood and urine.
Disorders of fructose metabolism cause milder symptoms than analogous disorders of galactose
metabolism.
Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-l-phospbate accumulates,
causing a i in available phosphate, which results in inhibition of glycogenolysis and
gluconeogenesis. Symptoms present following consumption of fruit, juice, or hones . Urine dipstick
will be (tests for glucose only); reducing sugar can be detected in the urine (nonspecific test for
inborn errors of carbohydrate metabolism).
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting.
Treatment: i intake of both fructose and sucrose ( glucose + fructose).
Fructose metabolism lliver)
Dihydroxyacetone

Fructose

Fructokinase

T^T
ATP

Fructose-1-P

Those phosphate
isomerase

Aldolase B

Glyceraldehyde- 3-P
Glyceraldehyde

ADP

NADH

Glycolysis

Revised

ATP

ADP

NAD*
Glycerol

Disorders of galactose metabolism

Galactokinase
deficiency

Classic galactosemia

Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet.


Relatively mild condition , Autosomal recessive.
{symptoms: galactose appears in blood ( galactosemia) and urine ( galactosuria); infantile cataracts.
May present as failure to track objects or to develop a social smile.
Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive Damage is caused b\
accumulation of toxic substances ( including galactitol, which accumulates in the lens of the eye).
Sy mptoms develop when infant begins feeding ( lactose present in breast milk and routine formula ).
Symptoms: failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can
lead to F coli sepsis in neonates.
Treatment: exclude galactose and lactose ( galactose + glucose: from diet.

Galactose metabolism
Galactokinase

Galactose

ATP

ADP
Aldose
reductase

Galactose -l-P

Uridyltransferase

TV

v_y

UDP-Glu UDP-Gal

4 - epimerase
Cialartitol

Glucose -l-P

Glycolysis/glycogenesis

Fructose is to Aldolase B as Galactose is to


UridylTransferase ( FAB CUT).
The more serious defects lead to PO+ depletion.

:igure

BIOCHEMISTRY

Sorbitol

BIOCHEMISTRY METABOLISM

77

SECTION I I

An alternative method of trapping glucose in the cell is to convert it to its alcohol counterpart
called sorbitol, via aldose reductase. Some tissues then convert sorbitol to fructose using
sorbitol dehydrogenase; tissues with an insufficient amount /activity of this enzyme are at risk
for intracellular sorbitol accumulation, causing osmotic damage (eg cataracts, retinopathy, and
peripheral neuropathy seen with chronic hyperglycemia in diabetes)
High blood levels of galactose also result in conversion to the osmotically active galactitol via aldose
reductase.

.
.

Liver, ovanes. and seminal vesicles have both enzymes


Sorbitol dehydrogenase

Aldose reductase

Glucose

Fructose

Sorbitol

NADPH

NAD *

Lens has primarily aldose reductase Retina, Kidneys and Schwann cells have only aldose reductase ILuRKS),
Aldose reductase

Glucose

NADPH

Sorbitol

FINDINGS

Insufficient lactase enzyme dietary lactose intolerance. Lactase functions on the brush border to
digest lactose (in human and cow milk ) into glucose and galactose.
Primary: age-dependent decline after childhood ( absence of lactase-persistent allele ), common in
people of Asian, African, or Native American descent.
Secondary : loss of brush border due to gastroenteritis ( eg, rotavirus), autoimmune disease, etc .
Congenital lactase deficiency: rare, due to defective gene.
Stool demonstrates i pll and breath shows t hydrogen content with lactose hydrogen breath test
Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
Bloating, cramps, flatulence, osmotic diarrhea.

TREATMENT

Avoid dairy products or add lactase pills to diet; lactose-free milk .

Lactase deficiency

'

Amino acids

Essential

Acidic
Basic

Only l,-amino acids are found in proteins.

Glucogenic: methionine ( Met ) histidiui


< (Hi.4)

valine ( Vail.
Glucogeme/ketogcnic: isoleucinc i lie),
phenylalanine (Phc), threonine (Thr),
tryptophan ( Trp).
Ketogenic: leucine (Leu), lysine ( Lys).
Aspartic acid (Asp ) and glutamic acid (Glu).
Negatively charged at body pH.
Histidine ( His), lvsinc ( Lvs ). arginine lArg).
Arg is most basic.
PIis has no charge at body piI.

I met his valentine, she is so sweet ( glucogenic ).


All essential amino acids need to be supplied in
the die!

His lvs ( lies) arc basic. Arg and His are reauired
during periods of groyvth. Arg and Lys are t in

histones, which bind negatively charged DNA.

Transport of ammonia by alanine and glutamine!


Muscle

Amino acids
(NH5)

u- Ketoacids

Liver
Alanine

u- Ketoglutarate

Glutamate INH3)

Alanine

(NHj)

Cahill cycle
Glucose

A^ i

Pyruvate

Cori cycle

Lactate

u-Ketoglutarate

. Glucose

Pyruvate

Lactate

Glutamate (NH3)

Urea (NH 3)

S3

Hyperammonemia

fikN
Asterixis

Can be acquired (eg. liver disease) or hereditary


( eg. urea cycle enzyme deficiencies).

Results in excess NI1 , which depletes


a-ketoglutarate, leading to inhibition of TCA
cycle.
Treatment: limit protein in diet.
May be given to l ammonia levels:
Lactulose to acidify the C[ tract and trap

NH+ * for excretion.


Antibiotics (eg, rifaxinrim tqj l colonic
ammoniagcnic bacteria.
Benzoate, phcnylacetatc, or phcnvlhutvrate
hind glycine to form hippurate and lead to
excretion of NILi
- ion

Ammonia accumulation tremor ( asterixis),

slurring of speech, somnolence, vomiting


cerebral edema, blurring of vision,

Catecholamine synthesis/tyrosine catabolism


Phenylalanine
BH<

PKU

Tyrosine
BH, Tyrosine

Homogentisic acid <

Alkaptonuria Homoq

Phenylalanine
hydroxylase

isate
oxidase

'

hydroxylase

Albinism

DOPA
Maleylacetoacetic acid (Dihydroxyphenylalanine)

B6

Fumarate

DOPA
1
decarboxylase "

Dopamine

(TCA cycle )

Tyrosinase
Carbidopa

'

Epinephrine

SECTION II

Phenylketonuria

Vitamin C Dopamine
I |J-hydroxylase
Catechol O- methyl transferase
Norepinephrine
Phenylethanolamine W
SAM mclhyltransferase

80

Melanin

BIOCHEMISTRY

- Cortisol

- -

Metanephrlne

Revise
Figure

Normetanephrine

Vanillytmandelic acid

Homovamllic acid 0

BIOCHEMISTRY METABOLISM

Due to I phenylalanine hydroxylase or


I lelralivdrohiopterin I hi Hcohiclor
(malignant PKU ). Tyrosine becomes essential
t phenylalanine excess phenylkctones in
urine.
Findings: intellectual disability, growth
retardation, seizures, fair skin, eczema, musty
body odor.
Treatment: t phenylalanine and f tyrosine in
diet, tetrahydrobiopterin supplementation.

Maternal PKU lack of proper dietary therapy

during pregnancy. Findings in infant:


microcephaly, intellectual disability, growth
retardation, congenital heart defects.

Autosomal recessive. Incidence = 1:10,000.


Screening occurs 2-5 days after birth (normal at
birth because of maternal enzyme during fetal
life).
Phenylkctones phcnylacetate, phenyllactatc,
and phenylpyruvatc
Disorder of aromatic amino acid metabolism
musty body odor.
PKU patients must avoid the artificial sweetener
aspartame, which contains phenylalanine.

Congenital deficiency ofhomogentisate oxidase in the degradative pathway of tyrosine to futnarate


pigment-forming homogentisic acid accumulates in tissue Q. Autosomal recessive. Usually

Alkaptonuria

benign.
Findings: bluish - black connective tissue, ear cartilage, and sclcrac ( ochronosis ); urincj turns black on
prolonged exposure to air. May have debilitating arthralgias ( homogentisic acid toxic to cartilage).

!
i

Homocystinuria

Types (all autosomal recessive ):


Cystathionine synthase deficiency
( treatment : t methionine , t cysteine, t B( ,
BJTJ and folate in diet)
i affinity of cystathionine synthase for
pyridoxal phosphate ( treatment: tt B6 and
t cysteine in diet )
Methionine synthase ( homocysteine
methyltransferase) deficiency ( treatment:
t methionine in dictl
)

Methionine <

Methionine
synthase

Homocysteine

All forms result in excess homocysteine.


11( ) \ l ( K Astinuiia tt I lomocvstcinc in

Cystathionine
synthase

/ B,
Serine

mine Osteoporosis. M ntannid habitus .


Ocular changes ( downward and inward
lens subluxation ) Cardiovascular effects
thrombosis and atherosclerosis stroke and
Ml ), kYphosis, intellectual disability

> Cystathionine

Cysteine

BIOCHEMISTRY

Glycogen storage
diseases

BIOCHEMISTRY METABOLISM

12 types, all resulting in abnormal glycogen


metabolism and an accumulation of glycogen
within cells Periodic acid Schiff stain
identifies glycogen and is useful in identifying
these diseases.

SECTION II

Very Poor Carbohydrate Metabolism


. and V arc autosomal recessive,
,

'lypes 1, 11, 111

DISEASE

FINDINGS

DEFICIENT ENZYME

COMMENTS

Von Gierke disease

Severe fasting hypoglycemia,


11 Glycogen in liver, t blood
lactate, t triglycerides,
t uric acid (Gout), and

Glucose-6-phosphatase

Treatment: frequent oral


glucose /cornstarch; avoidance

(type 1)

Pompe disease
(type II)

hepatomegaly.
Cardiomegaly, hypertrophic-

Lysosomal acid a-1,4glucosidase with a-1,6glucosidase activity (acid


cxcrcisrf intolerance, and
systemic findings lead to early
maltase)

cardlomvopaths, hypotonia

of fructose and galactose


Impaired gluconeogenesis and
glycogenolysis
Pomfje trashes the PumP(l,4 j
( heart, liver, and muscle)

death.

Cori disease
(type III)

Milder form of von Gierke


( type 11 with normal blood
lactate levels. Accumulation
of limit dextrin like
structures in cytosol.

Debranching enzyme
( a-1,6-glucosidase)

Gluconeogenesis is intact

McArdle disease
( type V )

t glycogen in muscle, but


muscle cannot break it down
painful Muscle cramps,

Skeletal muscle glycogen


phosphorvlase
(Myophosphorylase)

Bl< x >d glucose levels typically


unaffected

Myoglobinuria (red urine)


with strenuous exercise, and
arrhythmia from electrolyte
abnormalities. Second-wind
phenomenon noted during
exercise due to t muscular
blood flow.

McArdle = Muscle

BIOCHEMISTRY METABOLISM

BIOCHEMISTRY

Lysosomal storage
diseases
DISEASE

Each is caused by a deficiency in one of the many lysosomal enzymes. Results in an accumulation

of abnormal metabolic products.


FINDINGS

DEFICIENT ENZYME

ACCUMULATED SUBSTRATE

INHERITANCE

Early: Triad of episodic peripheral


neuropathy, angiokeratomas Q,

a-galactosidase A

Ceramide
trihexoside

XR

0 Glucocerebrosidase
(P-glucosidase); treat

Glueocerebroside

AR

AR

Sphingolipidoses
Fabry disease

hypohidrosis. Late: progressive renal


failure, cardiov ascular disease.
Gaucher disease

m,
A

Most common.

Hepatosplenomegaly, pancytopenia,
osteoporosis, avascular necrosis of
femuj bone crises, Gaucher cells fl
( lipid-laden macrophages resembling
crumpled tissue paper ).

with recombinant
glucocerebrosidase

Progressive neurodegencration,
hepatosplenomegaly, foam cells
i lipid-laden macrophages) H,
cherry-red spot on macula Q.

Sphingomyelinase

Sphingomyelin

Tay-Sachs disease

Progressiv e neurodegencration,
developmental delay, cherry-red
spot on macula 0, lysosomes with
onion skin, no hepatosplenomegaly
( vs Niemann-Pick).

O HeXosaminidase
( "TAv-SaX "!

GM ganglioside

Krabbe disease

Peripheral neuropathy, destruction of


oligodendrogliai, developmental delay,

0 Gaiactocerebrosi-

Galactocerebroside, AR
psychosine

Arylsulfatase A

Cerebroside sulfate

AR

1Icparan sulfate,
dermatan sulfate

AR

1 Icparan sulfate,
dermatan sulfate

XR

Niemann-Pick disease

-*
rX% * t:l

&

'C
.

Metachromatic
leukodystrophy

optic atrophy, globoid cells .


Central and peripheral demyelination

dasc

AR

with ataxia, dementia.

Mucopolysaccharidoses
Hurler syndrome

Hunter syndrome

a-L-iduronidase
Developmental delay, gargoylism,
airway obstruction, corneal clouding,
hepatosplenomegaly.
Mild Hurler + aggressive behavior, no Iduronate sulfatase
corneal clouding.
GM; Ceramide trihexoside

o,
GM,

Sulfatides

Gatactocerebroside

Glueocerebroside

Ceramide

No man picks ( Niemann-Pick) his nose with


his sphinger ( sphingomyelinase).
Tay SaX lacks heXosaminidase.
Ilunters sec clearly ( no corneal clouding) and
aggressively aim for the X ( X-linked recessive),
t incidence ofTay-Sachs, Niemann-Pick and
some forms of Gaucher disease in Ashkenazi

Sphingomyelin 119

Jews.

BIOCHEMISTRY

BIOCHEMISTRY

Degradation

Fatty acid synthesis


FA )

( palmitate, a 16C

Malonyl-CoA

f--

Acetyl CoA
Cell cytoplasm

Mitochondrial
membranes

Fatty acid * CoA


Fatty acid CoA
synthase

CO2 ( biotin )

JK

Citrate

)"" Malonyl- CoA

Systemic 1 carnitine deficiency inherited


defect in transport of LCFAs into the
mitochondria toxic accumulation. Causes
weakness, hypotonia, and hvpoketotic

Carnitine
shuttle

shuttle

II

SYtrate SYnthesis.
=
CARnitine = CARnage of fatty acids.

Fatty Acyl-CoA

ATP citrate
lyase

METABOLISM

Fatty ac id synthesis requires transport of citrate


from mitochondria to cytosol. Predominantly
occurs in liver, laetating mammary glands, and
adipose tissue.
Long-chain fatty acid I LCFAl degradation
requires carnitine-dependent transport into the
mitochondrial matrix.

Fatty acid metabolism


Synthesis

Mitochondrial
matrix

hypoglycemia.
Citrate

Fatty Acyl-CoA
[i oxidation
(Acyl CoA
dehydrogenases)
Acetyl-CoA

/\ TCA

Ketone
bodies

Medium -chain acyl -CoA dehydrogenase


deficiency 1 ability to break down fatty
acids into acetvl-CoA accumulation of lath
acyl carnitines in the blood with hvpoketotic
hvpoglvcemica. Causes vomiting, lethargy,
seizures, coma, liver dysfunction. Can lead to
sudden death in infants or children . Treat bv
avoiding fasting.

cycle

87

SECTION II

BIOCHEMISTRY METABOLISM

BIOCHEMISTRY

Metabolic fuel use

4 kcal = lg GARB
7 kcal = lg ALCOHOL
9 kcal = lg FATTY ACID!

100% -

-z

\ //
\f

j\ .

V
2 sec

10 sec

.\

-\
-4-

Stored ATP
Creatme phosphate
Anaerobic metabolism
Aerobic metabolism
Overall performance

1min

Duration of exercise

Fasting and starvation

2 hr
\a

Priorities are to supply sufficient glucose to the brain and RBGs and to preserve protein.

Fed state (after a


meal)

Glycolysis and aerobic respiration,

Fasting (between
meals)

Ilepatic glycogenolysis (major); hepatic


gluconeogenesis, adipose release of FFA

Starvation days 1- 3

Blood glucose levels maintained by:


Hepatic glycogenolysis
Adipose release of FFA
Muscle and liver, which shift fuel use from
glucose to FFA
Hepatic gluconeogenesis from peripheral
tissue lactate and alanine, and from
adipose tissue glycerol and propionylCoA ( from odd-chain FFA the only
triacylglvcerol components that contribute
to gluconeogenesis)

Insulin stimulates storage of lipids, proteins, and


glycogen.
Glucagon and epinephrine stimulate use of fuel
reserves.

(minor ).

Starvation after
day 3

Adipose stores ( ketone bodies become the main


source of energy for the brain). After these arc
depleted, vital protein degradation accelerates,
leading to organ failure and death.
Amount of excess stores determines surviv al
time.

Glycogen reserves depleted after day 1.


RBGs lack mitochondria and therefore cannot
use ketones.

Protein

10-

S'

F-

Fat

6L

5 <Carbohydrate
1

4
3
5
Weeks of starvation

8
ta

BIOCHEMISTRY

BIOCHEMISTRY METABOLISM

89

SECTION II

Major apolipoproteins

Chylomicron
Apolipoproteln

Function

E.

Mediates remnant uptake

Activates LCAT

Lipoprotein lipase cofactor

Chylomicron

VLDL

remnant

IDL

LDL

HDL

Mediates remnant
uptake (Everythinq

Except LDU

AT

Activates LCAT
C-ll.

Lipoprotein lipase

Cofactor that
Catalyzes Cleavaqe

B- 48

Mediates chylomicron
secretion into lymphatic

B-100

Binds LDL receptor

Lipoprotein functions

Lipoproteins are composed of varying


proportions of cholesterol, TGs, and
phospholipids. LDL and 1 IDL cart)' the
most cholesterol.

LDL transports cholesterol from liver to tissues.


HDL transports cholesterol from periphery to

LDL is Lousy.
1 IDL is Healths

liver.

Cholesterol

Needed to maintain cell membrane integrity and to synthesize bile acid, steroids, and vitamin Dj

Chylomicron

VLDL

Delivers dietarv TGs to peripheral tissue. Delivers cholesterol to liver in the form of chylomicron
remnants, which are mostly depleted of their TGs. Secreted bv intestinal epithelial cells
Delivers hepatic TGs to peripheral tissue. Secreted by liver.

IDL

Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.

LDL

Delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modification of IDL in
the liver and peripheral tissue. Taken up by target cells via receptor-mediated endocytosis.

HDL

Mediates reverse cholesterol transport from periphery to liver. Acts as a repository for
apolipoproteins C and E (which arc needed for chylomicron and VLDL metabolism). Secreted
from both liver and intestine. Alcohol t synthesis.

Abetalipoproteinemla

Autosomal recessive. Chylomicrons. VLDL, LDL absent. Deficiency in ApoB48, ApoBlOO.


Affected infants present with severe fat malabsorption, steatorrhea, failure to thrive. Retinitis
pigmentosa and spinocerebellar degeneration due to vitamin F, deficiency. Progressive ataxia .

Acanthocvtosis.
Treatment: Restriction of long-chain fattv acids, large doses of oral vitamin E.

1 76

SECTION II

IMMUNOLOGY
Immune system
organs

Follicle

Medulla

Paracortex

LYMPHOID STRUCTURES

LYMPHOID STRUCTURES

1 organs:

Bone marrow immune cell production B cell maturation!


T cell maturation!
2 organs:
Spleen, lymph nodes, tonsils, Peyer patches
Allow immune cells to interact with antigen
Thymus

Lymph node

IMMUNOLOGY

IMMUNOLOGY

A 2 lymphoid organ that has many afferents, 1 or more efferents. Encapsulated , with trabeculae.
Functions are nonspecific filtration by macrophages, storage of B and T cells, and immune
response activation .

Site of B cell localization and


proliferation . In outer cortex. 1 follicles
are dense and dormant . 2 follicles have
pale central germinal centers and are
active.

Consists of medullary cords (closely


packed lymphocytes and plasma cells)
and medullar)- sinuses. Medullary
sinuses communicate with efferent
lymphatics and contain reticular cells
and macrophages.

Houses T cells. Region of cortex between


follicles and medulla. Contains high
endothelial venules through which T
and B cells enter from blood . Not well
developed in patients with DiGeorge
syndrome.
Paracortex enlarges in an extreme cellular
immune response (eg, viral infection ).

Afferent
lymphatic
Follicles IB celts)

1 follicle

Paracortex
(T cells)

Germinal cente
Mantle zone
Medullary cord
( lymphocytes,
plasma cells)
Vein

Postcapillary
venule

Artery

Capillary
supply

SS0
Trabecula

Capsule

efferent
lymphatic

Medullary sinus
( reticular cells,
macrophages)

IMMUNOLOGY

IMMUNOLOGY

LYMPHOID STRUCTURES

Located in LUQ of abdomen, anterior to left


kidney, protected bv th - llth ribs.
{sinuosoids are long, vascular channels in red
pulp ired arrow in Q ) with fenestrated "barrel

is
Revised
Fact

Capsule

Red pulp IRBCs)


Sinusoid

Mantle zone

Marginal zone

White pulp ( WBCs)

Reticular fibrous
framework

Follicle ( B cells)

Penartenolar
lymphoid sheath

laeoi a

Germinal center

( PALS) (T cells )

Splenic dysfunction ( eg, postsplcnectoiny, sickle


cell disease): 1 IgM 1 complement activation
^
t C3b opsonization t susceptibility
to encapsulated organisms.
Postsplenectomy:
hoop basement membrane.
Howell-Jolly bodies ( nuclear remnants )
T cells are found in the periarteriolar
lymphatic sheath ( PALS ) within the white
Target cells
pulp (white arrow in Q ).
Thrombocytosis ( loss of sequestration and
B cells are found in follicles within the
removal )
Ly mphocytosis ( loss of sequestration )
white pulp.
The marginal zone, in between the red pulp Vaccinate patients undergoing splenectomy
and white pulp, contains macrophages and
against encapsulated organisms
( pneumococcal , Hib. meningococcal ) .
specialized B cells, and is where antigenpresenting cells ( APCs) capture blood-borne
antigens for recognition by lymphocytes.
Macrophages found nearby in spleen remove
encapsulated bacteria.

Spleen

-s

Open
cifcu at on

osed

Pulp vein

Vein

am
m
Thymus

Artery

'

I' I

i'

ILS

Located in the anterosuperior mediastinum .


Site of T-cell differentiation and maturation .
Encapsulated - Thymus is derived from the
Third pharyngeal pouch. Lymphocytes of
mesenchymal origin . Cortex is dense with
immature T cells; medulla is pale with mature
T cells and Hassall corpuscles Q containing
epithelial reticular cells.

T cells = Thymus
B cells = Bone marrow
Hypoplastic in DiGeorge syndrome and severe
combined immunodeficiency ( SC1D ).

Thymoma lienign neoplasm

mild association with

of thymus,

myasthenia gravis and

superior vena cava syndrome)

IMMUNOLOGY

IMMUNOLOGY LYMPHOCYTES

SECTION II

IMMUNOLOGY -- LYMPHOCYTES

innate vs adaptive immunity

COMPONENTS

MECHANISM

Innate immunity

Adaptive immunity

Neutrophils, macrophages, monocytes,


dendritic cells, natural killer (NK | cells
(lymphoid origin), complement
Germline encoded

T cells, B cells, circulating antibodies

RESISTANCE

Resistance persists through generations; does


not change within an organisms lifetime

RESPONSE TO PATHOGENS

Nonspecific
Occurs rapidly (minutes to hours ]
No memory response!

PHYSICAL BARRIERS
SECRETED PROTEINS

KEY FEATURES IN PATHOGEN


RECOGNITION

Epithelial tight junctions, mucus


Lysozyme, complement, C-reactive protein
(CRP), defensins
Toll-like receptors (TLRs): pattern recognition
receptors that recognize pathogen-associated
molecular patterns (PAMPs). Examples of
PAMPs include LPS ( gram bacteria),
flagcllin ( bacteria), nucleic acids (viruses).

Variation through V( DiJ recombination during

lymphocyte development
Microbial resistance not heritable
Highly specific, refined over time
Develops over long periods; memory response is
faster and more robust

Immunoglobulins
Memory cells: activated B and T cells;
subsequent exposure to a previously
encountered antigen stronger, quicker
immune response

180

SECTION II

Major
histocompatibility

IMMUNOLOGY

IMMUNOLOGY

LYMPHOCYTES

MI IC encoded by HLA genes. Present antigen fragments to T cells and bind T-cell receptors
( TCRs ).

complwjl and II
MHC II (2 letters)

MHC I (1 letter )

STRUCTURE

TCR and CD8


I long chain 1 short chain

HLA DP, HLA-DQ. HLA-DR


TCR and CD4
2 equal-length chains

EXPRESSION

All nucleated cells, APCs, platelets

J \ PCs

LOCI

BINDING

HLA-A, HLA- B. HLA C

Not on RBC 4

FUNCTION

Present endogenously synthesized antigens leg


viral or cytosolic proteins) to CD8+ cytotoxic

ANTIGEN LOADING

Antigen peptides loaded onto MHC I

Present exogenously synthesized antigens ( eg,


bacterial proteins) to CD4+ helper T cells

T cells

ASSOCIATED PROTEINS

in RPR
after delivery via TAP ( transporter associated
with antigen processing )
(5,- microglobulin

Antigen loaded following release of invariant


chain in an acidified endosome
Invariant chain
Peptide- binding

groove
Peptide binding
<

I '1 '

p, rracroglobutm
! membrane
Cel
iQOQOQQOOOOboOOOOQl

CeL membrane

HLA subtypes associated with diseases

A3

Hemochromatosis

B8

Addison disease, myasthenia gravi

B27

Psoriatic arthritis, Ankylosing spondylitis,


IBD-associatcd arthritis, Reactive arthritis
( formerly Reiter syndrome!

PAIR . Also known as seronegative arthropathies.

DQ2 / DQ8

Celiac disease!
Multiple sclerosis, hav fever, SLE ,

I ate (8) too ( 2) much gluten at Dairy Queen.

DR 2

Multiple has pastures have dirty

Goodpasture syndrome!

DR 3

Diabetes mcllitus type I , SI , I ',, Graves disease,


Hashimoto thyroiditis, Addison diseasej

2-3, S- l .- K

DR 4

Rheumatoid arthritis, diabetes mcllitus ri pe 1,

There are 4 walls in a "rheum ( room ).

DR 5

Pernicious anemia vitamin Bp deficiency,


Hashimoto thvroiditii

Addison disease!

IMMUNOLOGY LYMPHOCYTES

IMMUNOLOGY

Natural killer cells

SECTION II

181

Use perforin and granzymes to induce apoptosis of vitally infected cells and tumor cells.
Lymphocyte member of innate immune system.
Activity enhanced by IL-2, IL-12, IFN-a, and IFN-P.
Induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence
of class 1 Ml IC on target cell surface.
Also kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fe region of bound Ig,
activating the NK cell).

Major functions of B and T cells

Recognize antigen undergo somatic hypermutation to optimize antigen specificity .


Produce antibody differentiate into plasma cells to secrete specific immunoglobulins.
Maintain immunologic memory memory B cells persist and accelerate future response to antigen.

B cells (humoral
immunity!
]

T cells (cell-mediated
immunity)!

CD4+ 1 cells help B cells make antibodies and produce cytokines to recruit phagocytes and
activate other leukocytes.
CD8+ T cells directly kill virus-infected cells.
Delayed cell-mcdiatcd hypersensitivity ( type IV ).
Acute and chronic cellular organ rejection.
Rule of 8: MHC II x CD-I = 8; MHC I x CDS = 8.

Differentiation of T cells
Bone marrow

Lymph node

Thymus

CD8+ T cell

Cytotoxic T celt (kills virus-infected,


neoplastic, and donor graft cells!

Th cell

( D t ( Dar
.
'
.

Teel

T cell precursor

Th, cell
CD4 tT cell

Helper T celt

ll - 4

-cell receptor
Y (Tbinds
MHCI

rCf.
Cortex

or MHC III

Medul

Th , cell

CD8
k

| CD4

Positive selection

Thymic cortex. T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells
survive.

Negative selection

Thymic medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis.
Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune
regulator (AIRE); deficiency leads to autoimmune polycndocrinc syndromc-1.

1U <['] !

Helper T cells

I l lII MLliMaiMMWIillflSMBHMaaiailM

Thl cell

Th 2 cell

Secretes IFX -yand 1L-2

Secretes IL-4. ILo, IL-fj IL-10, IL- B

Activates macrophages and cytotoxic I cells

Recruits eosinophils for parasite defense and


promotes IgF production by B cells

Differentiation induced by IFN-yand IL-12


Differentiation induced by IL-4
Inhibited bv IL-4 and IL-10 ( from Th2 cell )
Inhibited bv IFN - y ( from 1 hl cell )
Macrophage-lymphocyte interaction dendritic cells, macrophages, and other Al'Cs release IL-12 ,
whichjstimulates T cells to differentiate into Thl cells. Till cells release IFN-y to stimulate
'

macrophages.
I Iclpcr T cells have CD4, which binds to Ml 1C II on AlCs

Cytotoxic T cells

Kill virus-infcctcd. neoplastic, and donor graft cells by inducing apoptosis.


Release cytotoxic granules containing preformed proteins ( eg, perforin , granzyme B).
Cytotoxic T cells have CD8, which binds to MHC 1 on virus-infected cells.

Regulatory T cells

Help maintain specific immune tolerance bv suppressing CD4 and CD8 T-cell effector functions.
Identified by expression of CD?, CD4, CD2S. and FOXlL
Activated regulatory T cells ( Trees j produce anti-inflammatory cytokines (eg, IL-10, TGF-fJ).

IPEX syndrome Dysfunction of FOXP? - autoimmunity. Characterized bv enteropathy ,


endocrinopatln , nail dystrophy, dermatitis, and /or other autoimmune dermatologic conditions.

IMMUNOLOGY

T- and B- cell activation

IMMUNOLOGY LYMPHOCYTES

SECTION II

183

APCs: B cells, dendritic cells. Langerhans cells, macrophages T helper cell 4


Two signals are required for T-cell activation, B-cell activation, and class switching.

Naive T-cell activation

1. Dendritic cell (specialized APC) samples and processes antigen.


2. Dendritic cell migrates to the draining lymph node.
3. T-cell activation (signal 1): antigen is presented on MHC II and recognized by TCR on Th
|antigen is presented on MHC I to Tc (CD8+) cell.
(CD4+) cell. Kndogcnous or cross-prcsentec
4. Proliferation and survival ( signal 2): costimulatory signal via interaction of B7 protein on
dendritic cell ( CDSO/86 ) and CD28 on naive T cell
5. Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virusinfected cell.

B -cell activation and


class switching

1. Th-cell activation as above.


2. B -cell receptor-mediated cndocytosis; foreign antigen is presented on Ml 1C !i and recognized
by TCR on Th cell.
3. CD40 receptor on B cell binds CD40 ligand ( CD40L) on Th cell.
4. I'll cell secretes cytokines that determine lg class switching of B cell. B cell activates and
undergoes class switching, affinity maturation, and antibody production.
g

Dendritic cell

m
1

Thcetl

ICD4+)

B7 (CD80/86)

Revised!
Figure [
Naive T cell

Bcell

IMMUNOLOGY IMMUNE RESPONSES

IMMUNOLOGY

SECTION II

187

System of hepatieallv synthesized plasma proteins that play a role in innate immunity and
inflammation. Membrane attack complex (MAC) defends against gram bacteria.

Complement

Classic pathway IgG or IgM mediated.


Alternative pathway microbe surface
molecules.
Lectin pathway mannose or other sugars on

ACTIVATION

GM makes classic cars.

microbe surface.

FUNCTIONS

C3b opsonization.
CTa, C4a, C5 a anaphylaxis.
C 5a neutrophil chemotaxis.
C5b 9 cytolysis by MAC.

C3b binds bacteria.

Opsonins Csb and IgG are Ihe two 1


opsonins in bacterial defense; enhance
phagocytosis. Clb also helps clear immune

Opsonin (Greek) = to prepare for eating,

complexes.
Inhibitors decay-accelerating factor ( DAF,
aka CD55 ) and Cl esterase inhibitor help
prevent complement activation on self cells
(eg, RBCs|.

HP1*

Alternative
C3 -

Spontaneous and

>

C3b

Bb

C3

C3bBb

C3bBb3b
IC5 convertasel

(C3 conwrtase)

microbial surfaces

Lectin

C5a

Cl-like

C5 .

C3b

complex

Microbial surfaces
leg. mannose)

C6-C9

fMACl (CSb- 9)

C4a

C4
Classic

Antigen antibody
complexes

Cl

C5a

C 46

clb

C2

*
Complement disorders

C 4b2b

lysis
cytotoxicity

C 4b2b3b

(C5 convertase)

(C3 convertase)

C3

'Historically, the larger fragment of C2 was


caked C2a but is now referred to as C2b.

C1 esterase inhibitor
deficiency

Causes hereditary angioedema due to unregulated activation of kallikrein t bradykinin. ACE


inhibitors are contraindicated. Causes hereditary angioedema due to unregulated activation of
kallikrein t bradykinin. Characterized bv 1 C 4 levels. ACE inhibitors are contraindicated.

C3 deficiency

Increases risk of severe, recurrent pyogenic sinus and respiratory tract infections; t susceptibility to
type 111 hypersensitivity reactions.
Terminal complement deficiency increases susceptibility to recurrent Neisseria bacteremia.

C 5-C9 deficiencies
CD55 deficiency!

Also called decav-accelerating factor ( DAF) deficiency. Causes complement-mediated lysis of RBCs
and paroxysmal nocturnal hemoglobinuria

188

SECTION II

IMMUNOLOGY

IMMUNOLOGY IMMUNE RESPONSES

Important cytokines
SECRETED BY MACROPHAGES

IL-1

pauses fever, acute inflammation. Activates


endothelium to express adhesion molecules.
Induces chemokiue secretion to recruit VVBCs.

Hot T-bone stF.AK"

IL-1: fever ( hot).


IL-2: stimulates T cells.
IL- s: stimulates bone marrow.
IL-4: stimulates IgE production.
IL 5: stimulates IgA production.
IL-6: stimulates aKute-phase protein
production.

IL- 6

IL-8

Causes fever and stimulates production of acutephase proteins.


Major chcmotactic factor for neutrophils.
Clean up on aisle 8. Neutrophils are recruited
by IL-8 to clear infections.

IL-12

Induces differentiation ofT cells into Till cells.


Activates NK cells.

TNF- ot

Activates endothelium. Causes VY'BC


recruitment, vascular leak.

Causes cachexia in malignancy


^
Maintains granuloma iin TR .

SECRETED BY ALLTCELLS

IL-2

Stimulates growth of helper, cytotoxic, and


regulatory Tcells, and NK cells.

IL-3

Supports growth and differentiation of bone


marrow stem cells. Functions like CM-CSF.

FROM Thl CELLS

Interferon-y

Secreted by NK cells and T cells in response to


antigen or IL-12|from macrophages; stimulates
macrophages to kill phagocytoscd pathogens.
Inhibits differentiation ofThl cells.

Also activates NK cells to kill virus-infected


cells. Increases MHC expression and antigen
presentation by all cells.

FROM Th2 CELLS

IL- 4

Induces differentiation of T cells into Th 2 cells.


Promotes growth of B cells. Enhances class
switching to IgE and IgG.

IL-5

Promotes growth and differentiation of B cells.

IL-10

Enhances class switching to IgA. Stimulates


growth and differentiation of eosinophils.
Attenuates inflammatory response. Decreases
TGF-P and IL-10 both attenuate the immune
response.
expression of MHC class II and Thl cytokines.
Inhibits activated macrophages and dendritic
cells. Also secreted bv regulators T cells.

Cell surface proteins

T cells

Helper T cells
Cytotoxic T cells

Regulatory T cells

B cells

Macrophages

MHC I present on all nucleated cells ( ie, not mature RBCs).

TCR (binds antigen MHC complex)


CD? (associated with TCR for signal
transduction)
CD28 ( binds B7 on APC )
CXCR4/CCR 5 (co-receptors for HIV)

CD4, CD40L
CD8
CXCR4/CCR 5
CD4, CD25
Ig ( binds antigen)
CD19, CD20, CD21 (receptor for EBV), CD40
MHC II, B7

You can drink Beer at the Bar when youre 21:


B cells, Epstein-Barr virus, CD21.

CD14 ( receptor for PAMPs, eg, LPS ), CD40


CCR5
MHC II B7 (CD80/86)
Fc and C?b receptors (enhanced phagocytosis)
ICD56 ( suggcstivdmarker for NK )

NK cells
Hematopoietic stem
cells

CD34

Anergy

State during which a cell cannot become activated by exposure to its antigen. T and B cells
become anergic when exposed to their antigen without costimulatory signal (signal 2). Another
mechanism of self-tolerance.

Effects of bacterial
toxins

Superantigens (S pyogenes and S aureus ) cross link the p region of the T-cell receptor to the MHC
class II on APCs. Can activate any CD4+ T cell massive release of cytokines.
Endotoxins/lipopolysaccharide (gram @ bacteria ) directly stimulate macrophages by binding to
endotoxin receptor TLR4/CD14; Th cells are not involved.

Antigenic variation

Classic examples:
Bacteria Salmonella ( 2 flagellar variants),
Borrelia recurrentis (relapsing fever).
N sionorrhoeae ( pilus protein )
Viruses-influenza , HIV, HCV
Parasites trypanosomes

Some mechanisms for variation include DNA


rearrangement and RNA segment rcassortmer
(eg. influenza maior shift ) or protein mutation
(eg. influenza minor drift).

IMMUNOLOGY

IMMUNOLOGY IMMUNE RESPONSES

SECTION II

Passive vs active immunity

Passive

Active

MEANS OF ACQUISITION

Receiving preformed antibodies

Exposure to foreign antigens

ONSET

Rapid

Slow

DURATION

Short span of antibodies (half-life = s weeks)

EXAMPLES

IgA in breast milk, maternal IgG crossing


placenta, antitoxin, humanized monoclonal

Long-lasting protection (memory)


Natural infection, vaccines, toxoid

NOTES

Vaccination

antibody
After exposure to Tetanus toxin. Botulinum
toxin, HBV, Varicella,fiabies virus, or
diphtheria antitoxin, unvaccinated patients are
given preformed antibodies (passive) To Be
Mealed Very Rapidly"

Combined passive and active immunizations


can be given for hepatitis B or rabies exposure

Induces an active immune response ( humoral and/or cellular ) to specific pathogens.

VACCINE TYPE

DESCRIPTION

Live attenuated
vaccine

Pro: induces strong,


Microorganism loses its pathogenicity but
retains capacity for transient growth within
often lifelong
inoculated host. Induces cellular and humoral immunity.
responses. MMR and varicella are live
Con: mav revert to
virulent form. Often
vaccines that can be given to patients with 111V
who have a CD4 cell count > 200/mmi
contraindicated
in pregnancy and
immunodeficiency.

BCC, influenza

Pathogen is inactivated by heal or chemicals.


Maintaining epitope structure on surface
antigens is important for immune response.
Mainly induces a humoral response.

Rabies, Influenza
(injection) Polio
(Salk ), hepatitis A
( R.l.P. Always ).

Inactivated or killed
vaccine

PROS /CONS

Pro: safer than live


vaccines.
Con: weaker immune
response; booster
shots usually
required.

EXAMPLES

( intranasal ), measles,

mumps, polio (Sabin),


rotavirus, rubella!
varicella, yellow fever.

IMMUNOLOGY

Hypersensitivity types ( continued )

Type III
l\

-it
A

IMMUNOLOGY

Immune complex antigen-antibody ( IgG)


complexes activate complement , which attracts
neutrophils; neutrophils release lysosomal
enzymes.
Can be associated with vasculitis and systemic
manifestations.

Serum sickness an immune complex disease


in which antibodies to foreign proteins are
produced ( takes 5 days ). Immune complexes
form and are deposited in membranes, where
they fix complement ( leads to tissue damage ) .

IMMUNE RESPONSES

193

SECTION II

In tv pc 111 reaction , imagine an immune


complex as 3 things stuck together: antigen
antibodv complement.

Examples:

Arthus reaction
SLE

Polyarteritis nodosa
Poststreptococcal glomerulonephritis
Serum sickness
Most serum sickness is now caused by drugs
( not serum ) acting as haptens. Fever, urticaria,
arthralgia, proteinuria, Ivmphadenopathy
occur 5-10 days after antigen exposure.

More common than Arthus reaction .

Arthus reaction a local subacute antibodymediated hypersensitivity reaction .


Intradermal injection of antigen into a

Antigen-antibody complexes cause the Arthus


reaction .
Test: immunofluorescent staining.

presensitized ( has circulating IgG ) individual


leads to immune complex formation in the
skin . Characterized by edema , necrosis, and
activ ation of complement.

Delayed (T-cell-mediated ) type sensitized


T cells encounter antigen and then release
cytokines ( leads to macrophage activation ).

Type IV

Response does not involve antibodies (vs types I ,


II. and III ).
Tl> cells

Fourth ( type) and last ( delayed ).


Pell mediated; therefore, it is not transferable by
serum .
4 T's = T cells Transplant rejections, TB skin
tests Touching (contact dermatitis).
Test: patch test , PPD.

Examples:
Contact dermatitis (eg, poison ivy, nickel

allergy )
a

Graft-versus-host disease
Multiple sclerosis
Pernicious anemia
Granulomatous inflammation

JA

IMMUNOLOGY

IMMUNOLOGY IMMUNE RESPONSES

Blood transfusion reactions


TYPE

PATHOGENESIS

CLINICAL PRESENTATION

TIMING

Allergic reaction

Type 1 hypersensitivity' reaction


against plasma proteins in
transfused blood.
Severe allergic reaction.
IgA-deficient individuals
must receive blood products
without IgA.

Urticaria, pruritus,
wheezing, fever. Treat with
antihistamines.

(Within 2- hours

Dyspnea, bronehospasm,
hypotension, respiratory

[Within minutes

Anaphylactic reaction

Febrile nonhemolytic
transfusion reaction

arrest, shock. Treat with

epinephrine.

Type II hypersensitivitv
reaction. Host antibodies
against donor HLA antigens
and WBCs

Fever, headaches, chills,


flushing.

Tvpc II hvpcrsensitivitv

Fever, hvpotcnsion, tachypnea, [V\ ithin 1 hour


tachycardia, flank pain,
hemoglobinuria ( intravascular

[Within 1-6 hours

Acute hemolytic
transfusion reaction

reaction. Intravascular

hcmolvsis ( ABO blood


group

incompatibility) or

cxtravascular hcmolvsis i host

hemolysis), jaundice
(

cxtravascular ).

antibodv reaction against


foreign antigen on donor
RBCs).
Transfusion-related
acute lung injury!

Donor anti-leukocvte
antibodies against recipient
neutrophils and pulmonary
endothelial cells!]

Respiratory distress and


noneardiogenic pulmonary

edema]

[Within 6 hours

IMMUNOLOGY

Autoantibodies

IMMUNOLOGY IMMUNE RESPONSES

SECTION II

AUTOANTIBODY

ASSOCIATED DISORDER

Anti-ACh reeeptoij

Myasthenia gravii

Anti-glomerular basement mcmbrane|

Goodpasture syndrome!

Anti-3 glycoproteiii
Anticardiolipin, lupus anticoagulant

Antiphospholipid syndrome!

Anticentromerel

Limited scleroderma ( CRPiST syndrome!


Pemphigus vulgaril

Anti-desmoglcin (anti-dcsniosomcil

Anti-glutamic acid decarboxvlase islet cell

SLE, antiphospholipid syndromtj

Type

1 diabetes mellituij

cvtoplasmic

antibodies
Antihemidesmosomej
Antisvnthetase (eg. anti-lo-1). anti-SRP. anti-

Bullous pemphigoid!
Poly myositis, dermatomyositii
'

lielicase (anti-Mi-2l

Antimicrosomal. antithy roglobulin. anti-thvroid

Uashimoto thvroiditi'j

peroxidase!

Antimitochrondrialj

1 biliars cirrhosi

Antioarietal cell, anti-intrinsic factoil


Antiphospholipasc A, receptoij

Pernicious anemia|

Anti-Scl-70 (anti-DNA topoisomerase l!

Scleroderma (diffuse!

Anti-smooth muscle|

Autoimmune hepatitis type lj

Anti-SSA , anti-SSB ( anti-Ro, anti-Lai

Sjiigren syndromej

Anti-TSH receptoij

Grases disease

Anti-press naptic voltage-gated calcium channel

Lambert-Eaton myasthenic syndrome!

1 ' membranous nephropathsj

IgA anti endomvsial IgA anti-tissue

transglutaminase!

MPO-ANCA/p-ANC.Ai

Celiac disease!

Microscopic polyangiitis eosinophilic

granulomatosis with pohangiitis ( Churg-Straus >


syndrome), ulccrathc

colitis!

PRVA \CA /c-ANC.\i

Granulomatosis with pohangiitis ( Wegener!

Rheumatoid factor ( IgM antibody against IgG


Fc region) anti-CCP ( more specific )!

Rheumatoid arthritii

Antinuclear (ANA!

Nonspecific screening antibody, often associated

Anti-dsDNA. anti- Smith!

SLPl

Anti-histone

Drug-induced lupus

Anti-Ul RNP ( ribonucleoprotein||

Mixed connectirc tissue disease!

with Sl Fi

196

SECTION I I

IMMUNOLOGY IMMUNE RESPONSES

IMMUNOLOGY

Immunodeficiencies
DISEASE

DEFECT

PRESENTATION

FINDINGS

B- cell disorders

Defect in BTK . a tyrosine


Recurrent bacterial and
X- linked (Bruton)
enteroviral infections after 6
agammaglobulinemia kinase gene no B-cell
months ( 1 maternal IgG).
maturation. X-linkcd recessive
(t in Boys)

Selective IgA
deficiency

Unknown. Most common 1

immunodcficiencv.

i IgA with normal IgG, IgM


Majority Asymptomatic.
Can see Airway and GI
levels, t suscentibilitv to
giardiasis. Common in
infections Autoimmune
patients with celiac diseasii
disease Atopy. Anaphylaxis to
IgA-containing products.

Common variable
immunodeficiency

Absent B cells in peripheral


blood, 1 Ig of all classes,
Absent /scanty lymph nodes
and tonsils. Live vaccines
contraindicate

Defect in B-cell differentiation. Can be acquired in 20s Alls;


t risk of autoimmune disease,
Many causes.
bronchiectasis, lymphoma,
sinopulmonary infections.

1 plasma cells

1 immunoglobulins.

T- cell disorders
Thymic aplasia
(DiGeorge syndrome)

22qll deletion; failure


to develop srd and 4th
pharyngeal pouches absent
thymus and parathyroids.

Tetany (hypocalcemia),
recurrent viral/fungal
infections (T-cell deficiency),

conotruncal abnormalities
(eg. tetralogy' of Fallot,

i T cells, 1 PTH, 1 Ca -*.

Absent thymic shadow on

CXRJ

truncus arteriosus).

IL-12 receptor
deficiency

1 Thl response. Autosomal

recessive.

Disseminated mycobacterial
l IFN-y.
and fungal infections; may
present after administration of
BCG vaccine

Autosomal dominant
hyper- lgE syndrome
( Job syndrome)

Chronic
mucocutaneous

candidiasis

t IgF, i IFN-y
Deficiency of Thl7 cells due to FATED: coarse Facies, cold
(noninflamed) staphylococcal
STAT5 mutation impaired
t eosinophils,
Abscesses, retained primary
recruitment of neutrophils to
sites of infection.
Teeth, t IgE, Dermatologic
problems (eczema).
Noninvasive Candida albicans Absent in vitro T-cell
T-cell dysfunction. Many
infections of skin and mucous
causes.
proliferation in response to
Candida antigens.
membranes.
Absent cutaneous reaction to
Candida antigens.

IMMUNOLOGY

IMMUNOLOGY

SECTION II

IMMUNE RESPONSES

Immunodeficiencies ( continued )
"

DISEASE

DEFECT

PRESENTATION

FINDINGS

B - and T-cell disorders


Severe combined
immunodeficiency

Ataxia -telangiectasia

Several types including


defective II.-2 R gamma chain
( most common , X-linkcd ),
adenosine deaminase
deficiency ( autosomal
recessive).

Failure to thrive, chronic


diarrhea , thrush . Recurrent
viral, bacterial , fungal, and
protozoal infections.
Treatment: bone marrowtransplant ( no concern for
rejection ).
Defects in ATM gene failure Triad : cerebellar defects
( Ataxia ), spider Angiomas
to repair DNA double strand
( telangiectasia y ), IgA
breaks cell cycle arrest .
deficiency.

Hyper- IgM syndrome

Wiskott-Aldrich
syndrome

Most commonly due to


defective CD40L on Th cells
class sw itching defect;
X-l inked recessive.
Mutation in WAS gene;
leukocytes and plateletj
unable to reorganize actin
cvtoskeleton defective
antigcn-presentatioiA X-linked
recessive.

Severe pyogenic infections


early in life; opportunistic

infection with Pneumocystis,


Cryptosporidium, CMV.
WATER: W iskott-Aldrich :
Thrombocytopenia, Eczema,
Recurrent ( pyogenic )
infection
t risk of autoimmune disease
and malignancy.

1 T cell receptor excision

circles ( TRFCs).
Absence of thymic shadow
(CXR), germinal centers
( lymph node biopsy), and
T cells ( flow cytometry ).

t AFP.
t IgA , IgG, and IgF.
Lymphopenia, cerebellar
atrophy.
t risk of Ivnrphoma and
leukemia .

Normal or t IgM.
it IgG, IgA, IgF,.
Failure to make germinal
centers.
1 to normal IgG , IgM.
t IgE, IgA.

Fewer and smaller platelets.

Phagocyte dysfunction
Leukocyte adhesion
deficiency (type 1 )

Chediak- Higashi

syndrome

Chronic
granulomatous
disease

Defect in LFA-1 integrin


(GDIS) protein on
phagocytes; impaired
migration and chemotaxis;
autosomal recessive.

Recurrent bacterial skin and


mucosal infections, absent
pus formation, impaired
wound healing, delayed
separation of umbilical cord
(> 40 days).

t neutrophils
Absence of neutrophils at
infection sites

Defect in lysosomal trafficking


regulator gene ( LY'ST ).
Microtubule dysfunction in
phagosotne-lysosome fusion;
autosomal recessive.

Recurrent pyogenic
infections by staphylococci
and streptococci, partial
albinism, peripheral
neuropathy, progressive
neurodegeneration , infiltrat
lymphohistioevtosis.

Giant granules [ Q, arrows) in


granulocytes and platelets.
Pancytopenia .
Mild coagulation defects.

t susceptibility to catalase

Abnormal dihydrorhodamine
(flow cytometry) test ( l green
fluorescence ).
Nitroblue tetrazolium dye
reduction test fails to turn
blue ( note, this test!is
obsolete!

Defect ofNADPIl oxidase


I reactive oxygen

species (eg, superoxide )


and i respiratory burst
in neutrophils; X-liuked
recessive most common .

organisms

198

SECTION II

IMMUNOLOGY

IMMUNOLOGY

IMMUNE RESPONSES

Infections in immunodeficiency
PATHOGEN

J!CELLS

JBCaLS

i GRANULOCYTES

l COMPLEMENT

Bacteria

Sepsis

F.neapsulated ( Please
SHINE mvSKiSi
Pseudomonas
aeruginosa,

Staphylococcus,
Burkholderia cepacia

Encapsulated species
with early component

Streptococcus
pneumoniae ,
Haemophilus
Influenzae type B,
Neisseria

Pseudomonas
aeruginosa , Serratia,
Nocardia

deficiencies
Neisseria with late
component { MAC )
deficiencies

meningitidis ,
Escherichia coli ,
Salmonella ,
Klebsiella
pneumoniae, group B
Group B
Viruses

CMV, EBV, JC
viru.' j VZV, chronic
infection with
respiratory/Gl viruses

Streptococcus

Entcroviral
encephalitis,
poliovirus
( live vaccine
contraindicated )
G1 giardiasis (no IgA)

N /A

N /A

Candida ( local ). PCP.


Candida (systemic),
N/A
Crvbtococcui
Asberzillus. Mucoii
Note: B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-ccll deficiencies produce more fungal and
viral infections.

Fungi / parasites

Grafts
Autograft
Syngeneic graft
( isograft )

From self.
From identical twin or clone.

Allograft

From nonidentical individual of same species.

Xenograft

From different species.

200

SECTION II

IMMUNOLOGY IMMUNOSUPPRESSANTS

IMMUNOLOGY

IMMUNOLOGY IMMUNOSUPPRESSANTS
Immunosuppressants

Agents that block lymphocyte activation and proliferation. Reduce acute transplant rejection by
suppressing cellular immunity Frequently combined to achieve greater efficacy with i toxicity.
Chronic suppression t risk of infection and malignancy.

DRUG

MECHANISM

USE

TOXICITY

Cyclosporine

Calcincurin inhibitor;
hinds cvclophilin.
Blocks T-cell
activation by
preventing IL-2
transcription.

Psoriasii rheumatoid

Nephrotoxicity
hypertension,

Tacrolimus (FK 506)

arthritis.

neurotoxicity;

gingival hyperplasia,
hirsutism.

Calcineurin inhibitor; Transplant rejection


binds FKS06 binding
prophylaxis.
protein (FKBP).
Blocks T-cell activation

mTORjmhibitor; binds
Blocks T-cell
activation and B-cell

differentiation by
preventing response
to IL-2

Kidney transplant
rejection prophy laxis

Kidney sir -vives.


Synergistic with
cyclosporine.
Also used in drugeluting stents.

insulin resistance,
hyperlipidemia;
not nephrotoxic.

specifically!

Azathioprine

Antimetabolite
precursor of
6-mercaptopurine.
Inhibits Ivmphocvte
proliferation by
blocking nucleotide
synthesis.

Rheumatoidarthritis

Reversibly inhibits

Lupu nephritis.

.
glomerulonephritis.
.

Edema, hy pertension
tremor.
Pancytopenia

6-MP degraded by

Crohn disease

xanthine oxidase;
toxicity t by

allopurinol.

other autoimmune
conditions.

IMP dehy drogenase


preventing purine
synthesis of B and T

Pronounce azathiopurine.
GJ upset,

Associated with
invasive CMV

pancytopenia
hypertension,

infection.

hyperglycemia.

cells.

Less nephrotoxic and


ncurotoxic.

Inhibit NF KB.
Suppress both B- and
T-cell function by
i transcription of
many cytokines.
Induce apoptosis ofT

celU

and neurotoxicity;

Monoclonal antibodies;
block 1L-2R.

nephrotoxic.

nojgingival

PanSirtopcnia
(pancytopenia )

Daclizumab,
basiliximab

Corticosteroid

t risk of diabetes

hy perplasia or

FKBP.

mofetil

Similar to cyclosporine,

Both calcineurin
inhibitors are highly

hirsutism.

transcription.

Mycophenolate

hyperlipidemia

b\ preventing IL-2
Sirolimus (RapamycinU

NOTES
,

\ lanv Autoimmune

and inflammatory
disorders, adrenal
insufficiency, asthma.
('LL. non-!lodgkin
lvmphonni

Mav experience

Cushing syndrome
osteoporosis.

hyperglycemia

diabetes, amenorrhea,

adrenocortical

atrophy , peptic ulcers


psychosis, cataracts.

avascular necrosis
( femoral head ) ]

adrenal insufficiency
if stopped abruptly
after chronic usdi

IMMUNOLOGY

IMMUNOLOGY IMMUNOSUPPRESSANTS

SECTION II

Immunosuppression targets
Basiiiximab.
dadizumab

FKBP +

FKBP +

Tacrolimus

CD3

/
Cydophilln +

Cyclosporine

6- MP

"

mTOR

NFAT

PRPP

IMP
dehydrogenase
rogenase

Corticosteroids
i

i
t

THELPER
caL

Mycophenolate

1 Calcineurin N

NFAT-P

Azathioprine

IL- 2R

Srolimus
(rapamycinl

Proliferation
genes

Denovo

Inflammatory

cytokine genes

Purine
nucleotides

>

W - KB

amidotransferase

purine

DNA replication

synthesis

Recombinant
cytokines and clinical
uses

AGENT

CLINICAL USES

Aldesleukin (IL-2)

Renal cell carcinoma, metastatic melanoma

Epoetin alfa (erythropoietin)

FilGRAstim iG CSFi GRAnulocvte

stimulating

Anemias (especially in renal failure)


Recovery of bone marrow

SarGRAMOSTIMl(GM-CSF)1

GRAnulocvte and MOnocvte STIMkilation


Recovery of bone marrow

IFN-a

Chronic hepatitis B and C, Kaposi sarcoma,


malignant melanoma, hairvcell leukemia,
condvloma acuminatum, renal cell eareinomal

IFN-P

IFN Y

Multiple sclerosis
Chronic granulomatous disease

' 1 h romhocy topenia


Romiplostim ( thrombopoictin analog),
eltrombopag ithrombopoietin receptor agonist!

Oprelvekin ( IL-ll )

Thrombocy topenia

Revised
Figure

202

SECTION II

IMMUNOLOGY

IMMUNOLOGY IMMUNOSUPPRESSANTS

Therapeutic antibodies
AGENT

TARGET

CLINICAL USE

NOTES

CD52

CLL, MS

"Alvmtuzumab chronic

Cancer therapy
Alemtuzumab

lymphocytic leukemia
Bevacizumab

VEGF

Colorectal cancer, renal cell


carcinoma, non-small cell

lung canceij

Cetuximab

ECFR

Stage IVr colorectal cancer,


head and neck cancer

Rituximab

CD20

B-cell non-Hodgkin
lymphoma, CLL, rheumatoid
arthritis, ITP

Trastuzumab

HFR 2 /neu

Breast cancer, gastric cancel

HER: Iras2zumab

IBD, rheumatoid arthritis,

F tanercept is a decoy
TNF- a receptor and not a
monoclonal antibody

Autoimmune disease therapy


Adalimumab,
certolizumab,

Soluble TNF-a

ankylosing spondylitis,
psoriasis

qolimumab,

infliximab!
Eculizumab

Complement protein C5

Natalizumab

a4-integrin

Paroxysmal nocturnal
hemoglobinuria
Multiple sclerosis, Crohn
disease

Ustekinumab

IL-12 /IL-2?

Psoriasis, psoriatic arthritis

Platelet glycoproteins llb/llla

Antiplatelet agent for


prevention of ischemic
complications in patients

a4-integrin; YVBC adhesion


Risk of PML in patients with
JC virus

Other applications

Abciximab

lib times Ilia equals


absiximab"

undergoing percutaneous
coronary intervention

Digoxin immune Fab

Digoxin

Osteoporosis; inhibits osteoclast Denosumab affects osteoclast:


maturation (mimics
osteoprotegerin)
Antidote for digoxin toxicity

Omalizumab

IgE

Refractory allergic asthma!

Denosumab

RANKL

prevents IgE binding to FceRI


Palivizumab

RSV F protein

RSV prophylaxis for high-risk

infants
Ranibizumab,
bevacizumab

VEGF

Neovascular age-related
macular degeneration;
proliferative diabetic
retinopathy and macular

edema!

PaliVIzumab Virus

Abetalipoproteinemia

Autosomal recessive. Chylomicrons, VLDL, LDL absent. Deficiency in ,\poB48, ApoBlOO.


Affected infants present with severe fat malabsorption, steatorrhea, failure to tliriu. Retinitis
1

pigmentosa and spinocerebellar degeneration due to vitamin F deficiency. Progressive ataxia.

Acanthocvtosis.
Treatment: Restriction of long- chain fattv ac ids, large doses of oral vitamin E

90

SECTION I I

BIOCHEMISTRY

BIOCHEMISTRY METABOLISM

Familial dyslipidemias
TYPE

INHERITANCE

PATHOGENESIS

T BLOOD LEVEL

CLINICAL

AR

Lipoprotein lipase or
apoUpoprotein C-ll
deficiency

Chylomicrons, TC,
cholesterol

Pancreatitis,

Absent or defective
LDL receptors

1 la: LDL. cholesterol


lib: 1.D1 cholesterol.

Hyper-

chylomicronemia

l| Familial hyper
cholesterolemia

AD

VLDLJ

hepatosplenoinegaly, and
eruptive/pruritie xanthomas
( no t risk for atherosclerosis).
Creamy layer in supernatant.
Ileterozygotes (1:500) have
cholesterol = TOOmg/dL;
homozygotes (sen rare| have
cholesterol 700+ mg/dL.
Accelerated atherosclerosis (may
have Ml before age 20), tendon
(Achilles) xanthomas, and

cornea] arcus

III Dvsbetalipoproteinemia

AR

Defective ApoE

Chvlomicrons. VLDL

IV Hyper

AD

Hepatic
overproduction of
VLDL

VLDL TC

triglyceridemia

Premature atherosclerosis.
tuberoeruptive xanthomas,
xanthoma striatum palmare

Hypertriglyceridemia (> 1000


mg/dL) can cause acute
pancreatitis

:f;i :f.Tn:inuntVi

Mu

r.f

Bacterial structures
CHEMICAL COMPOSITION

FUNCTION

Flagellum

Proteins.

Pilus/fimbria

Glycoprotein.

Motility.
Mediate adherence of bacteria to cell surface;
sex pilus forms during conjugation.

STRUCTURE

Appendages

Specialized structures

Gram only.
Survival: resist dehydration, heat, chemicals.

Keratin-like coat; dipicolinic acid;

Spore

peptidoglycan DNA.
Cell envelope
Capsule

Organized, discrete polysaccharide layer ( except


poly-D glutamate on B anthracis ).

Protects against phagocytosis.

Glycocalyx

Loose network of polysaccharides.

Mediates adherence to surfaces, especially


foreign surfaces (eg, indwelling catheters).

Outer membrane

Outer leaflet: contains endotoxin ( LPS/LOS).


Embedded proteins: porins and other outer
membrane proteins (OMPs)

Gram only.
Endotoxin: lipid A induces TMF and IL-I;

Inner leaflet: phospholipids.

Most OMPs are antigenic.


Porins: transport across outer membrane.

Periplasm

Space between cytoplasmic membrane


and outer membrane in gram bacteria.
(Peptidoglycan in middle.)

Cell wall

Peptidoglycan is a sugar backbone with peptide


side chains cross-linked by transpeptidase.
Phospholipid bilayer sac with embedded
proteins (eg penicillin-binding proteins
[ PBPs) ) and other enzymes.
Lipoteichoic acids ( gram only ) extend from

(Accumulates components exiting gram


cells, including hydrolytic enzymes
(eg. (3-lactamases).
Net-like structure gives rigtd support, protects
against osmotic pressure damage.
Site of oxidative and transport enzymes; PBPs
involved in cell wall synthesis.
Lipoteichoic acids induce I NF and 1L- 1.

Cytoplasmic
membrane

antigenic O polysaccharide component

membrane to exterior.
Cell walls
Unique to
gram

Unique to
gram 0

Common to both

Flagellum

Lipoteichoic acid

Pilus
jmsud

''WWV

Gfi i MNH

V-iPeptidoglycan
Gram (?)

outer
membrane

iRevis
Figu

Periplasmic space
((5- lactamase location)

Cytoplasmic
membrane "

Endotoxin /LPS
Ponn

Gram 0

>11 walls

Common to both

Unique to
gram

Lipoteichoic acfd

Flagellum

Unique to
gram 0

PH IS

IS
T
*

>
Ceil wall

Cytoplasmic

Gram

outer
membrane

Revised!

Figure |

P e n p l a s m i c space
- Penplasmic
((5-lactamase location)

i
Peptidoglycan

64kv. .

I - '-.
Endotoxin' /LPS

^
"
membrane "

Gram

<3

94

SECTION II

MICROBIOLOGY

MICROBIOLOGY

BASIC BACTERIOLOGY

Stains

Gram stain

First-line lab test in bacterial identification . Bacteria with thick peptidoglycan layer retain crystal
v iolet dye ( gram ); bacteria with thin peptidoglycan layer turn red or pink ( gram ) with
counterstain .
The bugs below do not Gram stain well.
These Microbes May Lack Real Color

Too thin to be visualized.


Cell wall has high lipid content.

Treponema Leptospira

Mycobacteria
Mycoplasma, Ureaplasma
Legionella, Rickettsia , Chlamydia , Bartonella ,
Ehrlichia , Anaplasma
Giemsa stain

Periodic acid -Schiff


stain
Ziehl - Neelsen stain
(carbol fuchsin )

India ink stain

Silver stain

Fluorescent antibody
stain

No cell wall.
Primarily intracellular; also, Chlamydia lack
classic peptidoglycan because of i muranuc
acid.
Certain Bugs Really Try my Patience.

Chlamydia , Borrelia. Rickettsia.


Trypanosomes Q, Plasmodium
Stains glvcogcn , mucopolysaccharides; used
to diagnose Whipple disease ( Tropheryma
whipplei )
Acid-fast bacteriajpg, Mycobacteria 0 .
*
blocardia: stains mvcolic acid in cell wall ) ;
protozoa ( eg, Cry0tos0oridium oocvstsj
Cr) ptococcus neofomwns 0; mucicarmine
can also be used to stain thick polysaccharide
capsule red
Fungi |cg, Coccidioides Q, Pneumocystis
jirovecii ), Legionella , Helicobacter pylori
Used to identify many bacteria and viruses.

PaSs the sugar.

Alternative is auramine-rhodamiue stain for


screening ( inexpensive, more sensitive but less
specific ).

Example is FTA-ABS for confirming syphilis.

aU
irv

Pf

Properties of growth
media

Selective media

Indicator (differential )
media

s.*

,
V

'

iD

The same type of media can possess both (or neither) of these properties.
Favors the growth of particular organism while preventing growth of other organisms, eg, ThaycrMartin agar contains antibiotics that allow the selective growth of Neisseria bv inhibiting the
growth of other sensitive organisms.
Yields a color change in response to the metabolism of certain organisms, eg, MaeConkey agar
contains a pi I indicator; a lactose fermenter like E coli will convert lactose to acidic metabolites
- color change.

SECTION II

MICROBIOLOGY

MICROBIOLOGY BASIC BACTERIOLOGY

Intracellular bugs
Obligate intracellular

Rickettsia , CHlamydia, COxiella. Rely on host


ATP.

Salmonella , \eisseria , Brucella. Mycobacterium, Some Nasty Bugs May Five FacultativcLY.
Listeria, Francisella , Legionella, Yersinia pestis .

Facultative
intracellular

Encapsulated bacteria

Stay inside (cells ) when it is Really Cl Lilly and


COld.

'

Examples are Pseudomonas aeruginosa


Streptococcus pneumoniae Q Haemophilus
Influenzae type B, Neisseria meningitidis ,
Escherichia coli , Salmonella. Klebsiella
pneumoniae, and group B Strep. Their
capsules serve as an antiphagocytic virulence
factor.
Capsular polysaccharide + protein conjugate
serves as an antigen in vaccines.

Encapsulated bacteria
vaccines

Some vaccines containing polysaccharide


capsule antigens are conjugated to a carrier
protein, enhancing immunogenicity by
promoting T-cell activation and subsequent
class switching. A polysaccharide antigen
alone cannot be presented to T cells.

Urease-positive
organisms

Proteus , Cryptococcus , II pylori , l reaplasma


Socardia , Klebsiella, S epidermidis,
S saprophyticus Urease hydrolyzes urea to
release ammonia and CO t pH. Potentiate
struvite ( ammonium magnesium phosphate)
stones. Proteus most likely to cause struvite

Please SHINE my SKiS.


Are opsonized, and then cleared by spleen.
Asplenics have l opsonizing ability and thus
t risk for severe infections. Give S pneumoniae
11 influenzae , N meningitidis vaccines.

Pneumococcal vaccine: PCVls ( pneumococcal

conjugate vaccine ) PPSV ? s i pneumococcal


polysaccharide vaccine with no coniugatcd
protein)
|f I influenzae type B ( conjugate vaccine)
Meningococcal vaccine ( conjugate vaccine)

Pee Cl I LIN KSS.

renal calculi]

Catalase- positive

organisms

Catalase degrades I ECU into H,0 and


bubbles of O,Q before it can be converted
to microbicidal products by the enzyme
myeloperoxidase. People with chronic
granulomatous disease (NADPH oxidase
deficiency) have recurrent infections with
certain catalase organisms.
Examples: Socardia, Pseudomonas , Listeria ,
Aspergillus, Candida, E coli , Staphylococci,
Serratia. B cepacia, H pylori.

Cats Need PLACESS to Belch their Hairballs.

Encapsulated bacteria
vaccines

Urease positive
organisms

Some vaccines containing polysaccharide


capsule antigens are conjugated to a carrier
protein , enhancing inununogcnicity by
promoting T-cell activation and subsequent
class switching. A polysaccharide antigen
alone cannot be presented to T cells.

Pneumococcal vaccine: PCVls ( pneumococcal


conjugate vaccine ). PPSV 2 s ( pneumococcal
polysaccharide vaccine with no conjugated
protein )

|f/ influenzae type B (conjugate vaccine)


Meningococcal vaccine ( conjugate vaccine)

Proteus , Cryptococcus, H pylori , Ureaplasma ,


iSocardia , Klebsiella , S epidermidis,
S saprophyticus I ' l e a s e hvdrolv /.e.s urea to
t pH . Potentiate
release ammonia and CO

PeeCHUNKSS.

struvite (ammonium magnesium phosphate )


stones. Proteus most likely to cause struvite

renal calculi!
Catalase- positive
organisms

V
A.
V

Catalase degrades 11 O, into H ?0 and


bubbles of O, Q before it can be converted
to microbicidal products by the enzyme
myeloperoxidase. People with chronic
granulomatous disease ( NADPH oxidase
deficiency) have recurrent infections with
certain catalase organisms.
Examples: Kocardia , Pseudomonas , Listeria ,
Aspergillus , Candida , E coli , Staphylococci,
Serratia , B cepacia , H pylori.

MICROBIOLOGY

Pigment producing
bacteria

MICROBIOLOGY

Cats Need PLACESS to Belch their Hairballs.

BASIC BACTERIOLOGY

Actinomyces israelii yellow "sulfur" granules,


w hich are composed of filaments of bacteria ,
S aureus yellow pigment.
1 aeruginosa blue-green pigment ( pvoevanin

and

Aureus ( Latin) = gold.

Acrugula is green .

S epidermidis
Viridans streptococci ( S mutans, S sanguinis)

nmmnte evadnn of IHKI

Catheter and prosthetic device infections


Dental plaques, infective endocarditis
Respirators tree colonization in patients
with evstic fibrosis, ventilator associated
pneumonia , contact lens-associated kcratitU
Otitis media

Nontypeable ( unencapsulated ) H influenza


Tlipse

Serratia marcescens think red maraschino


cherries.

Paeruginosa

Bacterial virulence

Israel has yellow sand .

p\ overdin )

Serratia marcescens red pigment .

In vivo biofilmproducing bacteria

SECTION II

inimiinp resnnnsp

Spore forming
bacteria

jr
MV
j

Some bacteria can form spores Q at tire end


of the stationary phase when nutrients are
limited.
Spores are highly resistant to heat and
chemicals. Have dipicolinic acid in their core.
1 lave no metabolic activity. Must autoclave to
potentially kill spores (as is done to surgical
equipment ) by steaming at 121C for 15
minutes.

MICROBIOLOGY

> MICROBIOLOGY

Bacillus anthracis
Bacillus cereus
Clostridium botulinum
Clostridium difficile

Anthrax
Food poisoning
Botulism
Pseudomembranous
colitis

Clostridium perfringens Gas gangrene


Clostridium tetani
Tetanus
Be Cerious About ALL Clostridia .

BASIC BACTERIOLOGY

[l

Main features of exotoxins and endotoxins

Exotoxin

Endotoxin

SOURCE

Certain species of gram and gram bacteria

Outer cell membrane of most gram bacteria

SECRETED FROM CELL

Yes
Polypeptide

No

PROPERTY

CHEMISTRY

Lipid A component of LPS (structural part of


bacteria; released when lysed )

ADVERSE EFFECTS

Plasmid or bacteriophage
High ( fatal dose on the order of 1 pg )

CLINICAL EFFECTS

Various effects (see following pages )

Low (fatal dose on the order of hundreds of


micrograms )
Fever, shock ( hypotension ), DIC

MODE OF ACTION

Various modes (see follow ing pages)

Induces TNF, IL-1, and IL-6

ANTIGENICITY

Induces high-titer antibodies called antitoxins

Poorly antigenic

VACCINES

Toxoids used as vaccines


Destroyed rapidly at 60 <>C (except
staphvlococc il enterotoxin and E coli heatstable toxin!
Tetanus, botulism, diphtheria

No toxoids formed and no vaccine available


Stable at 1 ()0C for 1 hr

LOCATION OF GENES

HEAT STABILITY

TYPICAL DISEASES

Bacterial chromosome

Mcningococcemia; sepsis by gram rods

MICROBIOLOGY

MICROBIOLOGY BASIC BACTERIOLOGY

101

SECTION II

Bugs with exotoxins (continued )


BACTERIA

TOXIN

MECHANISM

MANIFESTATION

Clostridium
perfringens

Alpha toxin

Phospholipase (Iccilhinase)

Degradation of phospholipids myonecrosis


( "gas gangrene") and hemolysis ( double zone
of hemolysis on blood agar)

Streptococcus
pyogenes

Streptolysin O

Lyse cell membranes

that degrades tissue and


cell membranes
Protein that degrades cell
membrane

Lyses RBCs; contributes to fj-hemolysis;


host antibodies against toxin (ASO) used to
diagnose rheumatic fever ( do not confuse
with immune complexes of poststreptococcal

glomerulonephritis)
Superantigens causing shock
Staphylococcus
aureus

Toxic shock

Streptococcus

Exotoxin A

syndrome toxin
( TSST-1)

pyogenes

Endotoxin

Toxic shock syndrome: fever, rash, shock; other


Binds to MHC II and ICR
outside of antigen binding
toxins cause scalded skin syndrome (exfoliative
site to cause overwhelming
toxin) and food poisoning ( cntcrotoxin)
release of IL-1, IL-2,
Toxic shock-like svndromd fever, rash, shock
IFN-v, and TNF-a
shock

LPS found in outer membrane of gram


bacteria ( both cocci and rods). Composed of
O antigen + core polysaccharide + lipid A itlie
toxic component).
Released upon cell lysis or by living cells by

blebs detaching from outer surface membrane


(vs exotoxin, which is actively secreted ).
Three main effects: macrophage activation
( TLR4), complement

activation, and tissue

factor activation.

FNDOTOXINS:
Edema
N itric oxide
DIC/Death
Outer membrane
TNF-a
O-antigen + core polysaccharide + lipid A
eXtrcmcly heat stable
IL-1 and IL-6
Neutrophil chcmotaxis
Shock

Macrophage activation
(TLR4)

Endotoxin
(lipid A component)

Complement activation

Tissue factor activation

rL

IL L IL-6

Fever

TNF-a

Fever and hypotension

Nitric oxide

Hypotension

Cfc

C5a

j
8

Coagulation
cascade

Histamine release
Hypotension and edema
Neutrophil chemotaxis

DIC

104

SECTION II

Staphylococcus
saprophyticus

MICROBIOLOGY

MICROBIOLOGY

CLINICAL BACTERIOLOGY

Gram , catalase , coagulase , urease cocci in clusters. Novobiocin resistant.


Normal flora of female genital tract and perineum .
Second most common cause of uncomplicated UTI in young women ( most common cause is

E coli ).
Streptococcus

pneumoniae

4
T
t
'

Gram . lancet-shaped diplococci Q

Encapsulated. IgA protease. Optochin


sensitive. Most common cause of:
*

Meningitis
Otitis media ( in children )
Pneumonia
Sinusitis

Viridans group
streptococci

Gram . a-hemolytic cocci. They arc normal


flora of the oropharynx that cause dental
caries ( Streptococcus mutam and S mitis)
and subacute bacterial endocarditis at
damaged heart valves (S sanguinis ) Resistant
to optochin. differentiating them from
Sjpneumoniae, which is a hemolytic hut is
optochin sensitise.

Sanguinis = blood. Think, "there is lots of


blood in the heart (endocarditis). S sanguinis
makes dextrans, which bind to fibrin -platelet
aggregates on damaged heart salves
Viridans group strep lise in the mouth because
they are not afraid of the chin (op to chin
resistant).

Gram cocci. Group A strep Q cause:

JvNF.S ( major criteria for acute rheumatic

Streptococcus
pyogenes ( group A
streptococci )

Pyogenic pharyngitis, cellulitis, impetigo


( " hones -crusted " lesions ) , ers sipelas
Toxigenic scarlet fever , toxic shock-like
syndrome, necrotizing fasciitis
Immunologic rheumatic feser,

Pneumococcus is associated with "rusts


sputum , sepsis in patients with sickle cell
disease and splenectomy.
No sarulencc without capsule.

glomerulonephritis
Bacitracin sensitise, P-hemolytic, pvrrolidonyl
arylamidase I PVRi . Hsaluronie acid capsule
inhibits phagocytosis. Antibodies to M protein
enhance host defenses against S pyogenes but
can give rise to rheumatic feser.
ASO titer or anti - PNasc B antibodies indicate
recent S pyogenes infectioij

- -

fever):

Joints polyarthritis

--

v carditis
Nodules (subcutaneous)
Erythema marginatum
Sydenham chorea
Pharyngitis can result in rheumatic phever"
and glomerulonephritis.
Impetigo usually precedes glomerulonephritis.
Scarlet fever blanching, sandpaper-like body
rash , strawberry tongue, and circumoral
pallor in the setting of group A streptococcal
pharyngitis (erythrogenic toxin ).

Bacillus anthracis

Cutaneous anthrax

Gram . spore-forming rod that produces anthrax toxin . The only bacterium with a polypeptide
capsule (contains D-glutamate ). Microscopy show ' s long chains resembling "medusa heads."
Painless papule surrounded hy vesicles ulcer with black eschar ( Q) ( painless, necrotic !
uncommonly progresses to bacteremia and death.

jp

Pulmonary anthrax

Inhalation of spores flu -like symptoms that rapidly progress to fever, pulmonary hemorrhage,
mediastinitis, and shock . Also known as woolsorter 's disease

106

SECTION II

Bacillus cereus

MICROBIOLOGY

Gram rod. Causes food poisoning.


Spores survive cooking rice. Keeping rice
warm results in germination of spores and
enterotoxin formation.
Emetic type usually seen with rice and pasta.
Nausea and vomiting within 1-5 hr. Caused
by cereulide, a preformed toxin.
Diarrheal type causes watery, nonbloody
diarrhea and C1 pain within 8 18 hr.

Clostridia ( with

MICROBIOLOGY CLINICAL BACTERIOLOGY

Reheated rice syndrome.

Gram , spore-forming, obligate anaerobic rods.

exotoxins)
C tetani

Produces tetanospasmin, an exotoxin causing


tetanus. Tetanus toxin (and botulinum toxin i
are proteases that cleave SNARE proteins for
neurotransmitters. Blocks release of inhibitory
neurotransmitters, GABA and glycine, from
Rcnshaw cells in spinal cord.
Causes spastic paralysis, trismus (lockjaw), risus
sardonicus (raised eyebrows and open grin ),
opisthotonos ( spasms of spinal extensorj).
Prevent with tetanus vaccine. Treat with
antitoxin +/- vaccine booster, diazepam ( for
muscle spasms), and wound debridement.

Tetanus is tetanic paralysis.

C botulinum

Produces a heat-labile toxin that inhibits


ACh release at the neuromuscular junction,
causing botulism. In adults, disease is caused
by ingestion of preformed toxin. In babies,
ingestion of spores (eg, in honey) leads to
disease ( floppy baby syndrome ). Treat with
antitoxin.

Symptoms of botulism ( the 4 D 'si: Diplopia


Dysarthria, Dvpshagia, Dyspnea

C perfringens

Produces a toxin ( lecithinase, a phospholipase)


that can cause myonecrosis ( gas gangrene Q)
and hemolysis.
Spores can survive in undercooked food:
when ingested, bacteria release heat-labile
enterotoxin food poisoning.

Botulinum is from bad bottles of food, juice, and


honey (causes a descending flaccid paralysis).
Local botox injections used to treat focal
dystonia, achalasia, and muscle spasms. Also
used for cosmetic reduction of facial wrinkles.
Perfringens perforates a gangrenous leg.

C difficile

Produces 2 toxins. Toxin A, enterotoxin, binds to


brush border of gut and alters fluid secretion.
Toxin B. evtotoxin, causes cvtoskcletal
disruption via actin depolvmerization. Both

Difficile causes diarrhea. Treatment:

metronidazole or oral vancomycin. For


recurrent cases, consider repeating prior
regimen, fidaxomicin, or fecal microbiota

Produces 2 toxins. Toxin A. cntcrotoxin, binds to


brush border of gut and alters fluid secretion.
Ihxin It cvlotoxin. (.Muses cvtoskclct il
disruption via actin depolv merization. Both
toxins lead to diarrhea pseudomembranous
colitis Q
|Often 2 to antibiotic use, especially
clindamycin or ampicilliu; associated with PP1
use. Diagnosed bv detecting one or both toxins
in stool by PCR ,

C difficile

Difficile causes diarrhea. Treatment:

metronidazole or oral vancomycin. For


recurrent cases, consider repeating prior
regimen, fidaxomicin, or fecal microbiota
transplant.

I
MICROBIOLOGY CLINICAL BACTERIOLOGY

MICROBIOLOGY

Corynebacterium
diphtheriae

Gram rod; transmitted via respirators


droplets. Causes diphtheria via exotoxin
encoded by Pprophage. Potent exotoxin
inhibits protein synthesis via ADP-ribosvIation
ofEF-2.
Symptoms include pseudomembranous
phary ngitis ( grayish-white membrane Q)
with lymphadenopathy, myocarditis, and

arrhythmias.
Lab diagnosis based on gram rods with
metaehromatic ( blue and red) granules and
Elek test for toxin

SECTION II

Coryne = club shaped.


Black colonies on cystine-tellurite agar.
ABCDEFG:
ADP-ribosylation
P-prophage

Corynebacterium
Diphtheriae
Elongation Factor 2
Granules

Toxoid vaccine prevents diphtheria.

Gram , facultativ e intracellular rod; acquired by ingestion of unpasteurized dairy products and
cold deli meats, via transplacental transmission, or by vaginal transmission during birth. Grows
well at refrigeration temperatures (4C-10C; cold enrichment "!
Forms rocket tails" (red in Q) via actin polymerization that allow intracellular movement and cellto-cell spread across cell membranes, thereby avoiding antibody. Characteristic tumbling motility'
in broth.
Can cause amnionitis, septicemia, and spontaneous abortion in pregnant women; granulomatosis
infantiseptica; neonatal meningitis; meningitis in immunocompromised patients; mild, selflimited gastroenteritis in healthy individuals.
Treatment: ampicillii)

Listeria
monocytogenes

V
Nocardia vs

Both are gram 0 and form long, brandling filaments resembling fungi.

Actinomyces

Nocardia

Actinomyces

Aerobe

Anaerobe

Acid fast ( weak) Q

Not acid fast Q

Found in soil

Normal oral, reproductive, and Gl flora

Causes pulmonary infections in


immunocompromised (can mimic TB but
with PPD ); cutaneous infections after
trauma ill immunocompetent

Causes oral/facial abscesses that drain through


sinus tracts, often associated with dental caries/
extraction; form jvcllovv sulfur granules;" can

Treat with sulfonamides (TMP-SMX )

Treat with penicillin

fV

w
T

also cause P1D with IUDs

Treatment is a SNAP: Sulfonamides Vocrmfia; Actinomyces Penicillin

Primary and secondary tuberculosis

PPD if current infection or past exposure.


PPD if no infection and in sarcoidosis or
HIV infection ( especially with low CD4+ cell

Mycobacterium
'*' * * tuberculosa

i
i

Ghon
com pie*

Ghon locus -v
(usually mid /
lower lobes!
Primary tuberculosis
1

__

> 90X

}< m
Progressive primary tuberculosis
(AIDS malnutrition)

Healing by fibrosis
Calcification
(tuberculin )

Reactivation

2*

tuberculosis

Fibrocaseous

count!
Interferon-y release assay ( IGRA) has fewer false
positives from BCG vaccination .
Caseating granulomas with central necrosis
( upper left) and Langhan jgiant cells (arrow)
are characteristic of 2 tuberculosis.

Progressive
lung disease

Bacteremia
1/

cavitary lesion

'

( usually upper

V Milia

lobes)

M'

.vv

rcrabne

!
Localized destructive disease

Cavity
Caseation
Scar

-4

Lymph nodes

i rt 1 . . v
'

amm &

rJ

tubercu

Lungs

V , '
Liver

--1

'

1 rin .l

V" Joints and


long bones

Mycobacteria

m>A

tuberculosis ( TB, often resistant TB symptoms include fever, night sweats,


to multiple drugs).
weight loss, cough ( nonproductive or
M avium intmcellulare ( causes disseminated ,
productive ), hemoptysis.
Cord factor creates a "serpentine cord
non- I B disease in AIDS; often resistant to
multiple drugs). Prophylaxis with azithromycin appearance in virulent M tuberculosis
when CDT + count < 50 cclls/mm '.
strains; inhibits macrophage maturation and
induces release ofT\ F-a. Sulfatides (surface
M scrofulaceum (cervical lymphadenitis in
glycolipids ) inhibit phagolysosomal fusion.
children ).
M marinum ( hand infection in aquarium
handlers).
All mycobacteria are acid-fast organisms ( pink
rods; arrows in Q),
Mycobacterium

MICROBIOLOGY

MICROBIOLOGY

Leprosy ( Hansen

disease)

CLINICAL BACTERIOLOGY

SECTION II

Caused by Mycobacterium leprae , an acid-fast bacillus that likes cool temperatures ( infects skin
and superficial nerves "glove and stocking loss of sensation Q) and cannot be grown in vitro .
Diagnosed via skin biopsy or tissue FCHj Reservoir in United States: armadillos.
Hansen disease has 2 forms:
Lepromatous presents diffusely over the skin, with leonine ( lion-like) facies 0, and is
communicable; characterized by low cell-medialcd immunity with a humoral Th 2 response.
Lepromatous form can be lethal .
Tuberculoid limited to a few hypocsthetic, hairless skin plaques; characterized by high cellmediated immunity with a largely Th 1-type immune response.
Treatment: dapsone and rifampin for tuberculoid form ; clofazimine is added for lepromatous form .

Neisseria

Gram diplococci. Metabolize glucose


and produce IgA proteases. Contain
lipooligosacclraridcs ( LOS ) with endotoxin like cytotoxic capabilities. N gonorrhoeae is
often intracellular (within neutrophils ) Q.

Gonococci

Meningococci

No polysaccharide capsule
No maltose metabolized
No vaccine due to antigenic variation of pilus
proteins
Sexually or perinatally transmitted
Causes gonorrhea, septic arthritis, neonatal
conjunctivitis ( 2 5 days after birth!pelvic
inflammatory disease ( PID), and Fitz- HughCurtis syndrome

Polysaccharide capsule
Maltose fermentation
Vaccine ( type B vaccine not widely available)

Condoms i sexual transmission , erythromycin


eye ointment prevents neonatal blindness

Treatment: ceftriaxone + ( azithromycin


or doxycycline ) for possible chlamydial
coinfection

Haemophilus
influenzae

MemnGococci ferment Maltose and Glucose.


Gonococci ferment Glucose.

Transmitted via respiratory and oral secretions


Causes mcningococcemia w ith petechial
hemorrhages and gangrene of toes ,
meningitis, Waterhouse Friderichsen
syndrome (adrenal insufficiency, fever, DIC,
shock1

Rifampin , ciprofloxacin, or ceftriaxone


prophylaxis in close contacts
Treatment: ceftriaxone or penicillin G

Vaccine contains tvpc b capsular polysaccharide


Small gram (coccobacillary ) rod . Aerosol
( pol \ ribosvlrihitol phosphatei conjugated
transmission . Nontypeable ( uncncapsulated )
ttjdiphthcria toxoid or other protein . Given
strains are the most common cause of mucosal
between 2 and 18 months of age.
infections iotitis media , conjunctivitis,
Does not cause the flu (influenza virus docsl.
bronchitis ) as well as invasive infections since
w
the vaccine for capsular type b as introduced.
Produces IgA protease. Culture on chocolate
agar, which contains factors V ( NAD*) and X
( hematin ) for growth ; can also be grown with
S aureus , which provides factor V through the
hemolysis of RBCs. HaEMOPhilus causes
Fpiglottitis ( endoscopic appearance in JJ
can be cherry red" in children; thumb sigrf
on x ray Q ) , Meningitis, Otitis media , and

Pneumonia.
Treatment: amoxicillin +/- clavulanate for

mucosal infections; ceftriaxone for meningitis;


rifampin prophylaxis for close contacts.

MICROBIOLOGY

Bordetella pertussis

MICROBIOLOGY

CLINICAL BACTERIOLOGY

SECTION II

Gram , aerobic coccobacillus. Virulence factors include pertussis toxin (disables Gj and tracheal
cytotoxin. Three clinical stages:
Catarrhal low -grade fevers, corvza .
Paroxysmal paroxysms of intense cough followed In inspirator! "w hoop" ( ''whooping cough " ) ,
posttussive vomiting.
Convalescent gradual recovery of chronic eouglj
Prevented by Tdap. DTaP vaccines. May be mistaken as viral infection due to lymphocytic

fr/ tni iinmnnn rpcnrtnco

Ecthyma gangrenosum
UTIs

Diabetes, drug use

Osteomyelitis (eg. puncture wounds)


Mucoid polysaccharide capsule
Otitis externa (swimmers car )
Nosocomial infections (catheters,
equipment)

exotoxin A
Skin infections ( hot tub folliculitis)

piperacillin , ticarcillin )

Aeruginosa aerobic.

Mucoid polysaccharide capsule max contribute


to chronic pneumonia in cystic fibrosis patients
due to biofilm formation.
Can cause wound infection in burn victims.
Corneal ulcers /keralitis in contact lens wearers/
minor cxc trauma .
Frequently found in water -* hot tub folliculitis.
Ecthyma gangrenosum rapidly progressive,
necrotic cutaneous lesion Q caused by
Pseudomonas bacteremia , ' typically seen in
immunocompromised patients.

SECTION II

Escherichitjcoli

MICROBIOLOGY

MICROBIOLOGY CLINICAL BACTERIOLOGY

Cram rod. coli virulence factors: fimbriae cystitis and pyelonephritis ( P-pili ); K capsulepneumonia neonatal meningitis; LPS endotoxin septic shock.

STRAIN

TOXIN ANO MECHANISM

PRESENTATION

EIEC

Microbe invades intestinal mucosa and causes


necrosis and inflammation.

Invasive; dysentery. Clinical manifestations


similar to Shigella.

ETEC

Produces heat-labile and heat-stable


enteroToxins. No inflammation or invasion.

Travelers' diarrhea ( watery).

EPEC

No toxin produced. Adheres to apical surface,


flattens villi, prevents absorption.

Diarrhea, usually in children ( Pediatrics).

EHEC

0157:H7 is most common serotype in US. Often Dysentery ( toxin alone causes necrosis and
transmitted via undercooked meat, raw leafs
inflammation).
Does not ferment sorbitol or produce
vegetables.
glucuronidase ( vs othciit' coli ).
Shiga-like toxin causes hemolytic- uremic
syndrome: triad of anemia, thrombocytopenia, Hemorrhagic, Hamburgers, Hemolytic-uremic
and acute renal failure due to microthrombi
syndrome.
forming on damaged endothelium
mechanical hemolysis (with schistocytes on
peripheral blood smear), platelet consumption,
and l renal blood flow.

Klebsiella

Gram rod; intestinal flora that causes lobar


pneumonia in alcoholics and diabetics when

aspirated. Very mucoid colonics [J caused by


abundant polysaccharide capsules. Dark red
"currant jelly" sputum ( blood/mucus).
Also cause of nosocomial UTIs.

|As of KlebsiellA:

Aspiration pneumonia
Abscess in lungs and liver
Alcoholics
di-A-betics

Curr-A -nt jelly sputum


1

liusc spms

UII d i i u o i i i c u ,

constipation, abdominal
pain , fever ); treat
with ceftriaxone or

sources

Antibiotics not
indicated

S flexneri , S boydii, S sannei


Invasion of M cells is kev to

Carrier state with

Gastroenteritis is
usually caused by non -

gallbladder colonization

typhoidal Salmonella

pathogenicity; organisms that


produce little toxin can cause disease
due to invasioij

fluoroquinolone

Vibrio choierae

Gram , flagellated , comma shaped 0, oxidase , grows in alkaline media. Endemic to


developing countries. Produces profuse rice-water diarrhea via enterotoxin that permanently
activates Gs, t cAMP. Sensitive to stomach acid ( acid labile ); requires large inoculum ( high ID- ( I )
unless host has l gastric acidity Associated with contaminated water and sealood . Prompt oral
rehydration is necessary.

Yersinia enterocolitica

Gram rod . Usually transmitted from pet feces (eg, puppies), contaminated milk , or pork . Causes
acute diarrhea or pseudoappendicitis ( right lower abdominal pain due to mesenteric adenitis and /
or terminal ileitis).

11

MICROBIOLOGY

MICROBIOLOGY

CLINICAL BACTERIOLOGY

Helicobacter pylori

Curved , terminally flagellated ( motile ), gram ) ) rod [|that is triple : catalase , oxidase , and
urease ( can use urea breath test or fecal antigen test for diagnosis). Urease produces ammonia ,
creating an alkaline environment, which helps H pylori survive in acidic mucosa. Colonizes
mainly antrum of stomach ; causes gastritis and peptic ulcers (especially duodenal i . Risk factor for
peptic ulcer disease, gastric adenocarcinoma , and M ALI ' lymphoma .
Most common initial treatment is triple therapy: Amoxicillin ( metronidazole if penicillin allergy )
+ Clarithromycin + Proton pump inhibitor; Antibiotics Cure Pylori .

Spirochetes

Spiral-shaped bacteria Q with axial filaments.


Includes Horrelia ( bigsize), Leptospira, and
Treponema. Only Horrelia can be visualized
using aniline dyes ( Wright or Gicmsa stain )
in light microscopy due to size. Treponema is
visualized by dark-field microscopy or direct
fluorescent antibods ( DFA ) microscopy.

Leptospira interrogans

Spirochete with hook-shaped ends found in water contaminated with animal urinejCausc 4
leptospirosis flu-like symptoms, myalgias (classically of calves), jaundice, photophobia with
conjunctival suffusion (erythema without exudate). Prevalent among surfers and in tropics ( eg,

BLT.
llorrelia is Big.

Hawaii ).

Weil disease ( ictcrohemorrhagic leptospirosis) severe form with jaundice and azotemia from liver
and kidney dysfunction, fever, hemorrhage, and anemia .

Lyme disease

Caused by Horrelia burgdorferi , which is


transmitted by the Ixodes deer tick ^3 (also
vector for Anaplasma spp. and protozoa
Habesia ). Natural reservoir is the mouse.
Mice are important to tick life cycle.
Common in northeastern United States.
Stage 1 early localized: erythema migrans Q,
flu -like symptoms.
Stage 2 early disseminated: secondary lesions,
carditis, AV block , facial nerve ( Bell ) palsy,
migratory myalgias/transient arthritis.
Stage s late disseminated: encephalopathies,
chronic arthritis.

A Key Lyme pie to the PACK:


Facial nerve palsy ( ty pically bilateral )
Arthritis
Cardiac block
Erythema migrans.
Treatment: doxvcvline ( 1st line ); amoxicillin and
cefuroxime in pregnant women and children .

MICROBIOLOGY

MTUUJDTUTUGT

UJNIIAL DALI tKiULUUY

1HIL 1i

Treatment for all: doxvcvclinc [ except during pregnancvil

Rickettsial diseases
and vector-borne
illnesses
RASH COMMON

Rickettsia rickettsii. vector is tick. Despite its


Classic triad headache, fever, rash (vasculitis).
Palms and soles rash is seen in Coxsackievirus
name, disease occurs primarily in the South
A infection ( hand, foot, and mouth disease),
Atlantic states, especially North Carolina.
Rash ty pically starts at wrists and ankles and
Roekv Mountain spotted fever, and 2 Syphilis
( you drive CARS using your palms and soles).
then spreads to trunk, palms, and soles.
Rickettsii on the wRists, Typhus on the Trunk.
Endemic ( fleas) R txplii.
Epidemic ( human body louse) R prowazekii .
Rash starts centrally and spreads out, sparing
palms and soles.

Rocky Mountain
spotted fever

Typhus

RASH RARE

Ehrlichia, vector is tick. Monocytes with


morulae J (mulberry-like inclusions ! in
cytoplasm.
Anaplasma, vector is tick. Granulocytes with
morulae Q in cytoplasm.
Coxiella burnetii , no arthropod vector. Spores
inhaled as aerosols from cattle/sheep amniotic
fluid. Presents as pneumonia. Common cause
of culture Endocarditis.

Ehrlichiosis

Anaplasmosis
Q fever

MEGA berry

Monocytes = Ehrlichiosis
Granulocytes = Anaplasmosis

y fever is Queer because it has no rash or vector


and its causative organism can survive outside

in its endospore form. Not in the Rickettsia


genus, but closely related.

B,

*'

4
118

SECTION II

Chlamydiae

MICROBIOLOGY

rul

1#

MICROBIOLOGY CLINICAL BACTERIOLOGY

Chlamydiae cannot make their own ATP. They


are obligate intracellular organisms that cause
mucosal infections. 2 fomis:
Elementary body (small, dense)
is "Knfectious" and Enters cell via
Endocytosis; transforms into reticulate body.
Reticulate body Replicates in cell by fission;
Reorganizes into elementary bodies.
Chlamydia trachomatis causes reactive arthritis
(Reiter syndrome ), follicular conjunctivitis Q,
nongonococcal urethritis, and Ill )
Chlamydophila pneumoniae and Chlamxdophila
psittaci cause atypical pneumonia; transmitted
by aerosol.
Treatment ' azithromycin ( favored because one
time treatment ) or doxvcvclinc; (+ ceftriaxone
C

;i- _i

Chlamys = cloak (intracellular).


C psittaci has an avian reservoir (parrots),
causes atypical pneumonia.
Lab diagnosis: PCR, nucleic acid amplification
test. Cvtoplasmiclinclusions seen on Giemsa or
fluorescent antibody stained smear.

The chlamydial cell wall lacks classic


peptidoglvcan ( due to reduced muramic acid ),
rendering (5-lactam antibiotics less effective.

118

SECTION II

MICROBIOLOGY

MICROBIOLOGY CLINICAL BACTERIOLOGY

Chlamydiac cannot make their own ATP. They


are obligate intracellular organisms that cause
mucosal infections. 2 forms:
Elementary body (small, dense)
is "Knfectious" and Enters cell via
Endocvtosis; transforms into reticulate body.
Reticulate body Replicates in cell by fission;
Reorganizes into elementary bodies.
Chlamydia trachomatis causes reactive arthritis
( Reiter syndrome ), follicular conjunctivitis ,
nongonococcal urethritis, and Ill)
Chlamydophila pneumoniae and Chlamxdopliila
psittaei cause atypical pneumonia; transmitted
by aerosol.
Treatment : azithromycin ( favored because one

Chlamydiae

Chlamys = cloak ( intracellular).


C psittaei has an avian reservoir ( parrots),
causes atypical pneumonia.
Lab diagnosis: PCR, nucleic acid amplification
test . Cytoplasmic!inclusions seen on Giemsa or
fluorescent antibody-stained smear.

The chlamydial cell wall lacks classic


peptidoglycan (due to reduced muramic acid),
rendering P-lactam antibiotics less effective.

time treatment ) or doxvcyclinc; ( + ceftriaxone


for possible concomitant gonorrheal

Chlamydia trachomatis serotypes


ABC = Africa, Blindness, Chronic infection.

Types A, B, and C

Chronic infection, cause blindness due to


follicular conjunctivitis in Africa.

Types D- K

Urethritis/PID, ectopic pregnancy, neonatal


D-K = everything else.
pneumonia (staccato cough) with eosinophilia, Neonatal disease can be acquired during
neonatal conjunctivitis ( 1 2 weeks after birthj
passage through infected birth canal.

Types LI, L2, and L3

Lymphogranuloma venereum small, painless

ulcers on genitals -* swollen, painful inguinal


lymph nodes that ulcerate ( buboes). Treat with
doxycycline.

Mycoplasma
pneumoniae

s'

Classic cause of atypical walking pneumonia


( insidious onset, headache, nonproductive
cough, patchy or diffuse interstitial infiltrate ).
X-ray looks worse than patient. High titer of
cold agglutinins (IgM), which can agglutinate
or lyse RBCs. Crown on Eaton agar.
Treatment: macrolides, doxycycline, or
fluoroquinolone (penicillin ineffective since
Mycoplasma have no cell wall).

No cell wall. Not seen on Gram stain.

Pleomorphic Q.
Bacterial membrane contains sterols for stability.
Mycoplasmal pneumonia is more common in
patients < 30 years old.
Erequcnt outbreaks in military recruits and
prisons.
Mycoplasma gets cold w ithout a coat (cell wall).

MICROBIOLOGY

MICROBIOLOGY MYCOLOGY

MICROBIOLOGY MYCOLOGY
ystemic mycoses

All of the following can cause pneumonia and can disseminate.


All are caused bv dimorphic fungi: cold (20C ) = mold; heat ( 37 ) = veast. The only exception is
Qiccidioidoe which is a spherule (not yeast) in tissue.
Svstemic mycoses can form granulomas i like TB ); cannot be transmitted person-to-person (unlike
TB ).
Treatment: fluconazole or itraconazole for local infection; amphotericin B for systemic infection !

DISEASE

Histoplasmosis

ENDEMIC lOCATIOIi|

PATHOtOGIC FEATURES

Mississippi and Ohio


River \Jillev4

Macrophage filled

with Histoplasnia
( smaller than
RBC ) Q

UNIQUE SIGNS/S VMPTOM

^
Palatal /tonguc ulcers.
splenomegaly]

Coccidioidomycosis

determination of
urme /scruni antigen.

Kastern and
Central US

Broad-base budding
of Blastomyces ( same
size as RBC) fj.

nodules]
Southwestern US!

Spherule ( much larger


than RBC ) filled
with endospores of

Coccidioides H.

*w

jiW

lung disease, can


disseminate to skin /
bone. Verrucous skin

lesions can simulate

Blasto Inids hroadlv.

Inflammatory

SCC. Forms
granulomatous

California

Para
coccidioidomycosis

Ilisto hides ( w ithin


macrophages ) Bird
(eg, starlings ) or bat
droppings.
Diagnosis made via

Blastomycosis

NOTES

Disseminates
to skin/bone.
Frslhema nodosum
( desert bumpsl
or multifonne.
Arthralgias (desert
rheumatism ). Can

Coccidio crowds
endospores.

cause meningitis!

Latin America!

Budding veast of

Iartjcoccidiodtrs with
captain's wheel

formation (much
larger than RBC j [ A .

Similar to
coccidiomvcosis
males > females]

Paracoccidio parasails
w ith the captain 's
wheel all the was to
Latin America.
'

120

SECTION II

MICROBIOLOGY

MICROBIOLOGY

MYCOLOGY

Cutaneous mycoses

Tinea is the clinical name given to dermatophyte ( cutaneous fungal ) infections. Dermatophytes
include Mictmporum, Trichophyton , and Epidermophyton. Branching septate hvphae visible on
KOH preparation with blue fungal stain . Associated with pruritu ' j

Tinea
(dermatophytes)

Tinea capitis

Occurs on head , scalp. Associated with lymphadenopathy, alopecia, scaling 0.

Tinea corporis

Occurs on torso. Characterized by erythematous scaling rings ( ringworm ) and central


clearing Q. Can be acquired from contact with an infected cat or dog.

Tinea cruris

Occurs in inguinal area | ]. Often does not show the central clearing seen in tinea corporis.

Tinea pedis

Three varieties:
Interdigital Q; most common
Moccasin distribution Q
Vesicular type
Onychomycosis; occurs on nails.

Tinea unguium

Caused by Alalassesia spp. ( Pityrosporum spp.), a yeast-like fungus ( not a dermatophyte despite
being called tinea ). Degradation of lipids produces acids Ibat damage melanocytes and cause
hvpopigmcntcd 3. hvperpigmcnted , and /or pink patches. Weaker association with pruritu 4
Can occur any time of year, but more common in summer ( hot , humid weather). Spaghetti and
meatballs" appearance on microscopy Q.
Treatment: selenium sulfide, topical and/or oral antifungal medications.

Tinea ( pityriasis)
versicolor

jft.

Jit *

'

Jk
M

MICROBIOLOGY MYCOLOGY

MICROBIOLOGY

SECTION I I

Opportunistic fungal infections


Candida albicans

Aspergillus
fumigatus

alba = white. Dimorphic; forms pseudohyphae and budding yeasts at 20C , germ tubes at
T7C O
Systemic or superficial fungal infection. Causes oral 0 and esophageal thrush in
immunocompromised (neonates, steroids, diabetes, AIDS), vulvovaginitis (diabetes, use of
antibiotics), diaper rash, endocarditis ( IV drug userst. disseminated candidiasis ( to any organ),
chronic mucocutaneous candidiasis.
Treatment; oral fluconazole/topical azole for vaginal nystatin, fluconazole, or caspofungin for oral /
esophageal; fluconazole, caspofungin, or amphotericin B for systemic,
Septate hvphae that branch at 45 Acute Angle [3- Produces conidia in radiating chains at end of
conidiophore 0.
Causes invasive aspergillosis in immunocompromised, patients with chronic granulomatous discascj
Can cause aspergillomas in pre-existing lung cavities, especially after TB infection.
Some species of Aspergillus produce Aflatoxin
Allergic bronchopulmonary aspergillosis ( ABPA): hypersensitivity response associated with
asthma and cystic fibrosis; may cause bronchiectasis and cosinophilia.
5-10 pm with narrow budding. Heavily encapsulated yeast. Not dimorphic.
Found in soil, pigeon droppings. Acquired through inhalation with hematogenous dissemination
to meninges. Culture on Sabouraud agar Highlighted with India ink ( clear halo Q) and
mucicarmine ( red inner capsule 0). Latex agglutination test detects polysaccharide capsular
antigen and is more specific.
Causes cryptococcosis, cryptococcal meningitis, cryptococcal encephalitis ( soap bubble" lesions
in brain), primarily in immunocompromised.
Treatment : amphotericin B + flucytosine followed bv fluconazole for cryptococcal meningitis.
Irregular, broad, nonseptate hvphae branching at w ide angles Q.
Mucormycosis. Causes disease mostly in ketoacidotic diabetic and/or neutropenic patients (eg
leukemia). Fungi proliferate in blood vessel walls, penetrate cribriform plate, and enter brain.
Rhinocerebral, frontal lobe abscess; cavernous sinus thrombosis Headache, facial pain, black
necrotic eschar on face; may have cranial nerve involvement.
Treatment: surgical debridement, amphotericin B.

Cryptococcus
neoformans

Mucor and Rhizopus


spp.

.
*

IV?

,<s

I O

7/o

fjMt
'

P
<

F
n
H

*%

.- v

MICROBIOLOGY

MICROBIOLOGY PARASITOLOGY

MICROBIOLOGY -PARASITOLOGY
rotozoa gastrointestinal infections
ORGANISM
DISEASE

Giardia lamblia

Giardiasis bloating, flatulence,


foul-smelling, fatty diarrhea
(often seen in campers/hikers)
think fat-rich Ghirardelli

TRANSMISSION

DIAGNOSIS

TREATMENT

Cysts in water

Multinucleated
trophozoites Q or
cysts Q in stool

Metronidazole

Cysts in water

Serology and /or

Metronidazole;

chocolates for fatty stools of


Giardia
Entamoeba
histolytica

Amebiasis bloody diarrhea


(dysentery), liver abscess
(anchovy paste exudate ),

RUQ pain; histology shows


flask-shaped ulcer

trophozoites (with

paromomycin or

engulfed RBCs
in the cytoplasm)

iodoquino! for
asymptomatic cyst

or cysts with up to

passerj

T nuclei in stool 1
Entamoeba Eats

Erythrocyte

Cryptosporidium

Severe diarrhea in AIDS


Mild disease (watery diarrhea) in
immunocompetent hosts

Oocysts on acid-fast

Oocysts in water

stain Q

Prevention i by
filtering city
water supplies);

nitazoxanide in
immunocompetent
hosts

>

124

SECTION II

MICROBIOLOGY PARASITOLOGY

MICROBIOLOGY

Protozoa CNS infections


ORGANISM

DISEASE

TRANSMISSION

DIAGNOSIS

TREATMENT

Toxoplasma
gondii

Congenital toxoplasmosis =

Cysts in meat (most


common); oocysts
in cat feces; crosses

Serology, biopsy
( tachyzoite) Q

Sulfadiazine +
pyrimethamine

Amoebas in spinal
fluid Q

Amphotericin B has
been effective for a
few survivors

Trypomastigotc in

Suramin for bloodborne disease or


mi larsoprol for
CNS penetration

classic triad of chorioretinitis,


hydrocephalus, and intracranial
calcifications; reactivation in
AIDS -* brain abscesses usually
seen as multiple ring- enhancing

Naegleria fowleri

placenta ( pregnant
women should
avoid cats)

lesions on MRtfl
Rapidly fatal meningoencephalitis Swimming in
freshwater lakes
( think Nalgene

bottle filled
with fresh water
containing

Naegleria ); enters
via cribriform plate
Trypanosoma
brucei

Tsetse flv a painful


African sleeping sicknessenlarged lymph nodes, recurring bite
fever (due to antigenic variation),

somnolence, coma
Two subspecies: Trypanosoma
brucei rhodesiense Trypanosoma
brucei gambiense

blood smear El

( "I sure am

mellow when
I'm sleeping;
remember
melatonin helps
with sleep!

cr

C>

. I*

k
>1

V.
r

MICROBIOLOGY PARASITOLOGY

MICROBIOLOGY

SECTION II

1 27

Nematodes (roundworms)
ORGANISM

DISEASE

TREATMENT

TRANSMISSION

Intestinal
Enterobius vermicularis
(pinworml|

Caused anal pruritus ( diagnosed bv seeing Fecal- oral


egg Q ia the tape test)

Ascaris lumbricoides
(giant roundworm)

May cause!obstruction at

Strongyloides

Caused vomiting, diarrhea, epigastric

'

ileocecal valve

Fecal-oral; knobbv -coated,


oval eggs seen in feces

Pvrantcl pamoate or
bendazoles ( because
worms are bendy)
Bendazoles

under microscope!
stercoralis
(threadworm)
Ancylostoma
duodenale, Necator
americanus
( hookworms)

pain (may mimic peptic ulcer)

Causedanemia bv sucking blood from

Larvae in soil penetrate skin;


rhabditiform larvae seen in
feces under microscope!

Ivermectin or

Larvae penetrate skin

Bendazoles or pvrantel

intestinal \val|

bendazoles

pamoate

Cutaneous larva migrans pruritic,

serpiginous rash from walking barefoot

on contaminated beach

Trichinella spiralis

Larvae enter bloodstream and enevst in


striated muscle cells inflammation of

muscle

Undercooked meat ( cspeciallv Bendazoles


pork ); fecal-oral ( less likely )

Trichinosis fever, vomiting, nausea.


periorbital edema, myalgia
Trichuris trichiura
( whipworm!

Often asymptomatic; can cause loose


stool and anemia, rectal prolapse in
children with heavy infection!

Fecal-ora!

Bendazole!

Visceral larva migrans nematodes

Fecal-oral

Bendazoles

Tissue
Toxocara canis

migrate to blood through intestinal wall


causing inflammation and damage.
Freuuentlv affects heart ( myocarditis)
liver, eves (visual impairment,
blindness), and CNS (seizures, coma |]

Onchocerca volvulus

Skin changes, loss of clastic fibers, and


Female blackfly
river blindness ( black flies, black skin
nodules, black sight ); allergic reaction

Loa loa

Swelling in skin, worm in conjunctiva

Deer fly. horse fly mango fly

Dicthylcarbamazinc

Wuchereria bancrofti

Lymphatic filariasis (elephantiasis!

Female mosquito

Diethylcarbamazine

Ivermectin ( ivermectin
for river blindness)

to microfilaria possible

worms invade lymph nodes and


cause inflammation, which can block
lymphatic vessels H, takes 9 nro-1 yr
after bite to become symptomatic!

Long page please


edit to fit

''m

128

SECTION II

MICROBIOLOGY

MICROBIOLOGY

PARASITOLOGY

Cestodes ( tapeworms )
ORGANISM

DISEASE

TRANSMISSION

TREATMENT

Taenia solium El

Intestinal tapeworm

Ingestion ol larvae encysted in


undercooked pork
Ingestion of eggs in food
contaminated with human
fece j
Ingestion of larvae from rawfreshwater fish

Praziquantel

Ingestion of eggs from dog

Albendazole

Cvsticercosis,
neurocysticcrcosis Q
Diphyllobothrium
latum

Vitamin Bp deficiency
(tapeworm competes for Bp
in intestine) megaloblastic
anemia

Echinococcus
granulosus Q

Hvdatid evsts |"eggshell


calcification" ) in liver H,

causing anaphylaxis

Praziquantel; albendazole for


neurocysticcrcosis

Praziquantel

feces
Sheep arc an intermediate host

mm
.

Trematodes (flukes )
ORGANISM

DISEASE

TRANSMISSION

TREATMENT

Schistosoma

User and spleen enlargement


( S mansoni , egg with lateral
spine El), fibrosis, and

Snails arc host; cercariac


penetrate skin of humans

Praziquantel

Undercooked fish

Praziquantel

Jt

f!
c

;o

Clonorchis sinensis

inflammation
Chronic infection with
S haematobium ( egg with
terminal spine O ) can lead
to squamous cell carcinoma
of the bladder ( painless
hematuria ) and pulmonary

hypertension

Biliary tract inflammation


pigmented gallstones
Associated with
cholangiocarcinoma

MICROBIOLOGY

MICROBIOLOGY

PARASITOLOGY

SECTION II

Ectoparasites

jSarcoptes scabie (

Mite burrow into stratum comcrum and


cause scabies: pruritus ( worse at night ) and
serpiginous burrows ilincsl in webspacc of
hands and feetO

Common in children , crowded populations


( jails, nursing homes); transmission through
skin -lo-skin contact ( most common ) or via
foniite4
Treatment: permethrin cream , washing/drying
all clothing / bedding, treat close contacts.

Blood-sucking insects that cause intense


pruritus with associated excoriations,
commonly on scalp and neck ( head lice ) or
)
waistband and axilla ( body lice!

Can transmit Rickettsia prowazekii ( epidemic


t \ plinj). Barrelia recurrentis ( relapsing fever),
Bartonella quintana ( trench fever ).

//
fediculus humanus/
Phthirus pubis(

Parasite hints

ASSOCIATIONS

Biliary

ORGANISM

tract disease , chol.iugiocarcinoma

Brain cysts, seizures

I leniaturia , squamous cell bladder cancer


Liver ( hydatid ) evsts
Microcytic

anemia

Mvalgias, periorbital edema

Perianal pruritus
Portal hypertension
Vitamin

Treatment includes pyrethroids, malathion , or


ivermectin lotion , and nit Q combing. Children
with head lice can be treated at home w ithout
interrupting school .

Bn deficiency

Clonorchis sinensis
Taenia solium ( neurocvsticercosis )
Schistosoma haematobium
Echinococcus granulosus
.\nc\lostoma ,\ecator

Tnchinella spiralis
Enterohius
Schistosoma mansoni Schistosoma japonicum
I 'iiplixllobothrium latum

130

SECTION II

MICROBIOLOGY

MICROBIOLOGY VIROLOGY

MICROBIOLOGY VIROLOGY
Viral structure
general features

Naked virus with


icosahedra! capsid

Enveloped virus with


icosahedra! capsid

Enveloped virus with


helical capsid

Surface
- protein

Capsid

Nucleic acid

tjgS /TV*
- Lipid

<:::
XK

V ,
V /

iZ bilayer

CapS d
Capsid

, ' s^ Nucleic'
\

acid

bilayer
Upid
Lipid blU

- Helical mnucleocapsid

integrated RNA ia
with into

Viral genetics
Recombination
Reassortment

Complementation

Phenotypic mixing

Exchange of genes between 2 chromosomes by crossing over within regions of significant base
sequence homology.
When viruses with segmented genomes ( eg, influenza virus) exchange genetic material. For
example, the 2009 novel H1N1 influenza A pandemic emerged via complex viral reassortment of
genes from human, swine, and avian viruses. lias potential to cause antigenic shift.
When I of 2 viruses that infect the cell has a mutation that results in a nonfunctional protein, the
nonnrutated virus complements the mutated one bv making a functional protein that serves
both v iruses. For example, hepatitis D virus requires the presence of replicating hepatitis B virus
to supply IIBsAg, the envelope protein for HDV.
Occurs with simultaneous infection of a cell with 2 v iruses. Genome of virus A can be partially or
completely coated (forming pseudovirion) with the surface proteins of virus B. Type B protein coat
determines the tropism (infectivity) of the hybrid virus. However, the progeny from this infection
have a type A coat that is encoded by its type A genetic material

Viral vaccines

Live attenuated
vaccines

MMR. Yellow fever. Rotavirus, Influenza


( intranasal i. Chickcnpox VCV ). Smallpox.

Sabin polio virus.

I
Killed

Rabies, Influenza ( injected), Salk Folio, and


HAV vaccines. Killed/inactivated vaccines

Subunit

HBV ( antigen = HBsAg), HPV ( types 6, 11, 16,


and 18).

induce only humoral immunity but arc stable.

Music andI.YRICSS are best enioved Live.


|MMR = measles, mumps, rubella; live
attenuated vaccine that can he given to
11IV patients who do not show' signs of

immunodeficiency.
SalK = Killed.
RIP Always.

MICROBIOLOGY

RNA viral genomes

MICROBIOLOGY VIROLOGY

All RNA viruses except Rcoviridae are ssRNA.


stranded RNA viruses: 1 went to a retro

SECTION I I

All are ssRNA ( like our mRNA), except


repeato-virus (reovirus) is dsRNA.

( retrovirus) toga ( togas irus| parts;svhcrc


I drank flavored (flavivirus) Corona
( coronavirus ) and ate hippie ( hepevirus)
California (calicivirus) pickles (picornavirus).

Naked viral genome


infectivity

Purified nucleic acids of most dsDNA (except poxviruses and HBV) and strand ssRNA
( = mRNA) viruses are infectious. Naked nucleic acids of strand ssRNA and dsRNA viruses are
not infectious. They require polymerases contained in the complete virion.

Viral replication

DNA viruses

All replicate in the nucleus ( except poxvirus ). "Pox is out of the box (nucleus).

RNA viruses

All replicate in the cytoplasm (except influenza virus and retroviruses ).

Viral envelopes

DNA virus
characteristics

Naked (nonenveloped ) viruses include


Papillomavirus, Adenovirus, Parvovirus,
Polyomavirus, Calicivirus, Picornavirus,
Reovirus, and 1 lepevirus.
Generally, enveloped viruses acquire their
envelopes from plasma membrane when
they exit from cell. Exceptions include
herpesviruses, which acquire envelopes from
nuclear membrane.

Give PAPP smears and CPR to a naked hippie

( hepevirus)

DNA = PAPP; RNA = CPR and hepevirus

Some general rules all DNA viruses:


GENERAL RULE

COMMENTS

Are HHAPPPPy viruses

Are icosahedral

Hepadna, Herpes, Adeno, Pox, Parvo,


Papilloma, Polyoma.
Except parvo (single stranded).
Except papilloma and polyoma (circular,
supercoiled ) and hepadna (circular,
incomplete).
Except pox (complex).

Replicate in the nucleus

Except pox (carries own DNA-dependent RNA

Are double stranded


Have linear genomes

polymerase).

MICROBIOLOGY

MICROBIOLOGY VIROLOGY

SECTION II

133

Long page please


edit to fit

Herpesviruses

Enveloped, DS, and linear viruses

VIRUS

ROUTE OF TRANSMISSION

CUNICAL SIGNIFICANCE

NOTES

Herpes
simplex
virus-1

Respirators
secretions, saliva

Gingivostomatitis, keratoconjunctivitis Q,
herpes labialis HI herpetic whitlow on finger
temporal lobe encephalitis, esophagitis,

Most common cause of sporadic


encephalitis, can present as altered
mental status, seizures, and/or

'

aphasia.

erythema multiform

Herpes
simplex
virus-2

Sexual contact,

Varicella Zoster virus


(HHV-3)

Respiratory

Latent in sacral ganglia. Viral


meningitis more common with
HSV 2 than with IISV-1.

Varicella-zoster (chickenpox 0, shingles Q ),


encephalitis, pneumonia.
Most common complication of shingles is post

Latent in dorsal root or trigeminal


ganglia; CN V, branch

perinatal

Epstein- Barr
virus (HHV- 4)

secretions

Respiratory

teens, young

adults )

virus (HHV-5 )

herpetic neuralgia.
Mononucleosis fever, hcpatosplenomegaly,

pharyngitis, and lvmphadenopathv


l especially posterior cervical nodes bi. Often
misdiagnosed as strep throat: can differentiate

secretions,
saliva; aka
"kissing disease,"
(common in

Cytomegalo

Herpes genitalis Q, neonatal herpes.

Congenital
transfusion,
sexual contact,

because amoxicillin in HHV-4 infection causes


maeulopapular rasli Avoid contact sports until
resolution due to risk of splenic rupture.
Associated with lymphomas (eg, endemic
Burkitt lymphoma), nasopharyngeal
carcinoma (especially Asian adults!

Mononucleosis ( Monospot ) in
immunocompetent patients; infection in
immunocompromised! especially pneumonia
in transplant patients; esophagitis; AIDS
Retinitis ( sightomcgalovirus"): hemorrhage,

saliva, urine,
transplant

Human
herpes
viruses 6
and 7

Saliva

Human
herpesvirus
8

Sexual contact

cotton-wool exudates, vision loss.


Congenital CMV
Roseola infantum (exanthem subitum); high
fevers for several days that can cause seizures,
followed by diffuse macular rash Q.

involvement can cause herpes


zoster ophthalmic mi

Infects B cells through CD21.

Atypical lymphocytes on peripheral


blood smear 0 not infected B
cells but reactive cytotoxic T cells.
Monospot test heterophile
antibodies detected by agglutination
of sheep or horse RBCs.

Infected cells have characteristic


"owl eve" inclusions Q.
Latent in mononuclear cells.

Roseola; fever first, Rosie (cheeks)

later.
IIIIV-7 less common cause of

roseola.

1
Kaposi sarcoma (neoplasm of endothelial cells).
Seen in HIV/AIDS and transplant patients.
Dark /violaceous plaques or nodules Q
representing vascular proliferations.

Can also affect Gl tract and lungs.

SLtfl

Sri

-L

S [

\
-

kl

te co

f
SECTION II

HSV identification

h\
*

rID

MICROBIOLOGY

MICROBIOLOGY VIROLOGY

Viral culture for skin/genitalia.


CSF PCR for herpes encephalitis.
Tzanck test a smear of an opened skin vesicle to detect multinuclcatcd giant cells Q commonly
seen in HSV-1, HSV-2, and YZV infection.
Intranuclear eosinophilic Cowdrv A inclusions also seen with IISV-I. IISV-2, WAj
Tzanck heavens I do not have herpes.

MICROBIOLOGY VIROLOGY

MICROBIOLOGY

SECTION I I

RNA viruses
VIRALFAMILY

ENVELOP

RNA STRUCTURE

CAPSIOSYMMETRV

MEDICAL IMPORTANCE

Reoviruses

No

DS linear
10-12 segments

leosahedral
(double)

Picornaviruses

No

SS linear

leosahedral

Coltivirus3 Colorado tick fever


Rotavirus cause of fatal diarrhea in childrcnl
Poliovirus polio-Salk /Sabin vaccines IPV/OPV
Echovirus aseptic meningitis

Rhinovirus "common cold


Coxsackievirus aseptic meningitis; herpangina
( mouth blisters, fever); hand, foot, and mouth
disease; myocarditis; pericarditis
11AY acute viral hepatitis
PERCH
Hepevirus

No

SS linear

leosahedral

HEV

Caliciviruses

No

SS linear

leosahedral

Norovirus viral gastroenteritis

Flaviviruses

Yes

SS linear

leosahedral

HCV

Yellow fever1
Dengue3
St. Louis encephalitis3
West Nile virus'1 ( meningoencephalitis)
Zika virus
Togaviruses

Yes

SS linear

leosahedral

Rubella
Western and Eastern euuine encephalitis^
Chikungunva viru4

Retroviruses

Yes

SS linear
2 copies

leosahedral
(HTLV),
complex
and conical

1 lave reverse transcriptase


HTLV T-cell leukemia
HIV AIDS

(HIV )
Coronaviruses

Yes

SS linear

Helical

"Common cold," SARS, MERS

Orthomyxoviruses

Yes

SS linear

Helical

Influenza virus

Helical

PaRaMyxovirus:

8 segments
Paramyxoviruses

Yes

SS linear
Nonsegmented

Parainfluenza croup
RSV bronchiolitis in babies; Rx ribavirin

Measles, Mumps

Rhabdoviruses

Yes

SS linear

Helical

Rabies

Filoviruses

Yes

SS linear

Helical

Ebola /Marburg hemorrhagic fever often fatal!

Arenaviruses

Yes

SS or

1 lelical

LCMV lymphocytic choriomeningitis virus


Lassa fever encephalitis spread by rodents

circular
2 segments
Bunyaviruses

Yes

SS circular
s segments

Helical

California encephalitis3
Sandfly/Rift Valley fevers'1
Crimean-Congo hemorrhagic fever 3
Hantavirus hemorrhagic fever, pneumonia

Delta virus

Yes

SS circular

Uncertain

11DV is a "defective" virus that requires the


presence of HBV to replicate

'll

tmaU-itritvlMl-

rlruiKl<*.i:lrjnrlwl' (?)

n/ wiHvp

CPIIW

upoifii 'p

. a lrlutt inic lrfltrnnn/l In >riu>

cpncP1

fm/EcrinilruAc Hr l'cl

MICROBIOLOGY

MICROBIOLOGY

Orthomyxoviruses. Enveloped, ssRNA


viruses with 8-segment genome. Contain
hemagglutinin ( binds sialic acid and promotes
viral cntrvt) and neuraminidase promotes
progeny virion release) antigens. Patients at
risk for fatal bacterial supcrinfection , most
commonly S aureus , S pneumoniae , and
11 jjn /luenzae.
Causes pandemics. Reassortment of viral
genome segments, such as when segments of
human flu A virus rcassort with swine flu A

Influenza viruses

Genetic shift/
antigenic shift

VIROLOGY

SECTION II

Reformulated vaccine ( the flu shot ) contains


viral strains most likely to appear during the flu
season , due to the virus' rapid genetic change.
Killed viral vaccine is most frequently used.
Live attenuated vaccine contains temperaturesensitive mutant that replicates in the nose but
not in the lung; administered ilitranasally.
Sudden shift is more deadlv than gradual drift

virus.
Reassortment

Causes epidemics. Minor (antigenic drift )


changes based on random mutation in
hemagglutinin or neuraminidase genes.

Genetic drift/
antigenic drift
Random
mutations '

v:
va

A togasirus. Causes rubella, once known as German ( s-dav i measles. Fever, postauricular and
other lymphadcnopathy. arthralgias, and fine, confluent rash that starts on face and spreads
centrifugally to involve trunk and extremities Q. Causes mild disease in children but serious
congenital disease (a ToRCHeS infection). Congenital rubella findings include blueberry
muffin" appearance due to dermal extramedullary hematopoiesis.

Rubella virus

Cl
Paramyxoviruses

Paramyxov iruses cause disease in children. They include those that cause parainfluenza (croup;
seal-like barking cough ), mumps, and measles as well as RSV, which causes respiratory tract
infection ( bronchiolitis, pneumonia ) in infants. All contain surface F ( fusion ) protein , which
causes respiratory epithelial cells to fuse and form multinuclcatcd cells. Palivizumab ( monoclonal
antibody against F protein ) prevents pneumonia caused by RSV infection in premature infants.
Palivizumab for Parainvxovirus ( RSV ) Prophvlaxis in Premies.

h 38

SECTION II

MICROBIOLOGY

MICROBIOLOGY VIROLOGY

Croup ( acute laryngotracheobronchitis)

Caused In parainfluenza viruses i paramyxovirus ), Virus mcmhranc contains hemagglutinin


( binds sialic acid and promotes viral entry ) and neuraminidase ( promotes progeny virion release )
antigens. Results in a "seal-like barking cough and inspiratory stridoj Narrowing of upper trachea
and subglottis leads to characteristic steeple sign on x-ray
Severe croup can result in pulsus
paradoxus 2 to upper airway obstruction.

Measles (rubeola )
virus

A paramyxovirus that causes measles. Usual


presentation involves prodromal fever with
cough, coryza, and conjunctivitis, then
eventually Koplik spots ( bright red spots with
blue-white center on buccal mucosa ),

followed 1-2 days later by a tnaculopapular


that starts at the head/neck and spreads
downward. Lymphadenitis with WarthinFinkeldey giant cells ( fused lymphocytes ) in
a background of paracortical hyperplasia.
SSPE (subacute sclerosing pancnccphalitis,
occurring years later ), encephalitis ( 1:2000),
and giant cell pneumonia (rarely, in
immunosuppressed ) are possible sequelae.
rash

Mumps virus

A paramyxovirus that causes mumps,


uncommon due to effectiveness of MMR

vaccine.
Symptoms: Parotitis d, Orchitis (inflammation
of testes), aseptic Meningitis, and Pancreatitis.
Can cause sterilitv (especially after pubertv).

T Cs of measles:

Cough
Coryza
Conjunctivitis
Vitamin A supplementation can reduce
morbidity and mortality from measles,
particularly in malnourished children.

Mumps makes your parotid glands and testes as


big as POM-Poms

MICROBIOLOGY

MICROBIOLOGY VIROLOGY

Bullet-shaped virus Q. Negri bodies


( cytoplasmic inclusions Qi commonly
found in Purkinje cells of cerebellum and
in hippocampal neurons. Rabies has long
incubation period (weeks to months) before
symptom onset. Postexposurc prophylaxis
is wound cleaning plus immunization with

Rabies virus

*
r:

SECTION II

Infection more commonly from bat, raccoon, and


skunk bites than from dog bites in the United
Stales; aerosol transmission leg, bat caves) also
possible.

killed vaccine and rabies immunoglobulin.


Example of passive-active immunity.
Travels to the CNS by migrating in a retrograde
fashion ( via dvnein motorsjiup nerve axons
after binding to ACh receptors.
Progression of disease: fever, malaise
- agitation, photophobia, hydrophobia,
*
hypersalivation -* paralysis, coma death.

Ebola virus

Zika virus
tor Zika virus
to come .

A filovirus Q that targets endothelial cells,


phagocytes, hepatocytes. Following an
incubation period of up to 21 days, presents
with abrupt onset of flu-like symptoms,
diarrhea/vomitiug, high fever, myalgia. Can
progress to DIG, diffuse hemorrhage, shock .
Diagnosed w itli RT-PCR within 48 hr ol
symptom onset. High mortality rate.

Transmission requires direct contact with bodily


fluids, fonntes (including dead bodies), infected
bats or primates (apes/monkeys); high incidence
of nosocomial infection.
Supportive care, no definitive treatment . Strict
isolation of infected individuals and barrier
practices for health care workers are kev to
preventing transmission.

MICROBIOLOGY VIROLOGY

MICROBIOLOGY

SECTION II

141

Hepatitis serologic markers


Anti-HAV (IgM)

IgM antibody to HAV; best test to detect acute hepatitis A.

Anti-HAV (IgG)

IgG antibody indicates prior HAV infection and/or prior vaccination; protects against reinfection.

HBsAg

Antigen found on surface of HBV; indicates hepatitis B infection.

Anti-HBs

Antibody to IIBsAg; indicates immunity to hepatitis B due to vaccination or recovery from


infection.

HBcAg

Antigen associated with core of HBV.

Anti- HBc

Antibody to HBcAg; IgM = acute/rcccnt infection; IgG = prior exposure or chronic infection. IgM
anti-HBc may be the sole marker of infection during window period.

HBeAg

Secreted by infected hepatocyte into circulation. Not part of mature HBV virion. Indicates active
viral replication and therefore high transmissibility.

Anti- HBe

Antibody to HBcAg; indicates low transmissibility.

Important
diagnostic

Incubation

Prodrome,

period

acute disease

Early

HBsAg
-HBc)

Anti-

Anti-HBs

HBc

land-HBc )

tests

HBsAg

Relative
concentration
of reactants

Convalescence
Late

(anti

Coat protein
IHBsAg)

Anti- HBc

DNA
polymerase

^ HBV particles^

Core (HBcAg)

3
i-

HBsAg

Anti - HBs

Window period

DNA genome

DNA polymerase

Anti-HBe

HBeAg

Virus particle

Level of
detection

V "7

Symptoms

exposure

tALT
HBsAg

Anti-HBs

a
HBeAg
/

Acute HBV

Window
Chronic HBV (high infectivity)

Months after

Anti- HBe

Anti-HBc

IgM
IgM

IgG

Chronic HBV (low infectivity)

IgC

Recovery

IgG

Immunized

142

SECTION I I

MICROBIOLOGY VIROLOGY

MICROBIOLOGY

HIV

Diploid genome ( 2 molecules of RNA).


The 5 structural genes ( protein coded for):
" env (gpl 20 and gp 41):
Formed from cleavage of gpl60 to form

Envelope proteins
acquired through budding from
host cell plasma membrane

p!7: Matrix protein

gpl20
Docking
glycoprotein

Lipid envelope

gp 41
Transmembrane
: reopt m

wts

apsid protein

transcriptase

envelope glycoproteins.
gpl20 attachment to host CD4+ T cell.
gp4l fusion and entry.
gag (p24 and pl7] capsid and matrix
proteins, respectively.
po/ reverse transcriptase, aspartate protease,
integrase.
Reverse transcriptase synthesizes dsDNA from
genomic RNA; dsDNA integrates into host
genome.

Virus binds CD4 as well as a coreceptor, either


CCR 5 on macrophages (carls' infection ) or
CXCR4 on T cells (late infection ).
Homozygous CCR 5 mutation = immunity.
Heterozygous CCR 5 mutation = slower course.

HIV diagnosis

Presumptive diagnosis made w ith ELISA


(sensitive, high false rate and low threshold,
rule out test ); results jeonfirmed with
Western blot assay ( specific, low false rate
and high threshold, rule in test).
Viral load tests determine the amount of viral
RNA in the plasma. High viral load associated
with poor prognosis. Also use viral load to
monitor effect of drug therapy.
AIDS diagnosis 200 CD4+ cells/innV
(normal: 500-1500 cclls/mml. HIV with
AlDS-defining condition (eg, Pneumocystis
pneumonial orCD4+ percentage < 14%.

ELISAAVestern blot tests look for antibodies to


viral proteins; these tests often are falsely
in the first 1-2 months of HIV infection and
falsely initially in babies bom to infected
mothers (anti-gpl 20 crosses placenta ). Use
I'CK m neon lies to detect viral load.

MICROBIOLOGY

Prions

MICROBIOLOGY

SYSTEMS

SECTION II

145

Prion diseases are caused by the conversion of a normal ( predominantly a-helical) protein termed
prion protein ( PrI*) to a (i-pleated form ( PrPsc ), which is transmissible via CNS- rclated tissue
( iatrogenic CJD ) or food contaminated bv BSE -infected animal products ( variant CJD). PrP'1
resists protease degradation and facilitates the conversion of still more PrP1 to PrP*c, Resistant to
standard sterilizing procedures, including standard autoclaving. Accumulation of PrP* results in
spongiform encephalopatlnjand dementia , ataxia , and death.

Creutzfeldt-Jakob disease rapidlv progressive dementia , typically sporadic (some familial forms).
Bovine spongiform encephalopathy ( BSE) also known as mad cow disease."
Kuru acquired prion disease noted in tribal populations practicing human cannibalism .

MICROBIOLOGY- SYSTEMS

Normal flora:
dominant

LOCATION

MICROORGANISM

Skin

S epidermidis

Nose

S epidermidis; colonized by S aureus

Oropharynx

Viridans group streptococci

S mutans
B fragilis > E coli
Lactobacillus , colonized by E coli and group
Vagina
B strep
Neonates delivered by C-section have no flora but are rapidly colonized after birth.

Dental plaque

Colon

Bugs causing food


poisoning

S aureus and B cereus food poisoning starts quickly and ends quickly.
MICROORGANISM

SOURC OF INFECTION

B cereus

Reheated rice. " Food poisoning from reheated


rice? Be serious! ( B cereus )

C botulinum

Improperly canned foods ( toxins ), raw honey


(spores)
C perfringens
Reheated meat
Undercooked meat
Ecoli 0157:117
Deli meats, soft cheeses
L monocytogenes
Salmonella
Poultry, meat , and eggs
Meats, mayonnaise, custard; preformed toxin
S aureus
V parahaemolyticus and V vulnificus?
Contaminated seafood
vulnificus
w
V
from
also
infections
contact with contaminated water or shellfish.
ound
can
cause

MICROBIOLOGY

Prions

MICROBIOLOGY SYSTEMS

SECTION II

145

Prion diseases are caused by the conversion of a normal (predominantly a-helical ) protein termed
prion protein ( Prlx ) to a 3-pleated form ( PrP51), which is transmissible via CNS-related tissue
( iatrogenic CJD) or food contaminated bv BSE -infected animal products ( variant CJD ) . PrP't
resists protease degradation and facilitates the conversion of still more PrP to PrPc. Resistant to
standard sterilizing procedures, including standard autoclaving. Accumulation of PrPc results in
spongiform enccphalopathsjand dementia, ataxia, and death.
Creutzfeldt-Jakob disease rapidly progressive dementia, typically sporadic isome familial forms).
Bovine spongiform encephalopathy ( BSE) also known as "mad cow disease."
Kuru acquired prion disease noted in tribal populations practicing human cannibalism.

MICROBIOLOGY SYSTEMS
Normal flora:
dominant

lOCAtlON

MICROORGANISM

Skin

S epidermidis

Nose

S epidermidis; colonized by S aureus

Oropharynx

Viridans group streptococci

Dental plaque

S mutant

Colon

B fragilis > E coli

Vagina

Lactobacillus, colonized by E coli and group


B strep

Neonates delivered by C-section have no flora but are rapidly colonized after birth

Bugs causing food


poisoning

S aureus and B ccreus food poisoning starts quicklv and ends quickly.
MICROORGANISM

SOURCE OF INFECTION

B cereus

Reheated rice. "Food poisoning from reheated


rice? Be serious!" (B cereus)

C botulinum

Improperly canned foods ( toxins ), raw hones


(spores)

C perfringens

Reheated meat

Eco/i 0157:117

Undercooked meat

L monocytogenes

Deli meats, soft cheeses

Salmonella

Poultry, meat, and eggs

S aureus

Meats, mayonnaise, custard; preformed toxin

V parahaemolyticus and V vulnificusa

aVvulnificus

Contaminated seafood

can also cause wound infections from contact with contaminated water or

shellfish.

148

SECTION I I

Urinary tract
infections

MICROBIOLOGY

MICROBIOLOGY SYSTEMS

Cystitis presents with dysuria, frequency, urgency, suprapubic pain, and WBCs ( but not WBC
casts) in urine. Primarily caused by ascension of microbes from urethra to bladder. Males
infants with congenital defects, vesicoureteral reflux. Elderlv enlarged prostate. Ascension to
kidney results in pyelonephritis, which presents with fever, chills, flank pain, costovertebral angle
tenderness, hematuria, and WBC casts.
Ten times more common in women (shorter urethras colonized by fecal flora). Other predisposing
factors: obstruction, kidney surgery, catheterization, GU malformation, diabetes, pregnancy.

UTI bugs
SPECIES

FEATURES

Escherichia coli

Leading cause of UTI. Colonies show green


Diagnostic markers:
metallic sheen on EMB agar.
Leukocyte esterase = evidence of WBC
activity.
2nd leading cause of UTI in sexually active
Nitrite test = reduction of urinary nitrates
women.
by bacterial species (eg, E coli ),
srd leading cause of UTI.Iairge mucoid capsule
Urease test = urease-producing bugs ( eg.
and v iscous colonies.
S saproplivticus. Proleus, Klebsiellct ).
Some strains produce a red pigment; often
nosocomial and drug resistant.

Staphylococcus
saprophyticus
Klebsiella pneumoniae

Serratia marcescens

COMMENTS

Proteus mirabilis

Often nosocomial and drug resistant.


Motility causes swarming" on agar; produces
urease; associated with struvite stones.

Pseudomonas
aeruginosa

Blue-green pigment and fruity odor; usually


nosocomial and drug resistant.

Enterococcus

Common vaginal infections

SIONS AND SYMPTOMS

Bacterial vaginosis

Trichomonas vaginitis

Candida vulvovaginitis

No inflammation

Inflammation ( strawberry
cervix)
Frothy, yellow-green, foul
smelling discharge

Inflammation
Thick, white, cottage cheese"
discharge Q

Motile trichomonads Q
pH > 4.5
Metronidazole
Treat sexual partner(s)

Pscudohyphae
pH normal (4.0-4.5)

Thin, white discharge Q with


fishy odor
LAB FINDINGS

TREATMENT

Clue cells
pH > 4.5
Metronidazole

I
-

'
\

-azoles

fv

SECTION II I MICROBIOLOGY

MICROBIOLOGY SYSTEMS

Red rashes of childhood


AGENT

ASSOCIATED SYNDROME / DISEASE

CLINICAL PRESENTATION

Coxsackievirus type A

Hand-foot-mouth disease

Oval-shaped vesicles on palms and soles Q;


vesicles and ulcers in oral mucosa

Human herpesvirus 6

Roseola (exanthem subitum )

Asymptomatic rose-colored macules appear


on body after several days of high fever; can
present with febrile seizures; usually affects

Measles virus

Measles (rubeola)

Confluent rash beeinning at head and moving


down; rash precededlbv cough, con / a,
conjunctivitis, and blue-white ( Koplik ) spots

infants

on buccal mucosa

Parvovirus B19

Erythema infectiosum ( fifth disease)

Slapped cheek" rash on face (can cause


hydrops fetalis in pregnant women)

Rubella virus

Rubella (German measles)

Pink macules and papules begin at head


and move down, remain discrete -* fine
desquamating truncal rash; postauricular

lymphadenopathx
Streptococcus pyogenes

Scarlet fever

Erythematous, sandpaper-like rash Q with fever


and sore throat

Varicella - Zoster virus

Chickenpox

Vesicular rash begins on trunk; spreads to face


and extremities with lesions of different stages

150

SECTION I I

MICROBIOLOGY

MICROBIOLOGY SYSTEMS

Red rashes of childhood


AGENT

ASSOCIATED SYNDROME/DISUSE

CLINICAL PRESENTATION

Coxsackievirus type A

Hand-foot-nioutli disease

Oval-shaped vesicles on palms and soles


vesicles and ulcers in oral mucosa

Human herpesvirus 6

Roseola (exanthem subitum )

Asymptomatic rose-colored macules appear


on body after several days of high fever; can
present with febrile seizures; usually affects
infants

Measles virus

Measles Irubeola i

Confluent rash beginning at head and moving


down; rash precedec|hy cough, coryza,
conjunctivitis, and blue-w hite i KLoplik ) spots

on buccal mucosa

Parvovirus B19

Erythema infectiosum ( fifth disease )

Slapped cheek" rash on face Q] ( can cause


hydrops fetalis in pregnant women)

Rubella virus

Rubella (German measles )

Fink macules and papules begin at head


fine
and move down, remain discrete
desquamating truncal rash; postauricular

Streptococcus pyogenes

Scarlet fever

lymphadenopathy
Erythematous, sandpaper-like rash Q with few
and sore throat

Varicella-Zoster virus

Chickcnpox

Y'esicular rash begins on trunk; spreads to face


and extremities with lesions of different stage

MICROBIOLOGY

MICROBIOLOGY SYSTEMS

SECTION II

151

Sexually transmitted infections


DISEASE

CLINICAL FEATURES

ORGANISM

AIDS

Opportunistic infections, Kaposi sarcoma,

HIV

lymphoma
Chancroid

Painful genital ulcer with exudate, inguinal

adenopathy

Haemophilus ducreyi (its so painful, vou "do


cry )

Chlamydia

Urethritis, cervicitis, epididymitis,


conjunctivitis, reactive arthritis, PID

Chlamydia trachomatis ( D-K )

Condylomata
acuminata

Genital warts, koilocytes

HPV-6 and - 11

Genital herpes

Painful penile, vulvar, or cervical vesicles and


ulcers; can cause systemic symptoms such as
fever, headache, myalgia

HSV-2, less commonly HSV-1

Gonorrhea

Urethritis, cervicitis, PID. prostatitis,


epididymitis, arthritis, creamy purulent
discharge
Painless, beefv red ulcer that bleeds rcadilv on

Neisseria gonorrhoeae

Granuloma inguinale
(donovanosis)

contact

Not common in US

Hepatitis B

Jaundice

Lymphogranuloma
venereum

Infection of lymphatics; painless genital ulcers,


painful lymphadenopathy ( ie, buboes)

Primary syphilis

Painless chancre

Secondary syphilis

Fever, lymphadenopathy, skin rashes,


condylomata lata

Tertiary syphilis

Gummas, tabes dorsalis, general paresis, aortitis,


Argyll Robertson pupil

Trichomoniasis

Vaginitis, strawberry cervix, motile in wet prep

Klebsiella (Calvmmatobacterium ) granulomatis:


cytoplasmic donovan bodies ( bipolar staining)
seen on microscopy

HBV
C trachomatis ( LI LA )
Treponema pallidum

Trichomonas vaginalis

MICROBIOLOGY

MICROBIOLOGY SYSTEMS

SECTION II

153

Bugs affecting unvaccinated children


CLINICAL PRESENTATION

FINDINGS/LABS

PATHOGEN

Beginning at head and moving down with

Rubella yirus

Dermatologic
Rash

postauricular lymphadenopathy
Beginning at head and moving down; rash
preceded by cough, conza. conjunctivitis, and
blue-white ( Koplik) spots on buccal mucosa

Measles virus

Neurologic

Microbe colonizes nasopharynx

11 influenzae type B

Can also lead to myalgia and paralysis

Poliovirus

Epiglottitis

Fever with dysphagia, drooling, and difficulty


breathing due to edematous cherry red"
epiglottis; " thumbprint sign" on x-ray

Pharyngitis

Grayish oropharyngeal exudate


( pseudomembranes" may obstruct airway);

Corynebaclerium diplitheriae (elaborates toxin

Meningitis

Respiratory

painful throat

Bug hints (if all else


fails)

influenzae type B (also capable of causing


epiglottitis in fully immunized children)

that causes necrosis in pharynx, cardiac, and


CNS tissue)

CHARACTERISTIC

ORGANISM

Asplcnic patient ( due to surgical splenectomy


or autosplenectomy, eg, chronic sickle cell

Encapsulated microbes, especially SHiN

disease )

(S pneumoniae H
N meningitidis )

influenzae type B >

Branching rods in oral infection, sulfur granules

Actinomyces israelii

Chronic granulomatous disease

Catalase microbes, especially S aureus


Klebsiella

Currant

jelly" sputum

Dog or cat hite


Facial nerve palsv (typically bilateral 1

Vasteurella multocida

Fungal infection in diabetic or


immunocompromised patient
1 lealth care provider
Neutropenic patients
Organ transplant recipient

A lucor or Rbizopus spp.

Borrelia burgdorferi ( Lyme disease)

HBV (from needlestick )

Candida albicans ( systemic), Aspergillus


CMV

Pediatric infection

Trophenma whipplei ( Whipple disease)


Haemophilus influenzae ( including epiglottitis)

Pneumonia in cystic fibrosis, burn infection

Pseudomonas aeruginosa

Pus, empyema, abscess

S aureus

Rash on hands and feet

Coxsackie A virus, Treponema pallidum,

Sepsis/mcnmgitis in newborn

Group B strep

Surgical wound

S aureus

Traumatic open wound

Clostridium perfringens

PAS

Rickettsia rickettsii

MICROBIOLOGY

MICROBIOLOGY

Penicillinase-sensitive
penicillins
MECHANISM

CLINICAL USE

ANTIMICROBIALS

SECTION II

Amoxicillin , ampicillin ; aminopenicillms.


Same as penicillin . Wider spectrum;
penicillinase sensitive. Also combine with
clavulanic acid to protect against destruction
by P -lactamase.
Kxtended-spectrum penicillin II influenzae,
H pylori , E coli Listeria monocytogenes ,
Proteus mirabilis , Salmonella , Shigella ,

Wlinolenicillins are AMPed-up penicillin .


AmOxicillin has greater Oral bioavailability
than ampicillin .

Coverage: ampicillin /amoxicillin 1 IIIEEPSS


kill enterococci.

enterococci.
ADVERSE EFFECTS
MECHANISM OF RESISTANCE

Penicillinase- resistant
penicillins
MECHANISM

CLINICAL USE
ADVERSE EFFECTS

Antipseudomonal
penicillins

1 Is persensitivily reactions; rash ;


pseudomembranous colitis.

Penicillinase in bacteria (a type of p-lactamase )


cleaves p-lactam ring.

Dieloxacillin , nafcillin , oxacillin.


Same as penicillin . Narrow spectrum;
penicillinase resistant because bulky R group
blocks access of p-lactamase to P-lactam ring.
S aureus (except MRSA; resistant because of
altered penicillin-binding protein target site ).

Use

naf ( nafcillin ) for staph ."

Hypersensitivity reactions, interstitial nephritis.

Piperacillin, ticarcillin.

MECHANISM

Same as penicillin . Extended spectrum .

CLINICAL USE

Pseudomonas spp. and gram rods; susceptible to penicillinase; use with P-lactamase inhibitors.

ADVERSE EFFECTS

Hypersensitivity reactions.

^-

lactamase inhibitors

Include Clavulanic acid , Avibactanr ,


Sulbactam. Tazobactani Often added
to penicillin antibiotics to protect the
antibiotic from destruction by P-lactamase

CAST.

155

56

SECTION II

MICROBIOLOGY

MICROBIOLOGY

ANTIMICROBIALS

Cephalosporins (generations i-V )


MECHANISM

P-lactam drugs that inhibit cell wall synthesis


but are less susceptible to penicillinases.
Bactericidal.

CLINICAL USE

1st generation (cefazolin, cephalexin) gram


cocci, Proteus mirabilis, E coli , Klebsiella
pneumoniae. Cefazolin used prior to surgery to
prevent S aureus wound infections.
2nd generation (cefaclor, cefoxitin,
cefuroximc) gram cocci, H influenzae,
Enterobacter aerogenes, Seisseria spp., Serratia
marcescens , Proteus mirabilis , E coli , Klebsiella
pneumoniae.
3rd generation (ceftriaxone, cefotaxime,
cefDodoxime. ceftazidimdl serious gram
infections resistant to other JJ-lactams.

4th generation (cefepime) gram organisms,


with t activity against Pseudomonas and gram
organisms.
5th generation (ceftaroline) broad gram and
grant organism coverage, including MRSA;
does not cover Pseudomonas.
Hypersensitivity reactions, autoimmune
hemolytic anemia, disulfiram-likc reaction,
vitamin K deficiency. Exhibit cross-reactivity
with penicillins, t nephrotoxicity of
aminoglycosides.
Structural change in penicillin -binding proteins
( transpeptidases ).

ADVERSE EFFECTS

MECHANISM Of RESISTANCE

Organisms typically not covered by 1st 4th


generation cephalosporins are LAME:
Listeria , Atypicals (Chlamydia, Mycoplasma ),
MRSA, and Enterococci. Exception:
ceftaroline ( 5th generation cephalosporin )
covers MRSA.

1st generation PEcK.

Fake fox fur.


2nd generation HENS PEcK.

Can cross blood-brain barrier.


Ceftriaxone meningitis. gonorrhea.
disseminated Lvme disease.
Ceftazidime Pseudomonas

MICROBIOLOGY

Tetracyclines
MECHANISM

MICROBIOLOGY

ANTIMICROBIALS

SECTION II

1 59

Tetracycline, doxycycline, minocycline.


Bacteriostatic; bind to sOS and prevent attachment of aminoacyl - tRNA; limited CNS penetration .
Doxycycline is fecally eliminated and can be used in patients with renal failure. Do not take
tetracyclines with milk ( Ca ~ ), antacids ( Ca -~ or Mg * ), or iron -containing preparations because
divalent cations inhibit drugs' absorption in the gut.

CLINICAL USE

Bonelia burgdorferi , M pneumoniae. Drugs' ability to accumulate intraccllularly makes them very
effective against Rickettsia and Chlamydia. Also used to treat acne. Doxvcveline effective against

ADVERSE EFFECTS

GI distress, discoloration of teeth and inhibition of bone growth in children , photosensitivity.


Contraindicated in pregnancy.

MECHANISM OF RESISTANCE

1 uptake or t efflux out of bacterial

MRSAt

cells by plasmid -encoded transport pumps.

Chloramphenicol
MECHANISM

CLINICAL USE

Blocks peptidyltransferase at 50S ribosomal subunit. Bacteriostatic.

Meningitis ( Haemophilus influenzae , Neisseria meningitidis Streptococcus pneumoniae ) and Rocky


Mountain spotted fever ( Rickettsia rickettsii ).
1 imiled use owing to toxicities but often still used in developing countries because of low cost.
Anemia ( dose dependent ), aplastic anemia (dose independent ), gray baby syndrome ( in premature
infants because they lack liver UDP-glucuronyl transferase).
Plasmid-encoded acetyltransferase inactivates the drug.

ADVERSE EFFECTS

MECHANISM OF RESISTANCE

Clindamycin
MECHANISM

CLINICAL USE

Blocks peptide transfer (translocation ) at 50S


ribosomal subunit . Bacteriostatic.
Anaerobic infections (eg, Bacteroides spp..

Clostridium perfringens ) in aspiration

ADVERSE EFFECTS

pneumonia, lung abscesses, and oral


infections. Also effective against invasive
group A streptococcal infection .
Pseudomembranous colitis (C difficile
overgrow th ), fever, diarrhea .

Treats anaerobic infections above the diaphragm


vs metronidazole (anaerobic infections below
diaphragm ),

162

SECTION II

Fluoroquinolones
MECHANISM

MICROBIOLOGY

MICROBIOLOGY

ANTIMICROBIALS

Ciprofloxacin, norfloxacin, levofloxacin. ofloxacin , moxifloxacin , gemifloxacin, enoxacin .


Inhibit prokaryotic enzymes topoisomerasc
II ( DNAgyrase) and topoisomerase IV.
Bactericidal. Must not be taken with antacids.

CLINICAL USE

Gram rods of urinary and Gl tracts ( including


Pseudomonas ), Neisseria , some gram
organisms, otitis externa.

ADVERSE EFFECTS

GI upset , superinfections, skin rashes, headache,


dizziness. Less commonly, can cause leg
cramps and myalgias. Contraindicated in
pregnant women , nursing mothers, and
children < 18 years old due to possible damage
to cartilage. Some may prolong QT interval.
May cause tendonitis or tendon rupture in
people > 60 years old and in patients taking
prednisone.

MECHANISM OF RESISTANCE

Fluoroquinolones hurl attachments to vour


bones.

Chromosome-encoded mutation in DNA


gyrase, plasmid-mediated resistance, efflux
pumps.

Daptomycin
MECHANISM

l .ipopeptide that disrupts cell membrane of


gram cocci.

CLINICAL USE

S aureus skin infections (especial!) MRSA ),


bacteremia, endocarditis, VRE.

ADVERSE EFFECTS

Myopathy, rhabdomvolysis.

Not used for pneumonia (avidly binds to and is


inactivated by surfactant ).

Metronidazole
MECHANISM

Forms toxic free radical metabolites in the


bacterial cell that damage DNA. Bactericidal ,
antiprotozoal.

CLINICAL USE

Treats Uiardia , Entamoeba , trichomonas


Gardnerella vaginalis Anaerobes ( Baeleroides ,
C difficile ). Used with a proton pump inhibitor
and clarithromycin for " triple therapy" against
H Pylori.
Disulfiram-like reaction (severe flushing,
tachycardia , hypotension ) with alcohol;
headache, metallic taste .

ADVERSE EFFECTS

GET GAP on the Metro with metronidazole!


Treats anaerobic infection below the diaphragm
vs clindamycin ( anaerobic infections above
diaphragm ).

164

SECTION I I

MICROBIOLOGY

MICROBIOLOGY ANTIMICROBIALS

Isoniazid
MECHANISM

CLINICAL USE

ADVERSE EFFECTS

. Bacterial catalaseperoxidase (encoded by KatG) needed to


convert INI 1 to active metabolite.
Mycobacterium tuberculosis . The only agent
used as solo prophylaxis against TB. Also used
as monotherapy for latent TB.
1 synthesis of mycolic acids

Hepatotoxicitv, P-450 inhibition, drug-induced

Different 1NH half-lives in fast vs slow


acetylators.
INH Injures Neurons and Hepatocvtes.

SLE. anion gap metabolic acidosis, vitamin


Bdeficiencvi ( peripheral neuropaths ,
sideroblastic anemia). Administer svith

pyridoxine ( Bh ).
MECHANISM OF RESISTANCE

Mutations leading to undcrcxpression of KatC.

Pyrazinamide
MECHANISM

Mechanism uncertain. Pyrazinamide is a prodrug that is converted to the active compounc


pyrazinoic acid. Works best at acidic pH ( eg, in host phagolysosomes).

CLINICAL USE

lycobacterium tuberculosis.
Hyperuricemia, hepatotoxicitv.

ADVERSE EFFECTS

i\

Ethambutol
MECHANISM

i carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferas

CLINICAL USE

A lycobacterium tuberculosis.

ADVERSE EFFECTS

Optic neuropathy (red-green color blindness). Pronounce evethambutol.

Streptomycin
MECHANISM

Interferes with 50S component of ribosome.

CLINICAL USE

Mycobacterium tuberculosis ( 2nd line).

ADVERSE EFFECTS

Tinnitus, vertigo, ataxia, nephrotoxicity.

MICROBIOLOGY

Echinocandins
MECHANISM

MICROBIOLOGY ANTIMICROBIALS

SECTION II

167

Anidulafungin, caspofungin, micafungin.


Inhibit cell wall synthesis by inhibiting synthesis of P-gluean.

CLINICAL USE

Invasive aspergillosis, Candida.

ADVERSE EFFECTS

GI upset, flushing (by histamine release).

Griseofulvin
MECHANISM

Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues (eg,

nails).
CLINICAL USE

Oral treatment of superficial infections; inhibits growth of dermatophytes ( tinea, ringworm).

ADVERSE EFFECTS

Teratogenic, carcinogenic, confusion, headaches, disulfiram-like reaction! t cytochrome P-450 and

warfarin metabolism.

Antiprotozoan therapy

Pyrimethamine (toxoplasmosis), suramin atrd melarsoprol (Trypanosoma brucei ), nifurtimox


( Tcruzi ). sodium stibogluconate ( leishmaniasis).

Anti-mite/louse
therapy

Pcrmethrin ( blocks Na* channels


-* neurotoxicity), malathion
(acetylcholinesterase inhibitor), lindane
( blocks GABA channels
neurotoxicity).
Used to treat scabies ( Sarcoptes scabiei ) and
lice lPediculus and Pthirus ).

Treat PML ( Pests Mites and I ice) with PML


( Permethrin, Malathion Lindane), because
they N \G you ( Na, AChE, GABA blockade ) ,

Chloroquine
MECHANISM

Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to plasmodia.

CLINICAL USE

Treatment of plasmodial species other than P falciparum (frequency of resistance in P falciparum


is too high ). Resistance due to membrane pump that l intracellular concentration of drug. Treat
P falciparum with artemether/lumefantrine or atovaquone/proguanil. For life-threatening malaria,
use quinidine in US ( quinine elsewhere) or artcsunatc.

ADVERSE EFFECTS

Retinopathy; pruritus (especially in dark-skinned individuals ).

Antihelminthic
therapy

Mebendazole (microtubule inhibitor), pyrantel pamoate, ivermectin, diethylcarbamazine,


praziquantel.

168

SECTION II

MICROBIOLOGY ANTIMICROBIALS

MICROBIOLOGY

Antiviral therapy
HIV ANTIVIRAL
THERAPY

FUSION

ATTA< HMENI

Ml IV ' K

OTHER ANTIVIRAL
THERAPY

.- w a s

PRO

REVERSE
TRANSCRIPTASE

Receptor
binding

SYNTHESIS

PENETRATION

UMMM

transcription

^ V/x

DNA

integration

INTEGRASE

Transcription

Dolutegravif

Elviiegravir

Interferon -a
IHBV. HCV)

NRTIs
Abacavir IABCI
Didanosine (ddl)
Emtncrtabine IFTC]
Lamivudme (3TQ
Stavudine (d4T)
Tenofovir (TDF)
Zidovudine (ZDV,
formerly AZT )

Atazanavir

AS

Indnavir
Loplnavir
Ritonavir
Saquinavir

Packaging
and assombly

'

SYNTHESIS

^ ^1

Amarudlne 1LtorlBItefWdM
!l 0 yefuse !
J
n
. ..
Rimantadine
/

LL

vr.

tfavirenz
Ncv m me

Virion
assembly

PROTEASE

Darunavir
Fosamprenavir

y
NUCLEIC ACID

ftMMWII
Proteolytic

UNCOATING

NNR1 Detavirdme

v /x

Endo
cytosis

3
MAMMALIAN
CELL

CD 4 + T CELL

Guanosine analogs
Acyclovir, etc IHSV VZV)

Ganciclovir (CMV)

Viral DNA polymerase


inhibitors

Cidolovir 1 HSV*
Foscarnet / CMV

Guanmcl
e nucleotide
synthesis
Ribavirin IRSv, HCVI

Acyclovir resistant

RELEASE OF PROGENY VIRUS

Neuraminidase inhibitors
Budding

Oseltarmvirl Inllucn
. ..
/ aA B
Zanamivit
.

Release

Oseltamivir, zanamivir

I release of progeny virus.

MECHANISM

Inhibit influenza neuraminidase

CLINICAL USE

Treatment and prevention of both influenza A and B . Start within 4S hours of influenza symptom
onset.

Acyclovir, famciclovir, valacydovir


MECHANISM

Guanosinc analogs. Monophospliorylated by HSV/VZV thymidine kinase and not phosphorylatcd


in uninfected cells - few adverse effects. Triphosphate formed by cellular enzymes. Preferentially
inhibit viral DNA polymerase by chain termination.

CLINICAL USE

HSV and VZV. Weak activity against EBV No activity against CMV. Used for HSVmduced mucocutaneous and genital lesions as well as for encephalitis. Prophylaxis in
immunocompromised patients. No effect on latent forms of HSV and VZV. Valacyclovir, a

prodrug of acyclovir, has better oral bioavailability .


For herpes zoster, use famciclovir.
ADVERSE EFFECTS

Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated.

MECHANISM OF RESISTANCE

Mutated viral thymidine kinase.

170

SECTION II

HIV therapy

MICROBIOLOGY

MICROBIOLOGY ANTIMICROBIALS

Highly active antiretroviral therapy (HAART): often initiated at the time of HIV diagnosis.
Strongest indication for patients presenting with AIDS defining illness, low CD4+ cell counts
(< 50( 1 cclls/nnn?), or high viral load. Regimen consists of 5 drugs to prevent resistance:
2 NRTIs and preferrablv an integrase inhibitor.

DRUG

MECHANISM

TOXICITY

Competitively inhibit nucleotide binding to

Bone marrow suppression lean be reversed


with granulocyte colons -stimulating factor
[G-CSF] and erythropoietin ), peripheral
neuropaths, lactic acidosis ( nucleosides ),
anemia ( ZDV ), pancreatitis (didanosine).
Abacavir contraindicated if patient has
1ILV-B 5701 mutation due to t risk of

NRTIs

Abacavir ( ABC)
Didanosine (ddl)
Emtricitabine (FTC)
Lamivudine ( 3TC)
Stavudine (d4T)
Tenofovir (TDF)
Zidovudine (ZDV,
formerly AZT)

transcriptase and terminate the DNA


chain (lack a V Ol 1 group). Tenofovir is a
nucleoTide; the others arc nucleosides and
need to be phosphorylated to be active.
ZDV' can be used for general prophslaxis
and during pregnane) to t risk of fetal
transmission.
1 lave vou dined ( vudinei w ith my nuclear
(nucleosides ) family?
reverse

'

hvperscnsitivitsl

NNRTIs

Delavirdine
Efavirenz
Nevirapine

Bind to reverse transcriptase at site different


from NRTIs. Do not require phosphorylation
to be active or compete w ith nucleotides.

Rash and hcpatotoxicity are common to all


NNRTIs. Vivid dreams and CNS symptoms
are common with efavirenz. Delavirdine and
efavirenz are contraindicated in pregnancy.

Protease inhibitors
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Ritonavir
Saquinavir

Assembly of virions depends on HIV-1 protease Hyperglycemia, GI intolerance (nausea,


{ pot gene ), which cleaves the polypeptide
diarrhea), lipodystrophy (Cushing-like
syndrome).
products of HIV mRNA into their functional
Nephropathv. hematuria! thrombocytopenia
parts. Thus, protease inhibitors prevent
(indinavm
maturation of new viruses.
Ritonavir can boost other drug concentrations Rifampin (potent CYI/UCT inducer )
contraindicated with protease inhibitors
by inhibiting cytochrome P-450.
All 111V protease inhibitors end iii-navir.
because it can decrease prolease inhibitor

Navir (never ) tease a protease.

concentration; instead use rifabutii

Integrase inhibitors
Raltegravir
Elvitegravir
Dolutegravir

Inhibits HIV genome integration into host cell

'

T creatine kinase.

chromosome by reversibly inhibiting HTV


integrase.

Fusion inhibitors

Enfuvirtide

Binds gp41 inhibiting viral entry.

Maraviroc

Binds CCR-5 on surface of T cells/monocytes,


inhibiting interaction w ith gpl 20.

Skin reaction at injection sites.

MICROBIOLOGY

MICROBIOLOGY ANTIMICROBIALS I SECTION I I

T7T

Interferons
MECHANISM

CLINICAL USt

ADVERSE EFFECTS

Glycoproteins normally synthesized by virus-infected cells, exhibiting a w ide range of antiviral and
antitumoral properties.
IFN-ot; chronic hepatitis B and C, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum,
renal cell carcinoma, malignant melanoma.
IK \ P: multiple sclerosis.
IFN-y: chronic granulomatous disease.
Flu-like symptoms, depression, neutropenia, myopathy.

Hepatitis C therapy
DRUG

MECHANISM

CUNICAL USE

Ribavirin

Inhibits synthesis of guanine nucleotides


by competitively inhibiting inosine
monophosphate dehydrogenase.

Chronic IICV; also used in RSV (palivizumab


preferred in children)
Adverse effects: hemolytic anemia; severe
teratogen.

Sofosbuvir

Inhibits IICV RNA-dependent RNA polymerase Chronic IICV' in combination with ribavirin.
simeprevir. ledipasvir (NS5A inhibitor ).
acting as a chain terminator.
+/ peginterferon alfi
Do not use as monotherapy.
Adverse effects; fatigue, headache, nausea.

Simeprevir

HCY' protease inhibitor; prevents viral

replication.

Infection control

techniques

Chronic HCY' in combination with ledipasvir


(NS5A inhibitor).
Do not use as monotherapy.
Adverse effects: photosensitivity reactions, rash.

Goals include the reduction of pathogenic organism counts to safe levels (disinfection ) and the
inactiv ation of self-propagating biological entities ( sterilization)

Autoclave

Pressurized steam at > 120C. May be sporicidal.

Alcohols

Denature proteins and disrupt cell membranes. Not sporicidal.

Chlorhexidine

Denatures proteins and disrupts cell membranes. Not sporicidal.

Hydrogen peroxide

Free radical oxidation. Sporicidal.

Iodine and iodophors

Halogcnation of DNA, RNA. and proteins. May be sporicidal.

Antimicrobials to
avoid in pregnancy

ANTIMICROBIAL

AOVERSE EFFECT

Sulfonamides

Kernicterus

Aminoglycosides
Fluoroquinolones
Clarithromycin

Ototoxicity

Cartilage damage

Tetracyclines

Discolored teeth, inhibition of bone grow th

Einbryotoxic

Ribavirin

Teratogenic

Griseofulvin

Teratogenic

Chloramphenicol

Gray baby syndrome

SAFe Children Take Really Good Care.

I Pathology

HIGH- YIELD PRINCIPLES IN

Pathology

Digressions , objections, delight in mockery, carefree mistrust are signs of


health; everything unconditional belongs in pathology."

Friedrich Nietzsche

You cannot separate passion from pathology any more than


separate a person's stririt from his body."

you

can

Richard Sclzer

The fundamental principles of pathology are key to understanding


diseases in all organ systems. Major topics such as inflammation and
neoplasia appear frequently in questions across different organ systems,
and such topics are definitely high yield. For example, the concepts of
cell injury and inflammation are key to understanding the inflammatory
response that follows myocardial infarction, a very' common subject of
board questions. Similarly, a familiarity with the early cellular changes
that culminate in the development of neoplasias for example,
esophageal or colon cancer is critical. Finally, make sure you
recognize the major tumor-associated genes and are comfortable with
key cancer concepts such as tumor staging and metastasis.

Inflammation

204

Neoplasia

214

204

SECTION II

PATHOLOGY INFLAMMATION

PATHOLOGY

PATHOLOGY INFLAMMATION
ATP-dependent programmed cell death intrinsic andicxtrinsic pathway both pathways activate caspascs (cytosolic proteases) cellular
breakdown including cell shrinkage, chromatin condensation, membrane blebbing, and
formation of apoptotic bodies, w hich arc then ph igocvtoscd
Characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pvknosis muelear
shrinkage ), and karvorrbexis ( fragmentation caused hv cndonuclease-mcdi,itct
|cleavagc).
Cell membrane typically remains intact without significant inflammation ( unlike necrosis ).
ONA laddering ( fragments in multiples of 180 bp) is a sensitive indicator of apoptosis ]

Apoptosis

Involved in tissue remodeling in embryogenesis. Occurs when a regulating factor is withdrawn


from a proliferating cell population (eg. 1 IL 2 after a completed immunologic reaction
apoptosis of proliferating effector cells ). Also occurs after exposure to injurious stimuli (eg,
radiation, toxins, hypoxia)
Regulated by Bc]-2 family of proteins such as BAX and BAK (proapoptotic ) and Bcl-2
(antiapoptotic).
Bcl-2 prevents cytochrome c release by binding to and inhibiting APAF 1. APAF-1 normally
binds cytochrome c and induces activation of caspase 9, initiating caspase cascade. If Bcl-2 is
overexpressed (eg, follicular lymphoma t[ 14;18] ), then APAF-1 is overly inhibited, t caspase
activation and tumorigenesis.

Intrinsic
(mitochondrial )

pathway

2 pathways:
Ligand receptor interactions ( FasL binding to Fas [CD95 ] or TNF-ot binding to its receptoj)
Immune cell (cytotoxic T-cell release of perforin and granzyme B)
Fas-FasL interaction is necessary in thymic medullary negative selection. Mutations in Fas
t numbers of circulating self-reacting lymphocytes due to failure of clonal deletion.
Defective Fas-FasL interactions cause autoimmune lymphoproliferative syndrome.

Extrinsic (death
receptor) pathway

Intrinsic

Extrinsic

(mitochondrial) pathway

(death receptor ) pathway

Fa$L /}
DNA damage
Radiation, ROS, toxins
Misfolded proteins
Hypoxia

r t

^ TNFu
J

Cytotoxic T cell
Granzyme

efforin

ospasa

pS 5 activation
ytoctirome C

BAXTBAK

be

KM

Execu m
caspases

.r

APAF-1

Macrophage

Initiator
caspases

ft
Wj/tefetal dispersion
rsion

Cytoplasmic
b eb

/ 2

,/

Ligands for
macrophage cell
receptors

_
Apoptotic
body

IA
H

i[
11 > 1
Figure

PATHOLOGY

PATHOLOGY

Necrosis

INFLAMMATION

Enzymatic degradation and protein denaturation of cell due to exogenous injury


components leak. Inflammatory process ( unlike apoptosis ).

TYPE

SEEN IN

DUE TO

Coagulative

Ischemia/infarcts in
most tissues (except
brain)

Ischemia or infarction ;

Liquefactive

Bacterial abscesses,
brain infarcti

Neutrophils release
lysosomal enzymes
that digest the

HISTOLOGY

205

SECTION II

intracellular

Cell outlines preserved but nuclei disappear


t cytoplasmic binding of eosinjdyes Q
proteins denature, then
enzymatic degradation

Early: cellular debris and macrophages


Late: cystic spaces and cavitation ( brain )
Neutrophils and cell dehris seen with
bacterial infection

tissue H: enzymatic

Caseous

TB, systemic fungi


( eg. Histoplasma
capsulation ), Nocardia

Fat

Enzymatic: acute
pancreatitis
(saponification of
peripancreatic fat )
Nonenzymatic:
traumatic (eg, breast

degradation first , then


proteins denature
Macrophages wall
off the infecting
microorganism
granular debris Q

Damaged

Fragmented cells and debris surrounded by


lymphocytes and macrophages

Outlines of dead fat cells without peripheral


nuclei ; saponification of fat ( combined with
C;r ' i appears dark blue on I I & E stain 0

cells release

lipase to break
down triglycerides.
liberating fatty acids

'

to bind calcium

-* saponification

injury )
Fibrinoid

Vessel walls are thick and pink 0

Immune complexes
Immune reactions in
vessels ( eg. polvartcritis combine with
nodosa ) , preedampsia .
fibrin - vessel wall
malignant
damage ( type III
hypertension!

hypersensitivity

reaction!
Gangrenous

Distal extremity and


Cl tractL after chronic
ischemia

48 - .
'

w*

Coagulative
Liquefactive superimposed on coagulative

Dry: ischemia Q
Wet: superinfection

v
w

.**

>

-- -

'

\
*

K
Uv

: SW

r,

YVI

*
Cell injury

PATHOLOGY

PATHOLOGY INFLAMMATION

REVERSIBLE WITH 02

IRREVERSIBLE

Cellular /mitoehondrial swelling (1 ATP


-* 1 activity of VC/ICL ami Ca niinml

Mitochondrial permeability /v acuolization;


phospholipid-containing amorphous densities
within mitochondria (swelling alone is
reversible)

Nuclear chromatin clumping

Nuclear pvknosis ( condensation), karvorrhexis


( fragmentation ), karyolysis ( fading)
Plasma membrane damage (degradation of
membrane phospholipid)

Membrane blebbing
1 glycogen
Fatty change
Kibosomal/polysomal detachment Ii protein
synthesis)

Ischemia

llmaael

Inadequate blood supply to meet demand.


Regions most vulnerable to hypoxia /ischemia and subsequent infarction:
ORGAN

REGION

Brain

ACA/MCA /PCA boundary areasjb

Heart

Subendocardium ( LV )

Kidney

Straight segment of proximal tubule (medulla )


Thick ascending limb (medulla)
Area around central vein (zone III)

Liver
I New I

Lysosomal rupture
Cali influx easpase activation - apoptosis

Splenic flexure,3 rectum'1


Watershed areas ( border zones) receive blood supply from most distal branches of 2 arteries with
limited collateral vascularity. These areas are susceptible to ischemia from hypoperfusion ( blue

Colon

area in Ql

^Neurons most vulnerable to hypoxic-ischemic insults include Purkinje cells of the cerebellum and
pyramidal cells of the hippocampus and neocortex ( zones 3, 5 , 6|

PATHOLOGY

PATHOLOGY INFLAMMATION

SECTION II

207

Types of Infarct j

Red Infarct!

Pale (anemic) infarcts Q occur in solid organs with a single (end-arterial ) blood supply, such as
heart, kidney, and spleen.

Pale Infarcti

L-

Red ( hemorrhagic ) infarcts Q occur in venous occlusion and tissues with multiple blood supplies,
such as liver, lung, intestine, testes; reperfusion ( eg, after angioplasty ). Reperfusion injury is due to
damage by free radicals.
Red = reperfusion.

m
'

Inflammation

Characterized by rubor (redness), dolor (pain ), color ( heat), tumor ( swelling), and

functio luesa ( loss of function).


Vascular component

t vascular permeability, vasodilation, endothelial injury.

Cellular component

Neutrophils extravasate from circulation to injured tissue to participate in inflammation through


phagocytosis, degranulation, and inflammatory mediator release.
Neutrophil, eosinophil, and antibody ( pre-existing), mast cell, and basophil mediatecj
Acute inflammation is rapid onset ( seconds to minutesl and of short duration (minutes to
days). Outcomes include complete resolution, abscess formation, or progression to chronic
inflammation.
Mononuclear cell (monocytes/macrophages, lymphocytes, plasma cells) and fibroblast mediated.
Characterized by persistent destruction and repair. Associated with blood vessel proliferation,
fibrosis. Granuloma: nodular collections of epithelioid macrophages and giant cells. Outcomes
include scarring and amyloidosis.

Acute

Chronic

208

SECTION II

PATHOLOGY

PATHOLOGY

INFLAMMATION

Types of calcification

Dystrophic
calcification

m
i

Ca -+ deposition in abnormal tissues 2 to injury or necrosis.


lends to be localized (eg, calcific aortic stenosis ). 3 shows dystrophic calcification ( yellow star),
small bony tissue ( yellow arrow's), and thick fibrotic wall (red arrows).
Seen in I B ( lung and pericardium ) and other granulomatous infectionj liquefactive necrosis
of chronic abscesses, fat necrosis, infarcts, thrombi, schistosomiasis, congenital CMV
+ toxoplasmosis + rubellij psammoma bodies. CREST svndronnj
Is not directly associated with scrum Ca + levels ( patients arc usually nomiocalccmic ).

&

Metastatic
calcification

1u.

Widespread ( ie, diffuse, metastatic) deposition of Ca-4 in normal tissue 2 to hypercalcemia (eg,
1 hyperparathyroidism, sarcoidosis, hvpervitaminosis D) or high calcium -phosphate product
levels (eg, chronic renal failure with 2 hyperparathyroidism, long-temi dialysis, calciphvlaxis,
multiple mvclom 4) .

shows metastatic calcifications of alveolar walls in acute pneumonitis rrows).


Ca + deposits predominantly in interstitial tissues of kidney, lung, and gastric mucosa (these tissues
lose acid quickly; t pH favors deposition ). Nephrocalcinosis of collecting ducts may lead to
nephrogenic diabetes insipidujand renal failurcj
Patients are usually not normocalcemic.

Inhalationlinjury and
sequelae

PATHOLOGY

PATHOLOGY INFLAMMATION

Pulmonary complication associated with smoke


and fire. Caused by heat , particulates (< 1 |im
diameter), or irritants (eg. NIK ) -* chemical
tracheobronchitis, edema , pneumonia,
ARDS. Many patients present 2 to burns,
COjjnhalation, or arsenic poisoning.

Bronchoscopy shows severe edema, congestion


of bronchus, and soot deposition (Q, 18 hours
after inhalation injury; Q, resolution at 11 days
after injury).

Scar formation

70-807c of tensile strength regained at T months iwhcn type I collagen is replaced with type III
collagent little additional tensile strength will be regained afterward.

SCAR TYPE

Hypertrophic Q

Keloid

COLLAGEN SYNTHESIS

t ftvne I collagen!

ttt ( type III collagen )

COLLAGEN ORGANIZATION

Parallel

Disorganized

EXTENT OF SCAR

Confined to borders of original wound

SCAR EVOLUTION OVER YEARS

RECURRENCE

Possible spontaneous regression


Infrequent

Extends beyond borders of original wound with


clawlike projections typically on earlobes,
face, upper extremities
Possible progressive grow'th

Frequent

PREDISPOSITION

None

t incidence in ethnic groups with darker skin

\"
\

*YS

PATHOLOGY

Wound healing
Tissue mediators

PATHOLOGY

INFLAMMATION

SECTION II

MEDIATOR

ROLE

PDGF

Secreted by activ ated platelets and macrophages


Induces vascular remodeling and smooth muscle

TC F-P

cell migration
Stimulates fibroblast growth for collagen synthesis
Stimulates angiogenesis
Stimulates cell growth via tyrosine kinases (eg,
EGFR /ErbBi )
Angiogenesis, fibrosi .

Metalloproteinases

Tissue remodeling

FCF

EGF

VEGF

Stimulates angiogenesis

PHASE OF WOUND HEAUNG

EFFECTOR CELLS

CHARACTERISTICS

Inflammatory (up to
3 days after wound)

Platelets, neutrophils, macrophages

Proliferative
(day 3-weeks after
wound )

Fibroblasts, myofibroblasts, endothelial cells,


keratinocytes, macrophages

Clot formation, t vessel permeability and


neutrophil migration into tissue; macrophages
clear debris 2 days later
Deposition of granulation tissue and type
III collagen, angiogenesis, epithelial cell
proliferation, dissolution of clot , and wound
contraction ( mediated by myofibroblasts)^
Delayed wound healing in vitamin C deficiency
and copper deficiency

Remodeling
( 1 week -6+ months
after wound )

Granulomatous
diseases

mmma

Fibroblasts

Type III collagen replaced by ty pe 1 collagen ,


t tensile strength of tissue
Delayed wound healing in zinc deficiency

Bacterial :
1

Mycobacteria (tuberculosis, leprosy)


Bartonella henselae (cat scratch disease)
Listeria monocytogenes ( granulomatosis

infantiseptica )
Treponema pallidum ( 3 syphilis)
Fungal: endemic mycoses ( eg, histoplasmosis)
Parasitic: schistosomiasis
Chronic granulomatous disease
Autoinflammatory:
Sarcoidosis Q
Crohn disease
* Primary biliary cirrhosis
Subacute (de Quervain/granulomatous )
thyroiditis
Granulomatosis with polyangiitis ( Wegener)
Eosinophilic granulomatosis with
polyangiitis ( Churg-Strauss)
Giant cell ( temporal ) arteritis
Takayasu arteritis
Foreign material : berylliosis, talcosis,
hypersensitivity pneumonitis

Granulomas arc composed of epitheloid cells


{ macrophages w ith abundant pink cytoplasm I
with surrounding multinucleated giant
cells and lymphocytes. ITiJcclls secrete
IFN-y, activating macrophages. TNF-a
from macrophages induces and maintains
granuloma formation . Anti-TNF drugs can , as
a side effect , cause sequestering granulomas to
break down , leading to disseminated disease.
Always test for latent TB before starting antiTNF therapy.
Associated with hypercalcemia due to caleitriol
( ],25-[OH], vitamin D?) production .
Caseating necrosis more common with
infectious causes (eg, TB). Diagnosing
sarcoidosis requires noncaseating granulomas
on biopsy.

Exudate vs transudate

Exudate

Transudatgl

Cellular (cloudy)
t protein ( > 2.9 e/dl .i
f LDH ( vs scrum )
Due to:
Lymphatic obstruction (chylous)
Inflammation /infection
- Malignancy

Hypocellular (clear)
i protein (< 2.5 g/dl
t LDH (vs serum )

Due to:

t
*

hydrostatic

pressure (eg, IIF, Na +

retention )
i oncotic pressure ( eg, cirrhosis, nephrotic

syndrome )

Lights criteria

Diagnostic analysis comparing serum and pleural fluid protein and LDII levels.
If > 1 criterion is met * effusion is likelv exudative.
IfO criteria are met by definition , effusion is transudative.
1 . Pleural protein /seruin protein ratio > 0.5
2. Pleural LDH /scrum LDH ratio > 0.6
r Pleural LDH > of Hie upper limit of normal for serum LDH

Erythrocyte
sedimentation rate

Products of inflammation ( eg, fibrinogen ) coat RBCs and cause aggregation . The denser RBC
aggregates fall at a faster rale within a pipette tube. Often co-tested with CRP levels.

t ESR

i ESR

Most anemias
Infections
Inflammation (eg, giant cell [temporal] arteritis,
polymyalgia rheumatica )
Cancer (eg, metastases, multiple myeloma )
Renal disease (end-stage or nephrotic syndrome )
Pregnancy

Sickle cell anemia (altered shape )


Polycythemia ( t RBCs "dilute aggregation
factors)
I IF
Microcytosis
Hvpofibrinogenemia

PATHOLOGY INFLAMMATION

PATHOLOGY

kocyte
avasation

SECTION II

209

Extravasation predominantlv occurs at postcapillary venules.


WBCs exit from blood vessels at sites of tissue injur) and inflammation in 4 steps:
VASCULATURE/STROMA

O Margination and rolling

K-sclectin ( from

defective in

WeibcT -

Palade bodies!

leukocyte adhesion deficiency type 2


( J Sialyl-Lewisx)

Tight binding (adhesion)

LEUKOCYTE

P-selectin
GlyCAM-1, CD54
ICAM-1 (CD54)

defectivjin

leukocyte adhesion deficiency type 1


(I CD18 integrin subunit)

Diapedesis WBC travels between

Sialyl-Lewisx
Sialyl-Lewisx
L-selectin

VCAM-1 (CD106)

COll /18 integrins


(LFA 1, Mac-1)
VLA-4 integrin

PECAM-1 (CD31)

PECAM-1 (CD31)

Chemotactic products
released in response
to bacteria: C5a, IL-8,
LTB4, kallikrein,
platelet-activating factor

Various

endothelial cells and exits blood vessel

Migration WBC travels through


interstitium to site of injury or infection
guided by chemotactic signals

I MN

O Margination 6 rolling

Diapedesis Migration

Tight binding
Sialyl-Lewis'

Vesse
umet

PMN
PMN

E- - ei 1

LFA -1

JJ

Ijg

Endothelium

Interstitium

ICAM-1

PMN

^^
Ml
PMN

>

radical injury

Free radicals damage cells via membrane lipid peroxidation, protein modification, and DNA
breakage.
Initiated via radiation exposure (eg, cancer therapy), metabolism of drugs ( phaseI), redox reactions,
nitric oxide (eg inflammation)!transition metals, WBC (eg, neutrophils, macrophages) oxidative
burst.
Free radicals can be eliminated by scavenging enzymes (eg, catalase, superoxide dismutase,
glutathione peroxidase), spontaneous decay, antioxidants (eg, vitamins A, C,E), and certain metal
carrier proteins (eg, transferrin, ceruloplasmin)

Examples:
Oxygen toxicity: retinopathy of prematurity ( abnormal vascularization), bronchopulmonary
dysplasia, reperfusion injury after thrombolytic thcrapsl
* Drug/chemical toxicity: carbon tetrachloride and acetaminophen overdose (hepatotoxicitv)
Metal storage diseases: hemochromatosis (iron) and Wilson disease (copper)

PATHOLOGY

PATHOLOGY

INFLAMMATION

213

SECTION II

Abnormal aggregation of protcins (or their fragments ) into (3-plcatcd linear sheets damage
and apoptosis. Amyloid deposits visualized by Congo red stain Q, polarized light ( apple green
birefringence) Q, and I l&E stain (Q shows deposits in glomerular mesangial areas [white arrows],
tubular basement membranes [ black arrows] ).

Amyloidosis

COMMON TYPES

DESCRIPTION

AL ( primary )

Due to deposition of proteins from Ig Light chains. Can occur as a plasma cell disorder or
associated with multiple myeloma. Often affects multiple organ systems, including renal
( nephrotic syndrome), cardiac ( restrictive cardiomyopathy, arrhythmia), hematologic (easy
bruising, splenomegaly). G1 ( hepatomegaly), and neurologic ( neuropathy).
Seen with chronic inflammatory conditions such as rheumatoid arthritis, IBD,
spondyloarthropathy, familial Mediterranean fever, protracted infection . Fibrils composed of
serum Amyloid A. Often multisystem like AL amyloidosis.
Fibrils composed of [A -inicroglobulni in patients with FSRD and /or on long-term dialysis. May
present as carpal tunnel syndrome.
Heterogeneous group of disorders, including familial amyloid polyneuropathies due to transthyretin
gene mutation.
Due to deposition of normal ( wild- type) transthyretin (TTR ) predominantly in cardiac ventricles.
Slower progression of cardiac dysfunction relative to AL amyloidosis.
Amyloid deposition localized to a single organ . Most important form is amyloidosis in Alzheimer
disease due to deposition of fT-amyloid protein cleaved from amyloid precursor protein ( APP).
Islet amyloid polypeptide ( IAPP ) is commonly seen in diabetes mcllitus type 2 and is caused by
deposition of amylin in pancreatic islets.
Isolated atrial amyloidosis due to atrial natriuretic peptide is common in normal aging, which can
predispose to t risk of atrial fibrillatiorj
Amyloid deposition lo ventricular eiidinmocardiinii in restrictive cardiomyopathy
Calcitonin deposition in tumor cells in medullary carcinoma of the thvroid.

AA (secondary)

Dialysis- related

Heritable
Age - related (senile)
systemic
Organ - specific

mm
n
a

'

'

rf s

'-

i.

Lipofuscin

im
/.

mm
fa

i
tv

\w

"

-V\ .

-6

.
.

'

rN

* 1
j

A yellow -brown "wear and tear * pigment associated w ith normal aging.
Formed by oxidation and polymerization of autophagoevtosed organellar membranes.
Autopsy of elderly person will reveal deposits in heart , colon Cl, liv er, kidney, eye, and other organs.

214

SECTION II

PATHOLOGY

PATHOLOGY NEOPLASIA

PATHOLOGY NEOPLASIA

Cjellular changes
Hyperplasia!

t in number of cells. May be a risk factor for future malignancy (eg, endometrial hyperplasia | but
not considered premalignanl!

Hypertrophy

f in size of cells.

Atrophy

iin tissue mass due to l in size and/or number of cells. Causes inc lude disuse, denervation, loss of
blood supply, loss of hormonal stimulation, poor nutrition.

Dysplasia

Disordered, non-neoplastic cell growth Term used only with epithelial cells. Mild dysplasia is
usually reversible: severe dysplasia usually progresses to carcinoma in situ.

Metaplasial

Replacement of one cell type by another. Usually due to exposure to an irritant, such as gastric
acid or cigarette smoke. Reversible if the irritant is removed but may undergo malignant
transformation with persistent insult leg, Barrett esophagus esophageal adenocarcinoma )!

Neoplasial

Uncontrolled, clonal proliferation of cells. Can be benign or malignant!


Complete lack of differentiation of cells in a malignant neoplasm.
The degree to which a malignant tumor resembles its tissue of origin;

Anaplasia

Differentiation!

Well-differentiated tumors ( often less aggressive) closely resemble t heir tissue of origin
Poorly differentiated tumors ( often more aggrcssivel look almost nothing like their tissue of
origiij

f * r>*\i

Hyperplasia

Change in cell size


and number

Reversible
Hypertrophy


Normal cells

Change in cell type


and structure

Dysplasia

Reversible

Atrophy

Irreversible

Metaplasia

Change in
cell type
and structure

ntfffy i '
Neoplasia

Anaplasia

I New I
[Figure ]

PATHOLOGY NEOPLASIA

PATHOLOGY

SECTION II

215

Hallmarks of cancer: evasion of apoptosis, growth signal self-sufficiency, anti-growth signal


insensitivity, sustained angiogenesis, limitless replicative potential, tissue invasion, and metastasis.

Neoplastic
progression

Normal cells w ith hasal apical pol rritvi See cervical example Q, which shows normal cells and
spectrum of dysplasia, as discussed below

Normal cells

OMOIOM o;

MM

Abnormal proliferation of cells with loss of si/c, shape, and orientation (eg, koilocvtic change, arrow
in ijComparc vs hyperplasia l cells t in number ).

Dysplasia

'

Neoplastic cells have not invaded the intact basement membrane,


t Ikiuclearcvtoplasmid ratio and clumped chromatin.
Neoplastic cells encompass entire thickness.

Carcinoma in situ/
preinvasive

m
sst

Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases).
Cell-cell contacts lost by inactivation of f -cadhcrin.

Invasive carcinoma

Spread to distant organ via lymphatics or bloodt

Metastasis

"Seed and soil

theory of metastasis:

* Seed = tumor embolus.


Soil = target organ is often the first-encountered capillary bed ( eg, liver, lungs, bone, brain, etc ).

J
Blood Of
tympfutic

Normal

Mild dysplasia

Moderate dysplasia

Severe dysplasia/
carcinoma in situ

216

SECTION II

PATHOLOGY

PATHOLOGY NEOPLASIA

Tumor grade vs stage

Grade

Degree of cellular differentiation and mitotic


activity on histology. Range from low grade
(well differentiated ) to high grade ( poorly
differentiated, undifferentiated or anaplastic).

Stage almost always has more prognostic value


than grade.
TNM staging system is used with mam
cancers ; exceptions include brain tumors and
leukemia jj

Stage

Degree of localization/spread based on site and


size of 1 lesion, spread to regional lymph
nodes, presence of metastases. Based on
clinical (c) or pathology (p) findings. Example:
cTsNlMO

TNM staging system ( Stage = Spread ):


T = Tumor size/local invasion!
N = Node involvement
M = Metastases
Each TNM factor has independent prognosticvalue; M factor often most important.

Tumor nomenclature

Carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms

imply malignancy.
Terms for non-neoplastic malformations include hamartoma (disorganized overgrowth of tissues in
their native location, eg, Peutz -Jeghers polyps) and choristoma (normal tissue in a foreign location,
eg, gastric tissue located in distal ileum in Meckel diverticulum).
Benign tumor is usually well differentiated, well demarcated, low mitotic activity, no metastasis, no

necrosis.
Malignant tumor may show poor differentiation, erratic growth, local invasion, metastasis, and
1 apoptosis. Upregulation of telomerase prevents chromosome shortening and cell death.
CELL TYPE

BENIGN

MALIGNANT

Epithelium

Adenoma, papilloma

Adenocarcinoma, papillary carcinoma

Blood vessels

Hemangioma

Angiosarcoma

Smooth muscle

Leiomyoma

Leiomyosarcoma

Mesenchyme

Leukemia, lymphoma

Blood cells

Striated muscle

Rhabdomyoma

Rhabdomyosarcoma

Connective tissue

Fibroma

Fibrosarcoma

Bone

Osteoma

Osteosarcoma

Fat

Lipoma

Melanocyte

Nevus/mole

Liposarcoma
Melanoma

Cancer epidemiology

Skin cancer ( basal > squamous melanoma) is the most common cancer ( not included in list).
MEM

Cancer incidencel

NOTES

1. Pros!

Coll Copied to clipboard.

: i .iitil
r

Cancer mortality

WQME'A

1. Lung
2. Prostate
v Colon /rectum

l. Lung
2. Breast
3. Colon /rectum

1. Leukemia
2. Brain and CNS
3,

Neuroblastoma

|Lung cancer incidence has


dropped in men, but has
not changed significantly in
women

Cancer is the 2nd leading cause


of death in the United States
(heart disease is 1st).

PATHOLOGY

PATHOLOGY NEOPLASIA

Tumor grade vs stage

Grade

Stage almost alw ays has more prognostic v alue


than grade.
TNM staging system is used with many
cancers; exceptions include brain tumors and

Degree of cellular differentiation and mitotic


activity on histology. Range from low grade
(well differentiated) to high grade (poorly
differentiated, undifferentiated or anaplastic).

leukemias!!
Stage

Tumor nomenclature

Degree of localization/spread based on site and


size of 1 lesion, spread to regional lymph
nodes, presence of metastases. Based on
clinical (c ) or pathology ip ) findings. Example:
CT3N1M0

TNM staging system ( Stage = Spread):


1 = Tumor sizc /local invasion!
N = Node involvement
M = Metastases
Each TNM factor has independent prognostic
value; M factor often most important.

Carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms

imply malignancy.
Terms for non-neoplastic malformations include hamartoma ( disorganized overgrow th of tissues in
their native location, eg, Peutz-Jeghers polyps) and choristoma (normal tissue in a foreign location,
eg, gastric tissue located in distal ileum in Meckel diverticulum ).
Benign tumor is usually well differentiated, well demarcated, low mitotic activity, no metastasis, no
necrosis.
Malignant tumor may show poor differentiation erratic grow th, local invasion, metastasis, and
t apoptosis. Uprcgulation of telomcrasc prevents chromosome shortening and cell death.

CELL TYPE

BENIGN

MALIGNANT

Epithelium

Adenoma, papilloma

Adenocarcinoma, papillary carcinoma

Mesenchyme

Leukemia, lymphoma

Blood cells

Blood vessels

Hemangioma

Angiosarcoma

Smooth muscle

Leiomyoma

Leiomyosarcoma

Striated muscle

Rhabdomyoma

Rhabdomyosarcoma

Connective tissue

Fibroma

Fibrosarcoma

Bone

Osteoma

Osteosarcoma

Fat

Lipoma
Nevus/mole

Liposarcoma
Melanoma

Melanocyte

Cancer epidemiology

Cancer incidence!

Skin cancer ( basal > squamous melanoma) is the most common cancer (not included in list ).
NOTES
CHILDREN (AGE 0-14)
WOMEU
MEty
I. Prostate
1. Breast
1. Leukemia
Lung cancer incidence has
2. Brain and CNS
2. Lung
2. Lung
dropped in men, but has
'
5. Colon/rectum
3. Colon /rcctum
not changed significantly ii
. Neuroblastoma

women

Cancer mortality

1. Lung
2. Prostate
3. Colon /rcctum

1. Lung
2. Breast
3. Colon /rcctum

1. Leukemia
2. Brain and CNS
v

Neuroblastoma

Cancer is the 2nd leading cause


of death in the United States
( heart disease is 1st ).

PATHOLOGY

PATHOLOGY NEOPLASIA

SECTION II

217

Paraneoplastic syndromes
DESCRIPTION /MECHANISM

MOST COMMONLY ASSOCIATED CANCER (S)

Acanthosis nigricans

1lyperpigmented velvety plagues in axilla and


neck

Gastric adenocarcinoma and other visceral


malignancies |but more commonly associated
with obesity and insulin resistance)

Sign of Leser-Trelat

Sudden onset of multiple seborrheic keratoses

GI adenocarcinomas and other visceral

MANIFESTATION

Cutaneous

malignancies
Endocrine

Hypercalcemia

Squamous cell carcinomas of lung, head, and


neck; renal, bladder, breast, and ovarian

PTHrP

carcinomas

t 1,25 -( OHN vitamin D (calcitriol )

Cushing syndrome

t ACTH

Lymphoma
Small cell lung cancer

Hyponatremia (SIADH)

t ADH

Small cell lung cancer

Polycythemia

T Krythropoietin

Renal cell carcinoma, hepatocellular


carcinoma, hemangioblastoma,
pheochroinocytoina, leiomyoma

Hematologic

Pure red cell aplasia

Anemia with low reticulocytes

Thymoma

Good syndrome

1 lypogammaglobulinemia

Thymoma

Trousseau syndrome

Migrators superficial thrombophlebitis

Adenocarcinomas, especially pancreatic

Nonbacterial
thrombotic (marantic)
endocarditis

Deposition of sterile platelet thrombi on heart


valves

Adenocarcinomas, especially pancreatic

Anti-NMDA receptor
encephalitis

Psychiatric disturbance, memory deficits,


seizures, dyskinesias, autonomic instability,
language dysfunction

Ovarian teratoma

Opsoclonusmyoclonus ataxia
syndrome

Dancing eyes, dancing feet

Neuroblastoma (children), small cell lung


cancer (adults)

Paraneoplastic
cerebellar
degeneration

Antibodies against antigens in Purkinjtlcells

Small cell lung cancer (anti-1lu ), gvnecologic

Paraneoplastic
encephalomyelitis

Antibodies against Hu antigens in neurons

Lambert-Eaton
myasthenic syndrome

Antibodies against prcsynaptic (P/Q type) Ca+


channels at NMJ

Myasthenia gravis

Antibodies against postsvnaptic ACh receptor

Neuromuscular

and breast cancers (anti-Yo) and Hodgkin


lymphoma ianti-Tri

Small cell lung cancer

at NMJ

Small cell lung cancer

Thymoma

218

SECTION II

Oncogenes

PATHOLOGY NEOPLASIA

PATHOLOGY

Gain of function - t cancer risk. Need damage to only one allele of an oncogens

GENE

GENE PRODUCT

ASSOCIATED NEOPLASM

ALK

Receptor tyrosine kinase

Lung adenocarcinoma

BCR- ABL

Tyrosine kinase

CML, ALL

BCL-2

Anliapoptotic molecule (inhibits apoptosis!

BRAF

Serinc /threonine kinase

Follicular and diffuse large B cell lymphomas


Melanoma. non-Hodgkin lvmphoma, papillary

c- KIT

Cytokine receptor

Gastrointestinal stromal tumor (GIST )

thy roid carcinoma!

c-MYC

Transcription factor

Burkitt lymphoma

HER2 / neu (c- erbB2 )

Receptor ty rosine kinasel

Breast and gastric carcinomas

JAK2

Tyrosine kinase

Chronic myeloproliferative disorders

KRAS

GTPase

Colon cancer, lung cancer, pancreatic cancer

mat
MYCN

Transcription factor
Transcription factor

Neuroblastoma

RET

Receptor tyrosine kinasa

MEN 2 A and 2B, medullary thyroid cancer

Tumor suppressor
genes

Loss of function

Lung tumor

t cancer risk; both ( trvni alleles of a tumor suppressor gene must be lost for

expression of disease

GENE

GENE PRODUCT

ASSOCIATED CONDITION

APC

Negative regulator of B-catenin/WNT pathway

Colorectal cancer (associated rvith FAP)

BRCA1/BRCA2

DNA repair protein

Breast, ovarian, and pancreatic canceil

CDKN2 A

Melanoma, pancreatic cancer

DCC

. blocks G, -* S phase
DCC Deleted in Colon Cancer

DPC4/SMAD4

DPC Deleted in Pancreatic Cancer

Pancreatic cancer

MEN!

Menin

MEN 1

NF1

Ras C 1 Pa sc activating protein (neurofibromin )

Neurofibromatosis type 1

Columns

NF2

Merlin ischwannomin) protein

Neurofibromatosis type 2

2 & 3 were

PTEN

pi 6

- .

Tyrosine phosphatase of PIP (eg protein kinase

B lAKTl activation)
Rb

Inhibits E2F; blocks G]

TPS3

p53 activates p21

-* S phase

. blocks Gi

S phase

Colon cancer

Breast cancer, prostate cancer, endometrial


cancer

Retinoblastoma, osteosarcoma

Most human cancers, Li Fraumeni syndrome


(multiple malignancies at early age aka, SBI ,A
cancer sy ndrome: Sarcoma, Breast, Leukemia,
)
Adrenal gland!

TSC1

Hamartin protein

Tuberous sclerosis

TSC2

Tuberin protein

Tuberous sclerosis

VHL

Inhibits hypoxia inducible factor la

von Hippel-Lindau discasej

WT 1{

Transcription factor that regulates urogenital


development

Wilms Tumor (nephroblastoma)

220

SECTION II

Psammoma bodies

PATHOLOGY

PATHOLOGY NEOPLASIA

Laminated, concentric spherules with dystrophic calcification Q, PSaMMoma bodies arc seen in:
Papillary carcinoma of thyroid
Serous papillary cystadenocarcinoma of ovary
Meningioma
Malignant mesothelioma
T

Serum tumor markers

Tumor markers should not be used as the 1 tool for cancer diagnosis or screening. T hey may be
used to monitor tumor recurrence and response to therapy, but definitive diagnosis is usually made
via biopsy.

MARKER

ASSOCIATED CANCER

Alkaline phosphatase

Mctastascs to bone or liver Paget disease of


bone, seminoma ( placental ALP).

a- fetoprotein

Hepatocellular carcinoma, hepatoblastoma, yolk Normally made by fetus. Transiently elevated in


sac (endodermal sinus) tumor, mixed germ
pregnancy. High levels associated with neural
cell tumor.
tube and abdominal wall defects, low levels
associated with Down syndrome.
Produced by syncyTiotrophoblasts of the
I lydatidiform moles and Choriocarcinomas
(Gestational trophoblastic disease), testicular
placenta.
cancer, mixed germ cell tumor.
Breast cancer.

PhCG
CA 15-3/CA 27-29

NOTES

CA 19- 9

Pancreatic adenocarcinoma.

CA 125

Ovarian cancer.

Calcitonin

Medullary thvroid carcinoma

Must exclude hepatic origin bv checking LKTs


and CCT levels.

..

lalone and in

MEN2 A MEN2B ) ]
CEA

Carcinoembrvonic antigen. Very nonspecific.

Major associations: colorectal and pancreatic


cancers.

Minor associations: gastric, breast, and


medullary thvroid carcinomas]

Chromoaranin

Neuroendocrine tumors.

PSA

Prostate cancer.

Prostate-specific antigen

Can also be elevated in BPH and prostatitis.


Questionable risk /benefit for screening.
Surveillance marker for recurrent disease after
prostatectonn]

P-glycoprotein

Also known as multidrug resistance protein 1 MDR 1). Classically seen in adrenocortical
carcinom hut also expressed bv other cancer cells ( eg colon, liver). Used to pump out toxins
including chemotherapeutic agents ( one mechanism of l responsiveness or resistance to
chemotherapy over time).
i

PATHOLOGY

PATHOLOGY NEOPLASIA

SECTION II

Cachexia

Weight loss, muscle atrophy, and fatigue that occur in chronic disease (eg, cancer, AIDS, heart
failure, COPD). Mediated by TNF, IFN-y, IL-1, and IL-6.

Common metastases

Most sarcomas spread hematogenously; most carcinomas spread via lymphatics. However, four
carcinomas route hcmatogcnouslv: follicular thyroid carcinoma, choriocarcinoma, renal cell
carcinoma, and hepatocellular carcinoma!

SITE OF METASTASIS

1 TUMOR

Brain

Lung > breas||> melanoma, colon, kidneii

221

NOTES

50% of brain tumors are from metastases Q 0.


Commonly seen as multiple well- circumscribed

tumors at gray/white matter junction

Liver

Colon stomach > pancreas.

Livcr Q 0 and lung are the most common sites


of metastasis after the regional lymph nodes.

Bone

Prostate, breast > lung, thyroid, kidney.

Bone metastasis Q Q 1 bone tumors (eg,


multiple myeloma, lytic). Common mets to
bone: breast (mixed),lung (mixed), thyroid
( lytic), kidney ( lytic), prostate ( blastic).

Predilection for axial skeleton 0

m
b.

m<

'

'

226

SECTION II

PHARMACOLOGY PHARMACOKINETICS & PHARMACODYNAMICS

PHARMACOLOGY

Elimination of drugs

Zero- order
elimination

Rate of elimination is constant regardless of Cp


( ie, constant amount of drug eliminated per
unit time ). C i linearly with time. Examples
of drugs Phcnytoin, Ethanol, and Aspirin ( at
high or toxic concentrations)

Capacity-limited elimination.
PEA . (A pea is round, shaped like the 0 in

Rate of elimination is directly proportional


to the drug concentration (ie, constant
fraction of drug eliminated per unit time).
Cp i exponentially with time. Applies to most
drugs.

Flow -dependent elimination.

zero-order.)

First- order elimination

Zero order elimination

First order elimination

Elimination rate
2 U/h

Elimination rate
4 U/ h

.
!

Time of tj/ j is constant

Time of tw J,as
concentration J.

:ui

Firjl lUj >

as concentration l

First ty2

2 U /h

lU/h

\ 2 U/ h

Second tl/2 >

devisee
Figure

Second

^ = TYlirdti

Q 5 U/h

/j

Time (h)

Time (h)

Urine pH and drug


elimination
Weak acids

Ionized species are trapped in urine and cleared quickly. Neutral forms can be reabsorbed.

Examples: phenobarbital, methotrexate, aspirin. Trapped in basic environments. Treat overdose


with bicarbonate to alkalinizc urincj
RCOOI 1
(lipid soluble )

Weak bases

S3

RCOO- + IP
(trapped )

Example: amphetamines, TCAs. Trapped in acidic environments. Treat overdose with ammonium
chloride to acidify urincj
RNH *

RNH:+ H+

( trapped )

(lipid soluble )

Drug metabolism

Geriatric patients lose phase I first.

Phase 1

Reduction, oxidation, hydrolysis with


cytochrome P-450 usually yield slightly polar,
water- soluble metabolites (often still active).

Phase II

Ccriatric patients have More GAS ( phase II ) .


Conjugation ( Mcthvlation, Glucuronidation,
Xcetylation, Sulfation) usually yields very polar, Patients who are slow acetylators have t side
effects from certain drugs because of l rate of
inactive metabolites (renally excreted ).

metabolism.

228

SECTION I I

PHARMACOLOGY PHARMACOKINETICS & PHARMACODYNAMICS

PHARMACOLOGY

Receptor binding

Agonist plus
competitive
antagonist

Agonist

alone

Agonist

al< ne

Effect of

antagonist

I 50

Lower
efficacy

Agonist
alone

Partial agonist

alone

"

Effect of
competitive

Agonist plus
noncompetitive
antagonist

antagonist

01

10
to
Agonist dose

100

1000

Ot

10

10

00

0.1

1000

Agonist dose

1.0
10
Agonist dose

100

1000
,1

AGONIST WITH

EFFECT

EXAMPLE

Competitive

Sliifts curve right (1 potency), no change


in efficacy. Can be overcome by t the
concentration of agonist substrate.
Shifts curve down (i efficacy). Cannot be
overcome by t agonist substrate concentration.

Diazepam (agonistl + flumazcnil (competitive


antagonist) on GABA receptor.
Norepinephrine ( agonist ) + phenoxvbenzamine
(noncompetitive antagonist) on a-receptors.

Acts at same site as full agonist, but with lower


maximal effect (i efficacy). Potency is an

Morphine ( full agonist) vs buprenorphine


(partial agonist) at opioid p-receptors.

antagonist

Noncompetitive
antagonist

Partial agonist
(alone)

Therapeutic index

independent variable.
Measurement of drug safety.

TITE: Therapeutic Index = TD-(i / ED50.


Safer drugs have higher IT values. Drugs with
lower TI v alues frequently require monitoring
( eg. Warfarin. Theophylline, Digoxin.
Lithium; Warning! T hese Drugs arc Lethal!).
ID;o ( lethal median dose) often replaces TD;o
in animal studies.

TDJO _ median toxic dose


EDJQ median effective dose
Therapeutic window dosage range that can
safely and effectively treat disease.

Efficacy

100

Therapeutic index

ED

Toxicity

ED = Effective dose
TD = Toxic dose

iu

0
Log (drug concentration)

E9

PHARMACOLOGY AUTONOMIC DRUGS

PHARMACOLOGY

SECTION I I

PHARMACOLOGY AUTONOMIC DRUGS


Central and peripheral nervous system

Medul a

* e r f

Parasympathetic
Pre (long)

V *-T

A
U
T
0

Spinal cord

Prc (short]

[ACh

Post (long)

| ACh

M Sweat glands

M
I
C

[ACh
Sympathetic

Cardiac and smooth


muscle, gland cells,

nerve terminals

fACh

Renal vasculature

smooth muscle

/*

-[ACh W,
r

Adrenal medulla

S..

Blood
Catecholamine

//

transmission

SOMATIC

Voluntary motor nerve

[ACh

5
a, Cardiac
u.

l1:

muscle, vessels

Skeletal muscle

Neuromuscular
junction

Adrenal medulla is directly innervated hv preganglionic sympathetic fibers.


Sweat glands are part of the sympathetic pathway but arc innervated bv cholinergic fibers.!

Acetylcholine

Receptors

Nicotinic ACh receptors are ligand-gated Na*/K4 channels. Two subtypes: \N ( found in autonomic
ganglia, adrenal medulla) and NM (found in neuromuscular junction of skeletal muscle).
Muscarinic ACh receptors are G-protein-coupled receptors that usually act through 2nd
messengers. 5 subty pes: M| f o u n d in heart, smooth muscle, brain, exocrine glands, and on sweat
glands (cholinergic sympathetic).

PHARMACOLOGY AUTONOMIC DRUGS

PHARMACOLOGY

G-protein-linked second messengers


G- PROTEIN CLASS

MAJOR FUNCTIONS

t vascular smooth muscle contraction, t pupillary dilator muscle


contraction ( mydriasis), t intestinal and bladder sphincter muscle
contraction

i sympathetic (adrenergic ) outflow, 1 insulin release, i lipolysis, t platelet


aggregation, l aqueous humor production

A
A

t heart rate, t contractility ( one heart!t renin release, t lipolvsis

Vasodilation, bronchodilation (two lungs)] t lipolysis, t insulin release,


t uterine toire ( tocolysis), ciliary muscle relaxation, t aqueous humor
production
t lipolysis, t thermogenesis in skeletal muscle

Mediates higher cognitive functions, stimulates enteric nervous system]

M2

i heart rate and contractility of atria

M3

t exocrine gland secretions (eg, lacrimal, sweat, salivary, gastric acid ),


t gut peristalsis, t bladder contraction, bronchoconstriction, t pupillary
sphincter muscle contraction ( miosis), ciliary muscle contraction
(accommodation), t insulin releast]

RECEPTOR

Sympathetic

Parasympathetic

Dopamine

Relaxes renal vascular smooth inuseki activates direct pathway of striatum

Modulates transmitter release, especially in brain, inhibits indirect


pathway of striatum

Histamine

t nasal and bronchial mucus production, t vascular permeability,


contraction of bronchioles, pruritus, pain

H2

t gastric acid secretion

v,

t vascular smooth muscle contraction

v2

t IRC) permeability and reabsorption in collecting tubules of kidney]

Vasopressin

After qisses ( kisses), you get a qii| 1 kick) out of siq (sick ) sqs (super qinky sex ).

,..

Hj

Uj, Vj,

M Mj

Receptor

DAG

Phospholipase C
Lipids

Pi. foPi 0,.

H2 V2

Receptor

MJ. < / j. Dj

Receptor

IP

HAVe 1 M&M.

Protein
kinase C

I i<*V

Smooth muscle contraction

ATP

Gs
G,

Adenylyl cyclase

f ia>x

i
cAMP

(heart)

Protein kinase A
Myosin light -chain
kinase (smooth
muscle)

MAD 2s.

Revised
Figure

PHARMACOLOGY AUTONOMIC DRUGS

PHARMACOLOGY

231

SECTION II

Release of norepinephrine from a sympathetic nerve ending is modulated bv NE itself, acting on


presMiaptic ou-autoreceptors negative feedback.
~
\ mphetamines use the NE transporter ( NET ) to enter the presvnaptic terminal, where they utilize
the vesicular monoamine transporter ( VMAT ) to enter neurosecretory vesicles. This displaces NK
from the vesicles. Once NE reaches a concentration threshold within the presvnaptic terminal
the action of NKT is reversed, and NE is expelled into the synaptic cleft, contributing to the
characteristics and effects of t NR observed in patients taking amphetamines.

Autonomic drugs

CHOLINERGIC

NORADRENERGIC
AXON

AXON

Tyrosine

Choline
Tyrosine

Metyrosme

i N im

Choline *
Acetyl- CoA

Hemicholinium

Dopamine

LhAT
\o

Reserpine

&

Release -modulating
receptors

Vesamicol

Ca2+
NE

Ca 2+

AO

,
Amphetamine
impnc
ephedrine

Botulinum

orl

Reuptake

Cocaine, TCAs,

Choline +

&

AT II

-OO

amphetamine

cetate

Revised

NEQ

Figure
Diffusion,

metabolism
00 '
receptor

AChE inhibitors

Adrenoreceptors or p

AChE

POSTSYNAPTIC MEMBRANE

Grcie will) routing arrow repreient tramporlrrv Drug n ifaWcs are of historical iignificance.

POSTSYNAPTIC MEMBRANE

232

SECTION II

PHARMACOLOGY

PHARMACOLOGY AUTONOMIC DRUGS

Cholinomimetic agents
DRUG

ACTION

APPLICATIONS

Activates bond and bladder smooth


muscle; resistant to ACliE. "Bethany, call
( bethanechol ) me to activate sour bonds and

Postoperative ileus, neurogenic ileus, urinary


retention

Direct agonists
Bethanechol

bladder.
Carbachol

Carbon copy of acetylcholine.

Constricts pupil and relieves intraocular


pressure in open-angle glaucoma

Methacholine

Stimulates muscarinic receptors in airway when

Challenge test for diagnosis of asthma

inhaled.
Pilocarpine

Contracts ciliary muscle of eye ( open-angle


glaucoma ), pupillary sphincter (closed-angle
glaucoma); resistant to AChE. You cry, drool,
and sweat on your
pilow.

Potent stimulator of sweat, tears, and saliva


Open-angle and closed-angle glaucoma,
xerostomia (Sjogren syndrome)

Indirect agonists (anticholinesterases)


Galantamine,
donepezil,

t ACh.

Alzheimer disease ( Alzheimer patients gallantly


swim down the riveri

rivastiqminel

Edrophonium

t ACh

Historically used to diagnose myasthenia gravis;


anti-AChRAb ( anti-acetvleholine receptor

Neostigmine

t ACh.
Nco CNS - No CNS penetration (quaternary

Postoperative and neurogenic ileus and


urinary retention, myasthenia gravis,
reversal of neuromuscular junction blockade
( postoperative).

antibody) test currently useqj

amine)
Physostigmine

t ACh Physostigmine plivxes atropine

overdose.

Anticholinergic toxicitv; phrccly (freely ) crosses


blood-brain barrier CNS ( tertiary amine).

t ACh; t muscle strength. Pyridostigmine gets

Myasthenia gravis ( long acting); does not


penetrate CNS (quaternary amine).
Note: With all cholinomimetic agents, watch for exacerbation of COPD, asthma, and peptic ulcers when giving to susceptible
patients.
Pyridostigmine

rid of myasthenia gravis.

Cholinesterase
inhibitor poisoning

Often due to organophosphates, such as


parathion, that irreversibly inhibit AChE.
Causes Diarrhea, Urination, Miosis,
Bronchospasm, Bradycardia, Excitation
of skeletal muscle and CNS, Lacrimation,
Sweating, and Salivation. May lead to
respiratory failure if untreated.

DUMBBELSS.
Organophosphates are often components of
insecticides; poisoning usually seen in farmers.
Antidote atropine (competitive inhibitor ) +
pralidoxime ( regenerates AChE if given early).

PHARMACOLOGY

PHARMACOLOGY

AUTONOMIC DRUGS

SECTION II

23

Muscarinic antagonists
DRUGS

ORGAN SYSTEMS

APPLICATIONS

Atropine,
homatropine,
tropicamide

Eye

Produce mydriasis and cycioplegia.

Benztropine

CNS

Parkinson disease ( park my Benz").


Acute dystonia.

Cl, respiratory

Parenteral: preoperative use to reduce airway

Hyoscyamine,
dicyclomine

GI

Oral: drooling, peptic ulcer .


Antispasmodics for irritable bowel syndrome.

Ipratropium,
tiotropium

Respiratory

COPD, asthma ( 1 pray 1 can breathe soonf ).

Oxybutynin,
solifenacin,
tolterodine

Genitourinary

Reduce bladder spasms and urge urinary


incontinence (overactive bladder).

Scopolamine

CNS

Motion sickness.

trihexyphenidyl

Glycopyrrolate

secretions.

Atropine

Muscarinic antagonist. Used to treat bradycardia and for ophthalmic applications.


ACTION

NOTES

Eye

t pupil dilation , cycioplegia

Airway

1 secretions

Blocks DUMBBeLSS in cholinesterase


inhibitor poisoning. Docs not block excitation
of skeletal muscle and CNS (mediated by
nicotinic receptors ) .

ORGAN SYSTEM

Stomach

J acid secretion

Gut

1 motility

Bladder

1 urgency in cystitis
t body temperature (due to t sweating);
rapid pulse; dry mouth ; dry, flushed skin ;
cycioplegia; constipation; disorientation
Can cause acute angle-closure glaucoma in
elderly ( due to mydriasis), urinary retention
in men with prostatic hyperplasia , and
hyperthermia in infants

ADVERSE EFFECTS

Side effects:
Hot as a hare
Drv as a bone
Red as a beet
Blind as a bat
Mad as a hatter
Jimson weed ( Datura) -* gardener's pupil
( mydriasis due to plant alkaloids)

PHARMACOLOGY

Rnd

ls

'

1$

Muscarinic antagonists
DRUGS

ORGAN SYSTEMS

APPLICATIONS

Atropine,
homatropine,
tropicamide

Eye

Produce mydriasis and cycloplegia.

Benztropine

CNS

Parkinson disease (park my Benz ).


Acute dystonia.

GI, respiratory

Parenteral: preoperative use to reduce airway

trihexyphenidyl

Glycopyrrolate

secretions.

Oral: drooling, peptic ulcer.

Hyoscyamine,
dicyclomine

C1

Antispasmodics for irritable bowel syndrome.

Ipratropium,
tiotropium

Respiratory

GOPD, asthma (I pray 1 can breathe soon!").

Oxybutynin,
solifenacin,

Genitourinary

Reduce bladder spasms and urge urinary


incontinence (overactive bladder).

CNS

Motion sickness.

tolterodine
Scopolamine

Atropine
ORGAN SYSTEM

Muscarinic antagonist. Used to treat bradycardia and for ophthalmic applications.


ACTION

NOTES

Eye

t pupil dilation, cycloplegia

Airway

i secretions

Blocks DUMBBeLSS in cholinesterase


inhibitor poisoning. Docs not block excitation
of skeletal muscle and CNS (mediated by
nicotinic receptors ).

Stomach

i acid secretion

Gut

1 motility

Bladder

1 urgency in cystitis

ADVERSE EFFECTS

t body temperature (due to t sweating);


rapid pulse; dry mouth; dry flushed skin;
cycloplegia; constipation; disorientation
Can cause acute angle-closure glaucoma in
elderly ( due to mydriasis), urinary retention
in men with prostatic hyperplasia, and
hyperthermia in infants

Side effects:
Hot as a hare
Dry as a bone
Red as a beet
Blind as a bat
Mad as a hatter
|imson weed ( Datura )

gardeners pupil

234

SECTION II

PHARMACOLOGY

PHARMACOLOGY

AUTONOMIC DRUGS

Sympathomimetic;
ACTION

APPLICATIONS

Albuterol, salmeterol

Pz > P,

Dobutamine

Pi > P;.

Dopamine

D| = D, > p > a

Epinephrine

P>a

Albuterol for acute asthma or COPD. Salmeterol


for long-term asthma or COPD control.
Heart failure ( HK| ( inotropic > chronotropic ),
cardiac stress testing.
Unstable bradycardia , HF, shock; inotropic and
chronotropic effects at lower doses due to (5
effects; vasoconstriction at high doses due to a
effects.
Anaphylaxis, asthma, open-angle glaucoma;
a effects predominate at high doses.
Significantly stronger effect at P receptor than
norepinephrine.
Postoperative hypertension , hypertensive crisis.
Vasodilator (coronary, peripheral, renal, and
splanchnic). Promotes natriuresis. Can cause
hypotension and tachycardia.
Flectrophvsiologic evaluation of
tachyarrhythmias. Can worsen ischemia.
Autonomic insufficiency and postural
hypotension. May exacerbate supine
hypertension.
Urinarv urge incontinence or overactive bladder.
Hypotension, septic shock.

DRUG

Direct sympathomimetics

Fenoldopam

Isoproterenol

P, = Pz

Midodrine

Mirabeqron

&

Norepinephrine

oi| >

Phenylephrine

ai > a:

a2 > P|

Hypotension ( vasoconstrictor), ocular procedures


( mydriatic ), rhinitis (decongestant ).

Indirect sympathomimetics
Amphetamine

Indirect general agonist , reuptake inhibitor, also


releases stored catecholamines

Narcolepsy, obesity, ADI ID.

Cocaine

Indirect general agonist , reuptake inhibitor

Causes vasoconstriction and local anesthesia.


Never give P- blockcrs if cocaine intoxication is
suspected (can lead to unopposed ot| activation
and extreme hypertension ).

Ephedrine

Indirect general agonist, releases stored

Nasal decongestion, urinary incontinence,


hypotension .

catecholamines

PHARMACOLOGY AUTONOMIC DRUGS

PHARMACOLOGY

Norepinephrine vs
isoproterenol

235

SECTION II

Nfcjt systolic and diastolic pressures as a result of aj-mediated vasoconstriction f mean arterial
pressure reflex bradycardia. I lowever, isoproterenol (no longer commonly used) has little a
effect but causes |J -mediated vasodilation, resulting in 1 mean arterial pressure and t heart rate
through P| and reflex activity.

Norepinephrine (a > p)

Widened

pulse

ptnswe

Epinephrine la p)

*\

\V~ Systole

Pi > ai

MAP
\ OMStohc

Isoproterenol ip > a)

/ ' \

ft

^
A

V* V

Reflex bxadycardu

p, >
CO < >
HR
MAP

PP

i
TT
T

CO
HR
MAP
PP

U n o p p o s e d P7

TT
TT
MAP i
PP TT

T
T
T
T

CO
HR

Sympatholytics (a2- agonists )


DRUG

APPLICATIONS

ADVERSE EFFECTS

Clonidine, guanfacine

Hypertensive urgency ( limited situations),


ADHD, Tourctte syndrome

CNS depression, bradycardia, hypotension,


respirators depression, miosis, rebound

a- methyldopa

Hypertension in pregnancy

hvpertension with abrupt cessation

Direct Coombs hemolysis, SLE like syndrome

236

SECTION I I

PHARMACOLOGY

PHARMACOLOGY AUTONOMIC DRUGS

a-blockers
DRUG

APPLICATIONS

ADVERSE EFFECTS

Irreversible. Plieochromocytomal ( used


preoperatively) to prevent catecholamine
(hypertensive) crisis
Reversible. Give!lo patients on MAO inhibitors
who eat tyramine-containing foods

Orthostatic hypotension, reflex tachycardia

Nonselective

Phenoxybenzaminel

Phentolamine|

a selective (-osin ending)


Prazosin, terazosin,
doxazosin,
tamsulosin

Urinary symptoms of BPH; PTSD ( prazosin);


hypertension (except tamsulosin)

lst-dose orthostatic hypotension, dizziness,


headache

Depression

Sedation, t serum cholesterol, t appetite

a2 selective
Mirtazapine

Effects of ot-blocker (eg, phentolamine) on BP responses to epinephrine and phenvlephrimj


Epinephrine

a.

1
55

Systolic

>a

_y
1

Net depressor

effect

Unopposed fl2

MAP

Jj

Before a-blockade

\\

Net prr
eifKt

Phenylephrine

Alter u-blockade

Before u- blockade

ft

Pj Reftei tachycardia

\_

1
i
a.

Time

Kpinephrine response exhibits reversal of mean arterial


pressure from net increase ( the q response) to a net

decrease (the 0-, response).

Suppression of
pressor effect

Net pressor

After a- blockade

Reflex bradycardia

Time

Pheny lephrine response is suppressed but not reversed


because it is a "pure" q- agonist I lacks fl-agonist
properties!
)

PHARMACOLOGY

PHARMACOLOGY

p- blockers

AUTONOMIC DRUGS

237

SECTION II

Accbutolol, atenolol, bctaxolol , bisoprolol , carvedilol, csmolol , labctalol , metoprolol, nadolol .


nebivolol , pindolol , propranolol , timolol .

APPLICATION

ACTIONS

NOTES/EXAMPLES

Angina pectoris

i heart rate and contractility, resulting in 1 O2

Myocardial infarction!

consumption
1 mortality

Supraventricular

i AV conduction velocity (class 11

tachycardial

Hypertension

Heart failure
Glaucoma!

Variceal bleeding

Metoprolol , esmolol

antiarrhythmic)
1 cardiac output , 1 renin secretion (due to
Pj-receptor blockade on JGA cells)
i mortality ( bisoprolol , carvedilol , metoprolol )
l production of aqueous humoii

Timolol

i hepatic venous pressure gradient and portal


hypertension

Nadolol , propranolol

ADVERSE EFFECTS

Erectile dysfunction, cardiovascular adverse


effects ( bradycardia , AV' block , HF), CNS
adverse effects (seizures , sedation , sleep
alterations ), dyslipidemia ( metoprolol ), and
astluna /COPD exacerbations

Use with caution in cocaine users due to risk


of unopposed a-adrenergic receptor agonist
activity
Despite theoretical concern of masking
hypoglycemia in diabetics, benefits likely
outweigh risks; not contraindicated

SELECTIVITY

selective antagonists ( P
Pi -partial

agonist), atenolol ,

> (5, ) acehutolol


bctaxolol , bisoprolol

Selective antagonists mostly go from A to M


with 1st half of alphabet )

P(

esinolol metoprolol
Nonselective antagonists (P| = P-, ) nadolol ,
pindolol ( partial agonist ), propranolol timolol
Nonselective a- and (3-antagonists carvedilol .
labetalol
Nebivolol combines cardiac-selective
Pi -adrenergic blockade with stimulation
of P -receptors, which activate nitric oxide
synthase in the vasculature
,

Nonselective antagonists mostly go from N to 7.


( P with 2nd half of alphabet )
Nonselective a- and P-antagonists have modified
suffixes ( instead of -olol")

238

SECTION I I

PHARMACOLOGY

PHARMACOLOGY AUTONOMIC DRUGS

Ingested seafood toxins


TOXIN

SOURCE

ACTION

SYMPTOMS

TREATMENT

Tetrodotoxin

Pufferfish.

Highly potent toxin;


binds fast voltagegated Na* channels

Nausea, diarrhea,
paresthesias,
weakness, dizziness,
loss of reflexes.

tjapportive.

Nausea, vomiting,

ijrpportive.

in cardiac /nerve
tissue, preventing
Ciguatoxin

Histamine
(scombroid
poisoning)

Reef fish such as


barracuda, snapper,
and moray eel .

depolarization.
Opens Na+
channels, causing
depolarization.

Spoiled dark-meat fish

Bacterial histidine

such as tuna, mahimahi, mackerel, and


bonito.

decarboxylase converts

histidine to histamine.

Frequently
misdiagnosed as fish

allergy .

diarrheal perioral
numbness;
reversal of hot and
cold sensations;
bradycardia, heart
block, hypotension!
Mimics anaphylaxis:
acute burning
sensation of mouth,
flushing of face,
erythema, urticaria,
itching. May progress
to bronchospasm,
angioedema
hypotension.

Antihistamines.
Albuterol and

epinephrine if needed.

Beers criteria

New

lEasil

Widely used criteria developed to reduce inappropriate prescribing and harmful polypharmacy in
the geriatric population. Includes > SO medications that should be avoided in elderly patients due
to 1 efficacy and/or t risk of adverse events. Examples include:

Anticholinergics, antihistamines, antidepressants, benzodiazepines, opioids ( t risk of delirium,


sedation, falls, constipation, urinary retention|
a-blockers It risk of hypotension)
PPIs ft risk of C difficile infection)
NSAlDs ( t risk of Cd bleeding, especially with concomitant anticoagulation )

PHARMACOLOGY

PHARMACOLOGY TOXICITIES AND SIDE EFFECTS

SECTION II

239

PHARMACOLOGY - TOXICITIES AND SIDE EFFECTS

Specific toxicity

TOXIN

TREATMENT

treatments

Acetaminophen

N-acetvlcystcine ( replenishes glutathione!

ACHE inhibitors, organophosphates

Atropine > pralidoxime

Antimuscarinic, anticholinergic agents

Physostigmine, control hyperthermia

Arsenic

Digitalis (digoxin)

Dimercaprol, succimer
Fluinazenil
ropine, glucagon
100% O,, hyperbaric O,
Penicillamine, trientine ( Copper pennv)
Nitrite + thiosulfate, hydroxocobalamin
Anti- dig Fab fragments

Heparin

Protamine sulfate

Benzodiazepines
(J-blockers

Carbon monoxide

Copper

Cyanide

Iron

Deferoxamine, deferasirox, deferiprone

Lead

EDTA, dimercaprol, succimer, penicillamine

Mercury

Dimercaprol, succimer
Fomcpizole > ethanol, dialysis
Methylene blue, vitamin C

Methanol, ethylene glycol (antifreeze)

Methemoglobin
Opioids

NalOjtCjie

Salicylates

NaHCO (alkalinize urine), dialysis

TCAs

NaHCO

Warfarin

Vitamin K (delayed effect), fresh frozen plasma


( immediate)

Drug reactions cardiovascular


DRUG REACTION

CAUSAL AGENTS

Coronary vasospasm

Amphetamines, cocaine, ergot alkaloids sumatriptanl

Cutaneous flushing

Vancomycin, Adenosine, Niacin, Nitrates, Ca= channel blockers, Kchinocandins ( VANNCKt

Dilated
cardiomyopathy

Anthracyclines (eg, doxorubicin, daunorubicin); prevent with dexrazoxane

Torsades de pointes

AntiArrhythmics (class L\, III), antiBiotics (eg, macrolides), antiCychotics ( eg, haloperidol ),
antiDepressants (eg, TCAs), antiEmetics (eg, ondansetron) (ABODE).

240

SECTION II

Drug reactions
DRUG REACTION

PHARMACOLOGY

PHARMACOLOGY

TOXICITIES AND SIDE EFFECTS

endocrine/ reproductive

Adrenocortical
insufficiency
Diabetes insipidus

Hot flashes
Hyperglycemia

CAUSAL AGENTS

NOTES

HPA suppression 2 to glucocorticoid

withdrawal
Lithium, demedocyclinc
Tamoxifen, clomiphene
Tacrolimus, Protease inhibitors Niacin, HCTZ, Taking Pills Necessitates Having blood

Corticosteroids
Hypothyroidism

Lithium, amiodarone, sulfonamides

SIADH

Carbamazcpine, Cyclophosphamide, SSRIs

Drug

reactions

DRUG REACTION

gastrointestinal

CAUSAL AGENTS

Erythromycin

Diarrhea

Acamprosatc, acarbosc, cholinesterase


inhibitors, colchicine, erythromycin,
czctimibc, metformin , misoprostol, orlistat,
pramlintide, quinidine, SSRIs
Ualothane, Amanita phalloides ( death cap
mushroom ) Valproic acid Acetaminophen

Hepatitis
Pancreatitis

Pill -induced
esophagitis
Pseudomembranous
colitis

Can t Concentrate Serum Sodium

NOTES

Acute cholestatic
hepatitis, jaundice

Focal to massive
hepatic necrosis

Checked

Rifampin, isoniazid , pyrazinamidc, statins,


fibrates
Didanosine, Corticosteroids, Alcohol , Valproic acid .
-Vzathioprinc, Diuretics (furosemide, HCTZ )
Bisphosphonates, ferrous sulfate, NSAIDs,
potassium chloride. tetracvcline4
Ampicillin. cephalosporins, clindamvcin.
fluoroquinolone

Liver HAVAc

Drugs Causing A Violent Abdominal Distress


Caustic effect minimized with upright posture
and adequate water ingestion .

Antibiotics predispose to superinfection by


resistant C difficile

PHARMACOLOGY TOXICITIES AND SIDE EFFECTS

PHARMACOLOGY

SECTION I I

241

Drug reactions hematologic


DRUG REACTION

CAUSALAGENT 5

NOTES

Agranulocytosis

Clozapine, Carbamazcpine, Propylthiouracil,


Methimazole, Colchicine, Ganciclovir
Carbamazepine, Methimazole, NSAIDs,
Benzene, Chloramphenicol, Propylthiouracil
Methyldopa, penicillin

Can Cause Pretty .Major Collapse of

Aplastic anemia

Direct Coombs
positive hemolytic
anemia

Druq reaction with

eosinophilia and
systemic symptoms
( DRESS

Allopurinol, anticonvulsants, antibiotics,


sulfonamides

Granulocytes
Cant Make New Blood Cells Properly

Potentially fatal delayed hypersensitivity

reaction. Latency period { 2-8 weeks)


followed bv fever, morbilliform!skin rash, and
frequent multiorgan involvement. Treatment:
withdrawal of offending drug, corticosteroids.

Gray baby syndrome

Chloramphenicol

Hemolysis in G6PD
deficiency

Isoniazid, Sulfonamides, Dapsone, Primaquine,


Aspirin, Ibuprofen, Nitrofurantoin

Hemolysis IS D PAIN

Megaloblastic anemia

Hvdroxvurea, Phcnvtoin, Methotrexate, Sulfa

Youre having a mega blast with PMSl

drug!

Thrombocytopenia

Heparin

Thrombotic

OCPs, hormone replacement therapy

complications

Drug reactions musculoskeletal / skin /connective tissue


DRUG REACTION

CAUSAL AGENTS

Fat redistribution

Protease inhibitors Glucocorticoids

Gingival hyperplasia

Phcnv toin, Ca+ channel blockers, cyclosporine

Hyperuricemia (gout)

Pyrazinamidc, Thiazides, Furosemidc, Niacin,


Cyclosporine
Statins, fibrates. niacin, colchicine, dantomvein.
hvdroxvehloroquinc, interferon-a,

Myopathy

NOTES

Fat PiG

Painful Tophi and Feet Need Care

penicillamine, glucocorticoid!

Osteoporosis

Corticosteroids, progesterone-only birth control,


aromatase inhibitors, anticonvulsants, heparin!

Photosensitivity

Sulfonamides, Amiodarone, Tetracyclines,

SAT For Photo

5-FU

Rash ( StevensJohnson syndrome)

Anti-epileptic drugs (especially lamotrigine),


allopurinol, sulfa drugs, penicillin

Steven Johnson has epileptic allergy to sulfa


drugs and penicillin

SLE- like syndrome

Sulfa drugs, Hydralazine, Isoniazid,


Procainamide, Phenytoin, Etanercept

Having lupus is "SHIPP-E

Teeth discoloration

Tetracyclines
Fluoroquinolones

Tendonitis, tendon
rupture, and
cartilage damage

242

SECTION I I

PHARMACOLOGY TOXICITIES AND SIDE EFFECTS

PHARMACOLOGY

Drug reactions neurologic


DRUG REACTION

CAUSAL AGENTS

NOTES

Cinchonismi

Quinidine, quinine!

Can present with tinnitus, psy chosis, hearing,

visual and cognitive impairment

*.

Antipsychotic Reserpine, Metodopramide

Cogwheel rigidity of ARM

Seizures

Isoniazid (vitamin B6 deficiency), Bupropion,


Imipenem/cilastatin, Tramadol, Enflurane

With seizures,IBITE my tongue

Tardive dyskinesia

Antipsychotics, metodopramide

Parkinson-like
syndrome

Drug reactions renal/genitourinary


DRUG REACTION

CAUSAL AGENTS

Fanconi syndrome

Cisplatin, ifosfamide expired tetracyclines

Hemorrhagic cystitis

Interstitial nephritis

NOTES

tenofovid
Cyclophosphamide, ifosfamide
Penicillins, furosemide. NSA 1IX proton pump
inhibitors

Prevent by coadministering with mesna

Drug reactions respiratory


DRUG REACTION

CAUSAL AGENTS

Dry cough

ACE inhibitors

Pulmonary fibrosis

Methotrexate, Nitrofurantoin, Carmustine,


Bleomycin, Busulfan, Amiodarone

NOTES

My Nose Cannot Breathe Bad Air

Drug reactions multiorgan


DRUG REACTION

CAUSAL AGENTS

Antimuscarinic

Atropine, TCAs, H|-blockers, antipsychotics

Disulfiram-like
reaction

lst-generation Sulfonvlurcas Procarbazine,


certain Cephalosporins Griseofulvin

Nephrotoxicity/
ototoxicity

Metronidazole!
Aminoglycosides, vancomycin, loop diuretics,
cisplatin. amphotericin Bil

NOTES

Sorrv Pals. Cant Go MingleJ

Cisplatin toxicity may respond to amifostinc.

PHARMACOLOGY

Cytochrome P- 450
interactions ( selected )

PHARMACOLOGY TOXICITIES AND SIDE EFFECTS

SECTION II

Inducers (+)

Substrates

Inhibitors (-)

Chronic alcohol use


St. John's wort

Anti-epilcptic!

Acute alcohol abuse


Macrolides
Isoniazid ( 1NH )

Phenytoin
Phcnobarbital
Nevirapine
Rifampin
Griseofulvin
Carbamazepine

Theophylline
Warfarin

243

Grapefruit
Omeprazole

OCPs

Sulfonamides
Ouiiiidine
Cimetidine
Ritonavir
Amiodarone
Ciprofloxacin

Ketoconazole
Chronic alcoholics Steal
Phen-Phcn and Never
Refuse Greasy Garbs

Sulfa drugs

Always Think When Outdoors

Sulfonamide antibiotics, Sulfasalazine,


Probenecid, Furoscmidc, Acetazolamidc,
Celecoxib, Thiazides, Sulfonylureas.
Patients with sulfa allergies may develop
fever, urinary tract infection, StevensJohnson syndrome, hemolytic anemia,
thrombocytopenia, agranulocytosis, acute
interstitial nephritis, and urticaria (hives)
Sy mptoms range from mild to life threatening.

Mv AMIGOS give me Quality


CRAC hi

Scary Sulfa Pharm FACTS

244
1

SECTION I I

PHARMACOLOGY

PHARMACOLOGY MISCELLANEOUS

PHARMACOLOGY MISCELLANEOUS

Drug names
ENDING

CATEGORY

EXAMPLE

Antimicrobial
- azole
- bendazole
-cillin

Ergosterol synthesis inhibitor


Antiparasitic/antihelminthic

Ketoconazole
Mebendazole
Ampicillin
Tetracycline
Oseltamivir

-cycline

-ivir

Peptidoglvcan cross-linking inhibit

Protein synthesis inhibitor


Neuraminidase inhibitor
Protease inhibitor
DNA polymerase inhibitor
Macrolide antibiotic

Ritonavir

Inhalational general anesthetic


Typical antipsychotic

Ilalothanc
Thioridazine

Barbiturate
Local anesthetic

Phenobarbital
Lidocaine

- etine

SSRI

-ipramine, -triptyline

TCA
5-HTIB/ID agonist
Benzodiazepine

Fluoxetine
Imipramine, amitriptyline

-navir

-ovir
-thromycin

Acyclovir
Azithromycin

CNS
- ane

-azine
-barbital

- caine

-triptan
-zepam, -zolam

Sumatriptan
Diazepam, alprazolam

Autonomic

-olol

Cholinergic agonist
Nondepolarizing paralytic
P-blocker

- stigmine

AChE inhibitor

- chol
-curium, -curonium

Bethanechol, carbachol
Atracurium, vecuronium

-terol

P;-agonist

Propranolol
Neostigmine
Albuterol

-zosin

aj-antagonist

Prazosin

Cardiovascular
- afil
- dipine
-pril
- sartan
- statin
- xaban

Other
- dronate
- glitazone
-prazole
-prost

PDE 5 inhibitor

Sildenafil

Dihydropvridine Ca2+ channel blocker


ACE inhibitor
Angiotensin-II receptor blocker
HMG-CoA reductase inhibitor
Direct factor Xa inhibitor!

Amlodipine
Captopril

Bisphosphonatc
PPAR-y activator
Proton pump inhibitor

Prostaglandin analog
-antagonist

Losartan
Atorvastatin
Apixaban, edoxaban rivaroxaban

Alendronate
Rosiglitazone
Omeprazole
Latanoprost

-tidine

Cimetidinc

-tinib

Tvrosine kinase inhibitoil

Imatinib

-tropin

Pituitary hormone

Somatotropin

-ximab

Chimeric monoclonal Ab
1Iumanized monoclonal Ab

Basiliximab
Daclizumab

-zumab

268

SECTION I I I

CARDIOVASCULAR EMBRYOLOGY

CARDIOVASCULAR

Blood in umbilical vein has a Po-, of = TO nun Hg


Umbilical
and is = 80% saturated with
arteries have low O, saturation.
T important shunts:
O Blood entering fetus through the
umbilical vein is conducted via the ductus
venosus into the IVC, bypassing hepatic
circulation.
0 Most of the highly Oxygenated blood
reaching the heart via the IVC is directed
through the foramen ( Jjvalc and pumped
into the aorta to supplv the head and bodv.
I)eoxygenated blood from the SVC passes
through the RA RV main pulmonary
artery |l Rictus arteriosus descending
aorta; shunt is due to high fetal pulmonary
artery resistance (due partly to low O,
tension).
At birth, infant lakes a breath; i resistance
in pulmonary vasculature t left atrial
pressure vs right atrial pressure; foramen ovale
closes (now called fossa ovalis); t in O, ( from
respiration) and 1 in prostaglandins (from
placental separation) - closure of ductus
arteriosus.
indomcthacin helps close PDA ligamentum
arteriosum (remnant of ductus arteriosus).
Prostaglandins K and 1 ki ll p PDA open.

Fetal circulation
To brain (high

02)

Ductus

arteriosus

To lungs
(high resistance)
\

Superior vena cava

Foramen ovale

To lungs
(high resistance)

Pulmonary

V
l

artery

'.

O Ductus

venosus

Aorta

Inferior vena cava

Portal vein

Umbilical vein

Internal iliac artery

To placenta

Umbilical

ft

arteries

From placenta

Fetal-postnatal derivatives

AllaNtois -* urachus

MediaN umbilical ligament

Ductus arteriosus

Ligamentum arteriosum

Ductus venosus

Ligamentum venosum

Foramen ovale

Fossa ovalis

Notochord

Nucleus pulposus

UmbiLical arteries

McdiaL umbilical ligaments

Umbilical vein

Ligamentum teres hepalis ( round ligament of

the livcrll

Urachus is part of allantoic duct between


bladder and umbilicus.

Contained in falciform ligament .

CARDIOVASCULAR

CARDIOVASCULAR ANATOMY

269

SECTION I I I

CARDIOVASCULAR ANATOMY
Coronary artery anatomy
Right coronary artery ( RCA)

Left main coronary artery (LCA)

left circumflex coronary


artery (LCX] supplies lateral
and posterior walls of left
ventricle, anterolateral papillary
muscle
Left anterior descending
artery ILADI supplies anterior !h

of interventricular septum,
anterolateral papillary muscle,
and antenor surface of left ventricle

Revised
Figure

Right (acute)
marginal artery
supplies right

left (obtuse) marginal artery

ventncle

Posterior descending/ interventricular artery ( PDA)


supplies AV node posterior Vrof interventricular septum,
posterior lh walls of ventndes, and posteromedial papillary muscle

SA undo is usually supplied hv RCA , AV node


is supplied by PDA lie, doiiiinanl circulationL
Infarct may cause nodal dysfunction
(brady cardia or heart block)
Right-dominant circulation ( 85%) = PDA arises

from RCA.
Left-dominant circulation (8%) = PDA arises
from LCX.
Codominant circulation ( 7%) = PDA arises
from both LCX and RCA.
Coronary artery occlusion most commonly
occurs in the LAD.
Coronary blood flow peaks in early diastole.
The most posterior part of the heart is the left
atrium; enlargement can cause dysphagia (due
to compression of the esophagus) or hoarseness
(due to compression of the left recurrent
laryngeal nerve, a branch of the vagus)
Pericardium consists of 5 layers ( from outer to
inner);
Fibrous pericardium
Parietal layer of serous pericardium
Visceral layer of serous pericardium
Pericardial cavity lies behveen parietal and
visceral layers.

CARDIOVASCULAR

CARDIOVASCULAR

PHYSIOLOGY

SECTION III

271

Cardiac output variables

Stroke volume

Stroke Volume affected by Contractility,


Aftcrload, and Preload
t SV with:
f Contractility (eg, anxiety, exercise )
t Preload (eg, early pregnancy)
i Aftcrload

SV CAP.
A failing heart has l SV (systolic and /or diastolic
dysfunction )

Contractility (and SV') t with:


Catecholamine stimulation via 0 i receptor
( inhibition of phospholambaii
t Cir '
entry into sarcoplasmic reticulum t Ca*induced Ca + release )
t intracellular Ca +
1 extracellular Na + ( 1 activity of Na + /Ca - ~
exchanger)
Digitalis ( blocks Na+/K+ pump
-* t intracellular Na* - i Na + /Ca'+
exchanger activity t intracellular Ca + )
fVlvoCARDial O, demand is t bv:
t Contractility
t Afterload ( proportional to arterial pressure )
t heart Rate
t Diameter of ventricle ( I wall tension )
Preload approximated by ventricular EDV;
depends on venous tone and circulating blood

Contractility (and SV' ) i with:


Ppblockade ( 1 cAMP)
HF with systolic dysfunction
Acidosis
Hvpoxia/hypercapnia ( 1 Po7 / f PcOj)
Non-dihydropyridine Ca 2+ channel blockers

Contractility

Myocardial oxygen

demand

Preload

volume.
Afterload

Afterload approximated by MAP.


t afterload t pressure t wall tension per
Laplaces law.

LV compensates for t aftcrload by thickening


(hypertrophy) itr order to 1 wall tension .
Ejection fraction

EDV ESV
EDV
Left ventricular EF is an index of ventricular
contractility; normal EF is > 55%.
hr

SV

= EDV =

Wall tension follows Laplaces law:


Wall tension

P urc x radms
2 x wall thickness

VEnodilators (eg, nitroglycerin ) t prEload

VAsodilators (eg, hydrAlAzine) 1 Aftcrload


( Arterial ).
ACE inhibitors and ARBs i both preload and
afterload .
Chronic hypertension ( t MAP ) LV
hypertrophy.
EF 1 in systolic HF.
EF normal in heart failure with preserved
ejection fraction 11 IFpEFA

272

SECTION I I I

CARDIOVASCULAR

Starling curve

CARDIOVASCULAR PHYSIOLOGY

Force of contraction is proportional to enddiastolie length of cardiac muscle fiber

Eercise

(preload).
t contractility with catecholamines, positive
inotropcs (eg, digoxin).
I contractility with loss of myocardium ( eg, MI ),
P-blockcrs (acutely),non-dihvdropyridine Ca*+

Ml t DM

I
E

'-' V '

-.

ll

. f.

=igure |

HF + digoxin

>
<
v

channel blockers, dilated cardiomyopathy.


HF

Ventricular EDV (preload)

Resistance, pressure,
flow

AP = Q x R
Capillaries have highest total cross-sectional
Similar to Ohms law: AV = IR
area and low est flow velocity.
Volumetric flow rate ( Q ) = flow velocity (v ) x
JPressure gradient drives flow from high pressure
to low pressure.
cross-scctional area ( A)
Arterioles account for most of TPR. Veins
Resistance
_ driving pressure (AP) _ 8r|(viscosity ) x length provide most of blood storage capacity.
Viscosity depends mostly on hematocrit
flow ( Q )
rtf
Viscosity t in hvpcrprotcinemic states (eg,
Total resistance of vessels in scries:
multiple myeloma ), polycy themia
R| Rj + R, + R . . .
V iscosity I in anemia
Total resistance of vessels in parallel:
1
1
1 I
T ~ Rj + R2 + R 1

276

SECTION III

CARDIOVASCULAR

CARDIOVASCULAR

PHYSIOLOGY

Auscultation of the heart


Where to listen: APT

Aortic area:
Pulmonic area :

Systolic murmur
Aortic stenosis
Flow murmur
(eg. physiologic murmur )
Aortic valve sclerosis

Left sternal border


Diastolic murmur
Aortic regurgitation
Pulmonic regurgitation
Systolic murmur
Hypertrophic
cardiomyopathy
Aortic
Pulmonic
Tricuspid
Mitral

Systolic ejection murmur


Pulmonic stenosis
Flow murmur

Tricuspid area:
Holosystolic murmur
Tricuspid regurgitat on
Ventncular septal defect
Diastolic murmur

Tricuspid stenosis
Atnal septal defect (T flow
across tricuspid valve)

T
M

Mitral area (apex ):


Holosystolic murmur
Mitral regurgitation

Diastolic murmur
Mitral stenosis
ia

BEDSIDE MANEUVER

EFFECT

Inspiration ( t venous return to right atrium )


Hand grip ( t afterload )

t intensity of right heart sounds


t intensity of MR, AR, VSD murmurs
1 hvpertroplhc cardiomyopathy murmurs, AS!
MVP: later onset of click /murmur

1 intensity of most murmurs ( including AS)


t intensity of hypertrophic cardiomyopathy murmur
MVP: earlier onset of click /murmur
t intensity of hypertrophic cardiomyopathy murmur
Rapid squatting ( t venous return, t preload , t aftcrload )
t intensity of AS, MR, and VSD
MVP: later onset of click /murmur
Svstolic heart sounds include aortic/pulmonic stenosis, mitral /tricuspid regurgitation, VSD M \ T, hypertrophic

Valsalva ( phase II ), standing up ( 1 preload )

murinuri

cardiomyopathy

Diastolic heart sounds include aortic/pulmonic regurgitation, mitral /tricuspid stenosis.

CARDIOVASCULAR

CARDIOVASCULAR

PHYSIOLOGY

SECTION III

277

Heart murmurs

Systolic

Cresccndo-decresccndo systolic ejection murmur (ejection click may he present ).


LV aortic pressure during systole . Loudest at heart base; radiates to carotids.
Pulsus parvus et tardus pulses are weak with a delayed peak. Can lead to
Syncope , Angina, and Dyspnea on exertion ( SAD ). Most commonly due to agerelated calcification in older patients (> 60 years old ) or in younger patients with
early-onset calcification of bicuspid aortic valve.
I lolosystolic, high-pitched blowing murmur.
Mitral loudest at apex and radiates toward axilla . MR is often due to ischemic heart
disease ( post-MI ), MVP, LV dilatation.
Tricuspid loudest at tricuspid a re4 TR commonly caused by RV dilatation .
Rheumatic fever and infective endocarditis can cause either MR or TR .

Aortic stenosis

S2

SI

LAAAAAAAAAMAMMM I
.

Mitral /tricuspid regurgitation

S2

St

LAAMAAAAAAAAAAAAAJ

late systolic crescendo murmur with midsystolic click ( MC; due to sudden tensing
of chordae tendineae). Most frequent valvular lesion . Best heard over apex. Loudest
just before S2. Usually benign . Can predispose to infective endocarditis. Can be
caused by myxomatous degeneration ( 1 or 2 to connective tissue disease such as
Marfan or Ehlers-Danlos syndrome), rheumatic fever , chordae rupture.

Mitral valve prolapse


St

MC

S2

L/rtl

Holosystolie, harsh-sounding murmur. Loudest at tricuspid area .

Ventricular septal defect


S2

SI

LVWMAAAAAAAAAAI
Diastolic
Aortic regurgitation
S2

SI

Lv /

' /M w y u

Mitral stenosis
SI

..

Follows opening snap ( OS; due to abrupt halt in leaflet motion in diastole, after
rapid opening due to fusion at leaflet tips) . Delayed rumbling mid-to-latc diastolic
niurimnjff interval between S2 and OS correlates with t severity ). LA L.V

S2 OS

I LMIW

High-pitched blowing early diastolic decrescendo murmur. Long diastolic


murmur, hyperdynamic pulse, and head bobbing when severe and chronic. Wide
pulse pressure. Often due to aortic root dilation, bicuspid aortic valve, endocarditis,
rheumatic fever. Progresses to left I IF.

aim

*.*

pressure during diastole. Often occurs 2 to rheumatic fever. Chronic MS can


result in LA dilatation.

Continuous
Patent ductus arteriosus
S2

LAAAAMAAAAAAAAIAAAA

Continuous machine like murmur . Loudest at S2. Often due to congenital rubella
or prematurity. Best heard at left infraclavicular area .

CARDIOVASCULAR

Electrocardiogram

CARDIOVASCULAR PHYSIOLOGY

Conduction pathway SA node

P wave atrial depolarization. Atrial


atria
repolarization is masked by QRS complex.
bundle
node
lis
and
of
I
AV
right
-*
PR interval time from start of atrial
left bundle branches -* Purkinje fibers
depolarization to start of ventricular
-* ventricles; left bundle branch divides into
depolarization ( normally < 200 msec).
left anterior and posterior fascicles.
SA node pacemaker" inherent dominance with QRS complex ventricular depolarization
(normally < 120 msec).
slow phase of upstroke.
AV node located in posteroinferior part of
QT interval ventricular depolarization,
mechanical contraction of the ventricles,
interatrial septum. Blood supply usually
ventricular repolarization.
from RCA. 100-msec delay allows time for
T wave ventricular repolarization. T-wave
ventricular filling.
inversion may indicate ischemia or recent \H
Pacemaker rates SA > AV > bundle of His/
|point junction betw een end of QRS complex
Purkinje/ventricles.
and start of ST segment.
Speed of conduction Purkinje > atria
ST segment isoelectric, ventricles depolarized.
> ventricles > AV node.
U wave prominent in hypokalemia,
bradycardia.

5 mm

0 2 seconds

Aorta

Superior
vena cava
SA node

N.

Bachmann
bundle

AV node

S-T

PR
segment

+05

segment

/ po re

Left bundle
branch

+1.0

u
0 m\

Bundle of His

--

interval

Right bundle
branch
Purkinje fibers

an

interval

Left anterior
fascicle

|_

Atm!

- Left postenor
fascicle

O T interval

VcntncuUr
depoUnzattor depounzaccm

-0.5
J

VCTtncuU
repoianrauon

fi

282

SECTION I I I

CARDIOVASCULAR

CARDIOVASCULAR PHYSIOLOGY

ECG tracings
RHYTHM

DESCRIPTION

Atrial fibrillation

Chaotic and erratic baseline with no discrete P waves in between

EXAMPLE
RR ,

irregularly spaced QRS complexes. Irregularly irregular

heartbeat . Most common risk factors include hypertension and


coronary artery disease (CADl. Can lead to thromboembolic
events, particularly stroke.
Treatment includes anticoagulation, rate control, rhythm control,
and/or cardioversion.
Atrial flutter

Ventricular
fibrillation

RR,

x RR ,

Irregular baseline (absent P wavesl

A rapid succession of identical, back-to-back atrial depolarization


waves. The identical appearance accounts for the saw tooth
appearance of the flutter waves.
Treat like atrial fibrillation. Definitive treatment is catheter
ablation.

A completely erratic rhythm with no identifiable w aves. Fatal


arrhythmia without immediate CPR and defibrillation.

RR ,

RR.

RR.

RR,

41 sawtooth pattern

AWVA/V
No discernible rhythm

AV block
Firstjdeqree

The PR interval is prolonged (> 200 msec). Benign and


asymptomatic. No treatment required.

Seconcjdegree
Mobitz type I
( Wenckebach)

Progressive lengthening of PR interval until a beat is dropped


(a P wave not followed by a QRS complex ). Usually
asymptomatic. Variable RR interval with a pattern (regularly

irregular).

Mobitz type II

Thirdjdegree
(complete )

Dropped beats tlrat are not preceded by a change in the length of


the PR interval (as in type I).
May progress to srd-degree block. Often treated with pacemaker.

pg

jr'
^

^PR

* PR(J =

'

"

PR

^PR

<

<

' PR

i4PR,

p ware, absent QRS u

^
P wave absent QRS

The atria and ventricles beat independently of each other. P waves and QRS complexes not rhythmically
associated. Atrial rate > ventricular rate. Usually treated with pacemaker. Can be caused by Lyme
disease.
RR,

RR,

I P wave on ORS compter

PP = PP, = PP, = PP

Pwave

CARDIOVASCULAR

Baroreceptors and chemoreceptors


EFFERENT

AFFERENT
Solitary nucleus

Mi au a

Vagus
nerve

- chain

y Sympathetic

'

Parasympathetic
vagus nerve

COfd

Receptors:
Aortic arch transmits via vagus nerve to solitary nucleus of
medulla (responds to i and t in BP).
Carotid sinus ( dilated region at carotid bifurcation) transmits via
glossopharyngeal nerve to solitary nucleus of medulla ( responds
to i and t in BP).
Baroreceptors:

- P n:t

Carotid body
chemoreceptor

Sympathetic

nerves

Hypotension 1 arterial pressure i stretch i afferent


baroreceptor firing t efferent sympathetic firing and
A efferent parasympathetic stimulation vasoconstriction,
t HR, T contractility, t BP. Important in the response to severe
hemorrhage.

Aortic
baroreceptor
SAnode

Blood
vessels
Avnode

Carotid massage t pressure on carotid sinus t stretch


-* t afferent baroreceptor firing -* t AV node refractory period
i HR.
Component ot Cushing reflex ( triad of hvpertensioij
bradycardia, and respirators depression) t intracranial
pressure constricts arterioles -* cerebral ischemia - t pCQ,
and 1 pH central reflex sympathetic t in perfusion pressure
t stretch peripheral reflex baroreceptor(hypertension )

Aortic
chemoreceptor

283

Released from ventricular myocytes in response to t tension. Similar physiologic action to ANP,
with longer half-life. B \ P blood test used for diagnosing HF ( very good negative predictive value).
Available in recombinant form (nesiritidc) for treatment of HK

B- type (brain )
natriuretic peptide

Carotid sinus
baroreceptor

SECTION I I I

Released from atrial myocytes in response to t blood volume and atrial pressure. Acts via cGMP.
Causes vasodilation and i Na* reabsorption at the renal collecting tubule. Dilates afferent renal
arterioles and constricts efferent arterioles, promoting diuresis and contributing to "aldosterone
escape mechanism.

Atrial natriuretic

peptide

IX:
Glossopharyngeal
nerve

CARDIOVASCULAR PHYSIOLOGY

induccd bradycardia.
Chemoreceptors:

Peripheral carotid and aortic bodies arc stimulated hv A Pa,


(< 60 mm Hg), t Pco7, and 1 pH of blood.
Central are stimulated by changes in pH and Pco, of brain
interstitial fluid, which in turn are influenced by arterial CO-,.
Do not directly respond to Po7.

CARDIOVASCULAR

Capillary fluid
exchange
Interstitial fluid
l

CARDIOVASCULAR PHYSIOLOGY

SECTION I I I

Starling forces determine fluid movement through capillary membranes:


Pc = capillary pressure pushes fluid out of capillary

Pl = interstitial fluid pressure pushes fluid into capillary


itc = plasma colloid osmotic (oncotic) pressure pulls fluid into capillary
It1 = interstitial fluid colloid osmotic pressure pulls fluid out of capillars
Jv = net fluid flow = Kf f(Pc - Pj) - g(ltc - ft,)]
Kf = permeability of capillary to fluid
C, = reflection coefficient ( measure of permeability of capillary to protein!
Edema excess fluid outflow into interstitium commonly caused by:

'

P n

Capillary

t capillary pressure ( t ; eg, HF)


* l plasma proteins ( t rtc; eg, nephrotic syndrome, liver failure, protein malnutrition)
t capillary permeability ( t ; eg, toxins, infections, burns)
t interstitial fluid colloid osmotic pressure ( t TTj; eg, lymphatic blockagel

Pc

Kf

285

CARDIOVASCULAR PATHOLOGY

CARDIOVASCULAR

SECTION III

287

Congenital heart diseases ( continued )

Right-to-L,eft shunts: caRLy cyanosis.


Left-to-Right shunts: I ateR cyanosis.

LEFTTO -RIGHT SHUNTS

Late cyanosis ( 2 to Eiscnmcngcr syndrome)


blue kids.
Frequency: V'SD > ASD > PDA.

Ventricular septal
defect

Most common congenital cardiac defect.


Asymptomatic at birth, may manifest weeks
later or remain asymptomatic throughout life.
Most self resolve; larger lesions may lead to L.V
overload and HF.

O saturation t in RV and pulmonary artery .

Atrial septal defect

Defect in interatrial septum Q; loud SI; wide,


fixed split S2. Ostium secundum defects
most common and usually occur as isolated
findings; ostium primum defects rarer yet
usually occur with other cardiac anomalies.
Symptoms range from none to HF. Distinct
from patent foramen ovale in that septa are
missing tissue rather than unfused.

CL saturation t in RA RV, and pulmonary


arterv. Mav lead to paradoxical cmbolj

In fetal period, shunt is right to left (normal).


In neonatal period, f pulmonary vascular
resistance -* shunt becomes left to right
progressive RVII and/or LVH and HF.
Associated with a continuous, "machine -like"
murmur. Patency is maintained by PGF
synthesis and low O tension. Uncorrcctcd
PDA Q can eventually result in late cyanosis
in the lower extremities (differential cyanosis).

Endomethacin (indomcthacin) ends patency


of PDA; PCF keeps ductus Going (may be
necessary to sustain life in conditions such as
transposition of the great vessels).
PDA is normal in utcro and normally closes only
after birth.

O'

rJ
Patent ductus
arteriosus

LF
PA

Eisenmenger
syndrome

LV

Uncorrcctcd Icft-to-right shunt ( VSD, ASD,


PDA ) t pulmonary blood flow
pathologic
remodeling of vasculature - pulmonary'
arterial hypertension. RVH occurs to
compensate -* shunt becomes right to
left. Causes late cy anosis, clubbing Q, and
polycythemia Age of onset varies.

VSD

RVII

OTHER ANOMALIES

Coarctation of the
aorta

Aortic narrowing near insertion of ductus arteriosus ( juxtaductal) Associated with bicuspid aorticvalve, other heart defects, and Turner syndrome. Hypertension in upper extremities and weak,
delayed pulse in lower extremities (brachial-femoral delay). With age, intercostal arteries enlarge
due to collateral circulation; arteries erode ribs notched appearance on CXR. Complications
include HF, t risk of cerebral hemorrhage ( berry aneurysms), aortic rupture, and possible
endocarditis.

288

SECTION III

Congenital cardiac
defect associations

CARDIOVASCULAR PATHOLOGY

CARDIOVASCULAR

DISORDER

DEFECT

Alcohol exposure in utero ( fetal alcohol


syndrome)
Congenital rubella

VSD, PDA, ASD, tetralogy of Fallot

Down syndrome

AV septal defect (endocardial cushion defect ),


VSD, ASD

Infant of diabetic mother

t ransposition of great vessels

Marfan syndrome

MVP, thoracic aortic aneurysm and dissection,


aortic regurgitation

Prenatal lithium exposure

Ebstein anomaly

Turner syndrome

Bicuspid aortic valve, coarctation of aorta

PDA, pulmonary artery stenosis, septal defects

Williams syndrome

Supravalvular aortic stenosis

22qll syndromes

Truneus arteriosus, tetralogy of Fallot

Defined as persistent systolic BP > 140 mm Hg and/or diastolic BP > 90 nun Hg

Hypertension
RISK FACTORS

t age, obesity, diabetes, physical inactivity, excess salt intake, excess alcohol intake, family history;
African American > Caucasian > Asian.

FEATURES

90% of hypertension is 1 (essential ) and related to t CTO or t TPR; remaining 10% mostly 2
to renal/renovascular disease (eg, atherosclerosis, fibromuscular dvsplasiaj [ string of beads"
appearance Q], usually found in younger women) and 1 hyperaldosteronism
Hypertensive urgency severe (> 180/> 120 mm Hg) hypertension without acute end-organ

damage.

Hypertensive emergency severe hypertension with evidence of acute end- organ damage (eg,
encephalopathy, stroke, retinal hemorrhages and exudates, papilledema, MI, HF, aortic dissection,
kidney injury, microangiopathic hemolytic anemia, eclampsia).

CAD, LVH, HF, AF; aortic dissection, aortic aneurysm; stroke; chronic kidney disease
( hypertensive nephropathy) Q; retinopathy.

PREDISPOSES TO

9}

tv^
* '

CARDIOVASCULAR

Aortic dissection

CARDIOVASCULAR PATHOLOGY

SECTION III

291

Longitudinal intimal tear forming a false lumen EJ. Associated with hypertension, bicuspid aortic
valve, inherited connective tissue disorders ( eg, Marfan syndrome). Can present with tearing
chest pain, of sudden onset, radiating to the back +/- markedly unequal BP in arms. CXR shows
mediastinal widening. Can result in organ ischemia, aortic rupture, death. Two types:
Stanford type A (proximal): involves Ascending aorta. May extend to aortic arch or descending
aorta. May result in acute aortic regurgitation or cardiac tamponade. Treatment: surgery.
Stanford type B ( distal ): only involves descending aorta ( Below liganrcntum arteriosum). No
ascending aorta involvement. Treat medically with {{-blockers, then vasodilators.

Ischemic heart disease manifestations


Angina

Chest pain due to ischemic myocardium 2 to coronary artery narrowing or spasm; no myocyte
necrosis.
Stable usually 2 to atherosclerosis; exertional chest pain in classic distribution (usually with
ST depression on KCG), resolving with rest or nitroglycerin.
Variant (Prinzmetal) occurs at rest 2 to coronary artery spasm; transient ST elevation on
ECC. Known triggers include tobacco, cocaine, and triptans, but trigger is often unknown.
Treat with Ca 2* channel blockers, nitrates, and smoking cessation (if applicable).
Unstable thrombosis with incomplete coronary artery occlusion; +/- ST depression and/or
T-wave inversion on ECG but no cardiac biomarker elevation ( unlike NSTEMI); t in frequency
or intensity of chest pain or any chest pain at rest.
:

Coronary steal
syndrome

Sudden cardiac death

Chronic ischemic
heart disease
Myocardial infarction

Distal to coronary stenosis, vessels are maximally dilated at baseline. Administration of vasodilators
(eg, dipyridamole, regadenoson) dilates normal vessels and shunts blood toward well-perfused
areas i flow and leads to ischemia in poststenotic regions Principle behind!pharmacologic
stress tests.
Death from cardiac causes within 1 hour of onset of symptoms, most commonly due to a lethal
arrhythmia (eg. VF). Associated with GAD (up to 70% of cases), cardiomyopathy ( hypertrophic,
dilated), and hereditary ion channelopathies ( eg, long QT syndrome, Brugada syndrome). Prevent
with implantable cardioverter-defibrillator (ICD).
Progressive onset of HF over many years due to chronic ischemic myocardial damage.

Most often acute thrombosis due to rupture of coronary artery atherosclerotic plaque, t cardiac
biomarkers (CK-MB, troponins) are diagnostic.
ST- segment elevation Ml ( STEMI)

Non- ST- segment elevation Ml (NSTEMI)

Transmural infarcts
Full thickness of myocardial wall involved
ST elevation on EGG, Q waves

Subendocardium (inner At especially

Subendocardial infarcts

vulnerable to ischemia

'

ST depression on ECG

V5

CARDIOVASCULAR

CARDIOVASCULAR PATHOLOGY

SECTION III

Cardiomyopathies

Dilated
cardiomyopathy

Most common cardiomyopathy (90% of cases).


Often idiopathic or familial. Other etiologies
include chronic Alcohol abuse, wet Beriberi,
Coxsackic B viral myocarditis, chronic
Cocaine use, Chagas disease Doxorubicin
toxicity, hemochromatosis, sarcoidosis,
peripartum cardiomyopathy,
bindings: HF, S 3, systolic regurgitant murmur,
dilated heart on echocardiogram, balloon
appearance of heart on CXR.
Treatment: Na+ restriction, ACE inhibitors,
p-blockers, diuretics, digoxin, ICD, heart

*>

Hypertrophic
cardiomyopathy

transplant.
60-70% of cases are familial, autosomal

Systolic dysfunction ensues.


Eccentric hypertrophy Q (sarcomeres added in
series).
\BCCCD.
Takotsubo cardiomyopathy: "broken heart
syndrome " ventricular apical ballooning
likely due to increased sympathetic stimulation
( stressful situations).

Diastolic dysfunction ensues.

dominant imost commonly due to mutations


in genes encoding sarcomeric proteins, such as
myosin binding protein C and 0-mvosin heavy
clnmt Can be associated with Friedreich
ataxia. Causes syncope during exercise and
may lead to sudden death in young athletes
due to ventricular arrhythmia.
Findings: S4, systolic murmur. May see mitral
regurgitation due to impaired mitral valve

Marked ventricular concentric hypertrophy


(sarcomeres added in parallel!H, often septal
predominance. Myofibrillar disarray and

fibrosis.
Obstructive hypertrophic cardiomyopathy
(subset ) asymmetric septal hypertrophy
and systolic anterior motion of mitral valve
outflow obstruction dyspnea, possible
syncope.

closure.
Treatment: cessation of high-intensity athletics,
use of 0 -blocker or non-dihydropyridine Ca-+
channel blockers (eg, verapamil). ICD if
patient is high risk.
Restrictive/infiltrative
cardiomyopathy

Puppy I.I ASII: Iostradiation fibrosis, loftier


syndrome, Endocardial fibroelastosis
( thick fihroelaslic tissue in endocardium of
voung children ! Amyloidosis, Sarcoidosis

Hemochromatosis ( although dilated


cardiomyopathy is more common )!

Diastolic dysfunction ensues. Can have loss voltage ECG despite thick myocardium
(especially amyloid).

SECTION III

Heart failure

HI

CARDIOVASCULAR PATHOLOGY

CARDIOVASCULAR

Clinical syndrome of cardiac pump dysfunction -* congestion and low perfusion. Symptoms
include dyspnea, orthopnea, fatigue; signs include Ss heart sound, ralej jugular venous distention
(J\'D), pitting edema Q.
Systolic dysfunction reduced EF, t EDY; J contractility often 2 to isehemia/MI or dilated
cardiomyopathy.
Diastolic dysfunction preserved EF, normal EDY; 1 compliance often 2 to myocardial
hypertrophy.
Right HF most often results from left HF. Cor pulmonale refers to isolated right HF due to
pulmonary cause.
ACE inhibitors or angiotensin 11 receptor blockers. [Yblockers ( except in acute decompensated HF ),
and spironolactone 1 mortality. Thiazide or loop diuretics are used mainly for symptomatic relief.
Hydralazine with nitrate therapy improves both symptoms and mortality in select patients.

Left heart failure

Orthopnea

Shortness of breath when supine: t venous


return from redistribution of blood (immediate

gravity effect ) exacerbates pulmonary vascular


congestion.
Paroxysmal
nocturnal dyspnea

Breathless awakening from sleep: t venous


return from redistribution of blood,
reabsorption of peripheral edema, etc.

Pulmonary edema

t pulmonary venous pressure pulmonary


venous distention and transudation of fluid.

1IV contract nty

Pulmonary
Jtrra

Pulmonary venous

lRv output

Presence of hemosiderin-laden macrophages


T System venous

tmm

ettema

Right heart failure

Hepatomegaly
(nutmeg liver)

t central venous pressure -* t resistance to


portal flow. Rarely, leads to "cardiac cirrhosis

Jugular venous
distention

t venous pressure.

Peripheral edema

t venous pressure

Shock

T PretoMl * cardoc
output 'compensation;

Hemorrhage, dehydration
burns

teauorpdon

f IV
.i-'i-i;of

* Sytnptfnetc
id fly

SVR

SKIN

(PRELOAD)

CO

(AFTERLOAD)

TREATMENT

Cold.

11

IV fluids

clammy

Acute MI, HF, valvular

dysfunction, arrhythmia
Obstructive

T Renal Na*
wdHO

Inadequate organ perfusion and delivery of nutrients necessary for normal tissue and cellular
function. Initially may be reversible but life-threatening if not treated promptly.
PCWP

Cardiogenic

fluid transudation.

CAUSED BY

Hypovolemic

Reno

..

It (t( XM

( HF" cells) in lungs.

1 Carctac

congestion

Cardiac tamponade

pulmonary embolism,
tension pncumothora 4

Inotropes, diuresis

Cold
clammy

11

Relieve obstruction

Warm
Dry

l
l

11
11

IV fluids, pressors

Distributive

Sepsis, anaphylaxis
CNS injury

CARDIOVASCULAR

CARDIOVASCULAR PATHOLOGY

Fever (most common symptom), new murmur,

Bacterial endocarditis

Roth spots (round white spots on retina


surrounded by hemorrhageJQ), Osier nodes
(tender raised lesions on finger or toe pads
due to immune complex depositing. Janeway

lesions (small, painless, erythematous lesions


on palm or sole) Q, glomerulonephritis,
septic arterial or pulmonary emboli, splinter
hemorrhages Q on nail bed. Multiple blood
cultures necessary for diagnosis.
Acute S aureus ( high virulence).
Large vegetations on previously normal
valves Q Rapid onset .
Subacute viridans streptococci I low
virulence ). Smaller vegetations on
congenitally abnormal or diseased valves.
Sequela of dental procedures. Gradual
onset.
S bovis ( gallolyticus ) is present in colon cancer,
S epidermidis on prosthetic valves.
Endocarditis may also be nonbacterial
(marantic /thrombotic) 2 to malignancy,
hypercoagulablc state, or lupus.

SECTION III

Mitral valve is most frequently involved.


Tricuspid valve endocarditis is associated with
IV drug abuse (don' t tri" drugs). Associated
with S aureus. Pseudomonas, and Candida .
Culture most likely Coxiella burnetii .
Bartonella spp., HACEK ( Haemophilus ,

Aggregatibacter ( formerly Actinobacillus ),


Cardiobacterium , Eikenella, Kingella )
V Bacteria FROM JANE V
Fever
Roth spots
Osier nodes
Murmur
Janeway lesions
Anemia
Nail-bed hemorrhage
Emboli

.
/i

c
a

297

7m

298

SECTION III

Rheumatic fever

if *J
term
'

.;

CARDIOVASCULAR

CARDIOVASCULAR PATHOLOGY

A consequence of pharyngeal infection with


group A P-hemolytic streptococci. Late
sequelae include rheumatic heart disease,
which affects heart valves mitral > aortic
tricuspid ( high-pressure valves affected most).
Early lesion is mitral valve regurgitation;
late lesion is mitral stenosis. Associated
with Aschoff bodies ( granuloma with giant
cells [blue arrows in 0)), Anitschkow cells
(enlarged macrophages with ovoid, wavy,
rod-like nucleus [red arrow in Q[ ), t anti
streptolysin O (ASO) titers.
Immune mediated (type II hypersensitivity);
not a direct effect of bacteria. Antibodies
to M protein cross-react with self antigens
(molecular mimicry).

JVNT.S (major criteria):


Joint (migratory polyarthritis)
V (carditis)
Nodules in skin (subcutaneous)
Erythema marginatum
Sydenham chorea

Treatment /prophylaxis: penicillin.

Acute pericarditis

Inflammation of the pericardium [ O, red arrows!. Commonly presents with sharp pain, aggravated
by inspiration, and relieved by sitting up and leaning forward. Often complicated by pericardia]
effusion [white arrow in O]. Presents with friction rub. ECG changes include widespread STsegment elevation and/or PR depression.
Causes include idiopathic (most common; presumed viral), confirmed infection (eg,
Coxsackievirus), neoplasia, autoimmune (eg, SLE, rheumatoid arthritis), uremia, cardiovascular
(acute STEMI or Dressier syndrome), radiation therapy.

Cardiac tamponade

Compression of the heart by fluid (eg, blood, effusions [arrows in 0] in pericardial space) I CO.
E q u i l i b r a t i o n of diastolic pressures in all 4 chambers.
Findings: Heck tri nl ( Inpotension. distended in i k wins, distant heuit sounds ;, I IK pulsus
p.uudoMJs ECO slums low voltage (JRS and eleetiR .ll ultcm.uis due
heart in large effusion).

Pulsus paradoxus 1 in amplitude of systolic BP by > 10 mm Hg during inspiration Seen in


cardiac tamponade, asthma, obstructive sleep apnea, pericarditis, croup.

Syphilitic heart
disease

3 syphilis disrupts the vasa vasorum of the


aorta with consequent atrophy of vessel wall
and dilatation of aorta and valve ring.
May see calcification of aortic root, ascending
aortic arch, and thoracic aortai Leads to tree
bark appearance of aorta.

Can result in aneurysm of ascending aorta or


aortic arch, aortic insufficiency,

CARDIOVASCULAR

Cardiac tumors
Myxomas

CARDIOVASCULAR PATHOLOGY

SECTION III

299

Most common heart tumor is a metastasis ( eg mclanomaj


Most common 1 cardiac tumor in adults Q. 907c occur in the atria (mostly left atrium). Myxomas
are usually described as a "hall valve obstruction in the left atrium ( associated with multiple
syncopal episodes ). Mas hear early diastolic " tumor plop sound. Histology: Gelatinous material,
myxoma cells immersed in glycosaminoglycans.

Rhabdomyomas

Kussmaul sign

Most frequent 1 cardiac tumor in children (associated with tuberous sclerosis ). I listology:
hamartomous growths.

t in ) \ T on inspiration instead of a normal L


Inspiration negative intTathoraeie pressure not transmitted to heart impaired filling of right
ventricle -* blood backs up into venae cavae -* JVD. May be seen with constrictive pericarditis,
restrictive cardiomyopathies, right atrial or ventricular tumors.

300

SECTION III

CARDIOVASCULAR PATHOLOGY

CARDIOVASCULAR

Vasculitides
EPIDEMI010GY/PRESENTATI0N

PATHOLOGY/LABS

Usually elderly females.


Unilateral headache ( temporal artery), jaw
claudication.
May lead to irreversible blindness due to
ophthalmic artery occlusion.
Associated with polymyalgia rheumatica.
Usually Asian females < 40 years old.
Pulseless disease" ( weak upper extremity
pulses), fever, night sweats, arthritis, myalgias,
skin nodules, ocular disturbances.

Most commonly affects branches of carotid


artery

Large vessel vasculitis


-

Giant cell (temporal)


arteritis

Takayasu arteritis

Focal granulomatous inflammation Q.


t ESR.
Treat with high-dose corticosteroids prior to
temporal artery biopsy to prevent blindness.

Granulomatous thickening and narrowing of


aortic arch Q and proximal great vessels,
t KSR.
Treat with corticosteroids.

Medium- vessel vasculitis


Polyarteritis nodosa

Kawasaki disease
(mucocutaneous

lymph node
syndrome )
Buerger disease
(thromboangiitis

obliterans)

middle-aged males]
1 lepatitis It seropositivity in W/ of patients.
Fever, weight loss, malaise, headache.
GI: abdominal pain, melena.
Hypertension, neurologic dysfunction,
cutaneous eruptions, renal damage.
Usually

Asian children < 4 vears old


Conjunctival injection Rash ( polymorphous
desquamating), Adenopathy (cervical),
Strawberry tongue (oral mucositis) 0, Handfoot changes ( edema, erythema), fever.

Heavy smokers, males < 40 years old.


Intermittent claudication may lead to
gangrene Q, autoamputation of digits,
superficial nodular phlebitis.
Raynaud phenomenon is often present.

Typically involves renal and visceral vessels, not


pulmonary arteries.

JTransmural inflammation of the arterial wall

with fibrinoid necrosis.


Different stages of inflammation may coexist in
different vessels.
Innumerable renal microaneurysms H and spasms
on arteriogram.
Treat with corticosteroids, cyclophosphamide.

CRASH and burn.

May develop coronary- artery- aneurysms 14


thrombosis or rupture can cause death.
Treat with IV immunoglobulin and aspirin.

Segmental thrombosing vasculitis.


Treat with smoking cessation.

Small-vessel vasculitis

Granulomatosis
with polyangiitis
( Wegener )

Upper respiratory tract : perforation of nasal


septum, chronic sinusitis, otitis media,
mastoiditis.
Lower respiratory tract: hemoptysis, cough,
dyspnea.
Renal: hematuria, red cell casts.

Triad:
Focal necrotizing vasculitis
* Necrotizing granulomas in the lung and
upper airway
Necrotizing glomerulonephritis
PR > -ANCA/c-ANCA Q (anti-proteinase 3).
CXR: large nodular densities.
Treat with cyclophosphamide, corticosteroids.

Microscopic
polyangiitis

Necrotizing vasculitis commonly involving


lung, kidneys, and skin with pauci-immunc
glomerulonephritis and palpable purpura.
Presentation similar to granulomatosis with
polyangiitis but without nasopharyngeal
involvement.

No granulomas.
MPO-ANCA /p-ANCAd (anti
myeloperoxidase).
Treat with cyclophosphamide, corticosteroids.

Vasculitides (continued )
PATHOLOGV/ WBS

EPIDEMIOLOGY/ PRESENTATION

Small- vessel vasculitis (continued)

Eosinophilic
granulomatosis with
polyangiitis (ChurgStrauss)

Asthma, sinusitis, skin nodules or purpura,


peripheral neuropath) (eg, wrist/foot drop).
Can also involve heart Cl, kidneys ( pauciimmune glomerulonephritis).

Granulomatous, necrotizing vasculitis with


eosinophilia Q.
MPO-ANCA/p-ANCA, t IgE level.

Henoch-Schonlein
purpura

Most common childhood systemic vasculitis.


Often follows URI.
Classic triad:
Skin: palpable purpura on buttocks/legs Q

Vasculitis 2 to IgA immune complex


deposition.
Associated with IgA nephropathy ( Berger

disease).

Arthralgias

GI: abdominal pain


L

3
i t

Y 4

ni

o)
'A
C
c

3?
is

02

SECTION III

CARDIOVASCULAR PHARMACOLOGY

CARDIOVASCULAR

CARDIOVASCULAR PHARMACOLOGY
Hypertension treatment

Hypertension with
heart failure

Thiazide diuretics, ACE inhibitors, angiotensin


II receptor blockers ( ARBs ), dihydrops ridine
Ca -+ channel blockers.
Diuretics, ACE inhibitors/ARBs, p-blockers
(compensated HE), aldosterone antagonists.

Hypertension with
diabetes mellitus

ACE inhibitors/ARBs, Ca -+ channel blockers,


thiazide diuretics, P-blockers.

Hypertension in
pregnancy

Hydralazine, labetalol, methyldopa, nifedipine.

Primary ( essential)
hypertension

Calcium channel
blockers
MECHANISM

CLINICAL USE

P-blockers must be used cautiously in


decompensated HE and are contraindicated in
cardiogenic shock.
ACE inhibitors/,\ RBs are protective against
diabetic nephropathy.

Amlodipine, clevidipine, nicardipine, nifedipine, niniodipine (dihydropyridines, act on vascular


smooth muscle); diltiazem, verapamil (non-dihydropyridines, act on heart).
Block vollage-dependeni 1 -type calcium channels of cardiac and smooth muscle 1 muscle
contractility.
Vascular smooth muscle amlodipine = nifedipine > diltiazem > verapamil.
Heart verapamil > diltiazem > amlodipine = nifedipine ( verapamil = ventricle).
Dihydropyridines (except niniodipine): hypertension, angina (including Prinzmetal), Raynaud
phenomenon.
Niniodipine: subarachnoid hemorrhage ( presents cerebral vasospasm).

Nicardipine, clevidipinci hypertensive urgenev or emergency


Non-dihydropyridines: hypertension, angina, atrial fibrillation/flutter.
ADVERSE EFFECTS

Non-dihvdropyridine: cardiac depression, AV block, hyperprolactinemia, constipation.


Dihvdropyridine: peripheral edema, flushing, dizziness, gingival hyperplasia.

Hydralazine

smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction.

MECHANISM

t cGMP

CLINICAL USE

Severe hypertension (particularly acute), III' ( with organic nitrate). Safe to use during pregnancy.
Frequently coadministered with a P-blocker to prevent reflex tachycardia.

ADVERSE EFFECTS

Compensatory tachycardia (contraindicated in angina /CAD), fluid retention, headache, angina.


Lupus-like syndrome.

Hypertensive

Drugs include clevidipine, fenoldopam, labetalol, nicardipine, nitroprusside.

emergency

Nitroprusside

Short acting; t cGMP via direct release of NO. Can cause cyanide toxicity (releases cyanide)

Fenoldopam

Dopamine D| receptor agonist coronary, peripheral, renal, and splanchnic vasodilation, t BP,
t natriuresis. Also used postoperatively as an antihypertensive. Can cause hypotension and
tachycardia.

CARDIOVASCULAR

CARDIOVASCULAR

Nitrates
MECHANISM

CLINICAL USE
ADVERSE EFFECTS

PHARMACOLOGY

Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.

Vasodilate by t NO in vascular smooth muscle t in cGMP and smooth muscle relaxation.


Dilate veins arteries, 4 preload.
Angina, acute coronary' syndrome, pulmonary edema.

Reflex tachycardia (treat with (3-blockers), hypotension, flushing, headache, Monday disease in
industrial exposure: development of tolerance for the vasodilating action during the work week
and loss of tolerance over the weekend tachycardia, dizziness, headache upon reexposure.
Contraindicated in right ventricular infarction.

Antianginal therapy

303

SECTION III

Goal is reduction of myocardial O-* consumption (MVOg) by i 1 or more of the determinants of


MV02: end-diastolic volume BP, MR, contractility.

COMPONENT

NITRATES

End- diastolic volume

p- BLOCKERS
No effect or t

Blood pressure

Contractility

No effect

Little/no effect

NITRATES p- BLOCKERS
No effect or 4

Heart rate

T (reflex response)

No effect or 4

Ejection time

L ittle/no effect

MVO2

Verapamil is similar to (3-blockers in effect.


Pindolol and accbutolol partial 3-agonists that should be used with caution in angintj
Ranolazine
MECHANISM

Inhibits the late phase of sodium current thereby reducing diastolic wall tension and oxygen
consumption. Does not affect heart rate or contractility.

CLINICAL USE

Angina refractory to other medical therapies.

ADVERSE EFFECTS

Constipation, dizziness, headache, nausea, QT prolongation.

Selective PDE- 3
inhibitor
MECHANISM

Milrinone

Selective PDK -3 inhibitor; 1 cAMP breakdown t Qu entry into cardiac mvocvtes and vascular
smooth muscle cells t inotropv, t peripheral arterial/venous vasodilation .

CLINICAL USE

Short term use in acute decompensated heart failure.

ADVERSE EFFECTS

Arrhy thmias, hypotension

CARDIOVASCULAR

CARDIOVASCULAR

PHARMACOLOGY

Lipid-lowering agents
DRUG

LDl

HDl

TRIGLYCERIDES

MECHANISMS OF ACTION

ADVERSE EFFECTS/PROBLEMS

HMG -CoA reductase


inhibitors

Hi

Hepatotoxicity (T LFTs),
myopathy (esp. when used
with fibrates or niacin )

Bile acid resins


Cholestyramine,
colestipol,
colesevelam

Slightly t

Slightly t

Inhibit conversion of HMGCoA to mevalonate, a


cholesterol precursor;
1 mortality in CAD patients
Prevent intestinal rcabsorption
of bile acids; liver must use
cholesterol to make more

Ezetimibe

Fibrates
Gemfibrozil,
bezafibrate,
fenofibrate

Niacin ( vitamin B3)

tt

(eg, lovastatin,
pravastatin )

Gl upset, 1 absorption of
other drugs and fat-soluble
vitamins

Prevent cholesterol absorption


at small intestine brush
border

Rare t LFTs, diarrhea

111

Upregulate LPL t TG
clearance
Activates PPAR-a to induce
HDL synthesis

Myopathy (t risk with


statins ), cholesterol
gallstones

Inhibits lipolysis ( hormonesensitive lipase ) in adipose


tissue; reduces hepatic VLDL
synthesis

Red , flushed face, which is


l by NSAIDs or long-term
use

Hyperglycemia
Hyperuricemia

PCSK9 inhibitors
alirocumab,
evolocumab

111

Myalgias, delirium.

Inactivation of LDL reccptor

degradation , increasing

dementia , other
neurocognitive effects

amount of LDL removed


from bloodstream
Liver

Enterocyte

Blood

Intestinal lumen

Acetyl CoA

HMG -CoA

ApoE
receptc i

HMG - CoA

CHOLESTEROL

Lymphatics

LHl

ABSORPTION

Ht

CHY

IC. dUC

rem

Mevalonate

/ Triacylglyceride

1 / /n

to esterol

MEVALONATE
SYNTHESIS

t L

/'

Niacin

Statins
Lovastatin
Pravastatin
Simvastatin
Atorvastatin

>

c+>-i
FFA

FFA

Lipolysis
Adipose tissue

LDL
receptor

LDL

LPL UPREGULATION

--

Cholesterol
FA
Bile acids
BILE ACID

REABSORPTION
Bile acid resins

HDL

Rosuvastatin

Cholesterol
FFA
Bile acids

receptor

HOL )

VLDL

LPt *

HDL

E20 - i be
*

FFA

'
pool

Fibrates
gemfibrozil
bezafibrate

fenofibrate

*
V. ADIPOSE LIPOLYSIS

cholestyramine
colestipol
colesevelam

B 06

SECTION I I I

Antiarrhythmics

sodium channel
blockers ( class I)

CARDIOVASCULAR

CARDIOVASCULAR PHARMACOLOGY

Slow or block ( t ) conduction (especially in depolarized cells). I slope of phase 0 depolarization. Are
state dependent ( selectively depress tissue that is frequently depolarized [eg, tachycardia] ).

Class IA

Quinidine, Procainamide, Disopyram idc.


The Queen Proclaims Diso's pyramid.

MECHANISM

t AP duration, t effective refractors period


( ERP ) in ventricular action potential, t QT
interval, some potassium channel blocking

CLINICAL USE

Both atrial and ventricular arrhythmias,


especially re-entrant and ectopic SVT and VT.

ADVERSE EFFECTS

Cinchonism ( headache, tinnitus with


quinidinc ), reversible SI.E-likc syndrome
(procainamide), heart failure (disopyramide),
thrombocytopenia, torsades dc pointes due to
t QT interval.

Class IB

Lidocaine, McxilcTinc. I'd Buy Liddy's

Class IA

/X

Slope of
phase 0

effects

Class IB

Mexican Tacos."
MECHANISM

1 AP duration. Preferentially affect ischemic or


depolarized Purkinje and ventricular tissue.
Phenytoin can also fall into the IB category.

CLINICAL USE

Acute ventricular arrhythmias (especially postM11, digitalis-induced arrhythmias. IB is Best


post-MI.

ADVERSE EFFECTS

CNS stimulation /depression, cardiovascular

Class 1C

I lecainide, Propafenone. Can 1 have Iries,

Slope of
phase 0

ADVERSE EFFECTS

Proarrhylhmic, especially post-MI


(contraindicated ). 1C is Contraindicated in
structural and ischemic heart disease.

r\

Class 1C

Please.

Significantly prolongs ERP in AV node and


accessors bypass tracts. No effect on ERP in
Purkinje and ventricular tissue
Minimal effect on AP duration.
SVIs, including atrial fibrillation. Only as a last
resort in refractory VT.

r\

Vv

depression.

MECHANISM

Slope of
phase 0

308

SECTION III

CARDIOVASCULAR

Verapamil, diltiazem .

Antiarrhythmics

CARDIOVASCULAR

PHARMACOLOGY

calcium channel
blockers ( class IV )
MECHANISM

I conduction velocity, f F.RP, t PR interval.

CLINICAL USE

Prevention of nodal arrhythmias (eg, SVT), rate control in atrial fibrillation .

ADVERSE EFFECTS

Constipation , flushing, edema, cardiovascular effects ( HF, AV block, sinus node depression ).

Class IV

60 i

1:
i

Slow rise of
action potential

- 30

Threshold

-60 |
- 90

Prolonged
repolarization
latAV node )

100

200

potential

500 400
Time ( ms)

500

600

r
700

Other antiarrhythmics

Adenosine

Mg 2 +

t K+ out of cells -* hvpcrpolarizing the cell and 1 1, decrease AV node conduction . Drug of
choice in diagnosing/terminating certain forms of SVT. Very short acting (~ 15 sec). F,ffects
blunted by theophylline and caffeine ( both arc adenosine receptor antagonists). Adverse effects
include flushing, hypotension, chest pain , sense of impending doom , bronchospasm .
Effective in torsades de pointes and digoxin toxicity .

Ivabradlne
MECHANISM

CLINICAL USE
ADVERSE EFFECTS

Selective inhibition of funny sodium channels Ilf I. prolonging slow depolarization phase I phase f ).
1 SA node firing; negative chronotropic effect without inotropv. Reduces cardiac O, requirement .
Chronic stable angina who cannot take [5-blockcrs. Chronic heart failure with reduced ejection
fraction.
Luminous phenomcna /visual brightness, hypertension , bradycardia .

HIGH- YIELD SYSTEMS

Endocrine

If you skew the endocrine system, you lose the


endocrine patterns change , it alters the way
in the battem tends to trib another.

pathways to self . When


think and feel. One shift

Embryology

310

Anatomy

310

Physiology

312

Pathology

321

Pharmacology

338

you

Hilary

Mantel

We have learned that there is an endocrinology of elation and despair, a


chemistry of mystical insight, and , in relation to the autonomic nervous
system, a meteorology and even . . . an astro- physics of changing moods.

Aldous (Leonard ) Huxley

Chocolate causes certain endocrine glands to secrete hormones that affect


your feelings and behavior by making you happy.
Elaine Sherman, Book of Divine Indulgences

309

310

SECTION I I I

ENDOCRINE EMBRYOLOGY

ENDOCRINE

ENDOCRINE EMBRYOLOGY
Thyroid development

Thyroid diverticulum arises from floor of


primitive pharvnx and descends into neck.
Connected to tongue by thyroglossal
duct, which normally disappears but may
persist as cysts or the pyramidal lobe of
thyroid. Foramen cecum is normal remnant
of thyroglossal duct. Most common
ectopic thyroid tissue site is the tongue
( lingual thyroid ). Removal may result in
hypothyroidism if it is the only thyroid tissue

Foramen cecum

Persistent
thyroglossal

duct
Thyroid
gland

Trachea

present.
Thyroglossal duct cyst Q presents as an anterior
midline neck mass that moves with swallowing

Thymus

or protrusion of the tongue (vs persistent


cervical sinus leading to branchial cleft cyst in
lateral neck ).
Thyroid tissue and parafollicular cells ( aka,
C cells, produce Calcitoniil) of the thyroid are
derived from endoderni

ENDOCRINE ANATOMY
Adrenal cortex and
medulla

Adrenal cortex (derived from mesoderm) and medulla (derived from neural crest ).
ANATOMY

iff ,

Zona Glomerulosa

PRIMARY REGULATORY CONTROL

SECRETORY PRODUCTS

Renin -angiotensin

Mineralocorticoids (aldosterone)

ACTH. CRH

Glucocorticoids (cortisol)

ACTH. CRH

Sex hormones tendrooens)

'itVvSi

CORTEX

Zona Fasciculate

Revised
)

Reticularis

3V

'

imaffin cells

Preganglionic sympathetic fibe

ids with Salt (mineralocorticoids Sugar ( glucocorticoi


vou go, the sweeter it gets.

Figure

SECTION III

ENDOCRINE PHYSIOLOGY

ENDOCRINE

ENDOCRINE PHYSIOLOGY
Insulin
SYNTHESIS

SOURCE
FUNCTION

Ircproinsulin ( synthesized in RFR ) cleavage


of presignal proinsulin (stored in secretory
granules ) cleavage of proinsulin exocytosis
of insulin and C-pcptidc equally. Insulin and
C'-peptide are t in insulinoma and sulfonylurea
use, whereas exogenous insulin lacks C-peptide.

C peptide

Promsulm

ii

'

p-chan

Released from pancreatic |3 cells.


Binds insulin receptors ( tyrosine kinase
activity ), inducing glucose uptake (carriermediated transport) into insulin-dependent
tissue 0 and gene transcription.
Anabolic effects of insulin:
t glucose transport in skeletal muscle and
adipose tissue
t glycogen synthesis and storage
t triglyceride synthesis
t Na* retention ( kidneys)
t protein synthesis ( muscles)
t cellular uptake of K and amino acids
i glucagon release
t lipolysis in adipose tissue
Unlike glucose, insulin does not cross placenta.

Insulin-dependent glucose transporters:


GLUTdt adipose tissue, striated muscle
( exercise can also increase GLUT-lt
expression)
Insulin-independent transporters:
GL.UT1L RBCs, brain, cornea, placenta
GLL 12jlbidirectional): P islet cells, liver,
kidney, small intestine
Gl.l"1 brain, placenta
"

GLUTEI ( fructose ): spermatocytes, GI tract


Brain utilizes glucose for metabolism normally
and ketone bodies during starvation. RBCs
require much glucose because tiles lack
mitochondria for aerobic metabolisirj

REGULATION

n-

BRICK L, (insulin-independent glucose uptake):


Brain, RBCs, Intestine, Cornea, Kidney,Liver.

Glucose is the major regulator of insulin release, t insulin response w ith oral vs IN glucose because of
incrctins such as elucagon-like peptide 1 ( GLIM ) and glucose-dependent insulinotropic polypeptide
( GIPi which are released after meals and t P cell sensitivity to glucose.
Glucose enters P cells t ATP generated from glucose metabolism closes K+ channels (target
of sulfonylureas 0 and depolarizes P cell membrane O. Voltage-gated Ca-+ channels open
Ca-+ influx Q and stimulation of insulin exocytosis

Insulin

ATP-sensitive
K* channels close

prasphonWnii

voltage -gited
Ca; chan: i -i
i

ATP

|/

'. v

-#

Depolarization
larization

-V

PtKxpborosilide- 3
knase pathway
GLUI 4
Glucose

:
an way
i

t ATP/ADP ratio f Intracellular


Ca

A MV

GLUT -2
Glucose

/Glycolysis

, \

C3 Glucose

Glycogen
protein
lipid, proie
thesis

bo
of insulin

e
vesicles
containing
GLUT 4

Cell growth

DNA
synthesis

Insulin-dependent glucose uptake

Irsu n

Bii i I
vessel

Insulin secretion by pancreatic (J cells

314

SECTION III

ENDOCRINE

ENDOCRINE

PHYSIOLOGY

Prolactin

Structurally homologous to growth hormone.


Excessive amounts of prolactin associated with
1 libido.

SOURCE

Secreted mainly by anterior pituitary.

FUNCTION

Stimulates milk production in breast; inhibits


ovulation in females and spermatogenesis
in males by inhibiting GnRH synthesis and
release.

REGULATION

Prolactin secretion from anterior pituitary


is topically inhibited bv dopamine from
tuberoinfundibular pathway of hypothalamu
Prolactin in turn inhibits its own secretion
by t dopamine synthesis and secretion from
hypothalamus. TRH t prolactin secretion (eg,
in 1 or 2 hypothyroidism).

Dopamine agonists (eg, bromocriptine) inhibit


prolactin secretion and can be used in
treatment of prolactinoma.
Dopamine antagonists (eg, most antipsychoties;
and estrogens (eg, OCPs, pregnancy) stimulat
prolactin secretion.

--

Sight/cry of baby

Higher cortical centers

Hypothalamus

~~

S
Medications
Chest wall injury (via ANSI
Nipple stimulation

T Plasma T3FT4

TRH

Dopamine

Posterior
pituitary

Anterior
pituitary

-0

Estrogen

SV FSH

--

Prolactin

Renal failure
Via reduced
prolactin elimination

iGnRH

S LH
'

<

Milk production

- Pregnancy
Ovulation
Spermatogenesis

ENDOCRINE

ENDOCRINE PHYSIOLOGY

SECTION III

315

Growth hormone ( somatotropin )


SOURCE
FUNCTION

REGULATION

Secreted by anterior pituitary.


Stimulates linear growth and muscle mass
through IGF-1 ( somatomedin C) secretion by
liver, t insulin resistance ( diabetogenic).

Released in pulses in response to growth


hormone-releasing hormone (GHRH ).
Secretion t during exercise, deep sleep,
puberty, hypoglycemia. Secretion inhibited by
glucose and somatostatin release via negative

Excess secretion ofGH (eg, pituitary adenoma )


may cause acromegaly ( adults ) or gigantism
(children). Treat with somatostatin analogs (eg,
octreotide) or surgery.

Stimulates hunger (orcxigcnic effect ) and GH


release (via GH seeretagog receptor ). Produced
by stomach. Sleep deprivation or Prader-Willi
syndrome t ghrelin production.
Satiety hormone. Produced by adipose tissue.
Mutation of leptin gene congenital obesity.
Sleep deprivation or starvation i leptin
production.
Act at cannabinoid receptors in hypothalamus
and nucleus accumbens, two key brain areas
for the homeostatic and hedonic control of
food intake t appetite.

Ghrelin makes you hunghre.

feedback by somatomedin.

Appetite regulation
Ghrelin

Leptin

Endocannabinoids

Leptin keeps you thin.

Exogenous cannabinoids cause " the munchics T

Antidiuretic hormone
SOURCE

FUNCTION

REGULATION

Synthesized in hypothalamus ( supraoptic


nuclei i. stored and secreted by posterior
pituitary.
Regulates serum osmolarity ( V 7-receptors)
and blood pressure ( V|-reccptorsl. Primary
function is serum osmolarity regulation (ADH
t serum osmolarity, t urine osmolarity) via
regulation of aquaporin channel insertion in
principal cells of renal collecting duct.
Osmoreceptors in hvpothalamus ( primarvj;

hvpovolemiaj

ADI 1 level is i in central diabetes insipidus ( Dl ),


normal or t in nephrogenic DI.
Nephrogenic Dl can be caused by mutation in
V, receptor.

Desmopressin acetate (ADH analog) is a


treatment for central DI and nocturnal
enuresis.

ENDOCRINE

ENDOCRINE PHYSIOLOGY

SECTION III

313

Glucagon
SOURCE

Made by a cells of pancreas.

REGULATION

Secreted in response to hypoglycemia. Inhibited by insulin, hyperglycemia, and somatostatin.

Hypothalamic- pituitary hormones


HORMONE

FUNCTION

CUNICAL NOTES

CRH

t AC'I'H, MSH, P-cndorphin

1 in chronic exogenous steroid use

Dopamine

1 prolactin, TSH

GHRH

t GH

Dopamine antagonists (eg, antipsychotics) can


cause galactorrhea due to hyperprolactinemia
Analog (tesamorelin) used to treat
HIV-associated lipodystrophy

GnRH

t FSH LH

Suppressed by hyperprolactinemia
Tonic GnRH suppresses 1liG axis
Pulsatile GnRH leads to puberty, fertility

Prolactin

l GnRH

Pituitary prolactinoma amenorrhea,


osteoporosis, hy pogonadism, galactorrhea

Somatostatin

t GH, TSH

Analogs used to treat acromegaly

TRH

t TSH, prolactin

t TRH ( eg, in 172: hvDothvroidisml mav


increase prolactin secretion - galactorrhea

ENDOCRINE

ENDOCRINE PHYSIOLOGY

SECTION III

315

Growth hormone ( somatotropin )


SOURCE

Secreted by anterior pituitary.

FUNCTION

Stimulates linear growth and muscle mass


through IGF-I (somatomedin C) secretion by
liver, f insulin resistance ( diabetogenic ).

REGULATION

Released in pulses in response to growth


hormone-releasing hormone ( GHRH).
Secretion t during exercise, deep sleep,
puberty, hypoglycemia. Secretion inhibited bv
glucose and somatostatin release via negative
feedback by somatomedin.

Excess secretion of GH (eg, pituitary adenoma 1


may cause acromegaly ( adults) or gigantism
(children). Treat with somatostatin analogs ( eg,
octreotide) or surgery.

Ghrelin

Stimulates hunger (orcxigcnic effect) and GH


release (via GH secretagog receptor ). Produced
by stomach. Sleep deprivation or Prader-Willi
syndrome t ghrelin production.

Ghrelin makes you hunghre.

Leptin

Satiety hormone. Produced by adipose tissue.


Mutation of leptin gene congenital obesity.
Sleep deprivation or starvation -* t leptin

Leptin keeps you thin.

Appetite regulation

Endocannabinoids

production.
Act at cannabinoid receptors in hypothalamus
and nucleus aceumbens, two key brain areas
for the homeostatic and hedonic control of
food intake - t appetite.

Exogenous cannabinoids cause the munchics.l

Antidiuretic hormone
SOURCE

Synthesized in hypothalamus ( supraoptic


nuclei), stored and secreted by posterior
pituitary.

FUNCTION

Regulates serum osmolarity ( VVreceptors)


and blood pressure ( V|-receptors). Primary
function is serum osmolarity regulation ( ADII
1 serum osmolarity, t urine osmolarity) via
regulation ofaquaporin channel insertion in
principal cells of renal collecting duct.

REGULATION

Osmoreceptors in hvpothalamus iprimarvi;

hvpovolemiai

ADI 1 level is 1 in central diabetes insipidus ( Dl ),


normal or t in nephrogenic DI.
Nephrogenic DI can be caused by mutation in
V -receptor.
Desmopressin acetate (ADH analog) is a
treatment for central DI and nocturnal
enuresis

Adrenal steroids and congenital adrenal hyperplasias


ACTH

Ke'oeofwole { blocks several steps in steroidogenesisI

i 1

Cholesterol

Anastrorole. exemeslsne

Cholesterol desmoUtse

Pregnenolone

l n i/ li

17 - hydroxypregnenolone

SJJ- hydroxysteroid

dehydrogenase

Progesterone

17u-hydroxylase

17-hydroxyprogesterone

21-hydroxylase
11-deoxycorticosterone

Aromatasc

Aromatase

Androstenedione

Testosterone

5-reductase

Cortisol

Corticosterone

11

Aldosterone synthase

ll-deoxycortiso(

Dehydroepiandrosterone (DHEA)

Estrone

Estradiol

Dihydrotestosterone

IDHT1

Glycyrrhetic acid

Aldosterone

Cortisone

ZONAGLOMERUIOSA

ZONA FASCICULATA
Glucocorticoids

Finasteride

Angiotensin II

Mineralocorticoids

ZONA RETICULARIS
Androgens

Estrogens DHT

Adrenal cortex

ENZYME DEFICIENCY
8

Q 17u-hydroxylase

MINERALOCORTICOIDS

CORTISOL

SEX
HORMONES

BP

[K+]

LABS

PRESENTATION

i androstenedione

XV: ambiguous
genitalia,

undescended testes
XX: lacks 2 sexual

development

21-hydroxylase

t renin activity
t 17 hvdroxy

progeslerone

0 lip-hydroxylase8

i aldosterone
t 11 deoxycorti

1 renin activity

Most common
Presents in infancy Is;

wasting) or childhoc
i precocious puberty
XX: virilization
XX: virilization

costerone
(results in
t BP)

by an enlargement of both adrenal glands due to t ACTH


All congenital adrenal enzyme deficiencies are characterized
hvpcrpigmentationi

stimulation ( in response to i cortisol i, and skin

ENDOCRINE

ENDOCRINE PHYSIOLOGY

SECTION III

317

Cortisol
SOURCE

Adrenal zona fasciculata.

Bound to corticosteroid-binding globulin.

FUNCTION

t Blood pressure:

Cortisol is a BIG FIB.


Exogenous corticosteroids can cause
reactivation of T B and candidiasis ( blocks IL-2
production).

Upregulates ot|-receptors on arterioles


t sensitivity to norepinephrine and

epinephrine |permissive action!


)

At high concentrations, can bind to


mineralocorticoid (aldosterone) receptors
t Insulin resistance (diabetogenic )
t Gluconeogenesis, lipolysis, and proteolysis
I Fibroblast activity ( causes striae)
i Inflammatory and Immune responses:
Inhibits production of leukotrienes and

prostaglandins
Inhibits WBC adhesion - neutrophilia
Blocks histamine release from mast cells

F osinopenia, lvinphopeiiial

Blocks IL-2 production


1 Bone formation (i osteoblast activity)
REGULATION

Calcium homeostasis

CRH ( hypothalamus ) stimulates ACTH release


(pituitary) cortisol production in adrenal
zona fasciculata. Excess cortisol 1 CRH,
ACTH, and cortisol secretion.

Chronic stress induces prolonged secretion.

Plasma Ca-+ exists in three forms:


lonized/free (~ 45%, active formj
Bound to albumin (- 40%)
Bound to anions (- 15%)

t in piI

Vitamin D|
SOURCE

D from exposure of skin to sun, ingestion of


fish and plants. D7 from ingestion of plants,
fungi, yeasts. Both converted to 25-011 in liver
and to l,25-( OH ) vitamin D ( active form) in
i

kidnevj
FUNCTION

,_.

t absorption of dietary Ca~* and P04

Enhances bone mineralization.


REGULATION

t l,25-(OH),
production.
l,25-(OH) j feedback inhibits its own
production.

'>-

t PTH, 1 Ca*,i P04

t affinity of albumin (t negative


charge ) to bind Ca+ hypocalcemia ( cramps,
pain, paresthesias, carpopedal spasm ) . Ionized /
free Cali is 1 regulator of PTH; changes in
pH alter PTII secretion, whereas changes in
albumin do not

Deficiency rickets in kids, osteomalacia in


adults. Caused by malabsorption, i sunlight,
poor diet, chronic kidney failure.
24,25-(OH), D is an inactive form of vitamin D
PPH leads to t Ca -+ rcabsorption and
i PO_ j reabsorption in the kidney, whereas
l,25-(OHl;D leads
_ to t absorption of both

,,

Ca+ and PO+ in the gut.

ENDOCRINE PHYSIOLOGY

ENDOCRINE

Calcitonin
SOURCE

Parafollicular cells ( C cells) of thyroid,

FUNCTION

i bone resorption of Ca-*.

REGULATION

t serum Ca-+ -* calcitonin secretion.

Calcitonin opposes actions of PTU. Not


important in normal Ca-+ homeostasis.
Calcitonin tones down Ca-' Calcitonin times
down Ca^ levels and keeps it in boncj

Iodine-containing hormones that control the bodys metabolic rate.

Thyroid hormones
( T3 /T4 )

Follicles of thyroid. Most T formed in target


tissues.

SOURCE

T functions

Bone growth (synergism with GH)


CNS maturation
t P| receptors in heart = t CO, HR, SV,

FUNCTION

contractility

t basal metabolic rate via t Na+/K+-ATPase


activity - t O-, consumption RR, body
temperature
t glycogenols sis, gluconeogenesis, lipolysis

production.

lBs:

TRH ( hypothalamus) stimulatesTSH


( pituitary), which stimulates follicular cells.
May also be stimulated by thyroid-stimulating
immunoglobulin ( TSI ) in Graves disease.
Negative feedback by free T?, Tj to anterior
pituitary i sensitivity to TRIP
Wolff-Chaikoff effect excess iodine
temporarily inhibits thyroid peroxidase
-* t iodine organification I T5/T4

REGULATION

Brain maturation
Bone growth
(l-adrcncrgic effects
Basal metabolic rate t
Thyroxine-binding globulin (TBG) hinds most
T;/Tj in blood; only free hormone is active,
i TBG in hepatic failure, steroids; t TBG in
pregnancy or OCP use (estrogen t TBG ).
Tj is major thyroid product; converted to T in
peripheral tissue by >'-deiodinasc.
T binds nuclear receptor w ith greater affinity
than T4
Thyroid peroxidase is the enzyme responsible
for oxidation and organification of iodide as
well as coupling of monoiodots rosine (MIT)
and di-iodotvrosinc ( Dl l ). 1111' + 1111 = Tg.
DIT + MIT = TV
Propylthiouracil inhibits both thyroid peroxidase
and 5'-dciodinasc. Methimazolc inhibits
thyroid peroxidase only. Glucocorticoids
inhibit peripheral conversion of 1 to IT

'

Hypothalamus

--

Thyroid follicular epithelial cell

Blood

Peripheral tissue

Follicular lumen

TRH
TG

TG

Thyroglobuiin

l V.-

Anterior pituitary \
Q
"
S
Somatostatin
TSH

Downstream thyroid
function

Thyroid

Deiodinase

l
Thyroid follicular ceils

iv

TJ,

J
;+

Effector organs

- Oxidation
on,

Na*

peroxidase

,*

T
T

5 -dciodinasc

TyTj

( to circulation)

Thyroid
peroxidase

MIT. DiT

TSI

Organification
of I

-orr
Tr
TG
Coupling reaction
Thyroid peroxidase

DIT

"

MIT

- DIT

,
.
tndocytosis

Tr
TG

DIT
MIT
MIT

320

SECTION I I I

ENDOCRINE PHYSIOLOGY

ENDOCRINE

Signaling pathways of endocrine hormones

cAMP

FSH,UI ACTH, TSH, GRII, I CG, ADI 1


FLAT ChAMP
( Vj receptor), MSH, PTH, calcitonin, GHRH,
glucagon, histamine ( H-,-receptorl

cGMP

BNP, ANP, EDRF (NO)

GnRH, Oxytocin, ADH ( Vprcccptor), TRH,


Histamine ( Hpreceptor) Angiotensin II,

P3

BAD GraMPa
Tliink vasodilators

GOAT HAG

Gastrin
Intracellular receptor

Progesterone, F,strogen, Testosterone, Cortisol,


Vldosterone, IVIp V'itamin D

Receptor tyrosine
kinase

Insulin, ICF-1, FGF, PDGF, EGF

Nonreceptor tyrosine
kinase

Signaling pathway of
steroid hormones

PET CAT on TV

MAP kinase pathway


Think Growth factors
Prolactin, Immunomodulators (eg, cytokines
JAK/STAT pathway
IL-2, IL-6, IKN) GH, G-GSF, Erythropoietin, Think acidophils and cytokine:
PIGGLET
Thrombopoietin

Steroid hormones are lipophilic and therefore


must circulate bound to specific binding
globulins, which t their solubility.
In men, f sex hormone-binding globulin
( SIIBG) lowers free testosterone
- gynecomastia.
In women, 1 SI 1BG raises free testosterone
- hirsutism.
t SI IBG.
OCPs, pregnancy

Cytoplasm

Nucleus

Binding to enhancer l e element In DNA

(WW
H

Transformation of
receptor to expose DNA

binding domain
Bmding to receptor
located in nucleus or
in cytoplasm

H) Hormone

I
^Pre-mRNA
mRNA

mRNA

I
I

I
1
BWBE

ENDOCRINE

ENDOCRINE PATHOLOGY

SECTION III

321

ENDOCRINE PATHOLOGY
Cushing syndrome
ETIOLOGY

FINDINGS

DIAGNOSIS

t cortisol due to a variety of causes:

Exogenous corticosteroids result in i ACTH, bilateral adrenal atrophy. Most common cause.
Primary adrenal adenoma, hyperplasia, or carcinoma result in t ACTH, atrophy of
uninvolved adrenal gland. Can also present with pseudohyperaldosteronism.
ACTH-sccrcting pituitary adenoma (Cushing disease); paraneoplastic ACTH secretion (eg,
small cell lung cancer, bronchial carcinoids) result in t ACTH, bilateral adrenal hyperplasia.
Cushing disease is responsible for the majority of endogenous cases of Cushing syndrome.
Hypertension, weight gain, moon facies Q, abdominal striae Q and truncal obesity, buffalo hump,
skin changes icg. thinning, striadl. osteoporosis, hyperglycemia (insulin resistance), amenorrhea,
immunosuppression.
Screening tests include: t free cortisol on 24-hr urinalysis, t midnight salivary cortisol, and no
suppression with overnight low - dose dexamethasone test. Measure serum ACTH. If I, suspect
adrenal tumor or exogenous glucocorticoids. If t, distinguish between Cushing disease and
ectopic ACTH secretion with a high-dose|dexamethasone suppression test and CRH stimulation
test. Ectopic secretion w ill not decrease with dexamethasone because the source is resistant to
negative feedback: ectopic secretion will not increase with CRH because pituitary ACTH is
suppressed.
Measure ACTH

v
Elevated

Suppressed

1
ACTH - independent
Cushing syndrome

ACTH-dependent
Cushing syndrome

r
or adrenal tumor (consider
MRI to confirm)

High-dose dexamethasone suppression test

CRH stimulation test

L
Adequate
suppression =

Cushing disease

No suppression =

ectopic ACTH
secretion

t ACTH. cortisol =
Cushing disease

1
.

No f ACTH cortisol =

ectopic
ACTH secretion

22

ENDOCRINE

Adrenal insufficiency

ENDOCRINE PATHOLOGY

Inability of adrenal glands to generate enough


glucocorticoids +/ mineralocorticoids for the
body's needs. Symptoms include weakness,
fatigue, orthostatic hypotension, muscle
aches, weight loss, GI disturbances, sugar and/
or salt cravings. Treatment: glucocorticoid/
mineralocorticoid replacement.

Primary adrenal
insufficiency
A
i

V7

s- l
/3

Diagnosis involves measurement of scrum


electrolytes, morning/random serum cortisol
and ACTH ( low cortisol, high ACTI1 in 1
adrenal insufficiency; low cortisol, low ACTH
in 27? adrenal insufficiency due to pituitary/
hypothalamic disease ), and response to ACTH
stimulation test .
Alternatively, can use metyrapone stimulation
test: metyrapone blocks last step of cortisol
synthesis ( ll-deoxycortisol -* cortisol). Normal
response is 1 cortisol and compensatory
t ACTH and 11-deoxycortisol. In 1 adrenal
insufficiency, ACTH is t but ll-deoxycortisol
remains 1 after test. In 273 adrenal
insufficiency, both ACTH and ll-deoxycortisol
remain l after test.

Deficiency of aldosterone and cortisol


Primary Pigments the skin/mucosa.
Associated with autoimmune polyglandular
production due to loss of gland function
- hypotension ( hvponatremie volume
syndromes.
contraction), hyperkalemia, metabolic acidosis, Waterhouse-Friderichsen syndrome acute
lc adrenal insufficiency due to adrenal
skin and mucosal hyperpigmentation Q ( due
to t MSII, a byproduct of ACTH production
hemorrhage associated with septicemia
from proopiomelanocortin [POMC ]).
(usually Neisseria meningitidis ), DIC,
Acute sudden onset (eg, due to massive
endotoxic shock.
hemorrhage). May present with shock in
acute adrenal crisis.
Chronic aka Addison disease. Due to
adrenal atrophy or destruction by disease
(autoimmune destruction most common in
the Western world; TB most common in the

developing world).

Secondary adrenal
insufficiency

Seen with 1 pituitary ACTH production.


No skin/mucosal hyperpigmentation, no

Secondary Spares the skin/mucosa.

hyperkalemia laldosterone synthesis preserved


due to intact RAA axi 4).
Tertiary adrenal
insufficiency

Hyperaldosteronism

Seen in patients with chronic exogenous

Tertiary from Treatment.

steroid use, precipitated by abrupt withdrawal.


Aldosterone synthesis unaffected.

Increased secretion of aldosterone from adrenal gland. Clinical features include hypertension, 1 or
normal K+, metabolic alkalosis. No edema due to aldosterone escape mechanism.

Primary
hyperaldosteronism

Seen with adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia! t aldosterone,
1 renin.

Secondary
hyperaldosteronism

Seen in patients w ith renovascular hypertension, juxtaglomerular cell tumor (due to independent
activation of rcnin-angiotensin-aldostcrone system), t aldosterone, t renin. Kdeina mav be seen 2
to causes such as heart failure or cirrhosis.

324

SECTION III

ENDOCRINE

ENDOCRINE PATHOLOGY

Pheochromocytoma
ETIOLOGY

7
SYMPTOMS

Most common tumor of the adrenal medulla in


adults Q. Derived from chromaffin cells (arise
from neural crest).
Up to 25% of cases associated with germline
mutations ( eg, NF I , VHL , RET [MEN 2A

Rule of 10's:
10% malignant
10% bilateral
10% extra-adrenal ( eg bladder wall, organ of
Zuckcrkandl1
10% calcify
10% kids

Most tumors secrete epinephrine,


norepinephrine, and dopamine, which can
cause episodic hypertension.
Symptoms occur in "spells relapse and remit.

Episodic hyperadrenergic symptoms ( 5 Ps):

my

Pressure ( t BP)
Pain ( headache)

Perspiration

Palpitations ( tachycardia)
Pallor

FINDINGS

TREATMENT

t catecholamines and metanephrines in urine

and plasma.
Irreversible a-antagonists (eg,
phenoxybenzamine) followed by (1-blockers
prior to tumor resection, a-blockade must be
achieved before giving [5-blockcrs to avoid a
hypertensive crisis.

Phenoxybenzamine (16 letters) is given for


phcochromocs Ionia (also 16 letters).

ENDOCRINE

ENDOCRINE PATHOLOGY

SECTION III

325

Hypothyroidism vs hyperthyroidism
SKiNS / SYMPTOMS

Hypothyroidism

Hyperthyroidism

Cold intolerance ( t heat production)

Heat intolerance ( t heal production!

Weight gain, t appetite

Weight loss, t appetite

Hvpoactivitv lethargy, fatigue, weakness,

Hyperactivity, anxiety, insomnia, hand tremor

depressed rnooq
Constipation
t reflexes (delayed/slow relaxing)
Hypothyroid myopathy ( proximal muscle
weakness, t CK )

Myxedema ( facial/periorbital )

Iivperdefecationl
t reflexes ( brisk )

Thyrotoxic myopathy ( proximal muscle


weakness, normal CK )

Pretibial myxedema ( Graves disease), periorbital


edema

Dry, cool skin; coarse, brittle hair


Bradycardia, dyspnea on exertion

LAB FINDINGS

Warm, moist skin; fine hair


Chest pain, palpitations, arrhythmias,
t number and sensitivity of |3-adrenergic
arrhvthmias (eg. atrial fibrillation!, receptors
(permissive effect )

t TSH (if 1)

A TSH (if 1)

t free T, and T+

t free or total T, and T

Hypercholesterolemia (due to 1 LDL receptor

Hypocholesterolcmia (due to t LDL receptor


expression)

expression)

Causes of goiter

Smooth/diffuse

Nodular

Graves disease
Hashimoto tliyroiditis
Iodine deficiency
TSH-sccreting pituitary adenoma

'loxic

multinodular goiter
Thyroid adenoma
Thyroid cancer
Thyroid cyst

326

SECTION III

ENDOCRINE PATHOLOGY

ENDOCRINE

Hypothyroidism

Hashimoto thyroiditis

Most common cause of hypothyroidism in iodine-sufficient regions; an autoimmune disorder with


antithyroid peroxidase (antiinicrosomal) and antithyroglobulin antibodies. Associated with HLADR3 and -DR t risk of non-Hodgkin lymphoma (typically of B-cell origin).
May be hvperthyroid early in course due to thyrotoxicosis during follicular rupture.
Histologic findings: Hurthle cells, lymphoid aggregates with germinal centers Q.
Findings: moderately enlarged, nontender thyroid.

Congenital
hypothyroidism
(cretinism)

Severe fetal hypothyroidism due to maternal hypothyroidism, thyroid agenesis, thyroid dysgenesis
(most common cause in US), iodine deficiency, dyshormonogenetic goiter.
Findings: Pot-bellied, Pale, Puffy-faced child with Protruding umbilicus Protuberant tongue, and
Poor brain development: the 6 Ps Q Q.

Subacute
granulomatous
thyroiditis (de
Quervain)

Self-limited disease often following a flu-like illness (eg, viral infection).


May be hyperthyroid early in course, followed by hypothyroidism.
Histology: granulomatous inflammation.
Findings: t ESR, jaw pain, very tender thyroid, (de Quervain is associated with pain.)

Riedel thyroiditis

Thyroid replaced by fibrous tissue with inflammatory infiltrate 0. Fibrosis may extend to local
structures (eg, trachea, esophagus), mimicking anaplastic carcinoma. A are hypothyroid.
Considered a manifestation of IgG -related systemic disease (eg, autoimmune pancreatitis,
^ aortitis).
retroperitoneal fibrosis, noninfectious
(
Findings: fixed, hard rock-like), painless goiter.
Iodine deficiency Q, goitrogens (eg, amiodarone, lithium), Wolff-Chaikoff effect (thyroid gland
downregulation in response to t iodide).

Other causes

m
m mm

&

BC

Before treatment

f t. j

Mm i\

After treatment

mmMX .
- r-V

."

ENDOCRINE PATHOLOGY

ENDOCRINE

SECTION III

329

Diagnosis of
parathyroid disease

l hy perparathyroidism
Ihypi rplasia, adenoma,
carcinoma ) :

2 hyperparathyroidism
( vitamin D deficiency,
chronic re lal failure)

jL. ,
,

Normal

1 hypoparathyroidism
(surgica resection,
autoi nmune)

PT H- independent
ypercalcemi

(excesi Ca2+ intake :ancer )

10

12

14

16

18

Ca2+ (mg /dL)

Hypoparathyroidism

20
0

Due to accidental surgical excision of parathyroid glands, autoimmune destruction, or DiGeorge


syndrome. Findings: tetany, hypocalcemia, hyperphosphatemia.
Chvostek sign tapping of facial nerve (tap the Cheek) contraction of facial muscles.
Trousseau sign occlusion of brachial artery with BP cuff (cuff the Triceps) carpal spasm.
Pseudohypoparathyroidism type 1A (Albright hereditary osteodystrophy) unresponsiveness of
kidney to PTH hypocalcemia despite t PTH levels. Characterized by shortened 4th/ 5th digits,
short stature. Autosomal dominant. Due to defective Gs protein a-subunit causing end-organ
resistance to PTH. Defect must be inherited from mother due to imprinting.
Pseudopseudohypoparathyroidism physical exam features of Albright hereditary
osteodystrophy but without end-organ PTH resistance (PTH level normal j Occurs when
defective G& protein a-subunit is inherited from father.

330

SECTION III

ENDOCRINE

ENDOCRINE

PATHOLOGY

Hyperparathyroidism
Primary
hyperparathyroidism

mI

Secondary
hyperparathyroidism

Usually due to parathyroid adenoma or


hyperplasia . Hypercalcemia , hypercalciuria
(renal stones), hypophosphatemia , t PTH,
t ALP, t cAMP in urine . Most often
asymptomatic. May present with weakness and
constipation ( groans"), abdominal /flank pain
( kidney stones, acute pancreatitis), depression
( psychiatric overtones ).

2 hyperplasia due to i Ca + absorption


and /or t PO 5-, most often in chronic
renal disease^ (causes hvpovitaminosis
D and hyperphosphatemia - I Calzj).
Hypocalcemia , hyperphosphatemia in
chronic renal failure (vs hypophosphatemia
with most other causes), t ALP, t PTH .

Osteitis fibrosa cystica cystic bone spaces


filled with brown fibrous tissue Q ( brown

tumor" consisting of osteoclasts and deposited


hemosiderin from hemorrhages; causes bone
pain ).
Stones, bones, groans, and psychiatric
overtones."

Tertiary
hyperparathyroidism

Familial hypocalciuric
He

hypercalcemia

located
Fact

Renal osteodystrophy renal disease 2 and


3 hyperparathyroidism bone lesions.

Refractory (autonomous) hyperparathyroidism


resulting from chronic renal disease tt PTH ,
t Ca 2+.
,

Defective G-coupled Ca = sensing receptors in multiple tissues (eg, parathyroids, kidneys). Higher
than normal Ca levels required to suppress PTIT . Excessive renal Ca reuptake -* mild
hypercalcemia and hvpocalciuria with normal to t PTH levels.

Pituitary adenoma

Benign tumor, most commonly prolactinoma (arises from lactotrophs). Adenoma Q may be
functional ( hormone producing) or nonfunctional (silent). Nonfunctional tumors present with
mass effect ( bitemporal hemianopia , hypopituitarism , headache). Functional tumor presentation
is based on the hormone produced .
Prolactinoma symptoms: females present with galactorrhea , amenorrhea , and 1 bone density due
to suppression of estrogen . Males present with low libido and infertility. Treatment includes
dopamine agonists (eg, bromocriptine, cabergoline), transsphenoidal resectioij

Nelson syndrome

Enlargement of existing ACTH-secreting pituitary adenoma after bilateral adrenalectomy for


refractory Cushing disease (due to removal of cortisol feedback mechanism ). Presents with
hyperpigmentation, headaches and bitemporal hemianopia . Treatment: pituitary irradiation or
surgical resection .

332

SECTION III

Diabetes insipidus

ETIOLOGY

FINDINGS

WATER DEPRIVATION TEST3

ENDOCRINE

ENDOCRINE

PATHOLOGY

Characterized by intense thirst and polyuria with inability to concentrate urine due to lack of ADH
(central ) or failure of response to circulating ADH (nephrogenic).
Central Dl

Nephrogenic Dl

Pituitary tumor, autoimmune, trauma , surgery,


ischemic encephalopathy, idiopathic

Hereditary (ADH receptor mutation ), 2


to hypercalcemia , hypokalemia , lithium ,
demeclocycline (ADH antagonist)

iADH
Urine specific gravity < 1.006
Serum osmolality > 290 mOsm/kg
Hyperosmotic volume contraction

Normal or t ADH levels


Urine specific gravity < 1.006
Serum osmolality > 290 mOsm /kg
Hyperosmotic volume contraction

> 50% t in urine osmolality only after


administration of ADH analog

Minimal change in urine osmolality, even after


administration of ADH analog

HCTZ, indomethacin , amiloride


Desmopressin acetate
Hydration
Hydration , avoidance of offending agent
aNo water intake for 2-3 hr followed by hourly measurements of urine volume and osmolarity and plasma Na + concentration
and osmolarity. ADH analog (desmopressin acetate) is administered if serum osmolality > 295-300 mOsm /kg, plasma
Na+ > 145, or urine osmolality does not rise despite a rising plasma osmolality.
TREATMENT

Syndrome of
inappropriate
antidiuretic

fiormone secretion

Characterized by:
Excessive free water retention
Euvolemic hyponatremia with continued
urinary Na + excretion
Urine osmolality > serum osmolality
Body responds to water retention with
1 aldosterone and t ANP and BNP
t urinary Na+ secretion -* normalization
of extracellular fluid volume euvolemic
hyponatremia. Very low serum Na+ levels
can lead to cerebral edema , seizures. Correct
slowly to prevent osmotic demyelination
syndrome (formerly known as central pontine
myelinolysis).
J

Causes include:
* Ectopic ADH (eg, small cell lung cancer)
CNS disorders/head trauma
Pulmonary disease
Drugs (eg, cyclophosphamide)
Treatment: fluid restriction, salt tablets, IV
hypertonic saline, diuretics, conivaptan,
5

tolvaptan, demeclocycline.

Increased urine osmolarity during water


deprivation test indicates psychogenic
polydipsia .

336

SECTION III

ENDOCRINE

ENDOCRINE

PATHOLOGY

Hyperosmolar
hyperqlycemid
nonketotic syndrome

State of profound hyperglycemia induced dehydration and t serum osmolalihl classically seen
in elderly type 2 diabetics with limited ability to drink . Hyperglycemia excessive osmotic
diuresis dehydration -* eventual onset of HHNS. Symptoms: thirst , polyuria , lethargy, focal
neurological deficits ( eg, seizures), can progress to coma and death if left untreated . Labs:
hyperglycemia (often > 600 mg /dL ), T serum osmolalihi (> 320 mOsm/kg), no acidosis ( pH >
7.3, ketone production inhibited by presence of insulin ). Treatment: aggressive IV fluids, insulin
therapy.

Glucagonoma

Tumor of pancreatic a cells -* overproduction of glucagon . Presents with dermatitis ( necrolvtic


migratory erythema), diabetes ( hyperglycemia), DVT, declining weight, depression. Treatment:
octreotide, surgery.

Insulinoma

Tumor of pancreatic P cells

Somatostatinoma

Tumor of pancreatic 6 cells

Carcinoid syndrome

mm

Rare syndrome caused by carcinoid tumors


( neuroendocrine cells Q; n le prominent

rosettes [arrow] ), especially metastatic small


bowel tumors, which secrete high levels
of serotonin ( 5-HT). Not seen if tumor is
limited to GI tract ( 5-HT undergoes first-pass
metabolism in liver). Results in recurrent
diarrhea , cutaneous flushing, asthmatic
wheezing, right-sided valvular heart disease
( tricuspid regurgitation , pulmonic stenosis) .
t 5-hydroxyindoleacetic acid ( 5-HIAA) in
urine, niacin deficiency ( pellagra ).
Treatment: surgical resection, somatostatin
analog (eg, octreotide).

Zollinger- Ellison
syndrome

Gastrin-secreting tumor ( gastrinoma ) of pancreas or duodenum . Acid hypersecretion causes


recurrent ulcers in duodenum and jejunum . Presents with abdominal pain ( peptic ulcer disease,
distal ulcers), diarrhea (malabsorption ). Positive secretin stimulation test: gastrin levels remain
elevated after administration of secretin , which normally inhibits gastrin release. May be
associated with MEN 1 .

overproduction of insulin hypoglycemia. May see Whipple triad:


low blood glucose, symptoms of hypoglycemia (eg, lethargy, syncope, diplopia ), and resolution of
symptoms after normalization of glucose levels. Symptomatic patients have i blood glucose and
t C -peptide levels (vs exogenous insulin use). ~ 10% of cases associated with MEN 1 syndrome .
Treatment: surgical resection.

overproduction of somatostatin 1 secretion of secretin ,


cholecvstokinin , glucagon , insulin, gastrin , gastric inhibitory peptide ( GIPl May present with
diabetes/glucose intolerance, steatorrhea , gallstones, achlorhvdrial Treatment: surgical resection;
somatostatin analogs (eg, octreotide) for symptom control .

Rule of l /3s:
1/ 3 metastasize
1/ 3 present with 2 nd malignancy
1 / 3 are multiple
Most common malignancy in the small
intestine.

338

SECTION III

ENDOCRINE

ENDOCRINE PHARMACOLOGY

ENDOCRINE PHARMACOLOGY
Diabetes mellitus
drugs

Treatment strategies:
Type 1 DM low-carbohydrate diet, insulin replacement
Type 2 DM dietary modification and exercise for weight loss; oral agents, non-insulin injectables,
insulin replacement
Gestational DM (GDM) dietary modifications, exercise, insulin replacement if lifestyle
modification fails
CLINICAL USE

ACTION

RISKS/CONCERNS

Insulin, rapid acting


Lispro,
Aspart,
Glulisine

Type 1 DM, type 2 DM,


GDM (postprandial glucose
control).

Binds insulin receptor (tyrosine


kinase activity) rapidly, no
LAG.
Liver: t glucose stored as
glycogen.
Muscle: t glycogen, protein
synthesis; t Ki uptake.
Fat: t TG storage.

Hypoglycemia, lipodystrophy,
rare hypersensitivity reactions.

Insulin, short acting


Regular

Type 1 DM, type 2 DM,


GDM, DKA (IV),
hyperkalemia (+ glucose),

Inhibits hepatic
gluconeogenesis and
the action of glucagon.
1 gluconeogenesis,
t glycolysis, t peripheral
glucose uptake ( t insulin

GI upset; most serious adverse


effect is lactic acidosis (thus
contraindicated in renal
insufficiency).

DRUG CLASSES

Insulin preparations

stress hyperglycemia.

Insulin, intermediate
acting

Type 1 DM, type 2 DM,


GDM.

NPH
Insulin, long acting
Detemir,
glargine

Type 1 DM, type 2 DM, GDM


( basal glucose control).

Oral hypoglycemic drugs


Biguanides
Metformin

Oral. First-line therapy in type


2 DM, causes modest weight
loss.
Can be used in patients
without islet function.

Sulfonylureas
First generation:

Stimulate release of
endogenous insulin in
type 2 DM. Require some
islet function, so useless in

chlorpropamide,
tolbutamide
Second generation:
glimepiride,
glipizide,
glyburide
Glitazones/
thiazolidinediones
Pioglitazone,

rosiglitazone

typeJi JDM.

Used as monotherapy in
typeJ2JDM or combined with
above agents. Safe to use in
renal impairment.

sensitivity).
Close IC channel in 3-cell
Risk of hypoglycemia t in renal
membrane cell depolarizes
failure, weight gain.
-* insulin release via t Ca
First generation: disulfiram-like
influx.
effects.
Second generation:

hypoglycemia.

insulin sensitivity in
peripheral tissue. Binds to
PPAR-Y nuclear transcription
regulator.-

Weight gain, edema.


Weight gain, edema, HH t risk
of fractures.

ENDOCRINE PHARMACOLOGY

ENDOCRINE

SECTION III

339

Diabetes mellitus drugs (continued )


DRUG CLASSES

CLINICAL USE

ACTION

RISKS /CONCERNS

Stimulate postprandial
insulin release by binding
to Kt channels on (3 -cell
membranes (site differs from
sulfonvlureas).

Hypoglycemia ( t risk with


renal failure), weight gain.

t glucose- dependent insulin

Nausea, vomiting, pancreatitis;


modest weight loss.

Oral hypoglycemic drugs (continued)


Meglitinides
Nateglinide,
repaglinide

Used as monotherapy in
type 2 DM or combined with

GLP- 1 analogs

Type 2 DM.

metformin.

release, 1 glucagon release.

Exenatide,
liraglutide (sc injection)
DPP- 4 inhibitors

1 gastric emptying, t satiety.

Type 2 DM.

Linagliptin,
saxagliptin,
sitagliptin

Inhibits DPP-4 enzyme that


deactivates GLP-1, thereby

Mild urinary or respiratory


infections; weight neutral.

t glucose-dependent insulin
release, 1 glucagon release,
1 gastric emptying, t satiety.

Amylin analogs
Pramlintide
(sc injection)

Type 1 DM, type 2 DM.

1 gastric emptying, 1 glucagon.

Hypoglycemia (in setting of


mistimed prandial insulin),

Sodium- glucose
co -transporter 2
( SGLT 3D inhibitors
Canagliflozin,
dapagliflozin,
empagliflozin

Type 2 DM.

Block reabsorption of glucose


in PCT.

Glucosuria, UTIs, vaginal yeast


infections, hyperkalemia,
dehydration (orthostatic

a- glucosidase
inhibitors
Acarbose,
miglitol

Type 2 DM.

nausea.

hypotension ), weight los 4

Inhibit intestinal brush-border

GI disturbances.

a-glucosidases.
Delayed carbohydrate
hydrolysis and glucose
absorption -* 1 postprandial
hyperglycemia.

aGenes activated by PPAR-y regulate fatty acid storage and glucose metabolism. Activation of PPAR-y t insulin sensitivity and
levels of adiponectin.

Thionamides
MECHANISM

CLINICAL USE

Propylthiouracil (PTU), methimazole.


Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling
of iodine inhibition of thyroid hormone synthesis. Propylthiouracil also blocks 5'-deiodinase
-* i peripheral conversion of
to T$.
Hyperthyroidism. PTU blocks Peripheral conversion PTU used in first trimester of pregnancy ( due
to methimazole teratogenicity); methimazole used in second and third trimesters of pregnancy

( due to risk of PTU-induced hepatotoxicityt


ADVERSE EFFECTS

Skin rash, agranulocytosis (rare), aplastic anemia, hepatotoxicity.


Methimazole is a possible teratogen (can cause aplasia cutis).

340

SECTION III

ENDOCRINE

ENDOCRINE PHARMACOLOGY

Levothyroxine (T4), triiodothyronine (T3 )


MECHANISM

Thyroid hormone replacement.

CLINICAL USE

Hypothyroidism, myxedema. Used off-label as weight loss supplements.

ADVERSE EFFECTS

Tachycardia, heat intolerance, tremors, arrhythmias.

Hypothalamic / pituitary drugs


DRUG

CLINICAL USE

ADH antagonists
(conivaptan,
tolvaptan)

SIADH, block action of ADH at V 7-receptor.

Desmopressin acetate

Central (not nephrogenic) DI, von Willebrand diseaseT sleep enuresi4

GH

GH deficiency, Turner syndrome.

Oxytocin

Stimulates labor, uterine contractions, milk let-down; controls uterine hemorrhage.

Somatostatin

Acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, esophageal varices.

(octreotide)

Demeclocycline
MECHANISM

ADH antagonist (member of tetracycline family).

CLINICAL USE

SIADH.

ADVERSE EFFECTS

Nephrogenic DI, photosensitivity, abnormalities of bone and teeth.

Fludrocortisone
MECHANISM

Synthetic analog of aldosterone with little glucocorticoid effects.

CLINICAL USE

Mineralocorticoid replacement in 1 adrenal insufficiency.

ADVERSE EFFECTS

Similar to glucocorticoids; also edema, exacerbation of heart failure, hyperpigmentation.

Cinacalcet
MECHANISM

Sensitizes Ca-+-sensing receptor (CaSR) in parathyroid gland to circulating Ca 2+

CLINICAL USE

1 or 2 hyperparathyroidism.

ADVERSE EFFECTS

Hypocalcemia.

1 PTH.

HIGH- YI E LD SYSTEMS

Gastrointestinal

good set of bowels is worth more to a man than any quantity of brains

Man

Embryology

342

Anatomy

343

Physiology

354

Pathology

357

Pharmacology

379

josh Billings

should strive to have his intestines relaxed all the days of his life

Moses Maimonides
Is life worth living? It all depends on the liver

William James

341

342

SECTION III

GASTROINTESTINAL

GASTROINTESTINAL EMBRYOLOGY

GASTROINTESTINAL EMBRYOLOGY
Normal
gastrointestinal
embryology

Foregut esophagus to upper duodenum


Midgut lower duodenum!to proximal 1h of transverse colon.
Hindgut distal /? of transverse colon to anal canal above pectinate line.

'

Midgut development:
" 6th week physiologic midgut herniates through umbilical ring
10 th week returns to abdominal cavity + rotates around superior mesenteric artery (SMA),
total 270 counterclockw ise
1

Ventral wall defects

Developmental defects due to failure of:


Rostral fold closure sternal defects
Lateral fold closure omphalocele,

Gastroschisis extrusion of abdominal


contents through abdominal folds (typically
right of umbilicus); not covered by peritoneum

gastroschisis
Caudal fold closure bladder exstrophy

or amnioij

Omphalocele |ierniation of abdominal


contents into umbilical cord, sealed by

peritoneum Q.

Congenital umbilical hernia

form of

incomplete closure of umbilical ring. Manyclose spontaneously.

Tracheoesophageal
anomalies

Esophageal atresia (EA) with distal tracheoesophageal fistula (TEF) is the most common (85%).
Polyhydramnios in utero. Neonates drool, choke, and vomit with first feeding. TEF allows air to
enter stomach (visible on CXR). Cyanosis is 2 to laryngospasm (to avoid reflux-related aspiration).
Clinical test: failure to pass nasogastric tube into stomach.
In Il-type, the fistula resembles the letter H. In pure EA the CXR shows gasless abdomen .
Esophagus

Tracheoesophageal
fistula

Trachea

1
S

V Esophageal

&

1
Normal anatomy

Pure EA
( atresia or stenosis)

Intestinal atresia

Pure TEF
(H- type)

atresia

EA with distal TEF


(most common)

E)

Presents w ith bilious vomiting and abdominal distension within first 1-2 days of life.
Duodenal atresia failure to recanalize dilation of stomach and proximal duodenum ( double
bubble on x-ray O). Associated with Down syndrome.
Jejunal and ileal atresia disruption of mesenteric vessels ischemic necrosis segmental
resorption (bowel discontinuity or apple peel ). lejunal atresia commonly associated with triple
bubble" sign on x-rav.

GASTROINTESTINAL ANATOMY

GASTROINTESTINAL

SECTION III

343

Hypertrophic pyloric
stenosis

Most common cause of gastric outlet obstruction in infants ( 1:600). Palpable olive mass in
epigastric region, visible peristaltic waves!and nonbilious projectile vomiting at ~ 2-6 weeks old.
More common in firstborn males; associated with exposure to macrolides. Results in hypokalemic
hypochloremic metabolic alkalosis ( 2 to vomiting of gastric acid and subsequent volume
contraction). Treatment is surgical incision ( pyloromyotomy).

Pancreas and spleen

Pancreas derived from foregut. Ventral pancreatic buds contribute to uncinate process and main
pancreatic duct. The dorsal pancreatic bud alone becomes the body, tail, isthmus, and accessory
pancreatic duct. Both the ventral and dorsal buds contribute to pancreatic head.
Annular pancreas ventral pancreatic bud abnormally encircles 2nd part of duodenum; forms a
ring of pancreatic tissue that may cause duodenal narrowing Q and Vomiting.
Pancreas divisum ventral and dorsal parts fail to fuse at 8 weeks. Common anomaly; mostly
asymptomatic, but may cause chronic abdominal pain and/or pancreatitis.
Spleen arises in mesentery of stomach (hence is mesodermal) but has foregut supply (celiac trunk
splenic artery).

embryology

Gallbladder

Accessory
pancreatic duct

Pancreat c
duct

Minoi
oapilla

Dorsal
pancreatic
bud

Major papilla

Ventral
pancreatic bud

Uncinate

Main
pancreatic
duct

process

GASTROINTESTINAL ANATOMY

Retroperitoneal structures include GI structures


that lack a mesentery and non-GI structures.
Injuries to retroperitoneal structures can cause
blood or gas accumulation in retroperitoneal

Retroperitoneal
structures

space.
Right

'

Ascending

colon

Av\

Duodenum

Kidneys
Esophagus (thoracic portion) [not shown]
Rectum ( partially) [not shown]

Peritoneum

Pancreas

^ MML .

Transversalis fascia

Left

Descending
renal
space
Kidney

Aorta

SAD PUCKER:
Suprarenal (adrenal) glands [not shown]
Aorta and IVC
Duodenum (2nd through 4th parts)
Pancreas (except tail)
Ureters [not shown]
Colon (descending and ascending)

GASTROINTESTINAL ANATOMY

GASTROINTESTINAL

Digestive tract
anatomy

SECTION III

345

Layers of gut wall (inside to outside MSMS):


Mucosa epithelium, lamina propria, muscularis mucosa
Submucosa includes Submucosal nerve plexus (Meissner), Secretes fluid
Muscularis externa includes Myenteric nerve plexus ( Auerbach), Motility
Serosa ( when intraperitoneal), adventitia (when retroperitoneal)
Ulcers can extend into submucosa, inner or outer muscular layer. Erosions are in the mucosa only.
Frequencies of basal electric rhythm ( slow waves):
Stomach 3 waves /min
* Duodenum 12 waves/min
11eum 8-9 waves/min
ri

Tunica muscularis

Mucosa
- pithelium
Lamina propria
Muscularis mucosa

externa

Tunica submucosa

Mesentery
Intestinal villi

m
-

submucosal

Vein
Artery

Submucosa

Lymph vessel

Epithelium

Lumen

Muscularis mucosa

>v Yv

' >

Myenteric nerve plexus


(Auerbach)

Iperitoneuml

Submucosal nerve
plexus (Meissner)
Muscularis
Inner circular layer
Myenteric nerve plexus
(Auerbach)

- Tunica serosa

Enlarged view
cross-section

Submucosal gland

Outer longitudinal layer


Serosa

Digestive tract histology

Esophagus

Nonkeratinized stratified squamous epithelium.

Stomach

Gastric glands.

Duodenum

Villi and microvilli t absorptive surface.


Brunner glands (HC02--secreting cells of submucosa) and crvpts of Lieberkuhn (contain stem cells
that replace enterocytes/goblet cells and Paneth cells that secrete defensins, lysozyme, and TNFl

Jejunum

Plicae circulares and crypts of Lieberkuhn.

Ileum

patches (lymphoid aggregates in lamina propria, submucosa), plicae circulares (proximal


ileum), and crypts of Lieberkuhn.
Largest number of goblet cells in the small intestine.
Crypts of Lieberkuhn but no villi; abundant goblet cells.

Colon

Peyer

GASTROINTESTINAL

GASTROINTESTINAL ANATOMY

Celiac trunk
Left gastric artery

Esophageal branch of
left gastric artery .

Short gastric arteries

Celiac artery

Proper hepatic
artery

Right gastric artery Common


hepatic artery
Gastroduodenal

Spleen

artery

Left gastroepiploic
artery

Splenic artery
Right gastroepiploic artery

-Posterior superior
Anterior superior
pancreaticoduodenal
arteries

pancreaticoduodenal artery

SECTION III

Branches of celiac trunk: common hepatic,


splenic, and left gastric. These constitute the
main blood supply of the stomach.
Strong anastomoses exist between:
Left and right gastroepiploics
Left and right gastrics
Posterior duodenal ulcers penetrate
gastroduodenal artery causing hemorrhage .

347

GASTROINTESTINAL

Pectinate ( dentate )
line
lemormoKK

J
r

S II

if

5
.

==

as

'amj$

External

Pect irate

lemorrhoid

line

ANATOMY

SECTION III

349

Formed where endoderm ( hindgut) meets ectoderm .

internal hemorrhoids,
adenocarcinoma .
Arterial supply from superior rectal artery
( branch of IMA) .
Venous drainage: superior rectal vein inferior
Above pectinate line

Internal

GASTROINTESTINAL

mesenteric vein
system!


splenic vein

Internal hemorrhoids receive visceral


innervation and are therefore not painful .
Lymphatic drainage to internal iliac lymph
nodes.

portal

External hemorrhoids receive somatic


Below pectinate line external hemorrhoids,
innervation (inferior rectal branch of pudendal
anal fissures, squamous cell carcinoma .
Arterial supply from inferior rectal artery ( branch nerve) and are therefore painful if thrombosed .
Lymphatic drainage to superficial inguinal nodes.
of internal pudendal artery).

Venous drainage: inferior rectal vein internal


Anal fissure tear in the anal mucosa below the
pudendal vein internal iliac vein -* common Pectinate line. Pain while Pooping; blood on
iliac vein * IVC.
toilet Paper. Located Posteriorly because this
area is Poorly Perfused . Associated with lowfiber diets and constipation .

GASTROINTESTINAL ANATOMY

GASTROINTESTINAL

Biliary structures

SECTION III

351

Gallstones ( filling defects, red arrows in Q) that reach the confluence of the common bile and
pancreatic ducts at the ampulla of Vater can block both the common bile and pancreatic ducts
(double duct sign), causing both cholangitis and pancreatitis, respectively.
Tumors that arise in head of pancreas (usually ductal adenocarcinoma) can cause obstruction of
enlarged gallbladder with painless jaundice (Courvoisier sign!
common bile duct

Cystic duct
Liver

Gallbladder

^
1

Common hepatic duct

Common bile duct

0
Accessory

Ned

Ron

pancreatic duct

Pancreas
Head

Sphincter of Oddi

Ampulla of Vater Main pancreatic duct


Duodenum

Femoral region

Lateral to medial: Nerve-Artery-VeinLymphatics.

You go from lateral to medial to find your


N AVeL.

Femoral triangle

Contains femoral nerve, artery, vein.

Venous near the penis.

Femoral sheath

Fascial tube 3-4 cm below inguinal ligament.


Contains femoral vein, artery, and canal (deep
inguinal lymph nodes) but not femoral nerve.

ORGANIZATION

'

Femoral Nerve

Inguinal
ligament

Femoral Artery

Sartorius

.ymphatics

Femoral Vein

muscle

Femoral ring-site of
femoral hernia

Revised
Figure
Femoral
sheath

Adductor longus
muscle

GASTROINTESTINAL

GASTROINTESTINAL ANATOMY

SECTION III

353

A protrusion of peritoneum through an opening, usually at a site of weakness. Contents may be at


risk for incarceration (not reducible back into abdomen/pelvis) and strangulation (ischemia and
necrosis). Complicated hernias can present with tenderness, erythema, fever.

Hernias

Diaphragmatic hernia

Indirect inguinal
hernia

Abdominal structures enter the thorax;


may occur due to congenital defect of
pleuroperitoneal membrane Q, or as a result
of trauma. Commonly occurs on left side due
to relative protection of right hemidiaphragm
by liver.
Most commonly a hiatal hernia, in which
stomach herniates upward through the
esophageal hiatus of the diaphragm.
Goes through the internal (deep) inguinal ring,
external (superficial) inguinal ring, and into
the scrotum. Enters internal inguinal ring
lateral to inferior epigastric vessels. Occurs in
infants owing to failure of processus vaginalis
to close (can form hydrocele). Much more
common in males Q.

Sliding hiatal hernia is most common.


Gastroesophageal junction is displaced
upward; hourglass stomach.
Paraesophageal hernia gastroesophageal
junction is usually normal. Fundus protrudes
into the thorax.

An indirect inguinal hernia follows the path of


descent of the testes. Covered by all 3 layers of

spermatic fascia.

Direct inguinal hernia

Protrudes through the inguinal ( Hesselbach)


MDs dont Lie:
Medial to inferior epigastric vessels = Direct
triangle. Bulges directly through abdominal
wall medial to inferior epigastric vessels. Goes
hernia.
Lateral to inferior epigastric vessels = Indirect
through the external (superficial) inguinal ring
hernia.
only. Covered by external spermatic fascia.
Usually in older men.

Femoral hernia

Protrudes below inguinal ligament through


femoral canal below and lateral to pubic
tubercle. More common in females, but
overall inguinal hernias are the most common.

Inguinal
(Poupart)

ligament.

Indirect
inguinal hernia

Femoral artery

.m

Rectus abdominis muscle

Inferior
epigastric vessels

Direct inguinal hernia

Inguinal ( Hesselbach) triangle


X

More likely to present with incarceration or


strangulation than inguinal hernias.

Femoral hernia

Femoral vein

Inguinal ( Hesselbach) triangle:


* Inferior epigastric vessels
Lateral border of rectus abdominis
Inguinal ligament

356

SECTION III

Pancreatic secretions

GASTROINTESTINAL

Isotonic fluid; low flow


ROLE

ENZYME

GASTROINTESTINAL PHYSIOLOGY

high Cl , high flow

high HCO -.
NOTES

Secreted in active form

a- amylase

Starch digestion

Lipases

Fat digestion

Proteases

Protein digestion

Trypsinogen

Converted to active enzyme trypsin


Converted to trypsin by enterokinase/
-* activation of other proenzymes and cleaving enteropeptidase, a brush-border enzyme on
duodenal and jejunal mucosa
of additional trypsinogen molecules into active
trypsin ( positive feedback loop)

Includes trypsin, chymotrvpsin, elastase,


carboxypeptidases
Secreted as proenzymes also known as
zymogens

Only monosaccharides ( glucose, galactose, fructose) are absorbed by enterocytes. Glucose and
galactose are taken up by SGLT1 (Na+ dependent). Fructose is taken up by facilitated diffusion by
GLUT-5. All are transported to blood by GLUT-2.
D-xylose absorption test: distinguishes GI mucosal damage from other causes of malabsorption.

Carbohydrate

absorption

Vitamin/mineral absorption
Iron

Absorbed as Fe-+ in duodenum.

Folate

Absorbed in small bowel.

b2

Absorbed in terminal ileum along with bile


salts, requires intrinsic factor.

Unencapsulated lymphoid tissue Q found in

Peyer patches

Wm
m

A&lMf

Bile

lamina propria and submucosa of ileum.


Contain specialized M cells that sample and
present antigens to immune cells.
B cells stimulated in germinal centers of Peyer
patches differentiate into IgA-secreting plasma
cells, which ultimately reside in lamina
propria. IgA receives protective secretory
component and is then transported across the
epithelium to the gut to deal with intraluminal
antigen.

Iron Fist, Bro


Clinically relevant in patients with small bowel
disease or after resection.

Think of IgA, the Intra-gut Antibody. And


always say secretory IgA.

Composed of bile salts (bile acids conjugated to glycine or taurine, making them water soluble),
phospholipids, cholesterol, bilirubin, water, and ions. Cholesterol 7a-hydroxylase catalyzes
rate-limiting step of bile acid synthesis.
Functions:

Digestion and absorption of lipids and fat-soluble vitamins


Cholesterol excretion ( bodvs primary means of eliminating cholesterol)
Antimicrobial activity (via membrane disruption)

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

SECTION III

357

Heme is metabolized by heme oxygenase to biliverdin, which is subsequently reduced to bilirubin.


Unconjugated bilirubin is removed from blood by liver, conjugated with glucuronate, and excreted
in bile.
Direct bilirubin conjugated with glucuronic acid; water soluble.
Indirect bilirubin unconjugated; water insoluble.

Bilirubin

Excreted in urine as

urobilin ( yellow color)

Kidney

90
mterohepatic

20%
Macrophages

Bloodstream

Gut

Liver

Albumin
RBCs

Heme

Unconjugated
bilirubin

Unconjugated bilirubinalbumin complex

JDP -

Conjugated
bilirubin

glucuronosyltransferase

Indirect bilirubin
( water insoluble)

Urobilinogen

'

Direct bilirubin
[ water soluble )

i'

bat ana

80 %

Excreted in feces as
stercobilin ( brown
color of stool)

GASTROINTESTINAL PATHOLOGY
Salivary gland tumors

wmm
mm g
-

Most commonly benign and in parotid gland. Tumors in smaller glands more likely malignant.
Typically present as painless mass/swelling. Facial pain or paralysis suggests malignant
involvement of CN VII.
Pleomorphic adenoma ( benign mixed tumor) most common salivary gland tumor Q.
Composed of chondromyxoid stroma and epithelium and recurs if incompletely excised or

ruptured intraoperativelv.
Mucoepidermoid carcinoma most common malignant tumor, has mucinous and squamous
components.
Warthin tumor (papillary cystadenoma lymphomatosum) benign cystic tumor with germinal
centers . Typically found in white smokers . Bilateral in 10%; malignant in 107c .

360

SECTION III

Gastritis

Acute gastritis

GASTROINTESTINAL

GASTROINTESTINAL

Erosions can be caused by:


NSAIDs i PGE -, i gastric mucosa

protection
Burns (Curling ulcer ) hypovolemia
-* mucosal ischemia
Brain injury (Cushing ulcer) t vagal
stimulation t ACh t H + production
Chronic gastritis

H pylori

Mucosal inflammation, often leading to atrophy


( hypochlorhydria hvpergastrinemia ) and
intestinal G -cell metaplasia ( t risk of gastric
cancers).
Most common t risk of peptic ulcer disease,
MALT lymphoma.
Autoantibodies to parietal cells and intrinsic
factor, t risk of pernicious anemia .
,

Autoimmune

Menetrier disease

PATHOLOGY

Especially common among alcoholics and


patients taking daily NSAIDs (eg, patients with
rheumatoid arthritis).
Burned by the Curling iron .

Always Cushion the brain .

Affects antrum first and spreads to body of


stomach .

Affects body/fundus of stomach.

Gastric hyperplasia of mucosa hypertrophied rugae ( looking like brain gyri Cl), excess
mucus production with resultant protein loss and parietal cell atrophy with I acid production .
Precancerous.

A
Gastric cancer

L <$

wr
i t f.

Virchow node involvement of left


Most commonly gastric adenocarcinoma ;
lymphoma , GI stromal tumor, carcinoid ( rare).
supraclavicular node by metastasis from
stomach .
Early aggressive local spread with node/liver
Krukenberg tumor bilateral metastases to
metastases. Often presents late, with weight
loss, early satiety, and in some cases acanthosis
ovaries. Abundant mucin-secreting, signet ring
cells.
nigricans or Leser-Trelat sign .
Intestinal associated with H pylori, dietary Sister Mary Joseph nodule subcutaneous
nitrosamines (smoked foods ), tobacco
periumbilical metastasis.
smoking, achlorhydria , chronic gastritis.
Commonly on lesser curvature; looks like
ulcer with raised margins.
Diffuse not associated with H pylori ; signet
ring cells ( mucin-filled cells with peripheral
nuclei) Q; stomach wall grossly thickened
and leathery ( linitis plastica ).

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

SECTION III

363

Inflammatory bowel diseases

Crohn disease

Ulcerative colitis

LOCATION

Any portion of the GI tract, usually the terminal


ileum and colon. Skip lesions, rectal sparing.

GROSS MORPHOLOGY

Transmural inflammation -* fistulas.


Cobblestone mucosa, creeping fat, bowel wall
thickening ( string sign on barium swallow
x-ray Q), linear ulcers, fissures.

MICROSCOPIC MORPHOLOGY

Noncaseating granulomas and lymphoid

Colitis = colon inflammation. Continuous


colonic lesions, always with rectal involvement.
Mucosal and submucosal inflammation only.
Friable mucosal pseudopolyps (compare
normal Q with diseased Q) w ith freely
hanging mesentery. Loss of haustra lead
pipe appearance on imaging.
Crypt abscesses and ulcers, bleeding, no
granulomas.
Malabsorption /malnutrition , colorectal cancer
( t risk with pancolitis).
Fulminant colitis, toxic megacolon , perforation .

COMPLICATIONS

INTESTINAL MANIFESTATION
EXTRAINTESTINAL MANIFESTATIONS

aggregates.
Malabsorption /malnutrition, colorectal cancer
( t risk with pancolitis).
Fistulas (eg, enterovesical fistulae, which can
cause recurrent UTI and pneumaturia ),
phlegmon /abscess, strictures (causing
obstruction ), perianal disease.
Diarrhea that may or may not be bloody.

Bloody diarrhea.

Rash ( pyoderma gangrenosum , erythema nodosum ), eye inflammation (episcleritis, uveitis), oral
ulcerations (aphthous stomatitis), arthritis ( peripheral, spondylitis).

1 sclerosing cholangitis. Associated with


p-ANCA.

Kidney stones (usually calcium oxalate),


gallstones. Mav be <> for anti-Saccharomyces
cervisiae antibodies (ASCA ) .
TREATMENT

5-aminosalicylic preparations (eg, mesalamine),


6-mercaptopurine, infliximab, colectomy.

Corticosteroids, azathioprine, antibiotics (eg,


ciprofloxacin , metronidazole), infliximab,

adalimumab.
For Crohn , think of a fat granny and an old
crone skipping down a cobblestone road away
from the wreck ( rectal sparing ).

Ulcerative colitis causes ULCCCERS:


Ulcers
Large intestine
Continuous, Colorectal carcinoma, Crypt
abscesses
Extends proximally
Red diarrhea

Sclerosing cholangitis

<

2,-

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

Pharyngoesophageal false diverticulum Q.


Esophageal dysmotility causes herniation of
mucosal tissue at Killian triangle between the
thyropharvngeal and cricopharyngeal parts of
the inferior pharyngeal constrictor. Presenting
symptoms: dysphagia , obstruction , gurgling,

Zenker diverticulum

aspiration, foul breath, neck mass. Most


common in elderly males.

SECTION III

365

Elder MIKE has bad breath .

Elderly
Males
Inferior pharyngeal constrictor
Killian triangle
Esophageal dysmotility
Halitosis

True diverticulum. Persistence of the vitelline


The rule oil 2 s:
2 times as likely in males.
duct . May contain ectopic acid-secreting
2 inches long.
gastric mucosa and/or pancreatic tissue. Most
common congenital anomaly of GI tract . Can
2 feet from the ileocecal valve.
cause hematochezia/melena ( less commonly!
2% of population .
Commonly presents in first 2 years of life.
RLQ pain, intussusception , volvulus, or
obstruction near terminal ileum . Contrast with
May have 2 types of epithelia ( gastric/
omphalomesenteric cyst = cystic dilation of
pancreatic).
vitelline duct .
Diagnosis: pertechnetate study for uptake by
ectopic gastric mucosa.

Meckel diverticulum
Umbilicus

t?

Meckel diverticulum

p.isk t with Down syndrome.


Congenital megacolon characterized by lack
Diagnosed hv rectal suction biopsy, which shows
of ganglion cells/enteric nervous plexuses
( Auerbach and Meissner plexuses) in distal
absence of ganglionic cell4
segment of colon. Due to failure of neural crest Treatment: resection .

Hirschsprung disease

cell migration . Associated with mutations in


RET.
Presents with bilious emesis, abdominal
distention , and failure to pass meconium
within 48 hours -* chronic constipation .
Normal portion of the colon proximal to the
aganglionic segment is dilated, resulting in a
transition zone.

Anomaly of midgut rotation during fetal development improper positioning of bowel , formation
of fibrous bands ( Ladd bands). Can lead to volvulus, duodenal obstruction.

Malrotation

L v ei
Ladd

rands
Small

Large
intestine

366

SECTION III

Volvulus

GASTROINTESTINAL

GASTROINTESTINAL

PATHOLOGY

Twisting of portion of bowel around its


mesentery; can lead to obstruction and
infarction Q 0. Can occur throughout the
GI tract. Midgut volvulus more common in
infants and children . Sigmoid volvulus more
common in elderly.

I New 1

llmagel

Intussusception

fl

Telescoping Q of proximal bowel segment into


distal segment, commonly at ileocecal junction .
Compromised blood supply intermittent
abdominal pain often with currant jelly stools.
Unusual in adults (associated with intraluminal
mass or tumor that acts as lead point that
is pulled into the lumen). Majority of cases
occur in children ( usually idiopathic; may be
associated with recent viral infection , such as
adenovirus -* Pever patch hypertrophy -* lead
point also associated with rotavirus vaccin ;
most common pathologic lead point is Meckel
diverticulum ). Abdominal emergency in early
childhood, with bulls-eye appearance on
ultrasound.

::

>

cfflMfiSl

GASTROINTESTINAL PATHOLOGY

GASTROINTESTINAL

SECTION III

367

Other intestinal disorders

Acute mesenteric
ischemia

Critical blockage of intestinal blood flow (often embolic occlusion of SMA) -* small bowel necrosis
-* abdominal pain out of proportion to physical findings. May see red currant jelly stools.

Chronic mesenteric

Intestinal angina: atherosclerosis of celiac artery, SMA, or IMA -* intestinal hypoperfusion


postprandial epigastric pain food aversion and weight loss.

ischemia

Colonic ischemia

Reduction in intestinal blood flow causes ischemia. Crampv abdominal pain followed by
hematochezia. Commonly occurs at watershed areas (splenic flexure, distal colon). Typically

Angiodysplasia

Tortuous dilation of vessels -* hematochezia. Most often found in the right- sided colori More
common in older patients. Confirmed by angiography.

Adhesion

Fibrous band of scar tissue; commonly forms after surgery; most common cause of small bowel
obstruction. Can have well-demarcated necrotic zones.

Ileus

Intestinal hypomotilitv without obstruction -* constipation and 1 flatus; distended/tympanic


abdomen with 1 bowel sounds. Associated with abdominal surgeries, opiates, hypokalemia, sepsis.
Treatment: bowel rest, electrolyte correction, cholinergic drugs (stimulate intestinal motility).
In cystic fibrosis, meconium plug obstructs intestine, preventing stool passage at birth.

affects elderly.

Meconium ileus
Necrotizing
enterocolitis

Seen in premature, formula-fed infants with immature immune system. Necrosis of intestinal
mucosa ( primarily colonic) with possible perforation, which can lead to pneumatosis intestinalis,
free air in abdomen, portal venous gas.

368

SECTION III

Colonic polyps

HISTOLOGIC TYPE

GASTROINTESTINAL PATHOLOGY

GASTROINTESTINAL

Growths of tissue within the colon Q. May be neoplastic or non-neoplastic. Grossly characterized
as flat, sessile, or pedunculated (on a stalk) on the basis of protrusion into colonic lumen.
Generally classified by histologic type.
CHARACTERISTICS

Generally non-neoplastic

Hamartomatous

Solitary lesions do not have significant risk of transformation. Growths of normal colonic tissue
with distorted architecture. Associated with Peutz- Jeghers syndrome and juvenile polyposis.

Mucosa)

Small, usually < 5 mm. Look similar to normal mucosa. Clinically insignificant
Result of mucosal erosion in inflammatory bowel disease. When in clusters may be associated with
dysplasia]

Inflammatory

pseudopolypst

Submucosal

May include lesions such as lipomas, leiomyomas, fibromas, and others.

Hyperplastic

Generally smaller and predominantly located in the rectosigmoid region. May occasionally evolve
into serrated polyps and more advanced lesions.

Malignant potential

Adenomatous

Neoplastic, via chromosomal instability pathway with mutations in APC and KRAS . Tubular |
histology has less malignant potential than villous H; tubulovillous has intermediate malignant
potential. Usually asymptomatic; may present with occult bleeding.

Serratedl

Premalignant, via CpG hypermethylation phenoty pe pathway with microsatellite instability and
mutations in BRAF. Saw-tooth pattern of crypts on biopsy. Up to 20% of cases of sporadic CRC J

"

Polyp

*
-

nm.
Essa
a

Polyposis syndromes

Familial adenomatous
polyposis

Autosomal dominant mutation of APC tumor suppressor gene on chromosome 5q. 2-hit hypothesis.
Thousands of polyps arise starting after puberty; pancolonic; always involves rectum. Prophylactic
colectomy or else 100% progress to CRC.

Gardner syndrome

FAP + osseous and soft tissue tumors, congenital hypertrophy of retinal pigment epithelium,
impacted/supernumerary teeth.

Turcot syndrome
Peutz-Jeghers
syndrome

FAP + malignant CNS tumor (eg, medulloblastoma, gliomaj Turcot = Turban .


Autosomal dominant syndrome featuring numerous hamartomas throughout GI tract, along with
hyperpigmented mouth, lips, hands, genitalia. Associated with t risk of breast and GI cancers (eg,
colorectal, stomach, small bowel, pancreatic).

Juvenile polyposis
syndrome

Autosomal dominant syndrome in children (typically < 5 years old) featuring numerous
hamartomatous polyps in the colon, stomach, small bowel. Associated with t risk of CRC.

GASTROINTESTINAL

Lynch syndrome

GASTROINTESTINAL PATHOLOGY

SECTION III

369

Previously known as hereditary nonpolyposis colorectal cancer (HNPCC). Autosomal dominant


mutation of DNA mismatch repair genes with subsequent microsatellite instability. ~ 80%
progress to CRC. Proximal colon is always involved. Associated with endometrial, ovarian, and
skin cancers.

Colorectal cancer
EPIDEMIOLOGY

Most patients are > 50 years old. ~ 25% have a

RISK FACTORS

Adenomatous and serrated polyps, familial


cancer syndromes, 1BD, tobacco use, diet of
processed meat with low fiber.

PRESENTATION

Rectosigmoid > ascending > descending.


Ascending exophytic mass, iron deficiency
anemia, weight loss.
Descending infiltrating mass, partial
obstruction, colicky pain, hematochezia.
Rarely, presents with S( bovis ( gallolvticus )

family history.

Right side bleeds; left side obstructs.

bacteremia.
Iron deficiency anemia in males (especially > 50
years old) and postmenopausal females raises
suspicion.
Screen patients > 50 years old with
colonoscopy Q, flexible sigmoidoscopy, fecal
occult blood test, or fecal DNA test.
Apple core lesion seen on barium enema
x-ray Q.
CEA tumor marker: good for monitoring
recurrence, should not be used for screening.

DIAGNOSIS

Molecular
pathogenesis of
colorectal cancer

Chromosomal instability pathway: mutations in APC cause FAP and most sporadic CRC (via
adenoma-carcinoma sequence; (firing) order of events is AK-53).
Microsatellite instability pathway: mutations or methylation of mismatch repair genes (eg, MLH 1 )
cause Lynch syndrome and some sporadic CRC (via serrated polyp pathway). Overexpression of
CQX-2 has been linked to colorectal cancer, NSAIDs may be chemopreventive.

Chromosomal instability pathway

Loss of tumor suppressor


Loss of APC gene
Normal colon

Colon at risk

-J. intercellular adhesion


t proliferation

gene( s) (p53, DCC)

KRAS mutation

Adenoma

Unregulated
intracellular
signaling

fffi

'

Carcinoma

T tumorigenesis
!

41

&

370

SECTION III

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

Cirrhosis and portal hypertension

Cirrhosis diffuse bridging fibrosis (via stellate cells) and regenerative nodules (red arrows in EJ;
whitqarrow shows splenomegaly) disrupt normal architecture of liver; t risk for hepatocellular
carcinoma (HCC ). Etiologies include alcohol (60-70% of cases in the US), nonalcoholic
steatohepatitis, chronic viral hepatitis, autoimmune hepatitis, biliary disease, genetic/metabolic
disorders.
Portal hypertension t pressure in portal venous system. Etiologies include cirrhosis (most
common cause in Western countries), vascular obstruction (eg, portal vein thrombosis, BuddChiari syndrome), schistosomiasis.

Es

(- hematemesis)

Gastric varices
(-* melena)

Hematologic
Thrombocytopenia
Anemia
Coagulation disorders

Metabolic
Hyperbilirubinemia
Hyponatremia
Gynecomastia
Amenorrhea
Cardiovascular

Cardiomyopathy

- Peripheral edema

Primary / spontaneous
bacterial peritonitis

Idiopathic infection of ascites fluid. Often asymptomatic, but can cause fevers, chills, abdominal
pain, ileus, or worsening encephalopathy. Most common pathogens are gram negatives, especially

E coli .

Diagnosis: Paracentesis with absolute neutrophil count ( ANC ) > 250 cells/mm

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

SECTION III

371

Serum markers of liver pathology


ENZYMES RELEASED IN LIVER DAMAGE

Aspartate
aminotransferase
and alanine
aminotransferase

t in most liver disease: ALT > AST


t in alcoholic liver disease: AST > ALT
AST > ALT in nonalcoholic liver disease suggests progression to advanced fibrosis or cirrhosis

Alkaline phosphatase

t in cholestasis (eg, biliary obstruction), infiltrative disorders, bone disease

y- glutamyl

t in various liver and biliary diseases ( just as ALP can), but not in bone disease; associated with

transpeptidase

alcohol use

FUNCTIONAL LIVER MARKERS

Bilirubin

t in various liver diseases (eg, biliary obstruction, alcoholic or viral hepatitis, cirrhosis), hemolysis

Albumin

1 in advanced liver disease, marker of livers synthetic function

Prothrombin

t in advanced liver disease (i production of clotting factors, thereby measuring the livers synthetic

Platelets

1 in advanced liver disease (1 thrombopoietin, liver sequestration) and portal hypertension


(splenomegaly/splenic sequestration)

function)

Reye syndrome

Rare, often fatal childhood hepatic encephalopathy. Findings: mitochondrial abnormalities, fattyliver (microvesicular fatty change), hypoglycemia, vomiting, hepatomegaly, coma. Associated with
viral infection (especially VZV and influenza B) that has been treated with aspirin. Mechanism:
aspirin metabolites 1 P-oxidation by reversible inhibition of mitochondrial enzymes. Avoid aspirin
in children, except in those with Kawasaki disease.

372

SECTION III

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

Alcoholic liver disease

Hepatic steatosis

Macrovesicular fatty change that may be


reversible with alcohol cessation.

Alcoholic hepatitis

Requires sustained, long-term consumption.


Swollen and necrotic hepatocytes with
neutrophilic infiltration. Mallory bodies Q
(intracytoplasmic eosinophilic inclusions of
damaged keratin filaments).

Alcoholic cirrhosis

Final and irreversible form. Micronodular,


irregularly shrunken liver with hobnail
appearance. Sclerosis (arrows in Q) around
central vein (zone III). Manifestations
of chronic liver disease (eg, jaundice,
hypoalbuminemia).

gg-

Nonalcoholic fatty
liver disease

.V.

-I

aim
.w

si

gP &ai|
i

Make a toAST with alcohol:


AST > ALT (ratio usually > 2:1).

SB

m m1
i
i

m .

Metabolic syndrome (insulin resistance);


ALT > AST (Lipids)
obesity fatty infiltration of hepatocytes
-* cellular ballooning and eventual necrosis.
May cause cirrhosis and HCC. Independent of
alcohol use.

7 -:

Hepatic
encephalopathy

portosystemic shunts I Nfty metabolism neuropsychiatric dysfunction,


Reversible neuropsychiatric dysfunction ranging from disorientation /asterixis (mild ) to difficult
arousal or coma (severe!Triggers:
t Nfty production and absorption (due to dietary protein, GI bleed, constipation, infection).
i NH removal (due to renal failure, diuretics, bypassed hepatic blood flow post-TIPS).
Treatment: lactulose ( t NPty+ generation) and rifaximin or neomycin (1 NH producing gut
Cirrhosis

bacteria).

X ..

372

SECTION III

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

Alcoholic liver disease

Hepatic steatosis

Macrovesicular fatty change that may be


reversible with alcohol cessation.

Alcoholic hepatitis

Requires sustained, long-term consumption.


Swollen and necrotic hepatocytes with
neutrophilic infiltration. Mallory bodies Q
(intracytoplasmic eosinophilic inclusions of
damaged keratin filaments).

Alcoholic cirrhosis

Final and irreversible form. Micronodular,


irregularly shrunken liver with hobnail
appearance. Sclerosis (arrows in Q) around
central vein (zone III). Manifestations
of chronic liver disease (eg, jaundice,
hypoalbuminemia).

gg-

Nonalcoholic fatty
liver disease

.V.

-I

aim
.w

si

gP &ai|
i

Make a toAST with alcohol:


AST > ALT (ratio usually > 2:1).

SB

m m1
i
i

m .

Metabolic syndrome (insulin resistance);


ALT > AST (Lipids)
obesity fatty infiltration of hepatocytes
-* cellular ballooning and eventual necrosis.
May cause cirrhosis and HCC. Independent of
alcohol use.

7 -:

Hepatic
encephalopathy

portosystemic shunts I Nfty metabolism neuropsychiatric dysfunction,


Reversible neuropsychiatric dysfunction ranging from disorientation /asterixis (mild ) to difficult
arousal or coma (severe!Triggers:
t Nfty production and absorption (due to dietary protein, GI bleed, constipation, infection).
i NH removal (due to renal failure, diuretics, bypassed hepatic blood flow post-TIPS).
Treatment: lactulose ( t NPty+ generation) and rifaximin or neomycin (1 NH producing gut
Cirrhosis

bacteria).

X ..

GASTROINTESTINAL

Hepatocellular
carcinoma / hepatoma

GASTROINTESTINAL PATHOLOGY

Most common 1 malignant tumor of liver


in adults Q. Associated with HBV (+/
cirrhosis) and all other causes of cirrhosis
(including HCV, alcoholic and nonalcoholic
fatty liver disease, autoimmune disease,
hemochromatosis, (Xj-antitrypsin deficiency)
and specific carcinogens (eg, aflatoxin
from Aspergillus ). May lead to Budd-Chiari

373

syndrome.

SECTION III

Ev * :I'#'
v

Findings: jaundice, tender hepatomegaly,


ascites, polycythemia, anorexia . Spreads

hematogenously.
Diagnosis: t a-fetoprotein ; ultrasound or
contrast CT/MRI Q, biopsy.

Other liver tumors

Common , benign liver tumor Q; typically occurs at age 30-50 years. Biopsy contraindicated
because of risk of hemorrhage.

Cavernous
hemangioma

7.

-y:
A

mi

Hepatic adenoma

Rare, benign liver tumor, often related to oral contraceptive or anabolic steroid use; may regress
spontaneously or rupture (abdominal pain and shock).

Angiosarcoma

Malignant tumor of endothelial origin; associated with exposure to arsenic, vinyl chloride.
GI malignancies, breast and lung cancer. Most common overall ; metastases rarely solitanj

Metastases

Budd -Chiari syndrome

Thrombosis or compression of hepatic veins with centrilobular congestion and necrosis


-* congestive liver disease ( hepatomegaly, ascites, varices, abdominal pain , liver failure). Absence
of JVD. Associated with hypercoagulable states, polycythemia vera , postpartum state, HCC. May
cause nutmeg liver ( mottled appearance).

-antitrypsin
^deficiency

Misfolded gene product protein aggregates in


hepatocellular ER cirrhosis with
PAS globules in liver. Codominant trait .

!m v

In lungs, 1 (X|-antitrypsin -* uninhibited elastase


I elastic tissue panacinar
in alveoli
emphysema .

374

SECTION III

Jaundice

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

Abnormal yellowing of the skin and/


or sclera Q due to bilirubin deposition.
Hyperbilirubinemia 2 to t production or
1 disposition ( impaired hepatic uptake,

HOT Liver Common causes of increased


levels of bilirubin.

Hemolysis
Obstruction
Tumor
Liver disease

conjugation, excretion).

Unconjugated
(indirect )
hyperbilirubinemia

Hemolytic, physiologic (newborns), Crigler-Najjar, Gilbert syndrome.

Conjugated (direct)
hyperbilirubinemia

Biliary tract obstruction: gallstones, cholangiocarcinoma, pancreatic or liver cancer, liver fluke.
Biliary tract disease:
1 sclerosing cholangitis
1 biliary cholangitij
Excretion defect: Dubin-Johnson syndrome Rotor syndrome .
Hepatitis, cirrhosis.

Mixed (direct
and indirect)
hyperbilirubinemia

Physiologic
neonatal jaundice

At birth, immature UDP-glucuronosyltransferase -* unconjugated hyperbilirubinemia


jaundice/
kernicterus ( deposition of unconjugated, lipid-soluble bilirubin in the brairj particularly basal
ganglia).
Occurs after first 24 hours of life and usually resolves without treatment in 1-2 weeks.
Treatment: phototherapy (non-UV) isomerizes unconjugated bilirubin to water-soluble form.

GASTROINTESTINAL PATHOLOGY

GASTROINTESTINAL

Hereditary
hyperbilirubinemias

O Gilbert syndrome

Crigler- Najjar
syndrome, type I

Dubin-Johnson
syndrome

SECTION III

375

All autosomal recessive.


Relatively common, benign condition!
Mildly 1 UDP-glucuronosyltransferase
conjugation and impaired bilirubin uptake.
Asymptomatic or mild jaundice usually with
stress, illness, or fasting t unconjugated
bilirubin without overt hemolysis. Bilirubin
t jLv ith fasting and stress.
Absent UDP-glucuronosyltransferase. Presents
Type II is less severe and responds to
early in life; patients die within a few years.
phenobarbital, which t liver enzyme synthesis.
Findings: jaundice, kernicterus (bilirubin
deposition in brain), t unconjugated bilirubin.
Treatment: plasmapheresis and phototherapy.
Conjugated hyperbilirubinemia due to defective Q Rotor syndrome is similar, but milder in
liver excretion. Grossly black liver. Benign.
presentation without black liver. Due to
impaired hepatic uptake and excretion.
HEPATIC SINUSOID
Hemoglobin
Circulating bilirubin
( albumin bound, unconjugated, water insoluble)

Kupffer cell
(macrophage)

Endothelial celt

Space of Disse
Hepatocyte
.

BILIRUBIN

UPTAKE

Unconjugated bilirubin

f
I2

o CONJUGATION
0

Conjugated bilirubin
(bilirubin diglucuronide water soluble)

INTRACELLULAR
TRANSPORT

-\

Bile

canaliculus
lumen

Sfas/ s

Bite low

Hepatocyte

Obstructive jaundice
( downstream)
0

376

SECTION III

Wilson disease
( hepatolenticular

degeneration )

GASTROINTESTINAL

GASTROINTESTINAL PATHOLOGY

Autosomal recessive!mutations in hepatocyte copper-transporting ATPase ( ATP7 B gene;


chromosome 13) 1 copper excretion into bile and incorporation into apoceruloplasmin
(I serum ceruloplasmin). Copper accumulates, especially in liver, brain, cornea, kidneys; t urine

copped
Presents before age 40 with liver disease (eg, hepatitis, acute liver failure, cirrhosis), neurologic
disease (eg, dysarthria, dystonia, tremor, parkinsonism), psychiatric disease, Kayser-Fleischer rings
(deposits in Descemet membrane of cornea) Q, hemolytic anemia, renal disease (eg, Fanconi

syndrome).
Treatment: chelation with penicillamine or trientine, oral zinc.

Hemochromatosis

Recessive mutations in HFE gene (C282Y > H63P, chromosome 6, associated with HLA-A j)
-* abnormal iron sensing and t intestinal absorption ( t ferritin, t iron, 1 TIBC -* t transferrin
saturation). Iron overload can also be 2 to chronic transfusion therapy (eg, (3-thalassemia major).
Iron accumulates, especially in liver, pancreas, skin, heart, pituitary, joints. Hemosiderin (iron)
can be identified on liver MRI or biopsy with Prussian blue stain Q.
Presents after age 40 when total bod}' iron > 20 g; iron loss through menstruation slows progression
in women. Classic triad of cirrhosis, diabetes mellitus, skin pigmentation ( bronze diabetes ). Also
causes restrictive cardiomyopathy ( classic ) or dilated cardiomyopathy ( reversibid), hypogonadism,
arthropathy (calcium pyrophosphate deposition; especially metacarpophalangeal joints). HCC is
common cause of death.
Treatment: repeated phlebotomy, chelation with deferasirox, deferoxamine, oral deferiprone.

Biliary tract disease

May present with pruritus, jaundice, dark urine, light-colored stool, hepatosplenomegaly. Typically
with cholestatic pattern of LFTs ( t conjugated bilirubin, t cholesterol, t ALP).

Primary sclerosing
cholangitis

ADDITIONAL FEATURES

PATHOLOGY

EPIDEMIOLOGY

Unknown cause of concentric


onion skin bile duct

Classically in middle-aged men Associated with ulcerative


colitis. p-ANCA . t IgM.
with IBD.
Can lead to 2 biliary
cholangitii t risk of
cholangiocarcinoma and
gallbladder cancer.

fibrosis - alternating
strictures and dilation with
beading of intra- and
extrahepatic bile ducts on
ERCP, magnetic resonance

cholangiopancreatography
(MRCP).
Primary biliary

cholanqitisi

Secondary biliary

cholanaitisi

Autoimmune reaction

-* lymphocytic infiltrate
+ granulomas -* destruction
of intralobular bile ducts.

Classically in middle-aged
women.

Anti-mitochondrial antibody ,
t IgM. Associated with other
autoimmune conditions
(eg, Sjogren syndrome,
Hashimoto thyroiditis,
CREST, rheumatoid arthritis,
celiac disease).

May be complicated by
Extrahepatic biliary obstruction Patients with known
-* t pressure in intrahepatic
obstructive lesions ( gallstones,
ascending cholangitis.
ducts -* injury/ fibrosis and
biliary strictures, pancreatic
bile stasis.
carcinoma).

GASTROINTESTINAL PATHOLOGY

GASTROINTESTINAL

SECTION III

377

Risk factors (4 F s):


t cholesterol and/or bilirubin, 1 bile salts, and
1. Female
gallbladder stasis all cause stone%
2. Fat
2 types of stones:
3. Fertile ( pregnant)
Cholesterol stones (radiolucent with 10-20%
4. Forty
opaque due to calcifications) 80% of stones.
Diagnose with ultrasound . Treat with elective
Associated with obesity, Crohn disease,
cholecystectomy if symptomatic!
advanced age, estrogen therapy, multiparity,
pan cause fistula between gallbladder and
rapid weight loss, Native American origin.
2
Gjtract air in biliary tree (pneumobilia)
Pigment stonesJQ (black = radiopaque, Ca +
bilirubinate, hemolysis; brown = radiolucent,
passage of gallstones into intestinal tract
obstruction of ileocecal valve (gallstone
infection). Associated!with Crohn disease,
ileus).
chronic hemolysis, alcoholic cirrhosis,
advanced age, biliary infections, total
parenteral nutrition ( TPN).
Most common complication is cholecystitis;
also, acute pancreatitis, ascending cholangitis]

Gallstones
( cholelithiasis)

RELATED PATHOLOGIES

CHARACTERISTICS

Biliary colic

Uncomplicated disease associated with nausea /vomiting and dull right upper quadrant ( RUQ) pain.
Neurohormonal activation (eg, by CCK after a fatty meal ) triggers contraction of gallbladder,
forcing stone into cystic duct. Labs are normal, ultrasound shows cholelithiasis.

Choledocholithiasis

Presence of gallstone(s) in common bile duct, often leading to elevated ALP, GGT, direct bilirubin,
and/or AST/ALT.

Cholecystitis

Acute or chronic inflammation of gallbladder usually from cholelithiasis (stone at neck of


gallbladder [red arrow in HI with gallbladder wall thickening [ yellow arrows!). Gallstones most
commonly blocking the cystic duct 2 infection; less commonly from acalculous due to
ischemia and stasis, or infection (eg, CMV ). Murphv sign: inspiratory arrest on RUQ palpation
due to pain. ALP if bile duct becomes involved (eg, ascending cholangitis).
Diagnose with ultrasound or cholescintigraphv ( HIDA scan ).

'

Porcelain gallbladder

tJ
Ascending cholangitis

Calcified gallbladder due to chronic cholecystitis; usually found incidentally on imaging [].
Treatment: prophylactic cholecystectomy due to high rates of gallbladder cancer (mostly
adenocarcinoma).

Infection of biliary tree usually due to obstruction that leads to stasis/bacterial overgrowth.
Charcot triad of cholangitis:

Jaundice
Fever

RUQ pain
Reynolds pentad adds:
Altered mental status
a

Shock

378

SECTION III

GASTROINTESTINAL PATHOLOGY

Autodigestion of pancreas by pancreatic enzymes (Q shows pancreas [ yellow arrows] surrounded by


edema [red arrows]).
Causes: Idiopathic, Gallstones, Ethanol, Trauma, Steroids, Mumps, Autoimmune disease,
Scorpion sting, Hypercalcemia /Hypertriglyceridemia (> 1000 mg/dL), ERCP, Drugs (eg, sulfa
drugs, NRTIs, protease inhibitors).I GET SMASHED.
Diagnosis by 2 of > criteria: acute epigastric pain often radiating to the back, t serum amylase or
lipase (more specific) to 3x upper limit of normal, or characteristic imaging findings.
Complications: pseudocyst Q (lined by granulation tissue, not epithelium), necrosis, hemorrhage,
infection, organ failure (ARDS, shock, renal failure), hypocalcemia (precipitation of Ca 2+ soaps).

Acute pancreatitis

GASTROINTESTINAL

'Art
*

Chronic pancreatitis

Chronic inflammation, atrophy, calcification of the pancreas Q. Major causes are alcohol abuse
and idiopathic. Complications include pancreatic insufficiency ( also a problem in cystic fibrosis)
and pseudocystfr
Pancreatic insufficiency may manifest with steatorrheaL fat-soluble vitamin deficiency, diabetes

mellitus.

Amylase and lipase may or may not be elevated (almost always elevated in acute pancreatitis).
rr,

Pancreatic
adenocarcinoma

>
'

...fW.

V V;/

.' r r V'

Very aggressive tumor arising from pancreatic ducts (disorganized glandular structure with cellular
infiltration Q); often metastatic at presentation, with average survival ~ 1 year after diagnosis.
Tumors more common in pancreatic head Q (-* obstructive jaundice). Associated with CA 19-9
tumor marker (also CEA, less specific).
Risk factors:
Tobacco use
Chronic pancreatitis (especially > 20 years)
Diabetes
Age > 50 years
Jewish and African-American males
Often presents with:
Abdominal pain radiating to back
Weight loss (due to malabsorption and anorexia)
Migratory thrombophlebitis redness and tenderness on palpation of extremities (Trousseau
syndrome)
* Obstructive jaundice with palpable, nontender gallbladder (Courvoisier sign)
Treatment: Whipple procedure, chemotherapy, radiation therapy.
a

GASTROINTESTINAL PHARMACOLOGY

GASTROINTESTINAL

GASTROINTESTINAL

SECTION III

379

PHARMACOLOGY

Acid suppression therapy


jRP

Vagus nerve
G cells

rQy+ ECL cells

H stam ne

A h

Atropine

-0

TT

HCOj (
alkaline tide"- T blood pH
after gastric acid secretion
(eg , after meals, vomiting )
"

NpY

l1

V
, receptor

LCK
ptor

HCO, t H*
"

_
_AT

H 2 blockers

s,
Ct

cAMP :

Proton pump inhibitors


Antacids

ADVERSE EFFECTS

-- &
Gastric
parietal

Cq+ H,

CLINICAL USE

|Carbonic anhydrase

MECHANISM

H , receptor

'

H2 blockers

Prostaglandins

Somatostatin

cell

ATPase

j [ ]*

Cimetidine, ranitidine, famotidine, nizatidine.

e
^

|*

Misoprostol
Sucralfate,

Lumen

bismuth

Take H ? blockers before you dine. Think table


for 2 to remember H7.

Reversible block of histamine H 7-receptors i H+ secretion by parietal cells.


Peptic ulcer, gastritis, mild esophageal reflux.
Cimetidine is a potent inhibitor of cytochrome P-450 ( multiple drug interactions); it also has
antiandrogenic effects ( prolactin release, gynecomastia , impotence, 1 libido in males); can
cross blood-brain barrier (confusion , dizziness, headaches) and placenta . Both cimetidine and
ranitidine 1 renal excretion of creatinine . Other H7 blockers are relatively free of these effects.

Proton pump inhibitors Omeprazole, lansoprazole, esomeprazole, pantoprazole, dexlansoprazole .


MECHANISM
CLINICAL USE

ADVERSE EFFECTS

Irreversibly inhibit H+/K+ ATPase in stomach parietal cells.


Peptic ulcer, gastritis, esophageal reflux, Zollinger-Ellison syndrome, component of triple therapy
for H pylori, stress ulcer prophylaxis
t risk of C difficile infection, pneumonia i serum Mg + with long-term use.
,

GASTROINTESTINAL PHARMACOLOGY

GASTROINTESTINAL

SECTION III

381

Loperamide
MECHANISM

Agonist at p- opioid receptors; slows gut motility. Poor CNS penetration ( low addictive potential).

CLINICAL USE

Diarrhea.

ADVERSE EFFECTS

Constipation, nausea.

Ondansetron
MECHANISM

5-HT antagonist; 1 vagal stimulation. Powerful central-acting antiemetic.

CLINICAL USE

Control vomiting postoperatively and in patients


undergoing cancer chemotherapy.
Headache, constipation, QT interval prolongation, serotonin syndrome

ADVERSE EFFECTS

Metoclopramide
MECHANISM

D,- receptor antagonist, t resting tone, contractility. LES tone, motility, promotes gastric emptying
Does not influence colon transport time.

CLINICAL USE

Diabetic and postsurgerv gastroparesis, antiemetic, persistent GERDi

ADVERSE EFFECTS

t parkinsonian effects, tardive dyskinesia. Restlessness, drowsiness, fatigue, depression, diarrhea.


Drug interaction with digoxin and diabetic agents. Contraindicated in patients with small bowel
obstruction or Parkinson disease (due to D? -receptor blockade).

Orlistat

MECHANISM

Inhibits gastric and pancreatic lipase

CLINICAL USE

Weight loss.

ADVERSE EFFECTS

Steatorrhea, 1 absorption of fat-soluble vitamins.

Laxatives

1 breakdown and absorption of dietary fats.

Indicated for constipation or patients on opiates requiring a bowel regimen.

TYPE

MECHANISM

ADVERSE EFFECTS

Bulk-forminq

Draws water into gut lumen, bulk forming

Bloating

(eq, psyllium,
methylcellulose)

Stimulant (eq, senna)

Enteric nerve stimulation

Emollients (eq,

Osmotic draw into lumen

colonic contraction Diarrhea, melanosis coli


Diarrhea

docusate)

Aprepitant

I Fact
i

MECHAN ) SM

Substance P antagonist. Blocks NKi receptors in brain.

CLINICAL USE

Antiemetic for chemotherapy-induced nausea and vomiting.

HIGH- YIELD SYSTEMS

Hematology
and Oncology
Of all that is written , I love only what a person has written with his own

Anatomy

384

Physiology

387

Pathology

392

Pharmacology

411

blood .

Friedrich Nietzsche
I used to get stressed out , but my cancer has put everything into
perspective."

Delta
The best blood will at some time get into a fool or a mosquito.

Goodrem

Austin OMalley

Carcinoma works cunningly from the inside out. Detection and


treatment often work more slowly and gropingly , from the outside in.

Christopher

Hitchens

Study tip: When reviewing oncologic drugs, focus on mechanisms and


side effects rather than details of clinical uses, which may be lower yield.

383

384

SECTION III

HEMATOLOGY AND ONCOLOGY ANATOMY

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY ANATOMY


Erythrocyte

Carries 0? to tissues and C02 to lungs.

Anucleate and lacks organelles; biconcave Q,


with large surface area-to-volume ratio for
rapid gas exchange. Life span of 120 days.
Source of energy is glucose (90% used
in glycolysis, 10% used in HMP shunt).
Membrane contains Cl-/HC(X - antiporter,
which allows RBCs to export HC05 and
transport CO? from the periphery to the lungs
for elimination.
"

Thrombocyte
( platelet )

Leukocyte

Eryth = red; cyte = cell.


Erythrocytosis = polycythemia = t hematocrit.
Anisocytosis = varying sizes.
Poikilocytosis = varying shapes.

Reticulocyte = immature RBC; reflects


erythroid proliferation.
Bluish color on Wright-Giemsa stain of
reticulocytes represents residual ribosomal
RNA.

Involved in 1 hemostasis. Small cytoplasmic


fragment Q derived from megakaryocytes.
Life span of 8-10 days. When activated by
endothelial injury, aggregates with other
platelets and interacts with fibrinogen to
form platelet plug. Contains dense granules
(ADP, Ca~+) and a granules (vWF, fibrinogen,
fibronectin). Approximately XA of platelet pool
is stored in the spleen .

Thrombocytopenia or i platelet function results


in petechiae.
vWF receptor: Gplb.
Fibrinogen receptor: GpIIb/IIIa.

Divided into granulocytes (neutrophil,


eosinophil, basophil, mast celt) and
mononuclear cells (monocytes, lymphocytes).
WBC differential count froirjl highest to lowest
(normal ranges per USMLE):
Neutrophils (~ 60% j
Lymphocytes (~ 30% j
Monocytes (~ 6%fe

Leuk = white; cyte = cell,

Neutrophils Like Making Everything Better.

Eosinophils (~
Basophils (~ YXj)

Neutrophil
L5

Acute inflammatory response cell. Increased in

Hypersegmented neutrophils (nucleus has 6+


bacterial infections. Phagocytic. Multilobed
lobes) are seen in vitamin BJ2/ folate deficiency,
nucleus Q. Specific granules contain leukocyte t band cells (immature neutrophils) reflect states
alkaline phosphatase (LAP), collagenase,
of t myeloid proliferation ( bacterial infections,
CML)
lysozyme, and lactoferrin. Azurophilic
granules (lysosomes) contain proteinases,
Important neutrophil chemotactic agents: C 5 a,
acid phosphatase, myeloperoxidase, and
IL- 8, LTB , kallikrein, platelet-activating
^
factor.
P-glucuronidase.

HEMATOLOGY AND ONCOLOGY

385

Phagocytoses bacteria , cellular debris, and


senescent RBCs. Long life in tissues.
Macrophages differentiate from circulating
blood monocytes Q. Activated by y-interferon.
Can function as antigen-presenting cell via
MHC II.

Macro = large; phage = eater.


Macrophage: in the tissue. Name differs in
each tissue tvpe ( eg, Kupffer cell in the liver,
histiocytes in connective tissue).
Important component of granuloma formation
( eg, TB, sarcoidosis).
Lipid A from bacterial LPS binds CD14 on
macrophages to initiate septic shock .

Eosin = pink dye; philic = loving.


Causes of eosinophilia = NAACP:

Defends against helminthic infections (major


basic protein ). Bilobate nucleus. Packed
with large eosinophilic granules of uniform
size Q. Highly phagocytic for antigen-

V# %/
A
* w

Produces histaminase, major basic protein


( MBP, a helminthotoxin ), eosinophil
peroxidase, eosinophil cationic protein , and
eosinophil -derived neurotoxiri

Macrophage

Hi

ISwappedl

Eosinophil

Q
r

SECTION III

Mono = one (nucleus); cyte = cell .


Monocyte: in the blood .

WJocFb

Image

ANATOMY

Differentiates into macrophage in tissues.


Large, kidney-shaped nucleus Q. Extensive
frosted glass cytoplasm.

Monocyte

HEMATOLOGY AND ONCOLOGY

antibody complexes.

Neoplasia
Asthma

Allergic processes
Chronic adrenal insufficiency
Parasites ( invasive)

Basophil

Mediates allergic reaction . Densely basophilic


granules Q contain heparin (anticoagulant )
and histamine (vasodilator). Leukotrienes
synthesized and released on demand .

Basophilic staining readily with basic stains.


Basophilia is uncommon, but can be a sign of
myeloproliferative disease, particularly CML .

Mast cell

Mediates allergic reaction in local tissues.


Mast cells contain basophilic granules Q and
originate from the same precursor as basophils
but are not the same cell type. Can bind the
Fc portion of IgE to membrane . IgE cross
links upon antigen binding degranulation
-* release of histamine , heparin , trvptase, and
eosinophil chemotactic factors.

Involved in type I hypersensitivity reactions.


Cromolyn sodium prevents mast cell
degranulation (used for asthma prophylaxis),

>

386

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY ANATOMY

Highly phagocytic APC Q. Functions as link between innate and adaptive immune systems.
Expresses MHC class II and Fc receptors on surface. Called Langerhans cell in the skin.

Dendritic cell

&

Lymphocyte

90 'p
Om

Refers to B cells, T cells, and NK cells. B cells and T cells mediate adaptive immunity. NK cells are
part of the innate immune response. Round, densely staining nucleus with small amount of pale

cytoplasm Q.

OaA
Bcell
CD20
CD19

CD21

...
'- '

LI

T cell

4 4

Part of humoral immune response. Originates


from stem cells in bone marrow and matures in
marrow. Migrates to peripheral lymphoid tissue
(follicles of lymph nodes, white pulp of spleen,
unencapsulated lymphoid tissue). When antigen
is encountered, B cells differentiate into plasma
cells (which produce antibodies) and memory
cells. Can function as an APC via MHC II.

B = Bone marrow,

Mediates cellular immune response. Originates


from stem cells in the bone marrow, but
matures in the thymus. T cells differentiate
into cytotoxic T cells (express CD8, recognize
MHC I), helper T cells (express CD4,
recognize MHC II), and regulatory T cells.
CD28 (costimulatory signal) necessary for
T-cell activation. The majority of circulating
lymphocytes are T cells (80%).

T is for Thymus.
CD4+ helper T cells are the primary target of
HIV.
MHC x CD = 8 (eg, MHC 2 x CD4 = 8, and
MHC 1 x CD8 = 8).

388

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY PHYSIOLOGY

Blood groups

Rh classification

ABO classification

RBC type

Group antigens on
RBC surface

Antibodies in plasma

Clinical relevance

lift

&

Anti- B

Anti- A

JOCC
YV

AX*

IgM

IgM

Receive B or AB
- hemolytic

Receive A or AB
- hemolytic

reaction

reaction

-fv

AB

A&B

()

NONE

Rh (D)

Anti- A
NOBE

Rh

0
Anti-B

yXc
Receive any non-0
- hemolytic
reaction
Universal donor
of RBCs; universal
recipient of plasma

NONE

Anti- D
NONE

IgM
Universal recipient
of RBCs; universal
donor of plasma

Rh

Y
IgG

Universal recipient
of RBCs

Treat mother with


anti-D Ig (RhoGAM)
during and after each
pregnancy to prevent
anti-D IgG formation

Rh hemolytic disease
of the newborn

IgM does not cross placenta; IgG does cross placenta.


Rh mothers exposed to fetal Rh blood (often during delivery) may make anti-D IgG. In
subsequent pregnancies, anti-D IgG crosses the placenta -* hemolytic disease of the newborn
(erythroblastosis fetalis) in the next fetus that is Rh. Administration of anti-D IgG ( RhoGAM)
to Rh pregnant women during third trimester and early postpartum period!prevents maternal
anti-D IgG production.
Rh mothers have anti-D IgG only if previously exposed to Rh blood.

ABO hemolytic disease


of the newborn

Most common form. Usually occurs in a type O mother with a type A, B, or AB fetus. Can occur in
a first pregnancy as maternal anti-A and/or anti-B IgG antibodies are formed early in life. Does not
worsen with future pregnancies. Presents as mild jaundice in the neonate within 24 hours of birth;
treatment is phototherapy or exchange transfusion.

HEMATOLOGY AND ONCOLOGY PHYSIOLOGY

HEMATOLOGY AND ONCOLOGY

389

SECTION III

Hemoglobin electrophoresis

On a gel, hemoglobin migrates from the


negatively charged cathode to the positively
charged anode. HbA migrates the farthest,
followed by HbF, HbS, and IIbfl This is
because the missense mutations in HbS and
HbC replace glutamic acid with valine
(neutral) and lysine , respectively, impacting
the net protein charge.

Origin

AA -^ Normal adult

1 T

^Normal newborn
AS Sickle cell trait
AF

SS - Sickle cell disease

i
AC

>Hb C trait

>Hb SC disease

CC Hb C disease

xx

Cathode

SC
F

Anode

A: normal hemoglobin (5 chain (HbA, adult)


F: normal hemoglobin y chain (HbF, fetal)
S: sickle cell hemoglobin p chain (HbS)
C hemoglobin C p chain (HbC)

A Fat Santa Claus


B

Coagulation and kinin pathways


Collagen,
basement membrane,

y'

Kallikrein

activated platelets
Contact
activation
(intrinsic)

pathway

(extrinsic)

V|

Tissue factor

li

XIla

XI

t Permeability

- *-

jVHIa

VIII
with vWF)

ANTICOAGULANTS: lla ( thrombin)


- heparin (greatest efficacy)
- LMWH (dalteparin, enoxaparin)
- direct thrombin inhibitors (argatroban,
bivalirudin, dabigatran)

pathway

ANTICOAGULANTS: factor Xa
- LMWH (greatest efficacy)
- heparin
- direct Xa inhibitors (apixaban, rivaroxaban)
- fondaparinux

Pain

Kinin cascade
Xla

Vila

Prothrombin Thrombin

Plasminogen

is

Fibrinogen Fibrin monomers

Hemophilia A: deficiency of factor VIII (XR)


Hemophilia B: deficiency of factor IX ( XR)
Hemophilia C: deficiency of factor XI (AR )

T Vasodilation

Bradykinin $;

XII

IX
Ticcu firtnr
Tissue
factor

HMWK

--

tPA

Plasmin
Combined
pathway

Note: Kallikrein activates bradykinin; ACE inactivates bradykinin


* = require Ca2*, phospholipid
= inhibited by vitamin K antagonist warfarin
= cofactor
activates but not part of coagulation cascade

>

,THROMBOLYTICS:
alteplase, reteplase,
streptokinase, tenecteplase

Aminocaproic acid
Fibrinolytic system

Xllla

Fibrin degradation
products
Fibrin mesh stabilizes
platelet plug

390

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PHYSIOLOGY

Coagulation cascade components

Procoagulation

Oxidized
vitamin K

Epoxide
reductase

reduced
vitamin K

(acts as
cofactor )

inactive precursors of II, VII, IX, X, C, S


y-glutamyl transferase
mature (active) II, VII, IX, X, C, S

Anticoagulation
Thrombin-thrombomodulin complex
Protein
{endothelial cells)
S
Protein C
cleaves and inactivates Va, Villa
activated protein C

tPA
Plasminogen

plasmin

Fibrinolysis:
1. cleavage of fibrin mesh
2. destruction of coagulation factors

Warfarin inhibits the enzyme vitamin K


epoxide reductase.
Neonates lack enteric bacteria , which produce
vitamin K .
Vitamin K deficiency: 1 synthesis of factors II,
VII , IX, X, protein C, protein S.
vWF carries/ protects VIII ( volksWagen
Factories make grS ( great ) car ? j
Antithrombin inhibits activated forms of factors
II , VII , IX, X, XI , XII.
Heparin enhances the activity of antithrombin .
Principal targets of antithrombin : thrombin and

factor Xa.
Factor V Leiden mutation produces a factor V
resistant to inhibition by activated protein C.
tPA is used clinically as a thrombolytic.

HEMATOLOGY AND ONCOLOGY PHYSIOLOGY

HEMATOLOGY AND ONCOLOGY

SECTION I I I

391

Platelet plug formation ( primary hemostasis)

o
INJURY
Endothelial damage
-* transient
vasoconstriction via
neural stimulation reflex
and endothelm (released
from damaged cell)

.!

St

EXPOSURE
vWF binds to exposed
collagen
vWF is from Weibel-Palade
bodies of endothelial
cells and a-granules of
platelets

(J)

ADHESION
Platelets bind vWF via Gplb
receptor at the site of injury
only (specific ) platelets
undergo conformational
change

AGGREGATION
Fibnnogen binds Gpllb /llla receptors and links platelets

ACTIVATION

ADP binding to receptor


induces Gpllb/ llla
expression at platelet
surface

Balance between
Pro-aggregation factors:
Anti- aggregation factors:
TXA2 (released PGI2 and NO (released
by platelets) by endothelial cells)
i blood flow T blood flow
T platelet aggregation i platelet aggregation

Platelets release ADP and


Ca 2+ (necessary
ary for
coagulation cascade), TXA2

Temporary plug stops bleeding; unstable, easily dislodged

atelets adhere
ADP helps platelets
to endothelium
urn

2* hemostasis
Coagulation cascade

Formation of insoluble fibrin mesh.


Aspirin irreversibly inhibits cyclooxygenase,
thereby inhibiting TXA 2 synthesis
Clopidogrel, prasugrel, and ticlopidine inhibit
ADP-induced expression of GpIIb/IIIa.
Abciximab, eptifibatide, and tirofiban inhibit
GpIIb/IIIa directly.
Ristocetin activates vWF to bind Gplb. Failure
of aggregation!with ristocetin assay occurs in
von Willebrand disease and Bernard-Soulier

Thrombogenesis

Clopidogrel, prasugrel,
ticlopidine

Platelet
(vWR

Aspirin

platelets

(fibrinogen)

Fibrinogen
Arachidonic

ADP receptor

COX

TXA

Platelet phospholipid

Kir:

syndrome.

Deficiency: Glanzmann thrombasthenia


Gpllb / llla

Deficiency: Bernard Soulier syndrome

)Gpllb/ llla

Abciximab,

n s e i on

0
Subendothel al
:ollagen

Thrombomodulin
Willebrand

lisease

Activated
protein C

Protein C

~ Vascular endothelial cells

Inside
endothelial
cells

|
|(vWF + factor VIII)
thromboplastin
tPA, PGI,

392

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY PATHOLOGY

HEMATOLOGY AND ONCOLOGY PATHOLOGY


Pathologic RBC forms
TYPE

EXAMPLE

ASSOCIATED PATHOLOGY

NOTES

Acanthocyte
("spur cell")JO

Vj

Liver disease,

Acantho = spiny.

Basophilic stippling Q

Dacrocyte
("teardrop cell") jg

Degmacyte
("bite cell")J0

yo

Mi

w1

abetalipoproteinemia (states of
cholesterol dysregulation).

Lead poisoning, sideroblastic


anemias, mvelodysplastic
syndromes.

Seen primarily in peripheral smear,


as opposed to ringed sideroblasts
seen in bone marrow.
Aggregation of residual ribosomes.

Bone marrow infiltration (eg,


myelofibrosis).

RBC sheds a tear because its


mechanically squeezed out of its
home in the bone marrow.

G6PD deficiency.

Echinocyte
("burrceinjg

Elliptocyte

W* SS*
*00

deficiency.

Hereditary elliptocytosis, usually


asymptomatic; caused by
mutation in genes encoding RBC
membrane proteins (eg, spectrin).

Macro- ovalocyteJO

End-stage renal disease, liver


disease, pyruvate kinase

? So!

Megaloblastic anemia (also


hvpersegmented PMNs), marrow
failure.

Different from acanthocyte; its


projections are more uniform and

smaller.

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

SECTION III

393

Pathologic RBC forms ( continued )


TYPE

EXAMPLE

Ringed siderobiast (JJ

QV

"

'

ASSOCIATED PATHOLOGY

NOTES

Sideroblastic anemia. Excess iron


in mitochondria .

Seen in bone marrow, as opposed


to basophilic stippling in
peripheral smear.

DIC , TTP/ HUS,


HELLP syndrome, mechanical
hemolysis (eg, heart valve
prosthesis).

Examples include helmet cell.

iW
DO

Schistocyte jj

Sickle cellJJJ

Spherocyte SJJ

Si
f%

Sickling occurs with dehydration ,


deoxvgenation , and at high
altitude.

Hereditary spherocytosis, drug- and


infection-induced hemolytic
anemia .

HbC disease, Asplenia , Liver


disease, Thalassemia.

Target celljQ

HALT, said the hunter to his

target.

Other RBC abnormalities


TYPE

EXAMPLE

Heinz bodies Q

ASSOCIATED PATHOLOGY

NOTES

Seen in G 6PD deficiency.

Oxidation of Hb -SH groups


to -S S- -* Hb precipitation
( Heinz bodies), with subsequent
phagocytic damage to RBC
membrane -* bite cells.

Seen in patients with functional


hvposplenia or asplenia.

Basophilic nuclear remnants found


in RBCs.
Howell-Jolly bodies are normally
removed from RBCs by splenic
macrophages.

Howell -Jolly bodiesJQJ


Swapped

Image

v .
_
(V
t

w . qi

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

SECTION III

393

Pathologic RBC forms ( continued )


TYPE

EXAMPLE

Ringed siderobiast (JJ

QV

"

'

ASSOCIATED PATHOLOGY

NOTES

Sideroblastic anemia. Excess iron


in mitochondria .

Seen in bone marrow, as opposed


to basophilic stippling in
peripheral smear.

DIC , TTP/ HUS,


HELLP syndrome, mechanical
hemolysis (eg, heart valve
prosthesis).

Examples include helmet cell.

iW
DO

Schistocyte jj

Sickle cellJJJ

Spherocyte SJJ

Si
f%

Sickling occurs with dehydration ,


deoxvgenation , and at high
altitude.

Hereditary spherocytosis, drug- and


infection-induced hemolytic
anemia .

HbC disease, Asplenia , Liver


disease, Thalassemia.

Target celljQ

HALT, said the hunter to his

target.

Other RBC abnormalities


TYPE

EXAMPLE

Heinz bodies Q

ASSOCIATED PATHOLOGY

NOTES

Seen in G 6PD deficiency.

Oxidation of Hb -SH groups


to -S S- -* Hb precipitation
( Heinz bodies), with subsequent
phagocytic damage to RBC
membrane -* bite cells.

Seen in patients with functional


hvposplenia or asplenia.

Basophilic nuclear remnants found


in RBCs.
Howell-Jolly bodies are normally
removed from RBCs by splenic
macrophages.

Howell -Jolly bodiesJQJ


Swapped

Image

v .
_
(V
t

w . qi

394

SECTION III

HEMATOLOGY AND ONCOLOGY PATHOLOGY

HEMATOLOGY AND ONCOLOGY

Anemias
ANEMIAS

1
MCV 80-100 fL
(Normocytic )

MCV < 80 fL
(Microcytic)

MCV > 100 fL


(Macrocytic )

NONHEMOLYTIC

HEMOLYTIC

(Reticulocyte count

(Reticulocyte count t )

NON MEGALOBLASTIC

MEGALOBLASTIC

normal or i)
INTRINSIC

[ Sideroblastic anemia3

C
(

ACD (late)

X
I

Lead poisoning

Thalassemias

Iron deficiency (late)

J (

I r o n deficiency (early)

D C

ACD (early)

] (

Aplastic anemia

) (

Chronic kidney disease

EXTRINSIC

RBC membrane defect:


hereditary spherocytosis
RBC enzyme deficiency:
G6PD pyruvate kinase

Autoimmune

F o l a t e deficiency
I
B deficiency

' '

J (

L i v e r disease

) (

Alcoholism

Orotic aciduria

] (

Diamond-Blackfan anemia

( Macroangiopathic ) f
Keetons

HbC disease

J(

'

( Microangiopathic ) (

""

Paroxysmal nocturnal
hemoglobinuria

( SALTI)

Sickle cell anemia

On a peripheral blood smear, a lymphocyte nucleus is approximately the same size as a normocytic RBC. If RBC is larger than lymphocyte nucleus, consider macrocytosis; if RBC is smaller,
consider microcytosis.
aCopper deficiency can cause a microcytic sideroblastic anemia .

Microcytic ( MCV < 80 fL ), hypochromic anemia


Iron deficiency

I iron due to chronic bleeding (eg, GI loss, menorrhagia), malnutrition, absorption disorders, GI
surgery (eg, gastrectomy! or t demand (eg, pregnancy) t final step in heme synthesis.
Labs: i iron, t TIBC, i ferritin, l transferrin saturation . Microcytosis and hypochromasia (central

pallor) ElSymptoms: fatigue, conjunctival pallor Q, pica (consumption of nonfood substances), spoon nails
(koilonychia).
May manifest as glossitis, cheilosis] Plummer-Vinson syndrome (triad of iron deficiency anemia,
esophageal webs, and dysphagia).
a- thalassemia

Defect: a-globin gene deletions

i a-globin synthesis, cis deletion ( both deletions occur on


deletion (deletions occur on separate
chromosomes) prevalent in African populations.
4 allele deletion: r o a-globin. Excess y-globin forms ( Hb Barts). Incompatible with life (causes
hydrops fetalis).
3 allele deletion: inheritance of chromosome with cis deletion + a chromosome with 1 allele
deleted HbH disease. Very little a-globin. Excess p-globin forms ( HbH)
2 allele deletion: less clinically severe anemia.
1 allele deletion: no anemia (clinically silent).
same chromosome) prevalent in Asian populations; trans

'

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

Microcytic ( MCV < 80 fL ), hypochromic anemia ( continued )

P-thalassemia

SECTION III

395

Point mutations in splice sites and promoter sequences i p-globin synthesis. Prevalent in
Mediterranean populations.
P-thalassemia minor ( heterozygote): p chain is underproduced. Usually asymptomatic. Diagnosis
confirmed by t HbA2 (> 3.5%) on electrophoresis.
P-thalassemia major ( homozygote): P chain is absent severe microcytic, hypochromic
anemia with target cells and increased anisopoikilocytosis Q requiring blood transfusion
( 2 hemochromatosis). Marrow expansion ( crew cut on skull x-ray) skeletal deformities.
Chipmunk facies . Extramedullary hematopoiesis hepatosplenomegaly. t risk of parvovirus
B19-induced aplastic crisis t HbF (a2y2). bF is protective in the infant and disease becomes
symptomatic only after 6 months, when fetal hemoglobin declines.
HbS/ p-thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of

P-globin production.

Lead poisoning

PATHOLOGY

Lead inhibits ferrochelatase and ALA dehydratase -* i heme synthesis and t RBC protoporphyrin .
Also inhibits rRNA degradation RBCs retain aggregates of rRNA ( basophilic stippling ).
Symptoms of LEAD poisoning:
Lead Lines on gingivae ( Burton lines) and on metaphyses of long bones Q] on x-ray.
Encephalopathy and Erythrocyte basophilic stippling.
* Abdominal colic and sideroblastic Anemia .
* Drops
wrist and foot drop. Dimercaprol and EDTA are 1st line of treatment .
Succimer used for chelation for kids ( It sucks to be a kid who eats lead ).
Exposure risk t in old houses with chipped paint .
1

>

Sideroblastic anemia

y.:
0O% O n
> Oft tt

[Causes: genetic (eg, X-linked defect in A-ALA synthase gene), acquired!( myelodvsplastic
syndromes), and reversible (alcohol is most common ; also lead , vitamin B6 deficiency, copper
deficiency, isoniazid ).
Lab findings: t iron , normal / i TIBC , t ferritin . Ringed sideroblasts ( with iron-laden, Prussian
blue-stained mitochondria ) seen in bone marrow Q. Peripheral blood smear: basophilic stippling
of RBCs.
Treatment: pyridoxine ( B6, cofactor for 5-ALA synthase).

2P 0rS5

m
q

396

SECTION III

HEMATOLOGY AND ONCOLOGY

Macrocytic ( MCV > 100 fL ) anemia


DESCRIPTION

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

FINDINGS

Impaired DNA synthesis maturation of


nucleus of precursor cells in bone marrow
delayed relative to maturation of cytoplasm .

RBC macrocvtosis, hypersegmented


neutrophils Q, glossitis.

Folate deficiency

Causes: malnutrition (eg, alcoholics),


malabsorption , drugs (eg, methotrexate,
trimethoprim , phenytoin ), t requirement (eg,
hemolytic anemia , pregnancy).

t homocysteine, normal methylmalonic acid.


No neurologic symptoms (vs Bp deficiency).

Vitamin B12
(cobalamin )
deficiency

Causes: insufficient intake (eg, veganism ),


malabsorption (eg, Crohn disease), pernicious
anemia , Diphyllobothrium latum (fish
tapeworm), gastrectomy.

t homocysteine, t methylmalonic acid.


Neurologic symptoms: dementia , subacutcl
combined degeneration (due to involvement of

Megaloblastic anemia
4Q

o^
0

Bp in fatty acid pathways and myelin synthesis):


spinocerebellar tract, lateral corticospinal tract,
dorsal column dysfunction .
Historically diagnosed with the Schilling test,
a 4-stage test that determines if the cause is
dietary insufficiency vs malabsorption .
Anemia secondary to insufficient intake may take
several years to develop due to livers ability to
store Bp (as opposed to folate deficiency).

Orotic aciduria

Inability to convert orotic acid to UMP


(de novo pyrimidine synthesis pathway)
because of defect in UMP synthase.
Autosomal recessive. Presents in children as
failure to thrive, developmental delay, and
megaloblastic anemia refractor}' to folate
and Bp. No hyperammonemia (vs ornithine
transcarbamylase deficiency t orotic acid
with hyperammonemia ).

Orotic acid in urine.


Treatment: uridine monophosphate to bypass
mutated enzyme.

Nonmegaloblastic
anemia

Diamond - Blackfan
anemia

Macrocytic anemia in which DNA synthesis is


unimpaired.
Causes: alcoholism , liver disease .

RBC macrocvtosis without hypersegmented

Rapid-onset anemia within 1st year of life due to


intrinsic defect in ervthroid progenitor cells.

t 7c HbF ( but i total Hb).


Short stature, craniofacial abnormalities, and
upper extremity malformations ( triphalangeal
thumbs) in up to 50% of cases.

neutrophils.

HEMATOLOGY AND ONCOLOGY

Normocytic,
normochromic anemia

HEMATOLOGY AND ONCOLOGY PATHOLOGY

SECTION III

397

Normocytic, normochromic anemias are classified as nonhemolytic or hemolytic. The hemolytic


anemias are further classified according to the cause of the hemolysis (intrinsic vs extrinsic to the
RBC ) and by the location of the hemolysis (intravascular vs extravascular).

Intravascular
hemolysis

Findings: 1 haptoglobin, t LDH, schistocytes and t reticulocytes on blood smear. Characteristic


hemoglobinuria, hemosiderinuria, and urobilinogen in urine. May also see t unconjugated
bilirubin. Notable causes are mechanical hemolysis (eg, prosthetic valve), paroxysmal nocturnal
hemoglobinuria, microangiopathic hemolytic anemias.

Extravascular
hemolysis

Findings: macrophages in spleen clear RBCs. Spherocytes in peripheral smear, t LDH, no


hemoglobinuria/hemosiderinuria, t unconjugated bilirubin, which can cause jaundice. Can
present with urobilinogen in urine.

Nonhemolytic, normocytic anemia


DESCRIPTION

Anemia of chronic
disease

Inflammation t hepcidin (released by liver,


binds ferroportin on intestinal mucosal
cells and macrophages, thus inhibiting
iron transport) -* I release of iron from
macrophages and i iron absorption from gut.

FINDINGS

1 iron, 1 TIBC, t ferritin.


Normocytic, but can become microcytic.
Treatment: EPO (chronic kidney disease only).

Associated with conditions such as rheumatoid


arthritis, SLE, neoplastic disorders, and
chronic kidney disease.
Aplastic anemia

>

m
?

X
t.

Caused by failure or destruction of myeloid


stem cells due to:
a Radiation and
drugs (benzene,
chloramphenicol, alkylating agents,
antimetabolites)
Viral agents (parvovirus B19, EBV, HIV,
hepatitis viruses)
Fanconi anemia (DNA repair defect
causing bone marrow failure; macrocytosis
may be seen on CBC ); also short staturej
t incidence of tumors/leukemia, cafe-au-lait
spots, thumb/radial defects
Idiopathic (immune mediated, 1 stem cell
defect); may follow acute hepatitis
5

1 reticulocyte count, t EPO.


Pancytopenia characterized by severe anemia,
leukopenia, and thrombocytopenia. Normal
cell morphology, but hvpocellular bone
marrow with fatty infiltration Q (dry bone
marrow tap).
Symptoms: fatigue, malaise, pallor, purpura,
mucosal bleeding, petechiae, infection.
Treatment: withdrawal of offending
agent, immunosuppressive regimens (eg,
antithvmocyte globulin, cyclosporine), bone
marrow allograft, RBC/platelet transfusion,
bone marrow stimulation (eg, GM-CSF).

398

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY PATHOLOGY

LONG PAGE - Edit to lose lines?

Intrinsic hemolytic anemia


DESCRIPTION

FINDINGS

Hereditary
spherocytosis

Extravascular hemolysis due to defect in


proteins interacting with RBC membrane
skeleton and plasma membrane (eg, ankyrin,
band 3, protein 4.2, spectrin). Mostly
autosomal dominant inheritance .
Results in small, round RBCs with less surface
area and no central pallor (t MCHC)
-* premature removal by spleen.

Splenomegaly, aplastic crisis ( parvovirus B19


infection).
Labs: osmotic fragility test . Normal to
l MCV with abundance of cells.
Treatment: splenectomy.

G6PD deficiency

Most common enzymatic disorder of RBCs.


Causes extravascular and intravascular

Back pain, hemoglobinuria a few days after


oxidant stress.
Labs: blood smear shows RBCs with Heinz
bodies and bite cells.
Stress makes me eat bites of fava beans with
Heinz ketchup.

hemolysis.
X-linked recessive.
Defect in G6PD 1 glutathione t RBC
susceptibility to oxidant stress. Hemolytic
anemia following oxidant stress (eg, sulfa
drugs, antimalarials, infections, fava beans).

Autosomal recessive. Defect in pyruvate kinase


1 ATP rigid RBCs extravascular
hemolysis.
Glutamic acid-to-lysine mutation in P-globin.
Causes extravascular hemolysis.

Pyruvate kinase
deficiency

HbC disease

Hemolytic anemia in a newborn.

Patients with HbSC ( 1 of each mutant gene)


have milder disease than HbSS patients.
Labs ( homozygotes): blood smear shows
hemoglobin crystals inside RBCs and target

cells.
Paroxysmal nocturnal
hemoglobinuria

t complement-mediated intravascular RBC


lysis (impaired synthesis of CPI anchor for
decay-accelerating factor that protects RBC
membrane from complement). Acquired
mutation in a hematopoietic stem cell,
t incidence of acute leukemias. Patients
may complain of red or pink urine ( from the

Sickle cell anemia

HbS point mutation causes a single amino


acid replacement in P chain (substitution
of glutamic acid with valine). Causes
extravascular and intravascular hemolysis.

Triad: Coombs hemolytic anemia,


pancytopenia, and venous thrombosis.
Labs: CD 55 /59 RBCs on flow cytometry.
Treatment: eculizumab (terminal complement
inhibitor).

hemoglobinuriaj

v
*
^

Pathogenesis: low 02, high altitude, or acidosis


precipitates sickling (deoxvgenated HbS
polymerizes) -* anemia and vaso-occlusive
disease.
Newborns are initially asymptomatic because of
t HbF and I HbS.
Heterozygotes (sickle cell trait) also have
resistance to malaria.
8% of African Americans carry an HbS allele.
Sickle cells are crescent-shaped RBCs EJ.
Crew cut on skull x-ray due to marrow
expansion from t erythropoiesis (also seen in

thalassemias).

Complications in sickle cell disease:


Aplastic crisis (due to parvovirus B19).
Autosplenectomv (Howell-Jolly bodies)
-* t risk of infection by encapsulated
organisms ( eg, S pneumoniae ).
Splenic infarct /sequestration crisis.
Salmonella osteomyelitis.
Painful crises (vaso-occlusive): dactylitis Q
(painful swelling of hands/feet), priapism,
acute chest syndrome, avascular necrosis,
0

stroke.

Renal papillary necrosis (1 Po2 in papilla) and


microhematuria (medullary infarcts).
Diagnosis: hemoglobin electrophoresis.
Treatment: hydroxyurea ( t HbF), hydration.

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

SECTION III

399

Extrinsic hemolytic anemia


DESCRIPTION

Autoimmune
hemolytic anemia

FINDINGS

Warm ( IgG) chronic anemia seen in SLE


and CLL and with certain drugs (eg,
a-methyldopa) ( warm weather is Great ).
Cold ( IgM and complement ) acute
anemia triggered by cold; seen in CLL,
infections, and
Mycoplasma
infectious Mononucleosis ( cold weather is
MMMiserable ). RBC agglutinates Q may
cause painful, blue fingers and toes with cold
exposure.
Many warm and cold AIHAs are idiopathic in

Autoimmune hemolytic anemias are usually


Coombs .
Direct Coombs test anti- Ig antibody ( Coombs
reagent ) added to patients RBC ? j RBCs
agglutinate if RBCs are coated with Ig.
Indirect Coombs test normal RBCs added to
patients serum . If serum has anti-RBC surface
Ig, RBCs agglutinate when Coombs reagent
added .

etiology.
Patient component

Reagent( s)

Result

( agglutination )

!
I

X/

RBCs +/- anti-RBC Ab

-<

A x

Patient serum +/anti-donor RBC Ab

0 Result

(no agglutination )

-C A

Anti- human globulin


(Coombs reagent )

j*

Y
0Result
Anti-RBC Ab present

Result
Anti-RBC Ab absent

K
Donor blood

.Sx
Anti-human globulin
(Coombs reagent)

Result
Anti-donor RBC Ab present

Y
Result
Anti-donor RBC Ab absent

Microangiopathic
anemia

Pathogenesis: RBCs are damaged when passing


through obstructed or narrowed vessel lumina.
Seen in PIC, TTP/ HUS, SLE, HELLP
syndrome, and malignant hypertensioij

Schistocytes (eg, helmet cells ) are seen on


peripheral blood smear due to mechanical
destruction ( schisto = to split) of RBCs.

Macroangiopathic
anemia

Prosthetic heart valves and aortic stenosis may


also cause hemolytic anemia 2 to mechanical
destruction of RBCs.

Schistocytes on peripheral blood smear.

Infections

t destruction of RBCs (eg, malaria , Babesia ).

HEMATOLOGY AND ONCOLOGY PATHOLOGY

HEMATOLOGY AND ONCOLOGY

Heme synthesis
porphyrias, and lead
poisoning

SECTION III

401

The porphyrias are hereditary or acquired conditions of defective heme synthesis that lead to the
accumulation of heme precursors. Lead inhibits specific enzymes needed in heme synthesis,
leading to a similar condition.

CONDITION

AFFECTED ENZYME

ACCUMULATED SUBSTRATE

Lead poisoning

Ferrochelatase and
ALA dehydratase

Protoporphyrin, 5-ALA Microcytic anemia ( basophilic stippling in


peripheral smear , ringed sideroblasts in
(blood)
bone marro\ , GI and kidney disease.
Children exposure to lead paint mental
deterioration.
Adults environmental exposure (eg, batteries,
ammunition) -* headache, memory loss,
demyelination.

PRESENTING SYMPTOMS

Acute intermittent
porphyria

Porphobilinogen
deaminase

Porphobilinogen,
5-ALA,
coporphobilinogen

Symptoms ( 5 Ps):
Painful abdomen
Port wine-colored urine
0

Polyneuropathy
Psychological disturbances
Precipitated by drugs (eg, cytochrome P-450
inducers), alcohol, starvation
Treatment: glucose and heme, which inhibit
ALA synthase. Exacerbated with alcohol
consumption.

(urine)

Porphyria cutanea
tarda

Uroporphyrinogen
decarboxylase

Uroporphyrin (teacolored urine)

Blistering cutaneous photosensitivitv and


hvperpigmentatioi Q. Most common
porphyria.
Most common porphyria. Exacerbated with

alcohol consumption.

V
Location

Enzymes

Intermediates

Diseases

Glucose, heme

Mitochondria

Glycine + succinyl-CoA
B
u

I'

6- aminolevulinic acid synthase:


rate-limiting step

Sideroblastic anemia (X linked)

Lead poisoning

( Acute intermittent porphyria

^
^

Uroporphyrinogen decarboxylase

Porphyria cutanea tarda

Ferrochelatase

Lead poisoning

5-aminolevulinic acid

5-aminolevulinic acid dehydratase

^
(

Porphobilinogen

Porphobilinogen deaminase

Hydroxymethylbilane

Cytoplasm

Uroporphyrinogen III

Coproporphyrinogen III

Mitochondria

-A

Protoporphyrin
f

Heme

iheme - T ALA synthase activity


T heme - l ALA synthase activity

402

SECTION III

Iron poisoning

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY PATHOLOGY

High mortality rate with accidental ingestion by children (adult iron tablets may look like candy).

MECHANISM

Cell death due to peroxidation of membrane lipids.

SYMPTOMS/SIGNS

Nausea, vomiting, gastric bleeding, lethargy, scarring leading to GI obstruction.

TREATMENT

Chelation (eg, IV deferoxamine, oral deferasirox) and dialysis.

Coagulation disorders

PT tests function of common and extrinsic pathway (factors I, II, V, VII, and X ). Defect t PT.
INR (international normalized ratio) calculated from PT. 1 = normal, > 1 = prolonged. Most
common test used to follow patients on warfarin.
PIT tests function of common and intrinsic pathway (all factors except VII and XIII). Defect
t PTT.
Coagulation disorders can be due to clotting factor deficiencies or acquired inhibitors. Diagnose
with a mixing study, where normal plasma is added to patient s plasma. Clotting factor
deficiencies are corrected, whereas factor inhibitors are not corrected.

PTT

MECHANISM AND COMMENTS

Hemophilia A , B, or C

Intrinsic pathway coagulation defect.


A: deficiency of factor VIII t PTT; X-linked recessive.
B: deficiency of factor IX t PTT; X-linked recessive.
* C: deficiency of factor XI t PTT; autosomal recessive.
Macrohemorrhage in hemophilia hemarthroses (bleeding into joints, such
as knee Q), easy bruising, bleeding after trauma or surgery (eg, dental
procedures).
Treatment: desmopressin + factor VIII concentrate (A); factor IX concentrate
(B); factor XI concentrate (C).

Vitamin K deficiency

General coagulation defect. Bleeding time normal.


I activity of factors II, VII, IX, X, protein C, protein S.

DISORDER

_PT

HEMATOLOGY AND ONCOLOGY

Platelet disorders

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

SECTION III

403

Defects in platelet plug formation t bleeding time ( BT ).


Platelet abnormalities -* microhemorrhage: mucous membrane bleeding, epistaxis, petechiae ,
purpura , t bleeding time, possibly decreased platelet count ( PC).

DISORDER

PC

BT

MECHANISM AND COMMENTS

Bernard -Soulier

-H

Defect in platelet plug formation . Large platelets.


1 Gplb -* defect in platelet-to-vWF adhesion.

Defect in platelet integrin (XmJT (GpIIb/ IIIa ) defect in platelet-to-platelet


aggregation , and therefore platelet plug formation!
fl^abs: blood smear shows no platelet clumping.

syndrome

Glanzmann
thrombasthenia

"

Hemolytic- uremic
syndrome

Characterized by thrombocytopenia , microangiopathic hemolytic anemia , and


acute renal failure.
Typical HUS is seen in children, accompanied by diarrhea and commonly
) (eg, 0157: H 7 ). HLJS in adults
caused by Enterohemorrhagic E coli ( EHEC|
does not present with diarrhea; EHECj infection not required .
Same spectrum as TIP, with a similar clinical presentation and same initial
treatment of plasmapheresis.

Immune
thrombocytopenia

Anti-GpIIb/ IIIa antibodies splenic macrophage consumption of


platelet-antibodv complex. May be primary disorder or secondary to
autoimmune disorder, viral illness, malignancy, or drug reaction!
Labs: t megakaryocytes on bone marrow biopsy.
Treatment: steroids, IVIG , splenectomy (for refractory ITP).

Thrombotic
thrombocytopenic

Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease)


-* 1 degradation of vWF multimers.
Pathogenesis: t large vWF multimers t platelet adhesion t platelet
aggregation and thrombosis.
Labs: schistocytes, t LDII .
Symptoms: pentad of neurologic and renal symptoms, fever, thrombocytopenia,
and microangiopathic hemolytic anemia .
Treatment: plasmapheresis, steroids.

purpura

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

SECTION III

405

Blood transfusion therapy


COMPONENT

DOSAGE EFFECT

CLINICAL USE

Packed RBCs

Acute blood loss, severe anemia

Platelets

t Hb and 07 carrying capacity


t platelet count ( t ~ 5000/mmVunit)

Fresh frozen plasma /

t coagulation factor levels

DIC, cirrhosis, immediate warfarin reversal

Stop significant bleeding (thrombocytopenia ,


qualitative platelet defects)

prothrombin complex

concentrate)

Coagulation factor deficiencies involving


fibrinogen and factor VIII
Blood transfusion risks include infection transmission ( low ), transfusion reactions, iron overload ( may lead to 2
hemochromatosis), hypocalcemia ( citrate is a Ca -+ chelator), and hyperkalemia ( RBCs may lyse in old blood units).

Cryoprecipitate

Contains fibrinogen , factor VIII , factor XIII,


vWF, and fibronectin

Leukemia vs lymphoma
Leukemia

Lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are
usually found in peripheral blood.

Lymphoma

Discrete tumor mass arising from lymph nodes. Presentations often blur definitions.

Hodgkin vs
non - Hodgkin
lymphoma

Hodgkin

Non - Hodgkin

Localized, single group of nodes; contiguous

Multiple lymph nodes involved ; extranodal

spread (stage is strongest predictor of


prognosis ). Many patients have a relatively
good prognosis.

involvement common; noncontiguous spread.

Characterized by Reed-Sternberg cells.

Majority involve B cells; a few are of T-cell

Bimodal distribution-young adulthood and


> 55 years; more common in men except for
nodular sclerosing type.

Can occur in children and adults.

Associated with EBV.

May be associated with HIV and autoimmune

Constitutional ( B ) signs/symptoms: low-grade


fever, night sweats, w eight loss]

May present with constitutional ( B ) signs/


symptoms]

lineage.

diseases.

Hodqkin lymphomal

if
I riC A

. -4

Contains Reed-Sternberg cells: distinctive tumor giant cells; binucleate or bilobec with the 2 halves
as mirror images ( owl eyes Q). 2 owl eyes x 15 = 30. RS cells are CD15+ and CD30+ B -cell
origin. Necessary but not sufficient for a diagnosis of Hodgkin lymphoma.
SUBTYPE

NOTES

Nodular sclerosis
Lymphocyte-rich

Most common

Mixed cellularity

Eosinophilia , seen in immunocompromised

Lymphocyte depleted

Seen in immunocompromised patients

Best prognosis

patients

406

SECTION III

HEMATOLOGY AND ONCOLOGY


LONG PAGE

HEMATOLOGY AND ONCOLOGY PATHOLOGY

- Edit to fit?

Non-Hodgkin lymphoma
TYPE

OCCURS IN

GENETICS

COMMENTS

t(8;14) translocation

Starry sky appearance, sheets of lymphocytes


with interspersed tingible body macrophages

Neoplasms of mature B cells


Burkitt lymphoma

Adolescents or young
adults

Diffuse large B- cell


lymphoma

Usually older adults,

Follicular lymphoma

Adults

Mantle cell lymphoma

Adult males

but 20% in children

of c-myc (8) and


heavy-chain Ig ( 14)

(arrows in Q).
Associated with EBV.
Jaw lesion [j] in endemic form in Africa; pelvis
or abdomen in sporadic form.

Alterations in Bcl-2,
Most common type of non-Hodgkin lymphoma
in adults.
Bcl-6
t(14;18) translocation Indolent course; Bcl-2 inhibits apoptosis.
of heavy-chain Ig ( 14)
Presents with painless waxing and waning
and BCL-2 (18)
lymphadenopathv. Follicular architecture:
small cleaved cells ( grade 1), large cells ( grade
3), or mixture ( grade 2).
translocation
t ( 11;14)
Very aggressive, patients typically present with
late-stage disease.
of cyclin D1 ( 11) and
heavy-chain Ig ( 14),
CD 5+
Associated with chronic inflammatorv diseases
tf 11,18)
( Sjogren syndrome, chronic gastritis [ MALT
lymphoma]).
Considered an AIDS-defining illness. Variable
Most commonly
associated with HIV/
presentation: confusion, memory loss,
AIDS; pathogenesis
seizures. Mass lesion(s) on MRI, needs to be
involves EBV
distinguished from toxoplasmosis via CSF
infection
analysis or other lab tests.

Marqinal cell
lymphoma

Adults

Primary central
nervous system
lymphoma

Adults

Neoplasms of mature T cells


Adult T- cell lymphoma

Adults

Mycosis fungoides/
Sezary syndrome

Adults

Caused by HTLV
(associated with IV
drug abuse)

Adults present with cutaneous lesions; especially


affects populations in Japan, West Africa, and
the Caribbean.
Lytic bone lesions, hypercalcemia.
Mycosis fungoides presents with skin patches 0/
plaques (cutaneous T-cell lymphoma),
characterized by atypical CD4+ cells with
cerebriform nuclei and intraepidermal
aggregates of neoplastic cells ( Pautrier
microabscess). May progress to Sezary

syndrome (T-cell leukemia).

fc

HEMATOLOGY AND ONCOLOGY

Multiple myeloma
M spike ;

Albumin

q 02

HEMATOLOGY AND ONCOLOGY PATHOLOGY

Monoclonal plasma cell ( fried egg"


appearance) cancer that arises in the marrow
and produces large amounts of IgG ( 55%) or
IgA ( 25%). Bone marrow > 10% monoclonal
plasma cells. Most common 1 tumor arising
within bone in people > 40-50 years old.
Associated with:
t susceptibility to infection
Primary amyloidosis (AL)
Punched-out lytic bone lesions on x-ray Q
M spike on serum protein electrophoresis
Ig light chains in urine ( Bence Jones
protein)
Rouleaux formation Q ( RBCs stacked like
poker chips in blood smear)
Numerous plasma cells Q with clock-face
chromatin and intracytoplasmic inclusions
0

SECTION III

Think CRAB:

HyperCalcemia
Renal involvement
Anemia
Bone lytic lesions/Back pain

Multiple Myeloma: Monoclonal M protein


spike
Distinguish from Waldenstrom
macroglobulinemia M spike = IgM
-* hyperviscosity syndrome (eg, blurred vision,
Raynaud phenomenon); no CRAB findings.

containing immunoglobulin.
Monoclonal gammopathy of undetermined
significance (MGUS) monoclonal expansion
of plasma cells (bone marrow < 10%
monoclonal plasma cells), asymptomatic,
may lead to multiple myeloma. No CRAB
findings. Patients with MGUS develop
multiple myeloma at a rate of 1-2% per year.

&

. Ar/\

<

Myelodysplastic
syndromes

Stem-cell disorders involving ineffective


hematopoiesis -* defects in cell maturation of
all nonlymphoid lineages. Caused by de novo
mutations or environmental exposure (eg,
radiation, benzene, chemotherapy). Risk of
transformation to AML .

407

Pseudo-Pelger-Huet anomaly neutrophils


with bilobed nuclei. Typically seen after

chemotherapy,

408

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

Unregulated growth and differentiation of WBCs in bone marrow -* marrow failure -* anemia
( A RBCs), infections ( 1 mature WBCs), and hemorrhage ( 1 platelets). Usually presents with
t circulating WBCs ( malignant leukocytes in blood ); rare cases present with normal /1 WBCs.
Leukemic cell infiltration of liver, spleen, lymph nodes, and skin ( leukemia cutis) possible.

Leukemias

TYPE

NOTES

Lymphoid neoplasms

Acute lymphoblastic
leukemia / lymphoma

Chronic lymphocytic
leukemia /small
lymphocytic
lymphoma

Hairy cell leukemia

Most frequently occurs in children; less common in adults (worse prognosis). T-cell ALL can
present as mediastinal mass ( presenting as SVC-like syndrome). Associated with Down syndrome.
Peripheral blood and bone marrow have 111 lymphoblasts Q.
TdT+ ( marker of pre-T and pre- B cells), CD10 + ( marker of pre- B cells).
Most responsive to therapy.
May spread to CNS and testes.
t (12;21) better prognosis.
Age: > 60 years. Most common adult leukemia. CCD20 +, CD2 > 4 j CD 5+ B-cell neoplasm .
Often asymptomatic, progresses slowly; smudge cells Q in peripheral blood smear; autoimmune
hemolytic anemia. CLL = Crushed Little Lymphocytes (smudge cells).
Richter transformation SLL /CLL transformation into an aggressive lymphoma , most commonly
diffuse large B-cell lymphoma ( DLBCL).

Age: Adult males. Mature B-cell tumor. Cells have filamentous, hair-like projections
(fuzzy appearing on LM H ).
Causes marrow fibrosis -* dry tap on aspiration . Patients usually present with massive splenomegaly
and pancytopenia!
Stains TRAP (tartrate-resistant acid phosphatase) . TRAP stain largely replaced with flow
cytometry.
Treatment: cladribine, pentostatin.

Myeloid neoplasms
Acute myelogenous
leukemia

Median onset 65 years. Auer rods 0; myeloperoxidase cytoplasmic inclusions seen mostly in
APL ( formerly M 3 AML); 111 circulating myeloblasts on peripheral smear; adults.
Risk factors: prior exposure to alkylating chemotherapy, radiation , myeloproliferative disorders,
Down syndrome. APL: t ( 15;17 ), responds to all-trans retinoic acid ( vitamin A ), inducing
differentiation of promyelocytes; D1C is a common presentation!

Chronic myelogenous
leukemia

Occurs across the age spectrum with peak incidence 45-85 years, median age at diagnosis 64 years
Defined by the Philadelphia chromosome (t[9;22], BCR-ABL ) and myeloid stem cell proliferation .
Presents with dysregulated production of mature and maturing granulocytes (eg, neutrophils,
metamyelocytes, myelocytes, basophils Q) and splenomegaly. May accelerate and transform to
AML or ALL ( blast crisis ).
Very low LAP as a result of low activity in malignant neutrophils (vs benign neutrophilia
[ leukemoid reaction], in which LAP is t ).
Responds to bcr-abl tyrosine kinase inhibitors (eg, imatinib).

<

m
^

:
9

La?0

HEMATOLOGY AND ONCOLOGY PATHOLOGY

HEMATOLOGY AND ONCOLOGY

Chronic
myeloproliferative
disorders

409

SECTION III

The myeloproliferative disorders (polycythemia vera, essential thrombocythemia, myelofibrosis, and


CML) are malignant hematopoietic neoplasms with varying impacts on WBCs and myeloid cell
lines. Associated with V617F JAK 2 mutation.

Polycythemia vera

A form of 1 polycythemia. Disorder of t hematocrit. May present as intense itching after


hot shower. Rare but classic symptom is erythromelalgia (severe, burning pain and red-blue
coloration) due to episodic blood clots in vessels of the extremities Q. J
1 EPO (vs 2 polycythemia, which presents with endogenous or artificially t EPO). Treatment is
phlebotomy, hydroxyurea, ruxolitinib ( JAK 1/ 2 inhibitor).

Essential
thrombocythemia

Characterized by massive proliferation of megakaryocytes and platelets. Symptoms include


bleeding and thrombosis. Blood smear shows markedly increased number of platelets, which may
be large or otherwise abnormally formed Q. Erythromelalgia may occur.

Myelofibrosis

Obliteration of bone marrow with fibrosis H due to t fibroblast activity. Often associated with
massive splenomegaly and teardrop RBCs Q. Bone marrow is crying because its fibrosed and
is a dry tap.
RBCs

WBCs

PLATELETS

PHILADELPHIA CHROMOSOME

M2 MUTATIONS

Polycythemia vera

Essential
thrombocythemia

e
e

( 30-50%)

Myelofibrosis

Variable

Variable

( 30-50%)

CML

ro

^
^

9G

Polycythemia
PLASMA VOLUME

Relative

EPO LEVELS

ASSOCIATIONS

02 SATURATION
-

Dehydration, burns.

Lung disease, congenital heart


disease, high altitude.

Malignancy (eg, renal cell


carcinoma, hepatocellular

RBCMASS

Appropriate absolute

Inappropriate absolute

carcinoma), hydronephrosis.
Due to ectopic EPO
secretion.

Polycythemia vera

tt

EPO i in PCV due to negative

feedback suppressing renal


EPO production.

410

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PATHOLOGY

Chromosomal translocations
TRANSLOCATION

t(8;14)
t (9;22) (Philadelphia
chromosome)

ASSOCIATED DISORDER

Burkitt lymphoma (c-tnyc activation )

CML ( BCR-ABL hybrid ), ALL ( less common ,


poor prognostic factor!

Philadelphia CreaML cheese.


The Ig heavy chain genes on chromosome 14
are constitutivelv expressed. When other
genes (eg, c-myc and BCL-2 ) are translocated
next to this heavy chain gene region , they are

overexpressed .

Mantle cell lymphoma (cyclin D1 activation )


Follicular lymphoma ( BCL-2 activation )
APL ( M 3 type of AML)

Responds to all-frans retinoic acid .

Maliqnant cell surface

DISEASE

SURFACE MARKERS

markers

ALL

CD 10

CLL

CD 5, 19, 20, 23

AML

CD 13. 15, 64

t( ll;14)
t(14;18)
t(15;17 )

CML

Langerhans cell
histiocytosis

Hodgkin Lymphoma

CD 15. 30

Non - Hodgkin Lymphoma

CD 5 (Mantlet CD 20

Collective group of proliferative disorders of


dendritic ( Langerhans) cells. Presents in a
child as lytic bone lesions Q and skin rash or
as recurrent otitis media with a mass involving
the mastoid bone. Cells are functionally
immature and do not effectively stimulate
primary T cells via antigen presentation .
Cells express S-100 (mesodermal origin ) and
CDla. Birbeck granules ( tennis rackets or
rod shaped on EM ) are characteristic Q.

g&at

am

' MS

fcfsjfi

i3

V i
'

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PHARMACOLOGY

411

SECTION III

PHARMACOLOGY

Heparin
MECHANISM

Lowers the activity of thrombin and factor Xa . Short half-life.

CLINICAL USE

Immediate anticoagulation for pulmonary embolism ( PE ), acute coronary syndrome, MI, deep
venous thrombosis ( DVT ). Used during pregnancy (does not cross placenta ). Follow FIT.

ADVERSE EFFECTS

Bleeding, thrombocytopenia ( HIT ), osteoporosis, drug-drug interactions. For rapid reversal


(antidote), use protamine sulfate ( positively charged molecule that binds negatively charged
heparin ).
Low-molecular-weight heparins (eg, enoxaparin , dalteparin ) act predominantly on factor Xa .
Fondaparinux acts only on factor Xa . Both have better bioavailabilitv, and 2-4 times longer half
life; car!be administered subcutaneously and without laboratory monitoring. Not easily reversible .

NOTES

Heparin - induced thrombocytopenia ( HIT ) development of IgG antibodies against heparin


bound platelet factor 4 ( PF4). Antibody-heparin -PF4 complex activates platelets thrombosis and

thrombocytopenia .

Direct thrombin
inhibitors
MECHANISM
CLINICAL USE

Bivalirudin ( related to hirudin , the anticoagulant used by leeches), dabigatran , argatrobanj

Directly inhibits activity of free and clot-associated thrombin .


Venous thromboembolism, atrial fibrillation. Can be used in HIT. Does not require lab
monitoring.

ADVERSE EFFECTS

Bleeding; reverse dabigatran with idaruci /. umab. Can attempt to use activated prothrombin
complex concentrates ( PCC ) and/or antifibrinolytics (eg, tranexamic acid ) if no reversal agent

available!

412

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY PHARMACOLOGY

Warfarin
MECHANISM

Interferes with y-carboxylation of vitamin In


dependent clotting factors II, VII, IX, and X,
and proteins C and S. Metabolism affected
by polymorphisms in the gene for vitamin
K epoxide reductase complex (VKORC1).
In laboratory assay, has effect on EXtrinsic
pathway and t PT. Long half-life.

CLINICAL USE

Chronic anticoagulation (eg, venous


thromboembolism prophylaxis, and prevention
of stroke in atrial fibrillation). Not used in
pregnant women ( because warfarin, unlike
heparin, crosses placenta). Follow PT/INR.

ADVERSE EFFECTS

Bleeding, teratogenic, skin/tissue necrosis Q,

drug-drug interactions. Proteins C and S have


shorter half-lives than clotting factors II,
VII, IX, and X, resulting in early transient
hypercoagulability with warfarin use. Skin /
tissue necrosis within first few days of large
doses believed to be due to small vessel
microthromboses.

The EX-PresidenT went to war(farin).

For reversal of warfarin, give vitamin K.


For rapid reversal, give fresh frozen plasma or
prothrombin complex concentrate
Heparin bridging: heparin frequently used
when starting warfarin. Ileparin s activation of
antithrombin enables anticoagulation during
initial, transient hypercoagulable state caused
by warfarin. Initial heparin therapy reduces
risk of recurrent venous thromboembolism
and skin/tissue necrosis.

Heparin vs warfarin

ROUTE OF ADMINISTRATION

Heparin

Warfarin

Parenteral (IV, SC)

Oral

SITE OF ACTION

Blood

Liver

ONSET OF ACTION

Rapid (seconds)

Slow, limited by half-lives of normal clotting


factors

MECHANISM OF ACTION

Activates antithrombin, which 1 the action of


Ila (thrombin) and factor Xa

Impairs synthesis of vitamin K-dependent


clotting factors II, VII, IX, and X, and anti
clotting proteins C and S
Dayj

DURATION OF ACTION

Hoursj

AGENTS FOR REVERSAL

Protamine sulfate

MONITORING

PTT (intrinsic pathway)

PT/INR (extrinsic pathway)

CROSSES PLACENTA

No

Yes (teratogenic)

Vitamin K, fresh frozen plasma, prothrombin


complex concentrate

HEMATOLOGY AND ONCOLOGY

Direct factor Xa
inhibitors

HEMATOLOGY AND ONCOLOGY PHARMACOLOGY

SECTION III

413

ApiXaban, rivaroXaban.

MECHANISM

Bind to and directly inhibit factor Xa.

CLINICAL USE

Treatment and prophylaxis for DVT and PEj stroke prophylaxis in patients with atrial fibrillation.
Oral agents do not usually require coagulation monitoring.

ADVERSE EFFECTS

Bleeding. Not easily reversible. Experimental reversal agents (eg, andexanet alfa) in development

MECHANISM

Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA).


Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin
clots t PT, t PIT,' no change in platelet count .

CLINICAL USE

Early MI, early ischemic stroke, direct thrombolysis of severe PE.

ADVERSE EFFECTS

Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding,


recent surgery, known bleeding diatheses, or severe hypertension. Reverse with antifibrinolvtics
( eg, aminocaproic acid, tranexamic acid ), platelet transfusions, and factor corrections ( eg,
crvopreeipitate, fresh frozen plasma, prothrombin complex concentrate). No specific reversal
agent

Thrombolytics

ADP receptor inhibitors


MECHANISM

Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine.


Inhibit platelet aggregation bv irreversibly blocking ADP ( P2Yn) receptot Prevent expression of
glycoproteins Ilb/IIIa on platelet surface.

CLINICAL USE

Acute coronary syndrome; coronary stenting. 1 incidence or recurrence of thrombotic stroke.

ADVERSE EFFECTS

Neutropenia (ticlopidine). TTP may be seen.

Cilostazol, dipyridamole
MECHANISM

Phosphodiesterase inhibitor ; t cAMP in platelets, resulting in inhibition of platelet aggregation;

vasodilators.

CLINICAL USE

Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with

ADVERSE EFFECTS

Nausea, headache, facial flushing, hypotension, abdominal pain.

aspiring

Glycoprotein Ilb/ IIIa


inhibitors

Abciximab, eptifibatide, tirofiban.

MECHANISM

Bind to the glycoprotein receptor Ilb/IIIa on activated platelets, preventing aggregation. Abciximab
is made from monoclonal antibody Fab fragments.

CLINICAL USE

Unstable angina, percutaneous transluminal coronary angioplasty.

ADVERSE EFFECTS

Bleeding, thrombocytopenia.

NEUROLOGY AND SPECIAL SENSES

NEUROLOGY PATHOLOGY

487

SECTION III

Movement disorders
DISORDER

PRESENTATION

CHARACTERISTIC LESION

NOTES

Restlessness and intense urge


to movq
Extension of wrists causes
flapping motion

Can be seen with neuroleptic

Athetosis

Slow, writhing movements;

Basal ganglia (eg, Huntington)

Writhing, snake-like
movement.

Chorea

Sudden, jerky, purposeless

Basal ganglia (eg, Huntington)

Chorea = dancing.

Akathisial
Asterixis

use or in Parkinson disease

Associated with hepatic


encephalopathy, Wilsons
disease, and other metabolic
derangements.

especially seen in fingers

Svndenham chorea seen in


acute rheumatic fever.

movements

Dystonia

Sustained, involuntary muscle


contractions

Writers cramp; blepharospasm;


torticollis

Essential tremor

High-frequency tremor
with sustained posture
(eg, outstretched arms),
worsened with movement or
when anxious

Often familial. Patients often


self-medicate with alcohol,
which 1 tremor amplitude.
Treatment: nonselective
P-blockers (eg, propranolol ),
primidone.

Hemiballismus

Sudden, wild flailing of 1 arm


+/ ipsilateral leg

Contralateral subthalamic
nucleus (eg, lacunar stroke)

Intention tremor

Slow, zigzag motion when


pointing/extending toward a

Cerebellar dysfunction

Myoclonus

Sudden, brief, uncontrolled


muscle contraction

Jerks; hiccups; common in

Uncontrolled movement of distal Parkinson disease


appendages (most noticeable
in hands); tremor alleviated by
intentional movement

Occurs at rest; pill-rolling


tremor of Parkinson disease.
When vou park your car, it is
at rest.

Pronounce Half-of-body
ballistic."

Contralateral lesion.

target

Resting tremor

metabolic abnormalities such


as renal and liver failure.

HEMATOLOGY AND ONCOLOGY PHARMACOLOGY

HEMATOLOGY AND ONCOLOGY

SECTION III

415

Antimetabolites
DRUG

MECHANISM3

CLINICAL USE

ADVERSE EFFECTS

Azathioprine,
6- mercaptopurine

Purine (thiol) analogs


-* 1 de novo purine synthesis.
Activated by HGPRT.
Azathioprine is metabolized
into 6-MP.

Preventing organ rejection,


rheumatoid arthritis, IBD,
SLE; used to wean patients
off steroids in chronic disease
and to treat steroid-refractor}'
chronic disease.

Mvelosuppression, GI, liver.


Azathioprine and 6-MP are
metabolized by xanthine

Purine analog -* multiple


mechanisms (eg, inhibition
of DNA polymerase, DNA
strand breaks).

Hairy cell leukemia.

Mvelosuppression,
nephrotoxicity, and

Cladribine

Cytarabine
(arabinofuranosyl
cytidine)

oxidase; thus both have


t toxicity with allopurinol or
febuxostat.

neurotoxicity.

Pyrimidine analog inhibition Leukemias (AML), lymphomas. Mvelosuppression with


of DNA polymerase.
megaloblastic anemia.
CYTarabine causes

panCYTopenia.
5 - fluorouracil

Pyrimidine analog bioactivated


to 5-FdUMP, which
covalently complexes folic

Colon cancer, pancreatic


cancer, basal cell carcinoma

acid. Capecitabine is a
prodrug with similar activity
This complex inhibits

Effects enhanced with the


addition of leucovorin.

Mvelosuppression, palmarplantar ervthrodvsesthesial

( topical).

thymidylate synthase

- .i dTMP

Methotrexate

1 dTMP

synthesis.

aAll arc S-phase specific.

1 DNA

synthesis
Folic acid analog that
competitively inhibits
dihydrofolate reductase

1 DNA

Cancers: leukemias
(ALL), lymphomas,
choriocarcinoma, sarcomas.
Non-neoplastic: ectopic
pregnancy, medical
abortion (with misoprostol),
rheumatoid arthritis, psoriasis,
IBD, vasculitis.

Mvelosuppression, which is
reversible with leucovorin
rescue.

Hepatotoxicity.
Mucositis (eg, mouth ulcers).
Pulmonary fibrosis.

416

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PHARMACOLOGY

Antitumor antibiotics
DRUG

MECHANISM

CLINICAL USE

ADVERSE EFFECTS

Bleomycin

Induces free radical formation


-* breaks in DNA strands.

Testicular cancer, Hodgkin


lymphoma.

Pulmonary fibrosis, skin


hyperpigmentation . Minimal
mvelosuppression.

Dactinomycin
(actinomycin D)

Intercalates in DNA.

Doxorubicin ,
daunorubicin

Wilms tumor, Ewing sarcoma ,


rhabdomyosarcoma . Used for
childhood tumors ( children
act out ).
Solid tumors, leukemias,
Generate free radicals.
Intercalate in DNA -* breaks in lymphomas.
DNA -* 1 replication .

Myelosuppression .

Cardiotoxicity (dilated
cardiomyopathy),
myelosuppression, alopecia.
Dexrazoxane ( iron chelating
agent), used to prevent
cardiotoxicity.

Alkylating agents
DRUG

MECHANISM

CLINICAL USE

ADVERSE EFFECTS

Busulfan

Cross-links DNA.

CML . Also used to ablate


patients bone marrow before
bone marrow transplantation .

Severe myelosuppression ( in
almost all cases), pulmonary
fibrosis, hyperpigmentation .

Cyclophosphamide,
ifosfamide

Nitrogen mustard; cross-link


DNA at guanine N-7. Require

Solid tumors, leukemia ,


lymphomas.

Myelosuppression; hemorrhagic

Brain tumors ( including

CNS toxicity (convulsions,


dizziness, ataxia).

bioactivation bv livei

cystitis, prevented with


mesna (thiol group of mesna
binds toxic metabolites) or

N-acetylcvsteine .
Nitrosoureas
(Carmustine,
lomustine,
semustine,
streptozotocini

Require bioactivation .
Cross blood-brain barrier
CNS. Cross link DNA.

glioblastoma multiforme).

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PHARMACOLOGY

SECTION III

417

Microtubule inhibitors
DRUG

MECHANISM

CLINICAL USE

ADVERSE EFFECTS

Paclitaxel, other taxols

Hyperstabilize polymerized
microtubules in M phase so
that mitotic spindle cannot
break down (anaphase cannot

Ovarian and breast carcinomas.

Mvelosuppression , neuropathy,
hypersensitivity.

Solid tumors, leukemias,


Hodgkin (vinblastine) and
non-Hodgkin ( vincristine)
lymphomas.

Vincristine: neurotoxicity
(areflexia , peripheral neuritis),

occur).
Vincristine, vinblastine Vinca alkaloids that bind
p-tubulin and inhibit
its polymerization into

microtubules -* prevent
mitotic spindle formation
( M-phase arrest).

constipation ( including
paralytic ileus).

Cisplatin, carboplatin
MECHANISM

Cross-link DNA.

CLINICAL USE

Testicular, bladder, ovary, and lung carcinomas.


Nephrotoxicity, peripheral neuropathy, ototoxicity. Prevent nephrotoxicity with amifostine (free
radical scavenger) and chloride (saline) diuresis.

ADVERSE EFFECTS

Etoposide, teniposide
MECHANISM
CLINICAL USE
ADVERSE EFFECTS

Etoposide inhibits topoisomerase II t DNA degradation .


Solid tumors ( particularly testicular and small cell lung cancer ), leukemias, lymphomas.
Mvelosuppression , alopecia .

Irinotecan, topotecan

CLINICAL USE

Inhibit topoisomerase I and prevent DNA unwinding and replication .


Colon cancer (irinotecan ); ovarian and small cell lung cancers (topotecan ).

ADVERSE EFFECTS

Severe mvelosuppression , diarrhea.

MECHANISM

Hydroxyurea

MECHANISM

Inhibits ribonucleotide reductase

CLINICAL USE

Melanoma , myeloproliferative syndromes (eg, CML, polvcvthemia vera ), sickle cell ( T HbF ) j

ADVERSE EFFECTS

Severe mvelosuppression .

1 DNA Synthesis (S phase specific).

418

SECTION III

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PHARMACOLOGY

Prednisone, prednisolone
MECHANISM

Various; bind intracvtoplasmic steroid receptor; alter gene transcription .

CLINICAL USE

Most commonly used glucocorticoids in cancer chemotherapy. Used in CLL, non-Hodgkin


lymphoma ( part of combination chemotherapy regimen ). Also used as immunosuppressants (eg,
in autoimmune diseases).
Cushing-like symptoms; weight gain , central obesity, muscle breakdown , cataracts, acne,
osteoporosis, hypertension , peptic ulcers, hyperglycemia , psychosis.

ADVERSE EFFECTS

Bevacizumab
MECHANISM

Monoclonal antibody against VEGF. Inhibits angiogenesis.

CLINICAL USE

Solid tumors (colorectal cancer, renal cell carcinoma ).

ADVERSE EFFECTS

Hemorrhage, blood clots, and impaired wound healing.

Erlotinib
MECHANISM

EGFR tyrosine kinase inhibitor.

CLINICAL USE

Non-small cell lung carcinoma .

ADVERSE EFFECTS

Rash .

Cetuximab
MECHANISM
CLINICAL USE
ADVERSE EFFECTS

Monoclonal antibody against EGFR .


Stage IV colorectal cancer ( wild-type KRAS ) , head and neck cancer.
Rash , elevated LFTs, diarrhea.

Imatinib

MECHANISM

Tyrosine kinase inhibitor of BCR ABL ( Philadelphia chromosome fusion gene in CML) and c-kit
(common in GI stromal tumors).

CLINICAL USE

CML, GI stromal tumors (GIST j

ADVERSE EFFECTS

Fluid retention .

Rituximab

CLINICAL USE

Monoclonal antibody against CD20, which is found on most B -cell neoplasms.


Non- Hodgkin lymphoma , CLL , ITP, rheumatoid arthritis,

ADVERSE EFFECTS

t risk of progressive multifocal leukoencephalopathy.

MECHANISM

HEMATOLOGY AND ONCOLOGY

HEMATOLOGY AND ONCOLOGY

PHARMACOLOGY

SECTION III

419

Tamoxifen, raloxifene
MECHANISM

CLINICAL USE

ADVERSE EFFECTS

Selective estrogen receptor modulators (SERMs) receptor antagonists in breast and agonists in
bone. Block the binding of estrogen to ER cells.
Breast cancer treatment ( tamoxifen only) and prevention. Raloxifene also useful to prevent
osteoporosis.

Tamoxifen partial agonist in endometrium, which t the risk of endometrial cancer; hot flashes.
Raloxifene no t in endometrial carcinoma because it is an estrogen receptor antagonist in
endometrial tissue.
Both t risk of thromboembolic events (eg, DVT, PE ).

Trastuzumab ( Herceptin )
MECHANISM

Monoclonal antibody against HER-2 (c-erbB2 ), a tyrosine kinase receptor. Helps kill cancer cells
that overexpress HER-2 , through inhibition of HER 2-initiated cellular signaling and antibodydependent cytotoxicity.

CLINICAL USE

HER-2 breast cancer and gastric cancer (trasZzumab).

ADVERSE EFFECTS

Cardiotoxicity. Heartceptin damages the heart.

Vemurafenib
MECHANISM

Small molecule inhibitor of BRAF oncogene melanoma. VEmuRAF-enib is for V600Emutated BRAF inhibition .

CLINICAL USE

Metastatic melanoma.

Common
chemotoxicities

Cisplatin /Carboplatin
nephrotoxicity)

ototoxicity (and

peripheral neuropathy
Bleomycin , Busulfan pulmonary fibrosis

Vincristine

Doxorubicin -* cardiotoxicity
Trastuzumab ( Herceptin ) cardiotoxicity
Cisplatin /Carboplatin nephrotoxic (and
ototoxicity

CYclophosphamide

hemorrhagic cystitis

5 FU -* myelosuppression
6-MP -* myelosuppression
Hydroxyurea - myelosuppression
Methotrexate myelosuppression

HIGH- YI E LD SYSTEMS

Musculoskeletal, Skin,
and Connective Tissue
Rigid , the skeleton of habit alone upholds the human frame.

Beauty may be skin deep , but ugly goes clear to the bone."

Virginia Woolf

Leonardo da Vinci
thrive in life

you

422

Pathology

433

Dermatology

443

Pharmacology

453

Redd Foxx

The function of muscle is to pull and not to push, except in the case of
the genitals and the tongue .
To

Anatomy and
Physiology

need three bones. A wishbone. A backbone. And a

tunny bone.

Reba McEntire

421

422

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE- ANATOMY AND PHYSIOLOGY


Knee exam

ACL: extends from lateral femoral condyle to


anterior tibia.
PCL: extends from medial femoral condyle to
posterior tibia.

Perform knee exam with patient supine.


TEST

PROCEDURE

Anterior drawer sign

Bending knee at 90 angle, t anterior gliding


of tibia due to ACL injury. Lachman test is
similar, but at 30 angle.

Posterior drawer sign

Femur
Lateral
condyle

-^-

ACL
LCL
Lateral
meniscus
Fibula

Medial
condyle
PCL

V-MCL

Medial

meniscus

Tibia gg

ACL tear
Antenor drawer sign

Bending knee at 90 angle, t posterior gliding of


tibia due to PCL injury.
PCL tear
Posterior drawer sign

Abnormal passive
abduction

Knee either extended or at ~ 30 angle, lateral


(valgus) force - medial space widening of
tibia -* MCL injury.

Abnormal passive
adduction

Knee either extended or at ~ 30 angle, medial


(varus) force lateral space widening of tibia
LCL injury.

McMurray test

During flexion and extension of knee with


rotation of tibia /foot:
Pain, popping on external rotation
-* medial meniscal tear
Pain, popping on internal rotation
lateral meniscal tear

Abduction
(valgus)
force

MCL tear

Adduction

LCL tear

(varus)

force

External

Medial tear

rotation

Internal

rotation

' P'

Lateral tear
0

Common fractures

Boxer 's fracture

Striking hard object with a closed fist

-* metacarpal neck fracture of 3th digit


Greenstick fracture

Bending force

radius
Torus fracture

compression fracture of distal

Axial force applied to immature bone -* simple


buckle fracture of cortex

ART GOES HERE FPO

424

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

Overuse injuries of the elbow

pain near medial epicondyle.

Medial epicondylitis
(golfer 's elbow )

Repetitive flexion (forehand shots) or idiopathic

Lateral epicondylitis
(tennis elbow )

Repetitive extension ( backhand shots) or idiopathic

Wrist bones

ANATOMY AND PHYSIOLOGY

pain near lateral epicondyle.

Scaphoid, Lunate, Triquetrum,


Pisiform, Hamate, Capitate, Trapezoid,
Trapezium Q. (So Long To Pinky, Here
Comes The Thumb).
Scaphoid ( palpated in anatomic snuffbox ) is
the most commonly fractured carpal bone,

typically due to a fall on an outstretched hand.


Complications of proximal scaphoid fractures
include avascular necrosis and nonunion
owing to retrograde blood supply
Dislocation of lunate may cause acute carpal

tunnel syndrome

Carpal tunnel
syndrome

Entrapment of median nerve in carpal tunnel; nerve compression paresthesia, pain, and
numbness in distribution of median nerve ( thenar eminence atrophies but sensation spared,
because palmar cutaneous branch enters the hand external to carpal tunnel). Associated with
pregnancy ( due to edema!rheumatoid arthritis, hypothyroidism, diabetes, acromegaly dialysisrelated amyloidosis; may be associated with repetitive use. Tinel sign ( on percussion) and Phalen
maneuver (on 90 flexion) of wrist produces tingling.

Guyon canal
syndrome

Compression of ulnar nerve at wrist or hand. Classically seen in cyclists due to pressure from
handlebars.

MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

SECTION III

425

Upper extremity nerves


NERVE

CAUSES OF INJURY

PRESENTATION

Axillary ( C5-C6)

Fractured surgical neck of humerus; anterior


dislocation of humerus

Flattened deltoid
Loss of arm abduction at shoulder (> 15 j)
Loss of sensation over deltoid muscle and lateral

Musculocutaneous

Upper trunk compression

Loss of forearm flexion and supination


Loss of sensation over lateral forearm

Radial (C 5-T1)

Midshaft fracture of humerus; compression of


axilla , eg, due to crutches or sleeping with arm
over chair ( Saturday night palsy )

Wrist drop: loss of elbow, wrist, and finger


extension
i grip strength (wrist extension necessary for
maximal action of flexors)
Loss of sensation over posterior arm /forearm and
dorsal hand

Median (C5-T1)

Supracondylar fracture of humerus ( proximal


lesion ); carpal tunnel syndrome and wrist
laceration (distal lesion )

Ape

Ulnar (C8-T1)

Fracture of medial epicondyle of humerus


funny bone ( proximal lesion ); fractured
hook of hamate (distal lesion ) from fall on
outstretched hancfl

Ulnar claw on digit extension


Radial deviation of w rist upon flexion ( proximal

Superficial laceration of palm

Ape

arm
(C5-C7 )

Recurrent branch of
median nerve (C5-T1)

Axillary nerve

^4

lesion )
Loss of w rist flexion , flexion of medial fingers,
abduction and adduction of fingers ( interossei),
actions of medial 2 lumbrical muscles
Loss of sensation over medial IV2 fingers
including hypothenar eminence
hand
Loss of thenar muscle group: opposition ,
abduction , and flexion of thumb
No loss of sensation

CB

Median nerve

Axillary nerve

Musculocutaneous nerve

Radial nerve

Ulnar nerve

Intercostobrachial
nerve

Medial antebrachial

Musculocutaneous nerve

"

cutaneous nerve

I
Radial nerve

Radial nerve

Medial brachial

Radial nerve
Recurrent branch
of median nerve

Ulnar nerve

^ cutaneous nerve

Radial nerve

,
Median nerve

hand and Popes blessing


Loss of wrist flexion, flexion of lateral fingers,
thumb opposition , lumbricals of 2nd and 3rd
digits
Loss of sensation over thenar eminence and
dorsal and palmar aspects of lateral 3 /2 fingers
with proximal lesionf

J
%

Palm of hand

Median nerve

Radial nerve

Ulnar nerve

Dorsum of hand

426

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

Brachial plexus lesions

O Erb palsy ('waiter's tip")


0 Klumpke palsy (claw hand)
0 Wrist drop
O Winged scapula
Deltoid paralysis
Saturday night palsy(wrist drop)
0 Difficulty flexing elbow, variable

sensory loss
Decreased thumb function,
'Pope's blessing'

C5

Randy

Lateral

Upper

Musculocutaneous

Travis
Drinks

Median (flexors)

Beer

Ulnar

C6
Axillary

Middle

Posterior 0

C7

(Extensors)

Cold

Radial

C8

Lower

Medial

Intrinsic muscles of hand,


claw hand

Trunks

T1

1 1

1 1 i

Divisions Cords

Branches

Long thoracic
J
L
Roots

CONDITION

INJURY

CAUSES

MUSCLE DEFICIT

FUNCTIONAL DEFICIT

Erb palsy ( waiter 's


tip")

Traction or
tear of upper
( Erb-er ) trunk:
C 5 -C6 roots

Infants lateral
traction on neck
during delivery

Deltoid,
supraspinatus

Abduction (arm
hangs by side)

Infraspinatus

Lateral rotation (arm


medially rotated)
Flexion, supination

Adults trauma

Biceps brachii

(arm extended and

pronated)
Klumpke palsy

Traction or tear
of lower trunk:
C8-T1 root

Infants upward
force on arm
during delivery

Adults trauma
(eg, grabbing a
tree branch to
break a fall)
Thoracic outlet
syndrome

Compression
of lower trunk
and subclavian
vessels

Cervical rib
(arrows in

Hi

Pancoast tumor

Intrinsic hand

muscles:
lumbricals,
interossei,
thenar,
hypothenar

Total claw hand:


lumbricals normally
flex MCP joints and
extend DIP and PIP
joints

Same as Klumpke Atrophy of intrinsic


hand muscles;
palsy
ischemia, pain,
and edema

due to vascular
compression
Winged scapula

Lesion of long
thoracic nerve

Axillary node
dissection after
mastectomy,
stab wounds

Serratus anterior

Inability to anchor
scapula to thoracic

cage cannot
abduct arm above
horizontal position

PRESENTATION

428

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

Lower extremity nerves


NERVE

INNERVATION

lliohypoqastric
(T12-L1)

Sensory

suprapubic region

CAUSE OF INJURY

PRESENTATION/COMMENTS

Abdominal surgery

Burning or tingling pain in


surgical incision site radiating

Motor transversus abdominis


and internal oblique

to inguinal and suprapubic

region
Genitofemoral nerve
(L1-L2)

Sensory

scrotum /labia

i anterior thigh sensation


beneath inguinal ligament;
absent cremasteric reflex

Laparoscopic surgery

majora, medial thigh

Motor cremaster
Lateral femoral
cutaneous (L2-L3 )
Obturator (L 2- L4)

Sensory: anterior and lateral

thigh
Sensory

medial thigh

Tight clothing, obesity


pregnancy

i thigh sensation (anterior and


lateral)

Pelvic surgery

i thigh sensation (medial) and

Motor obturator externus.


adductor longus, adductor
brevis, gracilis, pectineus.
adductor magnus
Femoral (L 2- L4)

Sensory

anterior thigh.

adduction

Pelvic fracture

Motor quadriceps, iliopsoas.


pectineus, sartorius
Sciatic ( L4-S3 )

Sensory posterior thigh

Herniated disc

Motor semitendinosus.
semimembranosus, biceps
femoris, adductor magnus
Common peroneal
(L4- S2)

Sensory dorsum of foot


Motor biceps femoris, tibialis
anterior, extensor muscles

1 thigh flexion and leg

extension.

medial leg

Splits into common peroneal

and tibial nerves

Trauma or compression of
lateral aspect of leg, fibular
neck fracture

PED = Peroneal Everts and


Dorsiflexes; if injured, foot
dropPED

Foot drop inverted and


plantarflexed at rest, loss of
eversion and dorsiflexion;
steppage gait ; loss of
sensation on dorsum of foot
Tibial (L4-S3)

Sensory sole of foot


Motor triceps surae, plantaris,
popliteus, flexor muscles

Knee trauma, Baker cyst


( proximal lesion); tarsal

tunnel syndrome (distal


lesion)

TIP = Tibial Inverts and


Plantarflexes; if injured, cant
stand on TIPtoes
Inability to curl toes and loss of
sensation on sole; in proximal
lesions, foot everted at rest
with loss of inversion and
plantar flexion

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

SECTION III

429

Lower extremity nerves ( continued )


CAUSE OF INJURY

NERVE

INNERVATION

Superior qluteal ( L4-

Motor gluteus medius, gluteus Iatrogenic injury during


intramuscular injection to
minimus, tensor fascia latae
upper medial gluteal region

11
Normal

Trendelenburg sign

1f.
Inferior qluteal ( L 5 - S2)

Pudendal (S 2- S 4)

PRESENTATION/COMMENTS

Trendelenburg sign /gait


pelvis tilts because weightbearing leg cannot maintain
alignment of pelvis through
hip abduction
Lesion is contralateral to the
side of the hip that drops,
ipsilateral to extremity' on
which the patient stands
Choose superolateral gluteal
quadrant as intramuscular
injection site to avoid nerve

injury
Motor gluteus maximus

Posterior hip dislocation

Difficulty climbing stairs, rising

from seated position; loss of


hip extension
Sensory

perineum

Stretch injury during childbirth

Motor urethral and anal


sphincters

1 sensation in perineum and


genital area; can cause fecal
or urinary incontinence
Can be blocked with local
anesthetic during childbirth
using ischial spine as a
landmark for injection

Hip muscles
ACTION

MUSCLES

Abductors

Gluteus medius, gluteus minimus

Adductors

Adductor magnus, adductor longus, adductor brevis

Extensors

Gluteus maximus semitendinosi, semimembranosus

Flexors

Iliopsoas, rectus femoris, tensor fascia lata, pectineus

Internal rotation

Gluteus medius, gluteus minimus, tensor fascia latae

External rotation

Iliopsoas, gluteus maximus, piriformis, obturator

430

SECTION III

Signs of lumbosacral
radiculopathy

MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE

Paresthesia and weakness related to specific


lumbosacral spinal nerves. Usually, the
intervertebral disc herniates into the central
canal , affecting the inferior nerves (eg,
herniation of L 3/4 disc affects L4 spinal nerve,
but not L3) j

ANATOMY AND PHYSIOLOGY

Intervertebral discs generally herniate


posterolaterally, due to the thin posterior
longitudinal ligament and thicker anterior
longitudinal ligament along the midline of the
vertebral bodies.

DISC LEVEL

FINDINGS

L3-L4

Weakness of knee extension , 1 patellar reflex

L4-L 5

Weakness of dorsiflexion , difficulty in heel-

L 5-S1

Weakness of plantar flexion, difficult} in toe


walking, i Achilles reflex

walking

Neurovascular pairing

Nerves and arteries are frequently named together by the bones/regions with which they are
associated . The following are exceptions to this naming convention .

LOCATION

NERVE

Axilla /lateral thorax

Long thoracic

Lateral thoracic

Surgical neck of
humerus

Axillary

Posterior circumflex

Midshaft of humerus

Radial
Median

Deep brachial
Brachial

Popliteal fossa

Tibial

Popliteal

Posterior to medial
malleolus

Tibial

Posterior tibial

Distal humerus/
cubital fossa

ARTERY

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

Muscle conduction to
contraction
Revised Exterior
| Figure | Cvtosol

Dihydropyridine receptor
T-tubule membrane

8$
Ryanodine
receptor

Sarcoplasmic
3
reticulum

ANATOMY AND PHYSIOLOGY

SECTION III

431

T-tubules are extensions of plasma membrane juxtaposed with terminal cisternae of the
sarcoplasmic reticulum, allowing for coordinated contraction of musclej
In skeletal muscle, 1 T-tubule + 2 terminal cisternae = triad.
In cardiac muscle, 1 T-tubule + 1 terminal cisterna = dyad.
1. Action potential depolarization opens presynaptic voltage-gated Ca2+ channels, inducing
neurotransmitter release.
2. Postsvnaptic ligand binding leads to muscle cell depolarization in the motor end plate.
3. Depolarization travels along muscle cell and down the T-tubule.
4. Depolarization of the voltage-sensitive dihydropyridine receptor, mechanically coupled to the
ryanodine receptor on the sarcoplasmic reticulum, induces a conformational change in both
receptors, causing Ca-+ release from sarcoplasmic reticulum.
5. Released Ca-+ binds to troponin C, causing a conformational change that moves tropomyosin
out of the myosin-binding groove on actin filaments.
6. Myosin releases bound ADP and P| displacement of myosin on the actin filament (power
stroke). Contraction results in shortening of H and I bands and between Z lines (IlIZ
shrinkage), but the A band remains the same length (A band is Always the same length) .
7. Binding of a new ATP molecule causes detachment of myosin head from actin filament.
Hydrolysis of bound ATP ADP, myosin head adopts high-energy position (cocked") for the
next contraction cycle.

T- tubule

Actin Myosin

li

Mitochondrion

M line
|

A band

|| I band |

U
H band

Types of muscle fibers

Type 1 muscle

Slow twitch; red fibers resulting from


t mitochondria and myoglobin concentration
( t oxidative phosphorylation) -* sustained
contraction. Proportion t after endurance
training.

Type 2 muscle

Fast twitch; white fibers resulting from


i mitochondria and myoglobin concentration
(t anaerobic glycolysis). Proportion t after
weight /resistance training, sprinting

Think 1 slow red ox.

432

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

Smooth muscle contraction


Agonist
Endothelial cells

o|_

L-arginine

L-type voltage
gated Ca2
channel

v ^

Action
potential +

Receptor

i
*

NO synthase

TCa - calmodulin
complex

CONTRACTION

CONTRACTION

NO

Smooth muscle cell

Myosin-light -chain
kinase
(MLCK )

T Ca2 -

Ca 2

NO diffusion

.
I

NO

TCa;*
+*

Acetylcholine
bradykinin, etc

GTP

Myosin
+ actin

cGMP

I
4

Myosin-light-chain
phosphatase
Myosin-P
+ actin

( MLCP)

RELAXATION

Nitric oXide

RELAXATION

Bone formation

Endochondral
ossification

Membranous
ossification

Bones of axial skeleton, appendicular skeleton, and base of skull. Cartilaginous model of bone is
first made by chondrocytes. Osteoclasts and osteoblasts later replace with woven bone and then
remodel to lamellar bone. In adults, woven bone occurs after fractures and in Paget disease.
Defective in achondroplasia.
Bones of calvarium and facial bones. Woven bone formed directly without cartilage. Later
remodeled to lamellar bone.

Cell biology of bone


Osteoblast

Builds bone by secreting collagen and catalyzing mineralization in alkaline environment via ALP.
Differentiates from mesenchymal stem cells in periosteum. Osteoblastic activity measured by
bone ALP, osteocalcin, propeptides of type I procollagen.

Osteoclast

Dissolves bone by secreting H+ and collagenases. Differentiates from a fusion of monocyte /


macrophage lineage precursors.

Parathyroid hormone

At low, intermittent levels, exerts anabolic effects ( building bone) on osteoblasts and osteoclasts
(indirect). Chronically t PTH levels (1 hyperparathyroidism) cause catabolic effects (osteitis

Estrogen

Inhibits apoptosis in bone-forming osteoblasts and induces apoptosis in bone-resorbing osteoclasts.


Causes closure of the epiphyseal plate during puberty. Estrogen deficiency (surgical or
postmenopausal), excess cycles of remodeling, and bone resorption lead to osteoporosis.

fibrosa cystica).

432

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

Smooth muscle contraction


Agonist
Endothelial cells

o|_

L-arginine

L-type voltage
gated Ca2
channel

v ^

Action
potential +

Receptor

i
*

NO synthase

TCa - calmodulin
complex

CONTRACTION

CONTRACTION

NO

Smooth muscle cell

Myosin-light -chain
kinase
(MLCK )

T Ca2 -

Ca 2

NO diffusion

.
I

NO

TCa;*
+*

Acetylcholine
bradykinin, etc

GTP

Myosin
+ actin

cGMP

I
4

Myosin-light-chain
phosphatase
Myosin-P
+ actin

( MLCP)

RELAXATION

Nitric oXide

RELAXATION

Bone formation

Endochondral
ossification

Membranous
ossification

Bones of axial skeleton, appendicular skeleton, and base of skull. Cartilaginous model of bone is
first made by chondrocytes. Osteoclasts and osteoblasts later replace with woven bone and then
remodel to lamellar bone. In adults, woven bone occurs after fractures and in Paget disease.
Defective in achondroplasia.
Bones of calvarium and facial bones. Woven bone formed directly without cartilage. Later
remodeled to lamellar bone.

Cell biology of bone


Osteoblast

Builds bone by secreting collagen and catalyzing mineralization in alkaline environment via ALP.
Differentiates from mesenchymal stem cells in periosteum. Osteoblastic activity measured by
bone ALP, osteocalcin, propeptides of type I procollagen.

Osteoclast

Dissolves bone by secreting H+ and collagenases. Differentiates from a fusion of monocyte /


macrophage lineage precursors.

Parathyroid hormone

At low, intermittent levels, exerts anabolic effects ( building bone) on osteoblasts and osteoclasts
(indirect). Chronically t PTH levels (1 hyperparathyroidism) cause catabolic effects (osteitis

Estrogen

Inhibits apoptosis in bone-forming osteoblasts and induces apoptosis in bone-resorbing osteoclasts.


Causes closure of the epiphyseal plate during puberty. Estrogen deficiency (surgical or
postmenopausal), excess cycles of remodeling, and bone resorption lead to osteoporosis.

fibrosa cystica).

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

PATHOLOGY

SECTION III

433

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE- PATHOLOGY


Achondroplasia

Failure of longitudinal bone growth (endochondral ossification) short limbs. Membranous


ossification is not affected -* large head relative to limbs. Constitutive activation of fibroblast
growth factor receptor (FGFR 3 ) actually inhibits chondrocyte proliferation. > 85% of mutations
occur sporadically; autosomal dominant with full penetrance (homozygosity is lethal). Most
common cause of dwarfism.

Osteoporosis

Trabecular (spongy) and cortical bone lose mass Can lead to vertebral compression fractures ( ,
small arrows; large arrows show normal-for-age
and interconnections despite normal bone
mineralization and lab values (serum Ca + and vertebral body height for comparison) acute
back pain, loss of height, kyphosis. Also can
P04'-).
Most commonly due to t bone resorption
present with fractures of femoral neck, distal
related to i estrogen levels and old age.
radius (Colles fracture).
Can be secondary to drugs (eg, steroids,
alcohol, anticonvulsants, anticoagulants,
thyroid replacement therapy) or other
medical conditions (eg, hyperparathyroidism,
hyperthyroidism, multiple myeloma,
malabsorption syndromes).
Diagnosed by a bone mineral density scan
(dual-energy x-ray absorptiome [DEXAp with
a|T-score of < 2.5 or by a fragility fracture of
hip or vertebra. Screening recommended in
women > 65 years olcjj
Prophylaxis: regular weight-bearing exercise
and adequate Ca~+ and vitamin D intake
throughout adulthood.
Treatment: bisphosphonates, teriparatide,
SERMs, rarely calcitonin; denosumab
(monoclonal antibody against RANKL).

Normal vertebrae

Mild compression fracture

Osteopetrosis ( marble
bone disease, AlbersSchonberq disease )!
A

Failure of normal bone resorption due to defective osteoclasts thickened, dense bones that are
prone to fracture. Defective osteoclasts cause overgrowth and sclerosis of cortical bone. Bone fillj
marrow space -* pancytopenia, extramedullary hematopoiesis. Mutations (eg, carbonic anhydrase
II) impair ability of osteoclast to generate acidic environment necessary for bone resorption.
X-rays show bone-in-bone ('stone bone) appearance Q. Can result in cranial nerve impingement
and palsies as a result of narrowed foramina. Bone marrow transplant is potentially curative as
osteoclasts are derived from monocytes.

434

SECTION III

Osteomalacia / rickets

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

Defective mineralization of osteoid


(osteomalacia) or cartilaginous growth plates
(rickets, only in children). Most commonly due
to vitamin D deficiency.
X-rays show osteopenia and Looser zones
(pseudofractures) in osteomalacia, epiphyseal
widening and metaphyseal cupping/fraying in
rickets. Children with rickets have pathological
boujlegs , bead-like costochondral junctions
(rachitic rosary), craniotabes (soft skull).
1 vitamin D 1 serum Ca2+
t PTH
secretion

i serum

Hyperactivity of osteoblasts

Paget disease of bone


( osteitis deformans)

Osteonecrosis
( avascular necrosis)

,j

t ALP.

Common, localized disorder of bone


remodeling caused by t osteoclastic activity
followed by t osteoblastic activity that forms
poor-quality bone. Serum Ca ~+, phosphorus,
and PTH levels are normal, t ALP. Mosaic
pattern of woven and lamellar bone (osteocytes
within!lacunae in chaotic juxtapositions); long
bone chalk-stick fractures, t blood flow from
t arteriovenous shunts may cause high-output
heart failure, t risk of osteogenic sarcoma.

Infarction of bone and marrow, usually very


painful. Most common site is femoral
head Q (due to insufficiency of medial
circumflex femoral artery). Causes include
Corticosteroids, Alcoholism, Sickle cell
disease, Trauma, the Bends (caisson /
decompression disease), LEgg-Calve-Perthes
disease (idiopathic), Gaucher disease, Slipped
capital femoral epiphysis CAST Bent LEGS.

PATHOLOGY

m'

A1
f

Hat size can be increased due to skull


thickening ; hearing loss is common due to
auditory foramen narrowing.
Stages of Paget disease:

Lytic osteoclasts
Mixed osteoclasts + osteoblasts

Sclerotic osteoblasts
Quiescent minimal osteoclast /osteoblast
activity.
Treatment: bisphosphonates, calcitonin.
a

D :

-v : \-

0'

obturator artery

Media femoral
circumflex artery

Lateral femoral
circumflex artery

cerstKM
zone infarcted

436

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

PATHOLOGY

Primary bone tumors


TUMOR TYPE

EPIDEMIOLOGY/LOCATION

CHARACTERISTICS

Osteochondroma

Most common benign bone tumor.


Males < 25 years old.

Bony exostosis with cartilaginous (chondroid)


capQ.
Rarely transforms to chondrosarcoma.

Giant cell tumor

20-40 years old.


Epiphyseal end of long bones. Arises most

Locally aggressive benign tumor.


Soap bubble appearance on x-ray Q.
Multinucleated giant cells that express RANKLj

Benign tumors

commonly at distal femur and proximal tibia!


Osteoclastoma.

Malignant tumors
Osteosarcoma
(osteogenic sarcoma)

Most common 1 malignant bone tumoj


Bimodal distribution: 10-20 years old (1), > 65
(2).

Predisposing factors: Paget disease of bone, bone


infarcts, radiation, familial retinoblastoma,
Li-Frauineni syndrome (germline pS 3

Codman triangle (from elevation of periosteum)


or sunburst pattern on x-ray.
Aggressive. Treat with surgical en bloc resection
(with limb salvage) and chemotherapy.

mutation).

Ewing sarcoma

Metaphysis of long bones, often around knee Q.


Anaplastic small blue cell malignant tumor QJ.
Boys < 15 years old.
Commonly appears in diaphysis of long bones,
Extremely aggressive with early metastases, but
pelvis, scapula, ribs.
responsive to chemotherapy.
Onion skin periosteal reaction in bone.
Associated with t(l1;22) translocation causing
fusion protein EWS-FLI 1.
11 + 22 = 33 (Patrick Ewings jersey number).

r
.

Round cell lesions


Ewing sarcoma

Myeloma

f<

Fibrous dysplasia

C5

Osteoid osteoma
( nighttime pan central nidusl

Osteosarcoma

I{

Simple bone cyst

Osteochondroma
Physis

Giant cell tumor

&4 \
7,

\
-

tti

hi
rn

1
>-

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

PATHOLOGY

SECTION III

437

Osteoarthritis and rheumatoid arthritis

PATHOGENESIS

Osteoarthritis

Rheumatoid arthritis

Mechanical wear and tear destroys articular

Autoimmune inflammatory cytokines and


cells induce pannus (proliferative granulation
tissue) formation, which erodes articular
cartilage and bone.

cartilage ( DID ) and causes inflammation with


inadequate repair. Chondrocytes mediate
degradation and inadequate repaid
PREDISPOSING FACTORS

Age, female, obesity, joint trauma.

Female, HLA-DR4, smoking, silica exposure.


rheumatoid factor ( IgM antibody that
targets IgC Fc rcgioij in 80%), anti-cyclic
citrullinated peptide antibody (more specific).
Pain, swelling, and morning stiffness lasting
> 1 hour, improving with use. Symmetric
joint involvement. Systemic symptoms
(fever, fatigue, weight loss). Extraarticular
manifestations common.*

PRESENTATION

Pain in weight-bearing joints after use (eg,


at the end of the day), improving with rest.
Asymmetric joint involvement. Knee cartilage
loss begins medially ( bowlegged ). No
systemic symptoms.

JOINT FINDINGS

Osteophytes (bone spurs), joint space narrowing, Erosions, juxtaarticular osteopenia, soft tissue
swelling, subchondral cysts, joint space
subchondral sclerosis and cysts. Synovial
narrowing ( more prominent as disease
fluid non-inflammatory ( WBC < 2000/mm5).
progresses Deformities include cervical
Involves DIP (Heberden nodes Q) and PIP
subluxatiorj fingers with ulnar deviation,
( Bouchard nodes), and 1st CMC; not MCP.
sw an neck Q, and boutonniere. Synovial fluid
inflammatory ( WBC > 2000/mm5). Involves
MCP, PIP, wrist; not DIP or 1st CMC.

TREATMENT

Acetaminophen, NSAIDs, intra-articular


glucocorticoids.

NSAIDs, glucocorticoids, disease-modifying


agents (methotrexate, sulfasalazine,
hydroxychloroquine, leflunomide), biologic
agents (eg, TNF-a inhibitors).

^ Extraarticular manifestations

include rheumatoid nodules (fibrinoid necrosis with palisading histiocytes) in subcutaneous


tissue and lung (+ pneumoconiosis -* Caplan syndrome), interstitial lung disease, pleuritis, pericarditis, anemia of chronic
disease, neutropenia + splenomegaly (Felty syndrome), AA amyloidosis, Sjogren syndrome, scleritis, carpal tunnel syndrome.

Normal

Normal

Osteoarthritis

Thickened

Joint capsule
and synovial
lining
Synovial
cavity
Cartilage

/I*0
-

capsule

slight synovial
nypertrophy

Osteophyte

U cerated

3^::-

sclerotic bone

Joint space

narrowing

sulxhondiai

bone cyst

Joint capsule
and synovial
lining

Synovial
cavity
Cartilage

\
v

Rheumatoid
arthritis

Bone and
cartilage
erosion

i creased

synovial fluid
Pannus
formation

Revised
Figure

438

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

PATHOLOGY

Gout

Acute inflammatory monoarthritis caused by precipitation of monosodium urate crystals in


joints Q. More common in males. Associated with hyperuricemia, which can be caused by:
Underexcretion of uric acid (90% of patients) largely idiopathic, potentiated by renal failure!;
can be exacerbated by certain medications (eg, thiazide diuretics).

Overproduction of uric acid ( 10% of patients) Lesch-Nyhan syndrome, PRPP excess, t cell
turnover (eg, tumor lysis syndrome), von Gierke disease.
Crystals are needle shaped and birefringent under polarized light (yellow under parallel light,
blue under perpendicular light Q).

FINDINGS

31

SYMPTOMS

Asymmetric joint distribution. Joint is swollen, red, and painful. Classic manifestation is painful
MTP joint of big toe (podagra). Tophus formation Q (often on external ear, olecranon bursa, or
Achilles tendon). Acute attack tends to occur after a large meal with foods rich in purines (eg, red
meat, seafood) or alcohol consumption!(alcohol metabolites compete for same excretion sites in
kidney as uric acid 1 uric acid secretion and subsequent buildup in blood).

TREATMENT

Acute: NSAIDs (eg, indomethacin), glucocorticoids, colchicine.


Chronic ( preventive): xanthine oxidase inhibitors (eg, allopurinol, febuxostat).

u
-J

'

*
Q

Calcium

pyrophosphate
deposition disease

Deposition of calcium pyrophosphate crystals within the joint space. Occurs in patients > 50 years
old; both sexes affected equally. Usually idiopathic, sometimes associated with hemochromatosis,
hyperparathyroidism, joint trauma.
Pain and swelling with acute inflammation ( pseudogout) and/or chronic degeneration ( pseudo
osteoarthritis). Knee most commonly affected joint.
Chondrocalcinosis (cartilage calcification) on x-ray.
Crystals are rhomboid and weakly birefringent under polarized light (blue when parallel to

r to-

light) .
Acute treatment: NSAIDs, colchicine, glucocorticoids.
Prophylaxis: colchicine.

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

Sjogren syndrome

a- #

szaerir

rA

Autoimmune disorder characterized by


destruction of exocrine glands (especially
lacrimal and salivary) by lymphocytic

infiltrates Q. Predominantly affects females


40-60 years old.

Findings:
Inflammatory joint pain

Keratoconjunctivitis sicca (1 tear production


and subsequent corneal damage)
Xerostomia (1 saliva production)
Presence of antinuclear antibodies,
rheumatoid factor (can be in the absence of
rheumatoid arthritis), antiribonucleoprotein
antibodies: SS-A ( anti-Ro) and/or SS-B ( anti-

PATHOLOGY

SECTION III

439

A common 1 disorder or a 2 syndrome


associated with other autoimmune disorders
(eg, rheumatoid arthritis, SLE, systemic

sclerosis).
Complications: dental caries; mucosa-associated
lymphoid tissue (MALT) lymphoma (may
present as parotid enlargement)
^
Salivary
gland biopsy can be used to confirm

diagnosis.

Laj
Bilateral parotid enlargement

Septic arthritis

S aureus, Streptococcus, and Neisseria gonorrhoeae are common causes. Affected joint is swollen
red, and painful. Synovial fluid purulent ( WBC > 50,000/mm ).
Gonococcal arthritis STI that presents as either purulent arthritis (eg, knee) or triad of
polyarthralgias, tenosynovitis (eg, hand), dermatitis (eg, pustules).

440

MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE

SECTION III

PATHOLOGY

Arthritis without rheumatoid factor ( no anti-IgG antibody). Strong association with HLA-B27
( MHC class I serotype). Subtypes ( PAIR) share variable occurrence of inflammatory back
pain (associated with morning stiffness, improves with exercise), peripheral arthritis, enthesitis
( inflamed insertion sites of tendons, eg, Achilles), dactylitis ( sausage fingers ), uveitis.

Seronegative
spondyloarthritis

Psoriatic arthritis

Associated with skin psoriasis and nail lesions.


Asymmetric and patch}' involvement Q.
Dactylitis and pencil-in-cup deformity of
DIP on x-ray Q.

Seen in fewer than lA of patients with psoriasis.

Ankylosing
spondylitis

Symmetric involvement of spine and sacroiliac


joints ankylosis ( joint fusion ), uveitis, aortic
regurgitation .

Bamboo spine (vertebral fusion ) H Can cause


restrictive lung disease due to limited chest wall

expansion .

More common in males.

Crohn disease and ulcerative colitis are often


associated with spondyloarthritis.

Inflammatory bowel

disease

Formerly known as Reiter syndrome.


Classic triad :

Reactive arthritis

Conjunctivitis
Urethritis
Arthritis

Can t see, can t pee, can t bend my knee.


Post-GI ( Shigella , Salmonella, Yersinia ,
Campylobacter ) or Chlamydia infections.

f
r

Wt

(r

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

PATHOLOGY

441

SECTION III

Systemic lupus erythematosus


SYMPTOMS

m
RU

Classic presentation: rash, joint pain, and fever,


most commonly in a female of reproductive
age and African-American descent.
Libman-Sacks Endocarditis nonbacterial,
verrucous thrombi usually on mitral or aortic
valve and can be present on either surface of
the valvdfLSE in SLE).
Lupus nephritis ( glomerular deposition of antiDNA immune complexes) can be nephritic
or nephrotic ( hematuria or proteinuria).
Most common and severe type is diffuse

proliferative.

RASH OR PAIN:
Rash (malar Q or discoid )
Arthritis (nonerosive)
Serositis
Hematologic disorders (eg, cvtopenias)
Oral/nasopharyngeal ulcers
Renal disease

Photosensitivity
Antinuclear antibodies

Immunologic disorder (anti-dsDNA, anti-Sm,


antiphospholipid)
Neurologic disorders (eg, seizures, psychosis)

Common causes of death in SLE:


*

FINDINGS

Cardiovascular disease
Infections
Renal disease

Antinuclear antibodies (ANA)

Sensitive, not specific

Anti-dsDNA antibodies

Specific, poor prognosis (renal disease)


Specific, not prognostic (directed against

Anti-Smith antibodies

snRNPs)
Antihistone antibodies

Sensitive for drug-induced lupus (eg,


hydralazine, procainamide)

i C3, C4, and CH50 due to immune complex

formation.

TREATMENT

Antiphospholipid
syndrome

NSAIDs, steroids, immunosuppressants,


hydroxychloroquine.

1 or 2 autoimmune disorder (most commonly


in SLE).
Diagnose based on clinical criteria including
history of thrombosis (arterial or venous)
or spontaneous abortion along with

Anticardiolipin antibodies can cause false


positive VDRL/RPR, and lupus anticoagulant
can cause prolonged PTT, which is not
corrected by the addition of normal platelet

free plasmaj

laboratory findings of lupus anticoagulant,


anticardiolipin, anti-Pi glycoprotein antibodies.
Treat with systemic anticoagulation.

Mixed connective
tissue disease

Features of SLE, systemic sclerosis, and/or polymyositis. Associated with anti-Ul RNP antibodies
(speckled ANA).

442

SECTION III

Sarcoidosis

MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE

PATHOLOGY

Characterized by immune mediated, widespread noncaseating granulomas Q, elevated serum


ACE levels, and elevated CD4+ /CD8+ ratio in bronchoalveolar lavage fluid . More common in
African-American females. Often asymptomatic except for enlarged lymph nodes. Findings on
CXR of bilateral adenopathy and coarse reticular opacities Q; CT of the chest better demonstrates
the extensive hilar and mediastinal adenopathy Q.
Associated with restrictive lung disease (interstitial fibrosis), erythema nodosum , lupus pernio (skin
lesions on face resembling lupus), Bell palsy, epithelioid granulomas containing microscopic
Schaumann and asteroid bodies, uveitis, hypercalcemia ( due to t la-hydroxylase-mediated
vitamin D activation in macrophages).
Treatment: steroids (if symptomatic).

'

r N

Polymyalgia rheumatica
SYMPTOMS

Pain and stiffness in shoulders and hips, often with fever, malaise, weight loss. Does not cause
muscular weakness. More common in women > 50 years old ; associated with giant cell (temporal )
arteritis.

FINDINGS

t ESR, t CRP, normal CK.


Rapid response to low-dose corticosteroids.

TREATMENT

Fibromyalqia

( central sensitization

svndromeL

Most commonly seen in females 20-50 years old. Chronic, widespread musculoskeletal pain
associated with stiffness , paresthesias, poor sleep, fatigue, cognitive disturbance ( fibro fog ).
Treatment: regular exercise, antidepressants (TCAs, SNRIs), anticonvulsants.

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

Polymyositis /
dermatomyositis

DERMATOLOGY

SECTION III

443

t CK, ANA, anti-Jo-1, anti-SRP, anti-Mi-2 antibodies. Treatment: steroids followed by


long-term immunosuppressant therapy (eg, methotrexate).

Polymyositis

Progressive symmetric proximal muscle weakness, characterized by endomvsial inflammation with


CD8+ T cells. Most often involves shoulders.

Dermatomyositis

Similar to polymyositis, but also involves malar rash (similar to SLE), Gottron papules Q,
heliotrope (erythematous periorbital) rash Q, shawl and face rash Q, mechanics hands. t risk
of occult malignancy. Perimysial inflammation and atrophy with CD4+ T cells.

k.

Neuromuscular junction diseases


Myasthenia gravis

Lambert-Eaton myasthenic syndrome

FREQUENCY

Most common NMJ disorder

Uncommon

PATHOPHYSIOLOGY

Autoantibodies to postsynaptic ACh receptor

Autoantibodies to presynaptic Ca~^ channel


-* 1 ACh release

CLINICAL

Ptosis, diplopia, weakness


Worsens with muscle use_

Proximal muscle weakness, autonomic


symptoms (dry mouth, impotence)
Improves with muscle use

Improvement after edrophonium ( tensilon) test


ASSOCIATED WITH

Thymoma, thymic hyperplasia

Small cell lung cancer

AChE INHIBITOR ADMINISTRATION

Reverses symptoms (edrophonium to diagnose,


pyridostigmine to treat)

Minimal effect

444

SECTION III

Scleroderma ( systemic

sclerosis)

MUSCULOSKELETAL, SKIN , AND CONNECTIVE TISSUE

DERMATOLOGY

Triad of autoimmunity, noninflammatory vasculopathy, and collagen deposition with fibrosis,


Commonly sclerosis of skin, manifesting as puffy, taut skin Q without wrinkles, fingertip pitting
Q- Also sclerosis of renal, pulmonary (most common cause of death), cardiovascular, GI systems.
75% female. 2 major types:
Diffuse scleroderma w idespread skin involvement, rapid progression, early visceral
involvement. Associated with anti-Scl-70 antibody (anti-DNA topoisomerase I antibody).
Limited scleroderma limited skin involvement confined to fingers and face. Also with
CREST syndrome: Calcinosis/anti-Centromere antibody 0, Raynaud phenomenon,
Esophageal dysmotility, Sclerodactyly, and Telangiectasia. More benign clinical cours

M
'

Raynaud phenomenon

1 blood flow to the skin due to arteriolar (small vessel) vasospasm in response to cold or stress:
color change from white (ischemia) to blue (hypoxia) to red (reperfusion). Most often in the
fingers Q and toes. Called Raynaud disease when 1 (idiopathic), Raynaud syndrome when 2
to a disease process such as mixed connective tissue disease, SLE, or CREST (limited form of
systemic sclerosis) syndrome. Digital ulceration (critical ischemia) seen in 2 Raynaud syndrome.
Treat with Ca-+ channel blockers.

MUSCULOSKELETAL, SKIN , ARP CONNECTIVE TISSUE- DERMATOLOGY


Skin has 3 layers: epidermis, dermis,
subcutaneous fat (hypodermis, subcutis).

Skin layers

Epidermis layers from surface to base Q:


0

'

p0

.. * <
sSPermis

';

[3

Stratum Corneum (keratin)


Stratum Lucidum
Stratum Granulosum
Stratum Spinosum (desmosomes)
Stratum Basale (stem cell site)

Californians Like Girls in String Bikinis.

446

MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE

SECTION III

DERMATOLOGY

Dermatologic microscopic terms


LESION

CHARACTERISTICS

EXAMPLES

Hyperkeratosis

t thickness of stratum corneum


Hyperkeratosis with retention of nuclei in

Psoriasis, calluses

Parakeratosis

Psoriasis

stratum corneum
Hypergranulosis
Spongiosis
Acantholysis

Acanthosis

t thickness of stratum granulosum


Epidermal accumulation of edematous fluid in
intercellular spaces
Separation of epidermal cells
Epidermal hyperplasia ( t spinosum)

Lichen planus

Eczematous dermatitis
Pemphigus vulgaris
Acanthosis nigricans, psoriasis

Pigmented skin disorders

Albinism
Melasma (chloasma )

Vitiligo

Normal melanocyte number with 4 melanin production Q due to 4 tyrosinase activity or defective
tyrosine transport , t risk of skin cancer.
Hyperpigmentation associated with pregnancy ( mask of pregnancy Q) or OCP use.
Irregular areas of complete depigmentation H- Caused by autoimmune destruction of melanocytes.

'
-r

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

DERMATOLOGY

SECTION III

447

Common skin disorders

Acne

Multifactorial etiology t sebum ( T androgens) production, abnormal keratinocvte desquamation,


Propionibacterium acnes colonization of the pilosebaceous unit, ( comedones), and inflammation
( papules /pustules , nodules, cysts). Treatment includes retinoids, benzoyl peroxide, and antibiotics!

Atopic dermatitis

Pruritic eruption, commonly on skin flexures. Often associated with other atopic diseases (asthma,
allergic rhinitis, food allergies); t serum IgE. Usually appears on face in infancy Q and then
antecubital fossalH when older.

(eczema)

Allergic contact
dermatitis

Type IV hypersensitivity reaction that follows exposure to allergen. Lesions occur at site of contact
(eg, nickel 0, poison ivy, neomycin Q).

Melanocytic nevus

Common mole. Benign, but melanoma can arise in congenital or atypical moles. Intradermal nevi
are papular Q. Junctional nevi are flat macules 0.

Pseudofolliculitis
barbae

Foreign body inflammatory facial skin disorder characterized by firm, hyperpigmented papules and
pustules that are painful and pruritic . Located on cheeks, jawline, and neck. Commonly occurs as
a result of shaving ( razor bumps), primarily affects African American males.

Psoriasis

Papules and plaques w ith silvery scaling Q, especially on knees and elbow s. Acanthosis with
parakeratotic scaling (nuclei still in stratum corneum), Munro microabscesses, t stratum
spinosum, \ stratum granulosum. Auspitz sign (arrow in Q) pinpoint bleeding spots from
exposure of dermal papillae w hen scales are scraped off. Can be associated w ith nail pitting and
psoriatic arthritis.

Rosacea

Seborrheic keratosis

Inflammatory facial skin disorder characterized by erythematous papules and pustules Q, but no
comedones. May be associated with facial flushing in response to external stimuli (eg, alcohol,
heat). Phymatous rosacea can cause rhinophvma ( bulbous deformation of nose).
Flat, greasy, pigmented squamous epithelial proliferation with keratin-filled cysts ( horn cysts) Q.
Looks stuck on. Lesions occur on head, trunk, and extremities. Common benign neoplasm of
older persons.
Leser-Trelat sign D sudden appearance of multiple seborrheic keratoses, indicating an underlying
malignancy (eg, GI, lymphoid).

Verrucae

Warts; caused by HPV. Soft, tan-colored, cauliflower-like papules G3. Epidermal hyperplasia,
hyperkeratosis, koilocvtosis. Condyloma acuminatum on genitals 0.

Urticaria

Hives. Pruritic wheals that form after mast cell degranulation 0. Characterized by superficial
dermal edema and lymphatic channel dilation.

L
')

^
1

n
VJ

'

PS
V

..
Ik

>
L

MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE

449

SECTION III

DERMATOLOGY

Skin infections

Bacterial infections
Impetigo

Erysipelas

Cellulitis

Abscess
Necrotizing fasciitis

Staphylococcal scalded
skin syndrome

Very superficial skin infection . Usually from S aureus or S pyogenes. Highly contagious. Honeycolored crusting Q.
Bullous impetigo Q has bullae and is usually caused by S aureus .
Infection involving upper dermis and superficial lymphatics, usually from S pyogenes. Presents with
well-defined demarcation between infected and normal skin QAcute, painful , spreading infection of deeper dermis and subcutaneous tissues. Usually from
S pyogenes or S aureus . Often starts with a break in skin from trauma or another infection 0.
Collection of pus from a walled-off infection within deeper layers of skin Q. Offending organism is
almost always S aureus.
Deeper tissue injury, usually from anaerobic bacteria or S pyogenes. Pain may be out of proportion
to exam . Results in crepitus from methane and CO, production . Flesh-eating bacteria . Causes
bullae and a purple color to the skin QExotoxin destroys keratinocvte attachments in stratum granulosum only (vs toxic epidermal
necrolysis, which destroys epidermal-dermal junction ). Characterized by fever and generalized
erythematous rash with sloughing of the upper layers of the epidermis 0 that heals completely.
Nikolsky sign. Seen in newborns and children, adults with renal insufficiency.

Viral infections

Herpes

Herpes virus infections ( HSV1 and HSV2 ) of skin can occur anywhere from mucosal surfaces to
normal skin . These include herpes labialis, herpes genitalis, herpetic whitlow Q (finger ).

Molluscum

Umbilicated papules Q caused by a poxvirus. While frequently seen in children, it may be sexually
transmitted in adults.
Causes varicella (chickenpox) and zoster (shingles). Varicella presents with multiple crops of
lesions in various stages from vesicles to crusts. Zoster is a reactivation of the virus in dermatomal
distribution (unless it is disseminated ).
Irregular, white, painless plaques on lateral tongue that cannot be scraped off Q. EBV mediated .
Occurs in HIV-positive patients, organ transplant recipients. Contrast with thrush (scrapable) and
leukoplakia ( precancerous).

contagiosum

Varicella zoster virus

Hairy leukoplakia

- VAA

'
iA;
*

SP
I

EE

1
.
n

L2

450

SECTION III

MUSCULOSKELETAL , SKIN , AND CONNECTIVE TISSUE

DERMATOLOGY

Blistering skin disorders

Pemphigus vulgaris

Potentially fatal autoimmune skin disorder with IgG antibody against desmoglein (component of
desmosomes).
Flaccid intraepidermal bullae Q caused by acantholvsis ( keratinocytes in stratum spinosum are
connected bv desmosomes, resembling a row of tombstones ); oral mucosa is also involved . Type
II hypersensitivity reaction
Immunofluorescence reveals antibodies around epidermal cells in a reticular ( net-like ) pattern Q.
Nikolsky sign (separation of epidermis upon manual stroking of skin ).
Less severe than pemphigus vulgaris. Involves IgG antibod} against hemidesmosomes (epidermal
basement membrane; antibodies are bullow the epidermis).
Tense blisters H containing eosinophils affect skin but spare oral mucosa.
Immunofluorescence reveals linear pattern at epidermal-dermal junction 0.
Nikolsky sign .
Pruritic papules, vesicles, and bullae (often found on elbows) Q- Deposits of IgA at tips of dermal
papillae. Associated with celiac disease. Treatment: dapsone, gluten-free diet .
Associated with infections (eg, Mycoplasma pneumoniae. IISV ), drugs (eg, sulfa drugs, P-lactams,
phenytoin), cancers, autoimmune disease . Presents with multiple types of lesions macules,
papules, vesicles, target lesions ( look like targets with multiple rings and dusky center showing
epithelial disruption ) QCharacterized by fever, bullae formation and necrosis, sloughing of skin at dermal -epidermal
junction , high mortality rate. Typically 2 mucous membranes are involved 0 Q, and targetoid
skin lesions may appear, as seen in erythema multiforme. Usually associated with adverse drug
reaction . A more severe form of Stevens-Johnson syndrome (SJS) with > 30 % of the body surface
area involved is toxic epidermal necrolysis Q Q (TEN ). 10-30 % involvement denotes SJS-TEN .

Bullous pemphigoid

Dermatitis
herpetiformis

Erythema multiforme

Stevens-Johnson
syndrome

<?

-%

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

SECTION III

DERMATOLOGY

451

Miscellaneous skin disorders

Acanthosis nigricans

Actinic keratosis

Erythema nodosum

Lichen Planus

Pityriasis rosea

Sunburn

Epidermal hyperplasia causing symmetric, hyperpigmented thickening of skin, especially in axilla


or on neck Q El- Associated with insulin resistance (eg, diabetes, obesity, Cushing syndrome),
visceral malignancy (eg, gastric adenocarcinoma).
Premalignant lesions caused by sun exposure. Small, rough, erythematous or brownish papules or
plaques Q 0. Risk of squamous cell carcinoma is proportional to degree of epithelial dysplasia.
Painful raised inflammatory lesions of subcutaneous fat ( panniculitis), usualhjon anterior shins.
Often idiopathic, but can be associated with sarcoidosis, coccidioidomycosis, histoplasmosis, TB,
streptococcal infections Q, leprosy Q, inflammatory bowel disease.
Pruritic, Purple, Polygonal Planar Papules and Plaques are the 6 Ps of lichen Planus 0 Q.
Mucosal involvement manifests as Wickham striae (reticular white lines) and hvpergranulosis.
Sawtooth infiltrate of lymphocytes at dermal-epidermal junction. Associated with hepatitis C.
Herald patch Q followed days later by other scaly erythematous plaques, often in a Christmas
tree distribution on trunk Q. Multiple plaques with collarette scale. Self-resolving in 6-8 weeks.
Acute cutaneous inflammatory reaction due to excessive UV irradiation. Causes DNA mutations,
inducing apoptosis of keratinocytes. UVB is dominant in sunBurn, UVA in tAnning and
photoAging. Exposure to UVA and UVB increase the risk of skin cancer. Can lead to impetigo,
skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma).

25

452

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

DERMATOLOGY

Skin cancer

Basal cell carcinoma

Most common skin cancer. Found in sun-exposed areas of body (eg, face). Locally invasive, but
rarely metastasizes. Waxv, pink, pearly nodules, commonhjwith telangiectasias, rolled borders,
central crusting or ulceration Q. BCCs also appear as nonhealing ulcers with infiltrating growth
Q or as a scaling plaque (superficial BCC ) Q. Basal cell tumors have palisading nuclei 0-

4
Squamous cell
carcinoma

Second most common skin cancer. Associated with excessive exposure to sunlight,
immunosuppression, chronically draining sinuses, and occasionalhiarsenic exposure. Commonly
appears on face Q, lower lip Q, ears, hands. Locally invasive, may spread to lymph nodes,
and will rarely metastasize. Ulcerative red lesions with frequent scale. ( listopathology: keratin

pearls 0.

Actinic keratosis, a scaly plaque, is a precursor to squamous cell carcinoma.


Keratoacanthoma is a variant that grows rapidly (4-6 weeks) and may regress spontaneously over
months 0.

%
Melanoma

Common tumor with significant risk of metastasis. S-100 tumor marker. Associated with sunlight
exposure and dysplastic nevi; fair-skinned persons are at t risk. Depth of tumor correlates with risk
of metastasis. Look for the ABCDEs: Asymmetry, Border irregularity, Color variation, Diameter
> 6 mm, and Evolution over time. At least 4 different types of melanoma, including superficial
spreading Q, nodular Q, lentigo maligna Q, and acral lentiginous Q Often driven by activating
mutation in BRAF kinase. Primary treatment is excision with appropriately wide margins.
Metastatic or unresectable melanoma in patients with BRAF V600E mutation may benefit from
vemurafenib, a BRAF kinase inhibitor.

llllp

r a
3

*^

454

SECTION III

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

PHARMACOLOGY

Aspirin
MECHANISM

NSAID that irreversibly inhibits cyclooxygenase ( both COX-1 and COX-2) by covalent acetylation
1 synthesis of TXA 7 and prostaglandins, t bleeding time. No effect on PT, PTT. Effect lasts
until new platelets are produced.

CLINICAL USE

Low dose (< 300 mg/day): 1 platelet aggregation. Intermediate dose ( 300-2400 mg/day): antipyretic
and analgesic. High dose ( 2400-4000 mg/day): anti-inflammatory.

ADVERSE EFFECTS

Gastric ulceration, tinnitus (CN VIII). Chronic use can lead to acute renal failure, interstitial
nephritis, GI bleeding. Risk of Reve syndrome in children treated with aspirin for viral infection.
Causes respiratory alkalosis early, but transitions to mixed metabolic acidosis-respiratory alkalosis.

Celecoxib

the cyclooxygenase (COX ) isoform 2 ( Selecoxib ), which!is found


in inflammatory cells and vascular endothelium and mediates inflammation and pain; spares
COX-1, which helps maintain gastric mucosa. Thus, does not have the corrosive effects of other
NSAIDs on the GI lining. Spares platelet function as TXA -, production is dependent on COX-1.

MECHANISM

Reversibly inhibits selectively

CLINICAL USE

Rheumatoid arthritis, osteoarthritis.

ADVERSE EFFECTS

t risk of thrombosis. Sulfa allergy.

Nonsteroidal
anti-inflammatory

Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac, meloxicam, piroxicam.

druqs ( NSAIDsL
MECHANISM

CLINICAL USE
ADVERSE EFFECTS

Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block prostaglandin synthesis.
Antipyretic, analgesic, anti-inflammatory. Indomethacin is used to close a PDA.
Interstitial nephritis, gastric ulcer (prostaglandins protect gastric mucosa), renal ischemia
( prostaglandins vasodilate afferent arteriole), aplastic anemia.

Leflunomide

CLINICAL USE

Reversibly inhibits dihydroorotate dehydrogenase, preventing pyrimidine synthesis. Suppresses


T-cell proliferation.
Rheumatoid arthritis, psoriatic arthritis.

ADVERSE EFFECTS

Diarrhea, hypertension, hepatotoxicity, teratogenicity.

MECHANISM

Bisphosphonates

Alendronate, ibandronate, risedronate, zoledronate.

MECHANISM

Pyrophosphate analogs; bind hydroxyapatite in bone, inhibiting osteoclast activity.

CLINICAL USE

Osteoporosis, hypercalcemia, Paget disease of bone, metastatic bone disease, osteogenesis

ADVERSE EFFECTS

Esophagitis (if taken orally, patients are advised to take with water and remain upright for 30
minutes), osteonecro sis of jaw, atypical stress fractures.

imperfecta.

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

455

SECTION III

PHARMACOLOGY

Teriparatide
MECHANISM

Recombinant PTH analog given subcutaneously daily, t osteoblastic activity.

CLINICAL USE

Osteoporosis. Causes t bone growth compared to antiresorptive therapies (eg, bisphosphonates).

ADVERSE EFFECTS

t risk of osteosarcoma ( avoid use in patients with Paget disease of the bone or unexplained
elevation of alkaline phosphatase).
Transient hypercalcemia.

Gout drugs

Chronic gout drugs (preventive)

Allopurinol

Competitive inhibitor of xanthine oxidase


i conversion of hypoxanthine and xanthine to
urate. Also used in lymphoma and leukemia
to prevent tumor lvsis-associated urate
nephropathy, t concentrations of azathioprine
and 6-MP ( both normally metabolized by
xanthine oxidase).
,

Febuxostat

Inhibits xanthine oxidase.

Pegloticase

Recombinant uricase that catalyzes metabolism


of uric acid to allantoin (a more water-soluble
product).

Probenecid

Inhibits reabsorption of uric acid in proximal


convoluted tubule (also inhibits secretion of
penicillin). Can precipitate uric acid calculi.

Diet

Purines

Hypoxanthine

I Xanthine
1 oxidase
Xanthine
I Xanthine
I oxidase
Plasma
uric acid

Allopurinol,
febuxostat

Urate crystals deposited


in joints

$
Probenecid and
high -dose salicylates

Acute gout drugs


NSAIDs

Nucleic acids

Naproxen, indomethacin.
Avoid salicylates; all but the highest doses
depress uric acid clearance. Other NSAIDs are
better tolerated]

Glucocorticoids

Oral, intra-articular, or parenteral.

Colchicine

Binds and stabilizes tubulin to inhibit

Urine

Gout

Tubular
reabsorption

Tubular
secretion

Diuretics and

low -dose salicylates

microtubule polymerization, impairing


neutrophil chemotaxis and degranulation.
Acute and prophylactic value. GI side effects.

TNF-a inhibitors

All TNF-a inhibitors predispose to infection, including reactivation of latent TB, since TNF is
important in granuloma formation and stabilization.

DRUG

MECHANISM

CLINICAL USE

Etanercept

Fusion protein (receptor for TNF-a + IgGj Fc),


produced by recombinant DNA.
Etanercept is a TNF decoy receptor.

Rheumatoid arthritis, psoriasis, ankylosing

Anti-TNF-a monoclonal antibody.

Inflammatory bowel disease, rheumatoid arthritis,


ankylosing spondylitis, psoriasis

Infliximab,
adalimumab,

certolizumabj

spondylitis

HIGH - YI E LD SYSTEMS

Neurology and
Special Senses
Estimated amount of glucose used by an adult human brain each day,
expressed in M & Ms: 250.

Harpers Index

Embryology

458

Anatomy and

Physiology

461

Pathology

479

Otology

500

Ophthalmology

502

Pharmacology

512

Anythings possible if youve got enough nerve.

J.K. Rowling Harry Potter and the Order of the Phoenix


,

I like nonsense ; it wakes up the brain cells.

Dr. Seuss
I

believe in an open mind , but not so olren that

your

brains fall out.

Arthur Hays Sulzberger


The chief junction of

the body is to earn the brain around ."

Thomas Edison

457

458

SECTION III

NEUROLOGY AND SPECIAL SENSES

NEUROLOGY EMBRYOLOGY

NEUROLOGY EMBRYOLOGY
Neural development
Neural plate
Day 18

'-Notochord
Neural fold

Notochord induces overlying ectoderm to differentiate into neuroectoderm and form neural plate.
Neural plate gives rise to neural tube and neural crest cells.
Notochord becomes nucleus pulposus of intervertebral disc in adults.

Alar plate (dorsal): sensory


Basal plate (ventral): motor

Same orientation as spinal cord.

Neural tube
Neural

Day 21

Regional specification of developing brain


Three primary

Five secondary

vesicles

vesicles

Telencephalon
Wall

Cavity

Forebrain
(prosencephalon)

Diencephalon

Midbrain
(mesencephalon)

Mesencephalon

Hindbrain
(rhombencephalon)

Metencephalon

Adult derivatives of:


Cavities

Walls

Cerebral

Lateral

hemispheres

ventricles

Thalamus,

Third

Hypothalamus

ventricle

Midbrain

Aqueduct

Rons

Upper part of
fourth ventricle

Cerebellum

Myelencephalon
Medulla

Spinal cord

CNS /PNS origins

Lower part of
fourth ventricle

113

Neuroepithelia in neural tubcj CNS neurons, ependymal cells ( inner lining of ventricles, make
CSF), oligodendroglia, astrocytes.
Neural crest PNS neurons, Schwann cells.
Mesoderm Microglia ( like Macrophages).

MUSCULOSKELETAL, SKIN, AND CONNECTIVE TISSUE

ANATOMY AND PHYSIOLOGY

SECTION III

423

Common knee conditions

"Unhappy triad"

Common injury in contact sports due to lateral force applied to a planted leg. Classically, consists
of damage to the ACL Q, MCL, and medial meniscus (attached to MCL); however, lateral
meniscus injury is more common. Presents with acute knee pain and signs of joint injury/
instability.

Prepatellar bursitis
Inflammation of the prepatellar bursa over the kneecaptp. Can be caused by repeated trauma or
("housemaid's knee" )j
pressure from excessive kneeling.

Baker cyst

Popliteal fluid collection in gastrocnemius-semimembranous bursa Q commonly communicating


with synovial space and related to chronic joint disease.

Rotator cuff muscles

'A

Shoulder muscles that form the rotator cuff:


SItS (small t is for teres minor).
Supraspinatus (suprascapular nerve)
Acromion
Supraspinatus
abducts arm initially ( before the action
Coracoid
of the deltoid); most common rotator cuff
Biceps tendon
injury Q (trauma or degeneration and
Infraspinatus
- Subscapularis
impingement tendinopathy or tear),
Teres minor
assessed by empty/full can test.
Infraspinatus (suprascapular nerve) laterally
Posterior
Anterior
rotates arm; pitching injury.
teres minor (axillary nerve) adducts and
a

laterally rotates arm.


Subscapularis (upper and lower subscapular
nerves) medially rotates and adducts arm.
Innervated primarily by C 5 -C6.
1

Arm abduction

New
Fact

DEGREE

MUSCLE

NERVE

0-15

Supraspinatus

Suprascapular

15-100

Deltoid

> 100

Serratus anterior

Long thoracic

Axillary-

NEUROLOGY AND SPECIAL SENSES

Neural tube defects

Spina bifida occulta


Meningocele
Meningomyelocele

EMBRYOLOGY

SECTION III

459

Neuropores fail to fuse (4th week) -* persistent connection between amniotic cavity and spinal
canal . Associated with maternal diabetes as well asjlow folic acid intake before conception and
during pregnancy, t a-fetoprotein (AFP ) in amniotic fluid and maternal serum (except spina
bifida occulta ) t acetylcholinesterase (AChE) in amniotic fluid is a helpful confirmatory test (fetal
AChE in CSF flows through defect into amniotic fluid ).
Failure of rostral neuropore to close no forebrain, open calvarium . Clinical findings: t AFP,
polyhydramnios ( no swallowing center in brain ) .
Failure of caudal neuroporejto close, but no herniation. Usually seen at lower vertebral levels. Dura
is intact . Associated with tuft of hair or skin dimple at level of bony defect. Normal AFP
Meninges ( but no neural tissue) herniate through bony defect . Associated with spina bifida cystic
Meninges and neural tissue (eg, cauda equina ) herniate through bony defect .
,

Anencephaly

NEUROLOGY

f /- Tuft of hair

Skin defect/thinning

- Skin thin or absent

+/- Skin dimple

Skin

subarachnoid

spai
Jjia

Leptomeninges

J
-j

Spinal
cord

Transverse

Normal

Holoprosencephaly

Spina bifida occulta


(most common)

Meningocele

Meningomyelocele

Failure of left and right hemispheres to separate; usually occurs during weeks 5-6. May be related
to mutations in sonic hedgehog signaling pathway. Moderate form has cleft lip/palate, most severe
form results in cyclopia . Seen in Patau syndrome and fetal alcohol syndrome.

RENAL

RENAL EMBRYOLOGY

SECTION III

547

Inferior poles of both kidneys fuse


abnormally Q. As they ascend from pelvis
/
fetal development, horseshoe kidneys
during
Renalartery
get trapped under inferior mesenteric
artery and remain low in the abdomen.
Kidneys function normally. Associated
with hydronephrosis (eg, ureteropelvic
^'CMnfeno
junction obstruction), renal stones, infection,
mesenteric
,
artery
chromosomal aneuploidv syndromes (eg,
Turner syndrome; trisomies 13, 18, 21), and
rarely renal cancer.

Horseshoe kidney
Horseshoe

Aorta

kidney

Ureteral

Unilateral renal
agenesis

Ureteric bud fails to develop and induce differentiation of metanephric mesenchyme -* complete
absence of kidney and ureter. Often diagnosed prenatally via ultrasound.

Multicystic dysplastic
kidney

Predominantly non-hereditarv condition where ureteric bud fails to induce differentiation of

Duplex collecting

Bifurcation of ureteric bud before it enters the metanephric blastema creates a Y-shaped bifid
ureter. Duplex collecting system can alternatively occur through two ureteric buds reaching and
interacting with metanephric blastema. Strongly associated with vesicoureteral reflux and/or
ureteral obstruction, t risk for UTIs.

system

New
Fact

metanephric mesenchvmet nonfunctional kidney consisting of cysts and connective tissue.


Often diagnosed prenatally via ultrasound.

Congenital solitary
functioning kidney

Condition of being born with only one functioning kidney. Majority asymptomatic with
compensator} hypertrophy of contralateral kidney, but anomalies in contralateral kidney are
common.

Posterior urethral
valves

Membrane obstructs the urethra due to abnormal development in utero. Found only in males. Can
be diagnosed prenatally by hydronephrosis and dilated bladder on ultrasound. Most common
cause of urinary obstruction in male infants.

460

SECTION III

NEUROLOGY AND SPECIAL SENSES

NEUROLOGY EMBRYOLOGY

Posterior fossa malformations

Chiari I malformation!

Ectopia of cerebellar tonsils ( 1 structure ) > 3-5 mm; congenital, usually asymptomatic in
childhood, manifests in adulthood with headaches and cerebellar symptoms. Associated with
spinal cavitations ( eg, syringomyelia ) , i

Chiari II malformation

Herniation of low-lying cerebellar vermis and tonsils ( 2 structures) through foramen


hydrocephalus. Usually associated with lumbosacral
magnum )] with aqueductal stenosis
meningomyelocele (may present as paralysis/sensory loss at and below the level of the lesion ) .

Dandy-Walker
syndrome|

Agenesis of cerebellar vermis with cvstic enlargement of 4th ventricle ( red arrow in ), fills the
enlarged posterior fossa. Associated with noncommunicating hydrocephalus, spina bifidaj

B=
New
Image

r#vV

wan

Syringomyelia

Cystic cavity (syrinx) within central canal


of spinal cord ( yellow arrow in Q). Fibers
crossing in anterior white commissure
(spinothalamic tract) are typically damaged
first. Results in a cape-like, bilateral loss
of pain and temperature sensation in upper
extremities (fine touch sensation is preserved).
Associated with Chiari malformations (red
arrow in EJ), trauma, and tumors.

Syrinx = tube, as in syringe.


Most common at C8-T1

NEUROLOGY AND SPECIAL SENSES

Tongue development
Anterior tongue

Arches
land 2
Sensation

vnaV

Taste
via VII

Revised
Figure |
Sensation
and taste
via IX

a cues
Sand 4

Sensation
and taste

NEUROLOGY ANATOMY AND PHYSIOLOGY

1st and 2nd branchial arches form anterior 2A


(thus sensation via CN V,, taste via CN VII).
3rd and 4th branchial arches form posterior A
(thus sensation and taste mainly via CN IX,
extreme posterior via CN X ).
Motor innervation is via CN XII to hyoglossus
(retracts and depresses tongue), genioglossus
(protrudes tongue), and styloglossus (draws
sides of tongue upward to create a trough for
swallowing).
Motor innervation is via CN X to palatoglossus
(elevates posterior tongue during swallowing).

SECTION III

461

Taste CN VII, IX, X (solitary nucleus).


Pain-CN V IX, X.
Motor-CN X, XII.

Posterior tongue

NEUROLOGY ANATOMY AND PHYSIOLOGY


Neurons

Signal-transmitting cells of the nervous system. Permanent cells do not divide in adulthood.
Signal-relaying cells with dendrites (receive input), cell bodies, and axons (send output). Cell bodies
and dendrites can be seen on Nissl staining (stains RER). RER is not present in the axon.
Injury to axon Wallerian degeneration degeneration distal to injury and axonal retraction
proximally; allows for potential regeneration of axon (if in PNS).

Astrocytes

Physical support, repair, buffers extracellular K4! removal of excess neurotransmitter, component
of blood-brain barrier, glycogen fuel reserve buffer. Reactive gliosis in response to neural injury.
Astrocyte marker: GFAP Derived from neuroectoderm.

Microglia

Phagocytic scavenger cells of CNS


(mesodermal, mononuclear origin). Activated
in response to tissue damage. Not readily
discernible by Nissl stain.

HIV-infected microglia fuse to form


multinucleated giant cells in CNS.

462

SECTION III

Myelin

NEUROLOGY AND SPECIAL SENSES

t conduction velocity of signals transmitted


down axons saltatory conduction of action
potential at the nodes of Ranvier, where there
are high concentrations of Na+ channels.
CNS oligodendrocytes; PNS Schwann

NEUROLOGY ANATOMY AND PHYSIOLOGY

Wraps and insulates axons (red arrow in H):


t pace constant and t conduction velocity,

cells.

Schwann cells
Nucleus -v

Node of Ranvier

Myelin sheath -*

Each Schwann cell myelinates only 1 PNS axon. May be injured in Guillain-Barre syndromeJ
Also promote axonal regeneration. Derived
from neural crest

V Schwann cell

Myelinates axons of neurons in CNS. Each


oligodendrocyte can myelinate many axons
(~ 50). Predominant type of glial cell in white

Oligodendroglia

-Node of Ranvier
Axon

matter.

Derived from neuroectoderm.


Fried egg appearance histologically.
Injured in multiple sclerosis, progressive
multifocal leukoencephalopathy (PML),
leukodystrophies.

Sensory receptors
RECEPTOR TYPE

SENSORY NEURON FIBER TYPE

LOCATION

SENSES

Free nerve endings

C slow, unmyelinated fibers


A8 fast, myelinated fibers

All skin, epidermis, some

Pain, temperature

Meissner corpuscles

Large, myelinated fibers; adapt

Glabrous (hairless) skin

Dynamic, fine/light touch,


position sense

Deep skin layers, ligaments,

Vibration, pressure

Pacinian corpuscles
Merkel discs

Ruffini corpuscles

quickly
Large, myelinated fibers; adapt
quickly
Large, myelinated fibers; adapt
slowly
Dendritic endings with

capsule; adapt slowly

viscera

joints

Finger tips, superficial skin

Pressure, deep static touch (eg,


shapes, edges), position sense

Finger tips, joints

Pressure, slippage of objects


along surface of skin, joint

angle change

NEUROLOGY AND SPECIAL SENSES

Peripheral nerve
Nerve trunk

Epineurium
Perineurium

Endoneurium
Nerve fibers

Chromatolysis

' .

***

NEUROLOGY ANATOMY AND PHYSIOLOGY

Endoneurium invests single nerve fiber layers


(inflammatory infiltrate in Guillain-Barre
syndrome).
Perineurium ( blood-nerve Permeability
barrier) surrounds a fascicle of nerve fibers.
Must be rejoined in microsurgery for limb
reattachment.
Epineurium dense connective tissue that
surrounds entire nerve (fascicles and blood
vessels).

SECTION III

Endo = inner.
Peri = around.
Epi = outer.

Reaction of neuronal cell body to axonal injury. Changes reflect t protein synthesis in effort to
repair the damaged axon. Characterized bv:
Round cellular swelling H
Displacement of the nucleus to the periphery
Dispersion ofNissl substance throughout cytoplasm
Concurrent with Wallerian degeneration degeneration of axon distal to site of injury.
Macrophages remove debris and mvelin.

Neurotransmitter changes with disease!


LOCATION OF

ANXIETY

DEPRESSION

SCHIZOPHRENIA

SYNTHESIS

Acetylcholine

Basal nucleus
of Meynert

Dopamine

Ventral

ALZHEIMER
DISEASE

HUNTINGTON
DISEASE

PARKINSON

tegmentum,

SNj
GABA

Nucleus

accumbens

Norepinephrine

Locus ceruleus

Serotonin

Raphe nucleus

DISEASE

463

464

SECTION III

Blood-brain barrier
processes

light

-4' ll

.i' y '

Sasement
membrane

Hypothalamus

NEUROLOGY ANATOMY AND PHYSIOLOGY

NEUROLOGY AND SPECIAL SENSES

Prevents circulating blood substances


(eg, bacteria, drugs) from reaching the CSF/
CNS. Formed by 3 structures:
Tight junctions between nonfenestrated
capillary endothelial cellsw
Basement
membrane

Astrocyte foot processes


Glucose and amino acids cross slowly by carriermediated transport mechanisms.
Nonpolar /1ipid-soluble substances cross rapidly
via diffusion.

A few specialized brain regions with fenestrated


capillaries and no blood-brain barrier allow
molecules in blood to affect brain function (eg,
area postrema vomiting after chemo; OVLT
[organum vasculosum laminar terminalisl
osmotijsensing) or neurosecretory products to
enter circulation (eg, neurohypophysis ADH

release).
Infarction and/or neoplasm destroys endothelial
cell tight junctions vasogenic edema.
Other notable barriers include:
Blood-testis barrier
* Maternal-fetal blood barrier of placenta

The hypothalamus wears TAN HATS Thirst and water balance, Adenohypophysis control
(regulates anterior pituitary), Neurohypophysis releases hormones produced in the hypothalamus
Hunger, Autonomic regulation, Temperature regulation, Sexual urges.
Inputs (areas not protected by blood-brain barrier): OVLlt senses change in osmolarity), area
postrema (found in medulla, responds to emetics)]

If you zap your lateral area, you shrink laterally.

Lateral area

Hunger. Destruction anorexia, failure


to thrive (infants). Stimulated by ghrelin,
inhibited by leptin.

Ventromedial area

Satiety. Destruction (eg, craniopharyngioma)


hyperphagia. Stimulated by leptin.

Anterior
hypothalamus

Cooling, parasympathetic.

Anterior nucleus = cool off (cooling,


pArasympathetic). A /C = anterior cooling.

Posterior
hypothalamus

Heating, sympathetic.

Posterior nucleus = get fired up (heating,


sympathetic). If you zap your posterior
hypothalamus, you become a poikilotherm
(cold-blooded, like a snake).

Suprachiasmatic
nucleus

Circadian rhythm.

You need sleep to be charismatic (chiasmatic).

Supraoptic nucleus

Releases ADI 1

Paraventricular
nucleus

Releases oxvtocin

ADH and oxvtoxin are carried by neurophvsins


down axons to posterior pituitary , where they arc
stored and released.

If you zap your ventromedial area, you grow


ventrally and medially.

NEUROLOGY ANATOMY AND PHYSIOLOGY

NEUROLOGY AND SPECIAL SENSES

Sleep physiology

SECTION III

465

Sleep cycle is regulated by the circadian rhythm, which is driven by suprachiasmatic nucleus (SCN)
of hypothalamus. Circadian rhythm controls nocturnal release of ACTH, prolactin, melatonin,
norepinephrine: SCN norepinephrine release pineal gland melatonin. SCN is regulated
by environment (eg, light).
Two stages: rapid-eve movement (REM) and non-REM|
Alcohol, benzodiazepines, and barbiturates are associated with l REM sleep and delta wave sleep;
norepinephrine also i REM sleep.

Oral desmopressin ( ADI 1 analog) is useful in treatment of bedwetting (sleep enuresis) j preferred over
imipramine because of the latters adverse effects.
Benzodiazepines are useful for night terrors and sleepwalking by decreasing N3 and REM sleep!
SLEEP STAGE (% OF TOTAL SLEEP
TIME IN YOUNG ADULTS)

DESCRIPTION

EEG WAVEFORM

Awake (eyes open)

Alert, active mental concentration

Beta ( highest frequency, lowest amplitude)

Alpha

Awake (eyes closed)


Non- REM sleep

Stage N1 (5%)

Light sleep

Theta

Stage N2 (45%)

Deeper sleep; when bruxism occurs


Deepest non-REM sleep (slow -wave sleep);
when sleepwalking, night terrors, and
bedwetting occur

Delta (lowest frequency, highest amplitude)

Stage N3 (25%)

REM sleep (25%)

Loss of motor tone, t brain O-, use, t and


variable pulse and blood pressure; when
dreaming, nightmares, and penile/clitoral
tumescence occur; may serve memory
processing function. Depression increases total
REM sleep but decreases REM latencvi
Extraocular movements due to activity of PPRF
( paramedian pontine reticular formation /
conjugate gaze center)
Occurs every 90 minutes, and duration
t through the night
t ACh in REM

Sleep spindles and K complexes

Beta
At night, BATS Drink Blood

466

SECTION III

Ventral

FJpsteroLjateral

NEUROLOGY ANATOMY AND PHYSIOLOGY

Major relay for all ascending sensory information except olfaction.

Thalamus
NUCLEUS

NEUROLOGY AND SPECIAL SENSES

INPUT

SENSES

DESTINATION

Spinothalamic and dorsal columns/


medial lemniscus

Vibration, Pain,
Pressure,

1 somatosensory-

MNEMONIC

cortex

Proprioception,
Light touch,
temperature!

nucleus

Face sensation,

1 somatosensory -

Ventral
posteroMedial
nucleus

Trigeminal and gustatory pathway

Lateral
geniculate
nucleus

CN II

Vision

Calcarine sulcus

Lateral = Light

Medial
geniculate
nucleus

Superior olive and inferior colliculus of

Hearing

Auditory cortex of
temporal lobe

Medial = Music

Motor

Motor cortex

cortex

taste

tectum

Ventral lateral Basal ganglia, cerebellum


nucleus

Collection of neural structures involved in


emotion, long-term memory, olfaction,
behavior modulation, ANS function.
The Pape / circuit consists of the following

Limbic system

jiCpA
- v;
;

Makeup goes on
the face (VPM)

The famous 5 Fs.

*
Dopaminergic
pathways

structures: hippocampus ( red arrows in H),


mammillary bodies, anterior thalamic nuclei,
cingulate gyrus ( yellow arrows in D),
entorhinal cortex ]Responsible for Feeding,
Fleeing, Fighting, Feeling, and Sex.

Commonly altered by drugs (eg, antipsychotics) and movement disorders (eg, Parkinson disease).

PATHWAY

SYMPTOMS OF ALTERED ACTIVITY

Mesocortical

1 activity

Mesolimblc

t activity -* positive symptoms (eg, delusions,


hallucinations).

Primary therapeutic target of antipsychotic drugs


-* 1 positive symptoms (eg, in schizophrenia).

Nigrostriatal

1 activity extrapyramidal symptoms


(eg, dystonia, akathisia, parkinsonism, tardive
dyskinesia).

Major dopaminergic pathway in brain.


Significantly affected by movement disorders
and antipsychotic drugs.

Tuberoinfundibular

1 activity -* t prolactin

NOTES

negative symptoms (eg, anergia,


apathy, lack of spontaneity!).

1 libido, sexual
dysfunction, galactorrhea, gynecomastia (in

men).

Antipsychotic drugs have limited effect.

NEUROLOGY ANATOMY AND PHYSIOLOGY

NEUROLOGY AND SPECIAL SENSES

Cerebellum

Modulates movement; aids in coordination and


balance.
Input:
Contralateral cortex via middle cerebellar
peduncle.
Ipsilateral proprioceptive information via
inferior cerebellar peduncle from spinal
cord.
Output:
The only output of cerebellar cortex =
Purkinje cells (always inhibitorydeep
nuclei of cerebellum contralateral cortex
via superior cerebellar peduncle.
Deep nuclei (lateral -* medial) Dentate,
Emboliform, Globose, Fastigial ( Dont Eat
Greasy Foods ).

SECTION III

467

Lateral lesions affect voluntary movement of


extremities ( Limbst when injured, propensity
to fall toward injured (ipsilateral) side.
Medial lesions involvement of Mjjdline
structures (vermal cortex, fastigial nuclei)
and/or flocculonodular lobe truncal ataxia
(wide-based cerebellar gait), nystagmus, head
tilting. Generally result in bilateral motor
deficits affecting axial and proximal limb
musculature.

NEUROLOGY

NEUROLOGY AND SPECIAL SENSES

ANATOMY AND PHYSIOLOGY

SECTION III

469

Cerebral cortex functions


Premotor

Re
located
Fact

Somatosensory
association cortex

Central sulcus

cortex

0i

Frontal eye
held

Frontal
ibc
'

Prefronl 3

T
Broca area

Wernicke area
Occipital
lobe

Temporal
mpo

lobe

Sylvian fissure

Limbic

Primary
visual cortex
Primary
auditory cortex

association area

Topographic representation of motor (shown )


and sensory areas in the cerebral cortex.
Distorted appearance is due to certain body
regions being more richly innervated and thus
having t cortical representation .

Homunculus
Re located

Fact

oooo0

-,x
fV i %
'

<

Tongue
Swallowing

Medial

11

Lateral

470

SECTION III

Cerebral perfusion
Re -

located
Fact

NEUROLOGY AND SPECIAL SENSES

Brain perfusion relies on tight autoregulation .


Cerebral perfusion is primarily driven by
Pco7 ( Po2 also modulates perfusion in severe
hypoxia).
Cerebral perfusion relies on a pressure gradient
between mean arterial pressure ( MAP) and
ICP. i blood pressure or t ICP -* 1 cerebral
perfusion pressure ( CPP ).

normal Po2

Normal

Hypoxemia increases
cerebral perfusion pressure
only when Po2 < 50 mm Hg

NEUROLOGY

ANATOMY AND PHYSIOLOGY

Therapeutic hyperventilation 1 Pco?


-* vasoconstriction i cerebral blood flow
1 intracranial pressure ( ICP) . May be used
to treat acute cerebral edema (eg, 2 to stroke )
unresponsive to other interventions.
CPP = MAP - ICP. If CPP = 0, there is no
cerebral perfusion brain death .

Cerebral perfusion
pressure * Pco2 until
Pco2 > 90 mm Hg

--02

I
Normal
normal Pco2

50

Re -

ISO
100
Arterial gas pressure (mm Hg )

120
80
Arterial gas pressure 1mm Hg)

40

located Cerebral arteries cortical distribution


Fact
Anterior cerebral artery (supplies anteromedial surface )

[ j Middle cerebral artery (supplies lateral surface)


| | Posterior cerebral artery (supplies posterior and inferior surfaces)

?T
A
Watershed zones

Between anterior cerebral /middle cerebral , posterior cerebral /middle cerebral arteries. Damage by
severe hypotension -* upper leg /upper arm weakness, defects in higher-order visual processing.

NEUROLOGY ANATOMY AND PHYSIOLOGY

NEUROLOGY AND SPECIAL SENSES

Re -

Circle of Willis

located
Fact

System of anastomoses between anterior and posterior blood supplies to brain.


ACom I Anterior

Optic chiasm

communicating

cerebral

Anterior
ACA
ICA
MCA

Anterior

ACA

circulation

MCA

Internal carotid | ICA

AT

Middle

zerebi ri

Posterior

communicating

PCA

-ni

CA

erebi il

cerebellar

if ^

Anterior inferior
cerebellar

> I i . l .TI

I/A

cephalic

- Basilar | BA

Posterior inferior
.

GCA

Ht

rr A Superior

PICA

BA
PCom

Posterior

AICA

Dural venous sinuses

CA

ft
WILLIS

9TPCA

INFERIOR VIEW

ACA

CIRCLE

OF

PCom

circulation

471

SECTION III

Aorta

- Vertebral | VA
OBLIQUE- LATERAL VIEW

Anterior spinal | ASA

Large venous channels that run through the dura. Drain blood from cerebral veins and receive CSF
from arachnoid granulations. Empty into internal jugular vein.
Venous sinus thrombosis presents with signs/symptoms of t ICP (eg, headache, seizures, focal
neurologic deficits). May lead to venous hemorrhage. Associated with hypercoagulable states (eg,
pregnancy, OCP use, factor V Leiden).

Superior sagittal sinus


(main location of CSF return

via arachnoid granulations )


Inferior sagittal sinus

Superior ophthalmic vein

Great cerebral vein of Galen

Sphenoparietal sinus

Straight sinus

Cavernous sinus
Confluence of the sinuses

Sigmoid sinus
Occipital sinus

Transverse sinus

Jugular foramen
Internal jugular vein

NEUROLOGY AND SPECIAL SENSES

NEUROLOGY PATHOLOGY

SECTION III

Effects of strokes ( continued )


ARTERY

AREA OF LESION

SYMPTOMS

NOTES

Basilar artery

Pons, medulla , lower niidbrain

RAS spared , therefore preserved


consciousness
Quadriplegia; loss of voluntary
facial , mouth , and tongue

Locked-in syndrome.

Corticospinal and corticobulbar


tracts

Posterior
cerebral

Ocular cranial nerve nuclei,


paramedian pontine reticular
formation
Occipital cortex, visual cortex.

movements
Loss of horizontal, but not vertical ,
eye movements

Contralateral hemianopia with


macular sparing.

artery

a
I New I

llmaqel

\
r

483

514

SECTION III

NEUROLOGY AND SPECIAL SENSES

NEUROLOGY

PHARMACOLOGY

Suvorexant
MECHANISM

I NeW I CLINICAL USE


| Fact |
ADVERSE EFFECTS

Triptans
MECHANISM

Hvpocretin (orexin) receptor antagonist.


Insomnia.
CNS depression , headache, dizziness, abnormal dreams, upper respiratory tract infection .
Contraindicated in patients with narcolepsy. Not recommended in patients with liver disease.

Sumatriptan
5- HT|B/1 p agonists. Inhibit trigeminal nerve
activation ; prevent vasoactive peptide release;
induce vasoconstriction .

CLINICAL USE

Acute migraine, cluster headache attacks.

ADVERSE EFFECTS

Coronary vasospasm (contraindicated in


patients with CAD or Prinzmetal angina),
mild paresthesia , serotonin syndrome ( in
combination with other 5 - HT agonists).

A SUMo wrestler TRIPs ANd falls on your


head
,

HIGH- YIELD PRINCIPLES IN

Psychiatry

A Freudian slip is when you say one thing but mean your mother.

Psychology

522

Pathology

524

Pharmacology

539

Anonymous

Men will always be mad , and those who think they can cure them are the
maddest of all.

Voltaire

Anyone who goes to a psychiatrist ought to have his head examined ."
Samuel Goldwyn

Words of comfort , skillfully administered , are the oldest therapy known to


man.

Louis Nizer

This chapter has been updated with PSM- 5 criteria .

521

522

SECTION III

PSYCHIATRY

PSYCHIATRY PSYCHOLOGY

PSYCHIATRY PSYCHOLOGY

Usually deals with involuntary responses.


Pavlovs classical experiments with dogs
ringing the bell provoked salivation.

Classical conditioning

Learning in which a natural response


(salivation) is elicited by a conditioned,
or learned, stimulus (bell) that previously
was presented in conjunction with an
unconditioned stimulus (food).

Operant conditioning

Learning in which a particular action is elicited because it produces a punishment or reward.


Usually deals with voluntary responses.

Reinforcement

Target behavior (response) is followed by desired reward (positive reinforcement) or removal of


aversive stimulus (negative reinforcement).

Punishment

Repeated application of aversive stimulus


(positive punishment) or removal of desired
reward (negative punishment) to extinguish
unwanted behavior.

Extinction

Skinners Operant Conditioning Quadrant


Decrease Behavior

Increase Behavior

Positive
Punishment

Positive
Reinforcement

Negative

Negative

Punishment

Reinforcement

<

Discontinuation of reinforcement (positive or negative) eventually eliminates behavior. Can occur

in operant or classical conditioning.

Transference and countertransference


Transference

Patient projects feelings about formative or other important persons onto physician (eg, psychiatrist
is seen as parent).

Countertransference

Doctor projects feelings about formative or other important persons onto patient (eg, patient
reminds physician of younger sibling).

Ego defenses

Mental processes (unconscious or conscious) used to resolve conflict and prevent undesirable
feelings (eg, anxiety, depression).

IMMATURE DEFENSES

DESCRIPTION

EXAMPLE

Acting out

Expressing unacceptable feelings and thoughts


through actions.

Tantrums.

Denial

Avoiding the awareness of some painful reality.

A cancer patient plans a full-time work schedule


despite being warned of significant fatigue

Displacement

Redirection of emotions or impulses to a neutral

Mother yells at her child, because her husband


yelled at her.

during chemotherapy

person or

Dissociation

object (vs projection)!

Temporary, drastic change in personality,


memory, consciousness, or motor behavior
to avoid emotional stress. Extreme forms can
result in dissociative identity disorder (multiple
personality disorder ]

Patient has incomplete or no memory of


traumatic event ]

PSYCHIATRY

PSYCHIATRY PSYCHOLOGY

SECTION III

523

Ego defenses ( continued )


IMMATURE DEFENSES

DESCRIPTION

EXAMPLE

Fixation

Partially remaining at a more childish level of

Adults that suck their thumbs (oral fixation!

Idealization
Identification

development (vs regression).


Expressing extremely positive thoughts of self
and others while ignoring negative thoughts.
Modeling behavior after another person who
is more powerful (though not necessarily

A patient boasts about his physician and his


accomplishments while ignoring any flaws.

Abused child later becomes a child abuser.

admired).
Intellectualization

Using facts and logic to emotionally distance


oneself from a stressful situation.

In a therapy session, patient diagnosed with

Isolation (of affect)

Separating feelings from ideas and events.

Describing murder in graphic detail with no


emotional response.

Passive aggression

Project hostile feelings in a non-confrontational

Disgruntled employee is repeatedly late to work.

cancer

focuses only on rates of survival.

manner ]

Projection

Attributing an unacceptable internal impulse to


an external source (vs displacement).

A man who wants to cheat on his wife accuses

Rationalization

Proclaiming logical reasons for actions actually


performed for other reasons, usually to avoid
self-blame.

After getting fired, claiming that the job was not


important anyway.

Reaction formation

Replacing a warded-off idea or feeling by an


(unconsciously derived) emphasis on its

A patient with libidinous thoughts enters a


monastery.

Regression

Involuntarily

Seen in children under stress such as illness,


punishment, or birth of a new sibling (eg,
bedwetting in a previously toilet-trained child
when hospitalized).

Repression

Involuntarily withholding an idea or feeling


from conscious awareness (vs suppression).

A 20-vear-old does not remember going to


counseling during his parents divorce 10 years
earlier.

Splitting

Believing that people are either all good or


all bad at different times due to intolerance
of ambiguity. Commonly seen in borderline
personality disorder.

A patient says that all the nurses are cold and


insensitive but that the doctors are warm and

Sublimation

Replacing an unacceptable wish with a course


of action that is similar to the wish but does
not conflict with one's value system (vs

Teenagers aggression toward his father is


redirected to perform well in sports.

Altruism

Alleviating negative feelings via unsolicited

opposite (vs sublimation).


turning back the maturational
clock and going back to earlier modes of
dealing with the world (vs fixation).

his wife of being unfaithful.

friendly.

MATURE DEFENSES

reaction formation).

Mafia boss makes large donation to charity.

generosity.
Suppression

Intentionally withholding an idea or feeling


from conscious awareness (vs repression);
temporary.

Choosing to not worry about the big game until


it is time to play.

Humor

Appreciating the amusing nature of an anxietyprovoking or adverse situation.

Nervous medical student jokes about the boards.

Mature adults wear a SASH.

524

SECTION III

PSYCHIATRY

PSYCHIATRY PATHOLOGY

PSYCHIATRY PATHOLOGY
Psychiatric genetics

Both genetic and environmental factors are involved in development of most psychiatric disorders.
For example, in bipolar disorder and schizophrenia, lifetime risk in general population (~ 1%)
< parent or sibling of someone affected (~ 10%) < monozygotic twin of someone affected (~ 50%).

Infant deprivation
effects

Long-term deprivation of affection results in:


Failure to thrive
Poor language/socialization skills
Lack of basic trust
Reactive attachment disorder (infant
withdrawn/unresponsive to comfort)

(Deprivation for > 6 months can lead to


irreversible changes.
Severe deprivation can result in infant death.

Child abuse

Physical abuse

Sexual abuse

Fractures (eg, ribs, long bone spiral, multiple


in different stages of healing), bruises (eg,
trunk, ear, neck; in pattern of implement),
burns (eg, cigarette, buttocks/thighs), subdural
hematomas, retinal hemorrhages. During
exam, children often avoid eye contact.

Genital, anal, or oral trauma; STIs; UTIs.

ABUSER

Usually biological mother.

Known to victim, usually male.

EPIDEMIOLOGY

40% of deaths related to child abuse or neglect


occur in children < 1 year old ]

Peak incidence 9-12 years old.

EVIDENCE

Child neglect

Failure to provide a child with adequate food, shelter, supervision, education, and/or affection.
Most common form of child maltreatment. Evidence: poor hygiene, malnutrition, withdrawal,
impaired social/emotional development, failure to thrive.
As with child abuse, suspected child neglect must be reported to local child protective services.

Vulnerable child
syndrome

Parents perceive the child as especially susceptible to illness or injury. Usually follows a serious
illness or life-threatening event. Can result in missed school or overuse of medical services.

PSYCHIATRY

PSYCHIATRY

PATHOLOGY

525

SECTION III

Childhood and early-onset disorders

Attention -deficit
hyperactivity
disorder

Onset before age 12. Limited attention span and poor impulse control. Characterized by
hyperactivity, impulsivity, and /or inattention in multiple settings (school , home, places of worship,
etc). Normal intelligence, but commonly coexists with difficulties in school . Continues into
adulthood in as many as 50% of individuals. Treatment: stimulants (eg, methylphenidate) +/
cognitive behavioral therapy (CBT ) ; alternatives include atomoxetine, guanfacine, clonidine.

Autism spectrum
disorder

Characterized by poor social interactions, social communication deficits, repetitive /ritualized


behaviors, restricted interests. Must present in early childhood. May be accompanied by
intellectual disability; rarely accompanied by unusual abilities (savants). More common in boys.
Associated with t head/brain size.

Rett syndrome

X-linked dominant disorder seen almost exclusively in girls (affected males die in utero or
shortly after birth ) . Symptoms usually become apparent around ages 1 4, including regression
characterized by loss of development , loss of verbal abilities, intellectual disability, ataxia ,
stereotyped hand-wringing.
Repetitive and pervasive behavior violating the basic rights of others or societal norms (eg,
aggression to people and animals, destruction of property, theft ). After age 18, many of these
patients will meet criteria for diagnosis of antisocial personality disorder. Treatment for both:
psychotherapy such as CBT.
Enduring pattern of hostile, defiant behavior toward authority figures in the absence of serious
violations of social norms. Treatment: psychotherapy such as CBT.
Common onset at 7-9 years. Overwhelming fear of separation from home or loss of attachment
figure. May lead to factitious physical complaints to avoid going to or staying at school . Treatment:
CBT, play therapy, family therapy.
Onset before age 18. Characterized by sudden , rapid , recurrent, nonrhythmic, stereotyped motor
and vocal tics that persist for > 1 year. Coprolalia ( involuntary obscene speech ) found in only
10-20% of patients. Associated with OCD and ADHD. Treatment: psychoeducation , behavioral
therapy. For intractable and distressing tics, high -potency antipsychotics (eg, fluphenazine,
pimozide), tetrabenazine, a,-agonists (eg , guanfacine and clonidine), or atypical antipsychotic
may be used.
Onset before age 10. Severe and recurrent temper outbursts out of proportion to situation . Child
is constantly angry and irritable between outbursts. Treatment: psychostimulants, antipsychotics.
behavioral therapy.

Conduct disorder

Oppositional defiant
disorder
Separation anxiety
disorder

Tourette syndrome

Disruptive mood

dysrequlation

disorder

Orientation

Patients ability to know who he or she is, where


he or she is, and the date and time.
Common causes of loss of orientation : alcohol,
drugs, fluid /electrolyte imbalance, head
trauma , hypoglycemia , infection, nutritional

deficiencies.

Order of loss: 1st time; 2 nd place; last

person .

PSYCHIATRY

Dementia

Psychosis

PSYCHIATRY

I in intellectual function without affecting


level of consciousness. Characterized by
memory deficits, apraxia, aphasia , agnosia ,
loss of abstract thought , behavioral / personality
changes, impaired judgment. A patient
with dementia can develop delirium (eg,
patient with Alzheimer disease who develops
pneumonia is at t risk for delirium ).
Irreversible causes: Alzheimer disease, Lewy
body dementia , Huntington disease, Pick
disease, cerebral infarct , Creutzfeldt-Jakob
disease, chronic substance abuse (due to
neurotoxicity of drugs).
Reversible causes: hypothyroidism, depression,
vitamin B ) 2 deficiency, normal pressure
hydrocephalus, neurosyphilis.
t incidence with age. EEG usually normal .

PATHOLOGY

SECTION III

is characterized by memory loss .


Usually irreversible.
In elderly patients, depression and
hypothyroidism may present like dementia

Dememtia

( pseudodementia). Screen for depression ,


exclude neurosyphilis with RPR if high clinical
suspicion!and measure TSH , Bp levels.

Distorted perception of reality characterized by delusions, hallucinations, and/or disorganized


thought /speeclj Can occur in patients with medical illness, psychiatric illness, or both .

Delusions

Unique, false beliefs that persist despite the facts, not typical of a patient s culture or religion ( eg,
thinking aliens are communicating with vouj Types include erotomanic, grandiose , jealous,
persecutory, somatic, mixed , and unspecified!

Disorganized thought

Speech may be incoherent ( word salad ), tangential , or derailed ( loose associations ).

Hallucinations

Perceptions in the absence of external stimuli (eg, seeing a light that is not actually present).
Contrast with illusions, misperceptions of real external stimuli. Types include:
a
Visual more commonly a feature of medical illness (eg, drug intoxication ) than psychiatric

illness.

Auditory more commonly a feature of psychiatric illness (eg, schizophrenia) than medical
illness.
Olfactory often occur as an aura of temporal lobe epilepsy (eg, burning rubber) and in brain
tumors.
Gustatory rare, but seen in epilepsy.
Tactile common in alcohol withdrawal and stimulant use (eg, cocaine, amphetamines),
delusional parasitosis, cocaine crawlies.
Hypnagogic occurs while going to sleep. Sometimes seen in narcolepsy.
Hypnopompic occurs while waking from sleep ( pompous upon awakening ). Sometimes
seen in narcolepsy.

527

528

SECTION III

Schizophrenia

PSYCHIATRY

PSYCHIATRY

PATHOLOGY

Chronic mental disorder with periods of


psychosis, disturbed behavior and thought,
and decline in functioning lasting > 6
months. Associated with t dopaminergic
activity, i dendritic branching.

Diagnosis requires at least 2 of the following,


and at least 1 of these should include 1-3
(first 4 are positive symptoms ):
1 . Delusions
2 . Hallucinations often auditory
3. Disorganized speech
4. Disorganized or catatonic behavior
5. Negative symptoms (affective flattening,
avolition , anhedonia , asociality, alogia)
Brief psychotic disorder lasting < 1 month ,
usually stress related.

Frequent cannabis use is associated with


psychosis/schizophrenia in teens.
Lifetime prevalence 1.5% ( males = females,
African Americans = Caucasians). Presents
earlier in men ( late teens to early 20s vs late
20s to early 30s in women ). Patients are at t
risk for suicide.
Ventriculomegaly on brain imaging.
Treatment: atypical antipsychotics (eg,
risperidone) are first line.
Negative symptoms often persist despite
resolution of positive symptoms.

Schizophreniform disorder lasting 1-6

months.

Schizoaffective disorder Meets criteria for


schizophrenia in addition to major mood
disorder ( major depressive or bipolar ) . To
differentiate from a major mood disorder
with psychotic features, patient must have
> 2 weeks of hallucinations or delusions
without major mood episode

Delusional disorder

Fixed , persistent, false belief system lasting > 1 month. Functioning otherwise not impaired
(eg, a woman who genuinely believes she is married to a celebrity when , in fact , she is not).
Can be shared by individuals in close relationships (folie a deux).

Mood disorder

Characterized by an abnormal range of moods or internal emotional states and loss of control over
them . Severity of moods causes distress and impairment in social and occupational functioning.
Includes major depressive disorder, bipolar disorder, dysthymic disorder, and cyclothymic
disorder. Episodic superimposed psychotic features (delusions or hallucinations) may be present.

Manic episode

Distinct period of abnormally and persistently elevated , expansive, or irritable mood and
abnormally and persistently t activity or energy lasting at least 1 week . Often disturbing to

patient .
Diagnosis requires hospitalization or at least 3 of the following ( manics DIG E\ST):
Flight of ideas racing thoughts
Distractibility
t in goal-directed Activity/psychomotor
Irresponsibility seeks pleasure without
Agitation
regard to consequences ( hedonistic)
1 need for Sleep
Grandiosity inflated self-esteem
Talkativeness or pressured speech

PSYCHIATRY

PSYCHIATRY PATHOLOGY

SECTION III

529

Hypomanic episode

Like a manic!episode except mood disturbance is not severe enough to cause marked impairment
in social and/or occupational functioning or to necessitate hospitalization. No psychotic features.
Lasts at least 4 consecutive days.

Bipolar disorder

Bipolar I defined by presence of at least 1 manic episode +/ a hypomanic or depressive episode,


Bipolar II defined by presence of a hypomanic and a depressive episode.
Patient s mood and functioning usually return to normal between episodes. Use of antidepressants
can precipitate mania. High suicide risk. Treatment: mood stabilizers (eg, lithium, valproic acid,
carbamazepine, lamotriginc!), atypical antipsychotics.
Cyclothymic disorder milder form of bipolar disorder lasting at least 2 years, fluctuating
between mild depressive and hypomanic symptoms.

(manic depression )

Major depressive
disorder

Episodes characterized by at least 5 of the


9 D+SIGECAPS symptoms for 2 or more
weekj(symptoms must include patientreported depressed mood or anhedonia).
Treatment: CBT and SSRIs are first line.
SNRIs, mirtazapine, bupropion can also be
considered. Electroconvulsive therapy (ECT)
in select patients.
Persistent depressive disorder (dysthymia)
depression, often milder, lasting at least
2 years. May be caused by low self- esteem.

SIG E CAPS:

" Depressed mood


Sleep disturbance
Loss of Interest (anhedonia)
Guilt or feelings of worthlessness
* Energy loss and fatigue
8

Concentration problems

Appetite/weight changes
x Psychomotor retardation or
agitation
Suicidal ideations
Patients with depression typically have the
following changes in their sleep stages:
c

1 slow-wave sleep
1 REM latency
t REM early in sleep cycle
t total REM sleep

Repeated nighttime awakenings


Earlv-morning awakening (terminal
insomnia)

Depression with
atypical features

pharacterized by mood reactivity ( being able to experience improved mood in response to positive
events, albeit briefly), reversed vegetative symptoms ( hypersomnia, hyperphagia), leaden
paralysis ( heavy feeling in arms and legs), long-standing interpersonal rejection sensitivity. Most
common subtype of depression. Treatment: CBT and SSRIs are first line. MAO inhibitors are
effective but not first line because of their risk profile.

PSYCHIATRY

PSYCHIATRY PATHOLOGY

SECTION III

529

Hypomanic episode

Like a manic!episode except mood disturbance is not severe enough to cause marked impairment
in social and/or occupational functioning or to necessitate hospitalization. No psychotic features.
Lasts at least 4 consecutive days.

Bipolar disorder

Bipolar I defined by presence of at least 1 manic episode +/ a hypomanic or depressive episode,


Bipolar II defined by presence of a hypomanic and a depressive episode.
Patient s mood and functioning usually return to normal between episodes. Use of antidepressants
can precipitate mania. High suicide risk. Treatment: mood stabilizers (eg, lithium, valproic acid,
carbamazepine, lamotriginc!), atypical antipsychotics.
Cyclothymic disorder milder form of bipolar disorder lasting at least 2 years, fluctuating
between mild depressive and hypomanic symptoms.

(manic depression )

Major depressive
disorder

Episodes characterized by at least 5 of the


9 D+SIGECAPS symptoms for 2 or more
weekj(symptoms must include patientreported depressed mood or anhedonia).
Treatment: CBT and SSRIs are first line.
SNRIs, mirtazapine, bupropion can also be
considered. Electroconvulsive therapy (ECT)
in select patients.
Persistent depressive disorder (dysthymia)
depression, often milder, lasting at least
2 years. May be caused by low self- esteem.

SIG E CAPS:

" Depressed mood


Sleep disturbance
Loss of Interest (anhedonia)
Guilt or feelings of worthlessness
* Energy loss and fatigue
8

Concentration problems

Appetite/weight changes
x Psychomotor retardation or
agitation
Suicidal ideations
Patients with depression typically have the
following changes in their sleep stages:
c

1 slow-wave sleep
1 REM latency
t REM early in sleep cycle
t total REM sleep

Repeated nighttime awakenings


Earlv-morning awakening (terminal
insomnia)

Depression with
atypical features

pharacterized by mood reactivity ( being able to experience improved mood in response to positive
events, albeit briefly), reversed vegetative symptoms ( hypersomnia, hyperphagia), leaden
paralysis ( heavy feeling in arms and legs), long-standing interpersonal rejection sensitivity. Most
common subtype of depression. Treatment: CBT and SSRIs are first line. MAO inhibitors are
effective but not first line because of their risk profile.

530

SECTION III

Postpartum mood
disturbances

PSYCHIATRY

PSYCHIATRY

PATHOLOGY

Onset within 4 weeks of delivery.

Maternal
( postpartum ) "blues"

50-85% incidence rate. Characterized by depressed affect , tearfulness, and fatigue starting 2-3
days after delivery. Usually resolves within 10 days. Treatment: supportive. Follow up to assess for
possible postpartum depression .

Postpartum
depression

10-15% incidence rate. Characterized by depressed affect , anxiety, and poor concentration .
Treatment: CBT and SSRIs are first line.
0.1-0.2% incidence rate. Characterized by mood-congruent delusions, hallucinations, and
thoughts of harming the baby or self. Risk factors include history of bipolar or psychotic disorder,
first pregnancy, family history, recent discontinuation of psychotropic medication . Treatment:
hospitalization and initiation of atypical antipsychotic; if insufficient, ECT may be used .

Postpartum psychosis

Grief

The five stages of grief are denial , anger, bargaining, depression , and acceptance, not necessarily
in that order. Other normal grief symptoms include shock, guilt , sadness, anxiety, yearning, and
somatic symptom Hallucinations of the deceased person are common . Duration varies widely;
usually < 6 months.
Pathologic grief is persistent and causes functional impairment . Can meet criteria for major
depressive episode.

Electroconvulsive
therapy

Used mainly for treatment-refractory depression, depression with psychotic symptoms, and acutely
suicidal patients. Produces grand mal seizure in an anesthetized patient . Adverse effects include
disorientation, temporary headache, partial anterograde /retrograde amnesia usually resolving in 6
months. Safe in pregnancy.

Risk factors for suicide

Sex ( male)
Age ( young adult or elderly)
Depression
)
Previous attempt ( highest risk factor!
Ethanol or drug use
Rational thinking loss ( psychosis)
Sickness (medical illness)
Organized plan
No spouse or other social support
Stated future intent

completion

Anxiety disorder

SAD PERSONS are more likely to complete

suicide.
Most common method in US is firearms; access
to guns t risk of suicide completion.
Women try more often; men complete!more
often.

Inappropriate experience of fear/worry and its physical manifestations (anxiety) incongruent with
the magnitude of the perceived stressor. Symptoms interfere with daily functioning. Includes
panic disorder, phobias, generalized anxiety disorder, and selective mutism . Treatment: CBT,
SSRIs, SNRIs.

PSYCHIATRY

Panic disorder

PSYCHIATRY PATHOLOGY

SECTION III

531

Defined by recurrent panic attacks ( periods


PANICS
of intense fear and discomfort peaking in
Diagnosis requires attack followed by 1 month
10 minutes with at least 4 of the following):
(or more) of 1 (or more) of the following:
Persistent concern of additional attacks
Palpitations, Paresthesias, dePersonalization or
derealization, Abdominal distress or Nausea,
Worrying about consequences of attack
Behavioral change related to attacks
Intense fear of dying, Intense fear of losing
control or going crazy, light-headedness,
Symptoms are the systemic manifestations of
fear.
Chest pain, Chills, Choking, Sweating,
Shaking, Shortness of breath. Strong genetic
component t risk of suicide! Treatment:
CBT, SSRIs, and venlafaxine are first line.
Benzodiazepines occasionally used in acute
setting.
,

Specific phobia

Severe, persistent (> 6 months) fear or anxiehidue to presence or anticipation of a specific object or
situation. Person recognizes fear is excessive. Can be treated with systematic desensitization.
Social anxiety disorder exaggerated fear of embarrassment in social situations (eg, public
speaking, using public restrooms). Treatment: CBT, SSRIs, venlafaxine. For only occasional

anxiety-inducing situations, benzodiazepine or P-blocker.


Agoraphobia exaggerated fear of open or enclosed places, using public transportation, being in
line or in crowds, or leaving home alone. Associated with panic disorder. Treatment: CBT, SSRI4

Generalized anxiety
disorder

Anxiety lasting > 6 months unrelated to a specific person, situation, or event. Associated with
restlessness, irritability, sleep disturbance, fatigue, muscle tension, difficulty concentrating.
Treatment: CBT, SSRIs, SNRIs are first line. Buspirone, TCAs, benzodiazepines are second line.
Adjustment disorder emotional symptoms (anxiety, depression) causing impairment following
an identifiable psychosocial stressor (eg, divorce, illness) and lasting < 6 months (> 6 months in
presence of chronic stressor). Treatment: CBT, SSRIs.

Obsessive- compulsive
disorder

Recurring intrusive thoughts, feelings, or sensations ( obsessions) that cause severe distress;
relieved in part by the performance of repetitive actions (compulsions). Ego-dystonic : behavior
inconsistent with ones own beliefs and attitudes (vs obsessive-compulsive personality disorder).
Associated with Tourette syndrome. Treatment : CBT, SSRIs, and clomipramine are first line.
Body dysmorphic disorder preoccupation with minor or imagined defect in appearance
significant emotional distress or impaired functioning; patients often repeatedly seek cosmetic
treatment. Treatment: CBT.

Post- traumatic stress


disorder

Exposure to prior trauma (eg, witnessing death, experiencing serious injury or rape) -* persistent
Hyperarousal Avoidance of associated stimuli, intrusive Reexperiencing of the event ( nightmares,
flashbacks), changes in cognition or mood (fear, horror Distress! Disturbance lasts > 1 month

with significant distress or impaired social-occupational functioning. Treatment: CBT, SSRIs, and
venlafaxine are first line. Having PTSD is HARD!
Acute stress disorder lasts between 3 days and 1 month. Treatment: CBT; pharmacotherapy is
usually not indicated.

532

SECTION III

PSYCHIATRY

PSYCHIATRY

PATHOLOGY

DSM -5 Timinq Criteria


DISORDER

DURATION OF SYMPTOMS FOR DIAGNOSIS

Brief psychotic
disorder

< 1 month

Schizophreniform

1-6 months

disorder
Schizophrenia

Schizoaffective
disorder

> 6 months
> 2 weeks

Maior depressive
disorder

> 2 weeks

Patholoqic qrief

> 6 months
> 2 weeks

Dysthvmia ,
cyclothymia

Delusional disorder
Generalized anxiety
disorder

> 1 month
> 6 months

Separation anxiety

disorder
Adjustment disorder

< 6 months
(> 6 months if presence of chronic stressor )

Acute stress disorder

3 days-1 month

PTSD

> 1 month

Malingering

Patient consciously fakes, profoundly exaggerates, or claims to have a disorder in order to attain a
specific 2 (external ) gain (eg, avoiding work , obtaining compensation ). Poor compliance with
treatment or follow-up of diagnostic tests. Complaints cease after gain (vs factitious disorder).

Factitious disorders

Patient consciously creates physical and/or psychological symptoms in order to assume sick role
and to set medical attention and sympathy (1 [ internal! gain ).

Factitious disorder
imposed on self
( Munchausen
syndrome)

Chronic factitious disorder with predominantly physical signs and symptoms. Characterized by
a history of multiple hospital admissions and willingness to undergo invasive procedures. Often
associated with healthcare worker

Factitious disorder
imposed on another
( Munchausen
syndrome by proxy)

Illness in a child or elderly patient is caused or fabricated by the caregiver. Motivation is to assume
a sick role by proxy. Form of child /elder abuse.

PSYCHIATRY

Somatic symptom and


related disorders
Somatic symptom

disorder

PSYCHIATRY PATHOLOGY

SECTION III

533

Category of disorders characterized by physical symptoms causing significant distress and


impairment . Both illness production and motivation are unconscious drives. Symptoms not
intentionally produced or feigned. More common in women.

Variety of bodily complaints (eg, pain, fatigue) lasting for months to years. Associated with
excessive, persistent thoughts and anxiety about symptoms. May co-occur with medical illness.
Treatment: Regular office visits with the same physician

Conversion disorder
(functional
neurologic symptom
disorder)

Loss of sensory or motor function ( eg, paralysis, blindness, mutism), often following an acute
stressor; patient is aware of but sometimes indifferent toward symptoms ( la belle indifference );
more common in females, adolescents, and young adults.

Illness anxiety
disorder

Excessive preoccupation with acquiring or having a serious illness, often despite medical
evaluation and reassurance; minimal somatic symptoms.

(Hypochondriasis|
]

Pseudocyesis

False, nondelusional belief of being pregnant. May have signs and symptoms of pregnancy but is
not pregnant.

Personality

Personality trait

An enduring, repetitive pattern of perceiving, relating to, and thinking about the environment and

Personality disorder

Inflexible, maladaptive, and rigidly pervasive pattern of behavior causing subjective distress
and/or impaired functioning; person is usually not aware of problem. Usually presents by early
adulthood.
Three clusters, A, B, and C; remember as Weird, Wild, and Worried based on symptoms.

oneself.

Cluster A personality
disorders

Odd or eccentric; inability to develop


meaningful social relationships. No psychosis;
genetic association with schizophrenia.

Weird ( Accusatory, Aloof, Awkward),

Paranoid

Pervasive distrust and suspiciousness; projection


is the major defense mechanism.

Schizoid

Voluntary social withdrawal, limited emotional


expression, content with social isolation (vs
avoidant).

Schizoid = distant,

Schizotypal

Eccentric appearance, odd beliefs or magical


thinking, interpersonal awkwardness.

Schizotypal = magical thinking

534

SECTION III

Cluster B personality
disorders

Antisocial

PSYCHIATRY

PSYCHIATRY

PATHOLOGY
( Bad to the Bone).

Dramatic, emotional , or erratic; genetic


association with mood disorders and substance
abuse.

"Wild

Disregard for and violation of rights of others


with lack of remorse, criminality, impulsivitw

Antisocial = sociopath.

males > females; must be > 18 years old and


have history of conduct disorder before age 15.
Conduct disorder if < 18 years old.
Borderline

Unstable mood and interpersonal relationships,


impulsivity, self-mutilation , suicidality, sense
of emptiness; females > males; splitting is a
major defense mechanism.

Histrionic

Excessive emotionality and excitability,


attention seeking, sexually provocative, overly
concerned with appearance.

Narcissistic

Grandiosity, sense of entitlement ; lacks empathy


and requires excessive admiration ; often
demands the best and reacts to criticism
with rage.

Cluster C personality
disorders
Avoidant

Obsessive-compulsive

Dependent

Anxious or fearful ; genetic association with


anxiety disorders.

Treatment: dialectical behavior therapy.

Worried ( Cowardly, Compulsive, Clingy).

Hypersensitive to rejection , socially inhibited ,


timid , feelings of inadequacy, desires
relationships with others (vs schizoid ).
Preoccupation with order, perfectionism , and
control ; ego-syntonic: behavior consistent with
ones own beliefs and attitudes (vs OCD).
Submissive and cling); excessive need to be
taken care of, low self-confidence.

Patients often get stuck in abusive relationships.

PSYCHIATRY

Eating disorders
Anorexia nervosa

PSYCHIATRY PATHOLOGY

SECTION III

535

Most common in young females. Note that bupropion should be avoided for management of
depression

Excessive dieting, exercise, or binge eating/purging with BMI < 18.5 kg/m2; intense fear of gaining
weight; and distortion or overvaluation of body image. Associated with A bone density, severe
weight loss, metatarsal stress fractures, amenorrhea (due to loss of pulsatile GnRH secretion),
lanugo, anemia, electrolyte disturbances. Commonly coexists with depression. Psychotherapy
and nutritional rehabilitation are first line. Refeeding syndrome ( t insulin hypophosphatemia
-* cardiac complications) can occur in significantly malnourished patients.

Bulimia nervosa

Binge eating with recurrent inappropriate compensatory behaviors (eg, self-induced vomiting,
using laxatives or diuretics, fasting, excessive exercise) occurring weekly for at least 3 months and
overvaluation of body image. Body weight often maintained within normal range. Associated with
parotitis, enamel erosion, electrolyte disturbances ( eg, hypokalemia, hvpochloremui metabolic
alkalosi dorsal hand calluses from induced vomiting ( Russell sign). Treatment: psychotherapy',
nutritional rehabilitation, antidepressants.

Binge eating disorder

Regular episodes of excessive, uncontrollable eating without inappropriate compensatory behaviors,


t risk of diabetes. Treatment: psychotherapy such as CBT is first-line; SSRIs, lisdexamfetaminel

Gender dysphoria

Strong, persistent cross-gender identification that leads to persistent discomfort with sex assigned at
birth, causing significant distress and/or impaired functioning. Transgender individuals may have
gender dysphoric disorder.
Transsexualism desire to live as the opposite sex, often through surgery or hormone treatment.

Transvestism paraphilia, not gender dysphoria. Wearing clothes (eg, vest) of the opposite sex
(cross-dressing).

Sexual dysfunction

Includes sexual desire disorders ( hypoactive sexual desire or sexual aversion), sexual arousal
disorders (erectile dysfunction), orgasmic disorders (anorgasmia, premature ejaculation), sexual
pain disorders (dyspareunia, vaginismus).
Differential diagnosis includes:
Drugs (eg, antihypertensives, neuroleptics, SSRIs, ethanol)
Diseases (eg, depression, diabetes, STIs)
Psychological (eg, performance anxiety)
0

Sleep terror disorder

Periods of terror with screaming in the middle of the night; occurs during slow-wave/deep (stage
N3) sleep. Most common in children . Occurs during non-REM sleep (no memory of arousal )
as opposed to nightmares that occur during REM sleep (memory of a scary dream). Cause
unknown, but triggers include emotional stress, fever, or lack of sleep. Usually self limited.

536

SECTION III

Narcolepsy

Substance use
disorder

PSYCHIATRY

PSYCHIATRY

PATHOLOGY

Disordered regulation of sleep-wake cycles; 1


characteristic is excessive daytime sleepiness
(awaken feeling rested ).
Caused by 1 hypocretin (orexin ) production in
lateral hypothalamus.
Also associated with:
" Hypnagogic ( just before sleep) or
hypnopompic ( just before awakening)
hallucinations.
Nocturnal and narcoleptic sleep episodes
that start with REM sleep ( sleep paralysis!
e Cataplexy loss of all muscle tone following
(
strong emotional stimulus, such as laughter)
in some patients.
Strong genetic component . Treatment: daytime
stimulants (eg, amphetamines, modafinil ) and
nighttime sodium oxybate (GHB).

Hypnagogic going to sleep


Hvpnopompic pompous upon awakening

Maladaptive pattern of substance use defined as 2 or more of the following signs in 1 year related
specifically to substance

uset

Tolerance need more to achieve same effect


Withdrawal
Substance taken in larger amounts, or over longer time, than desired
Persistent desire or unsuccessful attempts to cut down
Significant energy spent obtaining, using, or recovering from substance
Important social, occupational , or recreational activities reduceq
Continued use despite knowing substance causes physical and /or psychological problems
Craving
Recurrent use in physically dangerous situations
Failure to fulfill major obligations at work, school , or homq
Social or interpersonal conflict

Stages of change in
overcoming substance

addiction

1. Precontemplation not yet acknowledging that there is a problem


2. Contemplation acknowledging that there is a problem , but not yet ready or willing to make a
change
3. Preparation /determination getting ready to change behaviors
4. Action/willpower changing behaviors
5. Maintenance maintaining the behavior changes
6. Relapse returning to old behaviors and abandoning new changes

538

SECTION III

PSYCHIATRY

PSYCHIATRY

PATHOLOGY

Psychoactive drug intoxication and withdrawal ( continued )


DRUG

INTOXICATION

WITHDRAWAL

Hallucinogens
Phencyclidine ( PCP,

anqel

dustil

Lysergic acid
diethylamide ( LSD|
)

Marijuana
(cannabinoid )

Violence, impulsivity, psychomotor agitation ,


nystagmus, tachycardia , hypertension ,
analgesia , psychosis, delirium , seizures.
Trauma is most common complication.
Treatment: benzodiazepines, rapid-acting
antipsychotic.
Perceptual distortion (visual, auditory),
depersonalization, anxiety, paranoia ,
psychosis, possible flashbacks.
Irritability, anxiety, depression, insomnia ,
Euphoria , anxiety, paranoid delusions,
restlessness, 1 appetite. Generally detectable in
perception of slowed time, impaired judgment,
social withdrawal, t appetite, dry mouth,
urine for up to 1 month
conjunctival injection, hallucinations.
Pharmaceutical form is dronabinol
( tetrahydrocannabinol isomer): used as
antiemetic (chemotherapy) and appetite
stimulant ( in AIDS).
Hallucinogenic stimulant: euphoria ,
Depression , fatigue, change in appetite, difficulty
concentrating, anxiety
disinhibition , hy peractivity, distorted sensory
and time perception , teeth clenching Lifethreatening effects include hypertension ,
tachycardia , hyperthermia , hyponatremia ,
serotonin syndrome.
,

MDMA (ecstasy )

Heroin addiction

Users at t risk for hepatitis, HIV, abscesses, bacteremia , right-heart endocarditis. Treatment is
described below.

Methadone

Long-acting oral opiate used for heroin detoxification or long-term maintenance.

Naloxone +
buprenorphine

Antagonist + partial agonist. Naloxone is not orally bioavailable, so withdrawal symptoms occur
only if injected (lower abuse potential ).

Naltrexone

Long-acting opioid antagonist used for relapse prevention once detoxified .

Alcoholism

Wernicke- Korsakoff
syndrome

Physiologic tolerance and dependence with symptoms of withdrawal ( tremor, tachycardia ,


hypertension , malaise, nausea , DTs) when intake is interrupted .
Complications: alcoholic cirrhosis, hepatitis, pancreatitis, peripheral neuropathy, testicular atrophy.
Treatment: disulfiram ( to condition the patient to abstain from alcohol use), acamprosate,
naltrexone, supportive care. Support groups such as Alcoholics Anonymous are helpful in
sustaining abstinence and supporting patient and family.
Caused by vitamin Bj (thiamine) deficiency. Triad of confusion , ophthalmoplegia , ataxia ( Wernicke
encephalopathy ). May progress to irreversible memory loss, confabulation , personality change
( Korsakoff syndrome) . Associated with periventricular hemorrhage /necrosis of mammillary
bodies. Treatment: IV vitamin Bj .

PSYCHIATRY

Delirium tremens

PSYCHIATRY

PHARMACOLOGY

SECTION III

539

Life-threatening alcohol withdrawal syndrome that peaks 2-4 days after last drink .
Characterized by autonomic hyperactivity (eg, tachycardia, tremors, anxiety, seizures). Classically
occurs in hospital setting (eg, 2-4 days postsurgery) in alcoholics not able to drink as inpatients.
Treatment: benzodiazepines ( eg, chlordiazepoxide, lorazepam , diazepam
Alcoholic hallucinosis is a distinct condition characterized by visual hallucinations 12-48 hours after
last drink . Treatment: benzodiazepines (eg, chlordiazepoxide, lorazepam , diazepam ).

PSYCHIATRY

PHARMACOLOGY

Preferred medications
for selected
psychiatric conditions

PSYCHIATRIC CONDITION

PREFERRED DRUGS

ADHD

Stimulants ( methylphenidate, amphetamines)

Alcohol withdrawal

Bipolar disorder

Benzodiazepines (eg, chlordiazepoxide,


lorazepam, diazepam )
Lithium , valproic acid , carbamazepine,

Bulimia nervosa

SSRIs

Depression

SSRIs

Generalized anxiety disorder


Obsessive-compulsive disorder

SSRIs, SNRIs
SSRIs, venlafaxine, clomipramine

Panic disorder

SSRIs, venlafaxine, benzodiazepines

PTSD

SSRIs, venlafaxine
Atypical antipsychotics
SSRIs, venlafaxine
Performance only: P-blockers, benzodiazepines
Antipsychotics (eg, fluphenazine, pimozide),

lamotrigine, aty pical antipsychotics

Schizophrenia
Social anxiety disorder
Tourette syndrome

tetrabenazine

Central nervous system! Methylphenidate, dextroamphetamine, methamphetamine .


stimulants
MECHANISM

t catecholamines in the synaptic cleft , especially norepinephrine and dopamine.

CLINICAL USE

ADHD, narcolepsy, appetite control.

ADVERSE EFFECTS

Nervousness, agitation , anxiety, insomnia , anorexia , tachycardia , hypertension .

540

SECTION III

Antipsychotics
( neuroleptics )
MECHANISM

CLINICAL USE

PSYCHIATRY

PSYCHIATRY

PHARMACOLOGY

Haloperidol , pimozide , trifluoperazine , fluphenazine , thioridazine, chlorpromazinej

All typical antipsychotics block dopamine D2


receptors ( t [cAMP] ).
Schizophrenia ( primarily positive symptoms),
psychosis , bipolar disorder, delirium , Tourette
Highly lipid soluble and stored in body fat; thus,
very slow to be removed from body.
Extrapvramidal system side effects (eg,
dyskinesias). Treatment: benztropine,
diphenhydramine , benzodiazepines.

Endocrine side effects (veg, dopamine


v
receptor antagonism hyperprolactinemia

galactorrhea , oligomenorrhea .

gynecomastia ) .
Side effects arising from blocking muscarinic
(dry mouth , constipation ), a (orthostatic
hypotension ), and histamine (sedation)
tors
Can cause QT prolongation .
OTHER TOXICITIES

'

Low potency: Chlorpromazine , Thioridazine


(Cheating Thieves are low) non-neurologic
side effects (anticholinergic, antihistamine, and

arblockade effects).
Chlorpromazine - Comeal deposits;
.
. .
.
.1
rmal, ,
rrllnoridazine
reI
I

deposit

Onset of EPS: ADAP 1


* Hours to da> s: Acute Dystonia (muscle
sPasm stiffness oculyric crisis)
* Da >s to months: Akathisia (restlessness) and
Parkinsonism ( bradykinesia ) .
" Months to years: Tardive dyskinesia
For NMS> think FEVER :

Fever

Neuroleptic malignant syndrome ( NMS)


rigidity, myoglobinuria , autonomic instability,
,
hyperpyrexia Treatment: dantrolene, D
agonists (eg. bromocriptme).

Encephalopathy
\ jt fls unstable

Enzymes

Tardive dyskinesia orofacial chorea as a result


of long-term antipsychotic use .

Atypical
antipsychotics

Haloperidol NMS, tardive dy skinesia .

syndrome, Huntington disease , OCD.


ADVERSE EFFECTS

High potency: Trifluoperazine , Fluphenazine ,


Haloperidol ( Try to Fly High) neurologic
s dc c ec s
extrapyramidal symptoms

of muscles

Aripiprazole , asenapine , clozapine , olanzapine , quetiapine , iloperidone , paliperidone , lurasidone,

risperidoneT ziprasidonej

MECHANISM

Not completely understood . Most are D?


antagonists; aripiprazole is D-, partial agonist .
Varied effects on 5 -HT2, dopamine, and
a- and Hj-receptors.

CLINICAL USE

Schizophrenia both positive and negative

Also used for bipolar disorder,


OCD, anxiety disorder, depression , mania ,

symptoms .

Use clozapine for treatment-resistant


schizophrenia .

Tourette syndrome .
ADVERSE EFFECTS

All prolonged QT interval , fewer EPS and


anticholinergic side effects than typical
antipsychotics.
- pines metabolic syndrome (weight gain ,
diabetes , hyperlipidemia ).

Clozapine agranulocytosis ( monitor WBC


w eekly) and seizures ( dose-relatedl) .

Risperidone hyperprolactinemia (amenorrhea ,


galactorrhea , gynecomastia ).

Olanzapine

Obesity

Must watch bone marrow clozely with clozapine

PSYCHIATRY

PSYCHIATRY

PHARMACOLOGY

SECTION III

541

Lithium
MECHANISM

Not established; possibly related to inhibition of


phosphoinositol cascade.

CLINICAL USE

Mood stabilizer for bipolar disorder; blocks


relapse and acute manic events.

ADVERSE EFFECTS

Tremor, hypothyroidism, polyuria (causes


nephrogenic diabetes insipidus), teratogenesis.
Causes Ebstein anomaly in newborn if taken
by pregnant mother. Narrow therapeutic
window requires close monitoring of serum
levels. Almost exclusively excreted by kidneys;
most is reabsorbed at PCT with Na+. Thiazide
use is implicated in lithium toxicity in bipolar
patients.

LiTHIUM:
Low Thyroid ( hypothyroidism )
Heart ( Ebstein anomaly)
Insipidus ( nephrogenic diabetes insipidus )
Unwanted Movements ( tremor)

Buspirone
MECHANISM

Stimulates 5- HTJ A receptors.

CLINICAL USE

Generalized anxiety disorder. Does not cause


sedation , addiction, or tolerance. Takes 1-2
weeks to take effect. Does not interact with
alcohol (vs barbiturates, benzodiazepines).

Im always anxious if the bus will be on time, so


buspirone.

Antidepressants
SEROTONERGIC

NORADRENERGIC
AXON

AXON
MAO inhibitors .
Metabolites

MAO

MAO

Metabolites

Bupropion

oc

V*

Oi 2 ( autoreceptor )

TCAs, SNRIs

adrenergic

receptor

/
1

Mirtazapme

NE reuptake

5- HT

:>
'

V 5-HT reuptake k

^o

&S
NE receptor

POSTSYNAPTIC NEURON

-o-

TCAs SSRis,
SNRIs, trazodone

542

SECTION III

Selective serotonin
reuptake inhibitors

PSYCHIATRY

PSYCHIATRY PHARMACOLOGY

Fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopramll

MECHANISM

5-HT-specific reuptake inhibitors.

CLINICAL USE

Depression, generalized anxiety disorder,


panic disorder, OCD, bulimia, social anxiety
disorder, PTSD, premature ejaculation,
premenstrual dysphoric disorder.

ADVERSE EFFECTS

Fewer than TCAs. GI distress, SIADH, sexual


dysfunction (anorgasmia, 1 libido).

Serotonin-

It normally takes 4-8 weeks for antidepressants


have an effect,

Venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran.

norepinephrine
reuptake inhibitors
MECHANISM

Inhibit 5 -HT and norepinephrine reuptake.

CLINICAL USE

Depression, general anxiety disorder, diabetic neuropathy. Venlafaxine is also indicated for social
anxiety disorder, panic disorder, PTSD, OCD. Duloxetine is also indicated for fibromyalgia!

ADVERSE EFFECTS

t BP most common; also stimulant effects, sedation, nausea._


Serotonin syndrome Can occur with any drug that t 5 -HT (eg, MAOIs, SSRIs, SNRIs, TCAs,
tramadol, ondansetron, triptans). Characterized by 3 As: neuromuscular hvperActivity (clonus,
hyperreflexia, hypertonia, tremor, seizure) Autonomic stimulation (hyperthermia, diaphoresis,
diarrhea), and Agitation. Treatment: cyproheptadine ( 5 -HT, receptor antagonist).

Tricyclic
antidepressants

Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin, amoxapine.

MECHANISM

Block reuptake of norepinephrine and 5-HT.

CLINICAL USE

Major depression, OCD (clomipramine), peripheral neuropathy, chronic pain, migraine


prophylaxis. Nocturnal enuresis (imipraminej

ADVERSE EFFECTS

Sedation, (Xj-blocking effects including postural hypotension, and atropine-like (anticholinergic)


side effects (tachycardia, urinary retention, dry mouth). 3 TCAs (amitriptyline) have more
anticholinergic effects than 2 TCAs (nortriptyline). Can prolong QT interval.
Tri-Cs: Convulsions, Coma, Cardiotoxicity (arrhythmia due to Na+ channel inhibition);
also respiratory depression, hyperpyrexia. Confusion and hallucinations in elderly due to
anticholinergic side effects (nortriptyline better tolerated in the elderl . Treatment: NaHCO, to
prevent arrhythmia.

PSYCHIATRY

Monoamine oxidase
inhibitors
MECHANISM

PSYCHIATRY PHARMACOLOGY

SECTION III

543

Tranylcypromine, Phenelzine, Isocarboxazid, Selegiline (selective MAO-B inhibitor).


(MAO Takes Pride In Shanghai).

Nonselective MAO inhibition t levels of amine neurotransmitters (norepinephrine, 5 -HT,


dopamine).

CLINICAL USE

Atypical depression, anxiety. Parkinson disease (Selegiline!

ADVERSE EFFECTS

Hypertensive crisis (most notably with ingestion of tyramine, which is found in many foods such
as aged cheese and wine); CNS stimulation. Contraindicated with SSRIs, TCAs, St. Johns wort,
meperidine, dextromethorphan (to prevent serotonin syndrome).
Wait 2 weeks after stopping MAO inhibitors before starting serotonergic drugs or stopping dietary
restrictions.

Atypical antidepressants
Bupropion

t norepinephrine and dopamine via unknown mechanism. Also used for smoking cessation.
Known to cause weight losi Toxicity: stimulant effects (tachycardia, insomnia), headache,
seizures in anorexic /bulimic patients. May help alleviate sexual dvsfunctioli

Mirtazapine

a-,-antagonist (t release of NE and 5-HT), potent 5-HT? and 5 -HT5 receptor antagonist and Hj
antagonist. Toxicity: sedation ( which may be desirable in depressed patients with insomnia),
t appetite, yveight gain (yvhich may be desirable in elderly or anorexic patients), dry mouth.

Trazodone

Primarily blocks 5 -HT-,, apadrenergic, and H receptors; also weakly inhibits 5 -HT reuptake. Used
primarily for insomnia, as high doses are needed for antidepressant effects. Toxicity: sedation,
nausea, priapism, postural hypotension. Called traZZZobone due to sedative and male-specific

side effects.
Varenicline

Tyramine

Nicotinic ACh receptor partial agonist. Used for smoking cessation. Toxicity: sleep disturbance.

Normally degraded by monoamine oxidase (MAO). Levels t in patients

taking MAO inhibitors


who ingest tyramine-rich foods (eg, cheese, yvine). Excess tyramine enters presvnaptic vesicles and
displaces other neurotransmitters (eg, NE) t active presvnaptic neurotransmitters -* t diffusion
of neurotransmitters into synaptic cleft t sympathetic stimulation. Classically results in a
hypertensive crisis (treatment: phentolamine).

Placement of "Tyramine ' fact here OK ? Added per


comment ("pis delete Tyramine Fact here, moving
to Psych chapter") on page 243 in Pharmacology
1

chapter.

HIGH- YI E LD SYSTEMS

Renal

But I know all about love already. 1 know precious little still about

Embryology

546

Anatomy

547

Physiology

549

Pathology

560

Pharmacology

572

kidneys."

Aldous Huxley, Antic Hay


This too shall pass. Just like a kidney stone."

Hunter Madsen

I drink too much. The last time I gave a urine sample it had an olive

in it.

Rodney Dangerfield

545

RENAL

RENAL

as
II
11

SECTION III

549

HIKIN': High K+ INtracellularly.

Body mass: 70 kg
X Non water mass (NWM) 1

Total body water (TBW )


60% of body mass = 42 kg = 42 L

60-40-20 rule (% of body weight for average


person ):
60% total body water
40% ICF
20% ECF
Plasma volume can be measured by

40% of body mass * 28 kg

Interstitial fluid
fit
75% ECF 10.5 L 10.5 kg

ss

radiolabeling albumin .
Extracellular volume can be measured by inulin
or mannitol .
Osmolality = 285-295 mOsm /kg H ^ O.

2/ 3

PHYSIOLOGY

PHYSIOLOGY

Fluid compartments

1/ 3

RENAL

85
Ij

Is

Normal HCT = 45%

HCT (%) ~ 3 x|Hbl in g/dL

Glomerular filtration
barrier

:
if
Renal clearance

Responsible for filtration of plasma according to


size and charge selectivity

Composed of:
e Fenestrated capillary endothelium (size
barrier)
Fused basement membrane with heparan
sulfate ( negative charge and size barrier)
Epithelial layer consisting of podocvte foot
processes Q ( negative charge barrier)

Charge barrier is lost in nephrotic syndrome


-* albuminuria , hypoproteinemia, generalized
edema , hyperlipidemia .

Cx = UXV/PX = volume of plasma from which the Cx = clearance of X (mL/min).


substance is completely cleared per unit time.
Ux = urine concentration of X (eg, mg/mL).
If Cx < GFR: net tubular reabsorption of X.
Px = plasma concentration of X (eg, mg/mL).
V = urine flow rate ( mL /min ).
If Cx > GFR: net tubular secretion of X.
If Cx = GFR: no net secretion or reabsorption .

RENAL PHYSIOLOGY

RENAL

Filtration fraction ( FF) = GFR / RPF.


Normal FF = 20% .
Filtered load (mg/min) = GFR (mL/min )
x plasma concentration ( mg/mL).

Filtration

NSAIDs I

Prostaglandins preferentially
dilate afferent arteriole
( T RPF, T GFR, so noAFF)

551

SECTION III

GFR can be estimated with creatinine

clearance.
RPF is best estimated with PAH clearance .

Parietal layer of
Bowman capsule

ocuNmaf1 s space

Juxtaglomerular
cel :

PS

* "

"

Macula densa

Excreted

Filtered

rP
Reabsorbed

Distal renal
Mb - e

Secreted
iecreie
Peritubular
'- capillary

Net filtration pressure


Endothelia ce Is

PK + 7tas ) - (PBS + Tt^ )

Basement

Mesangial
c e .l:

membrane

Cerent arteriole
Angiotensin II preferentially

ACE inhibitors

OH

constricts efferent arteriole


(4 RPF, T GFR, so T FF)

Changes in glomerular dynamics

Effect
Afferent arteriole constriction
Efferent arteriole constriction
t plasma protein concentration
i plasma protein concentration
Constriction of ureter
Dehydration

Calculation of

reabsorption and
secretion rate

GFR

RPF

l
t
i
t
i
i

1
l

Filtered load = GFR x .


Excretion rate = V x Ux.
Reabsorption rate|= filtered - excreted .
Secretion rate|= excreted filtered .

Px

FENa = Na+ excreted/Na + filtered = V X UNa /GFR x PNa (GFR = UCr X V/PCr) =
PCr X UNi/UCr X FNa

FF (GFR/ RPF )

t
t
t
1
t

554

SECTION III

Renal tubular defects


Fanconi syndrome

RENAL

RENAL

PHYSIOLOGY

Fanconi syndrome is first ( PCT ), the rest are in alphabetic order.

Generalized reabsorptive defect in PCT.


_
Associated with t excretion of nearly all amino acids, glucose, HCCX-, and PO . May result in
metabolic acidosis ( proximal renal tubular acidosis).
Causes include hereditary defects (eg, Wilson disease, tyrosinemia , glycogen storage disease,
cystinosis), ischemia, multiple myeloma , nephrotoxins/drugs (eg, ifosfamide, cisplatin, tenofovir,
expired tetracyclines), lead poisoning.

Bartter syndrome

Reabsorptive defect in thick ascending loop of Henle . Affects Nai/ Ki/ 2C1- cotransporter. Results
in hypokalemia and metabolic alkalosis with hypercalciuria. Presents similarly to chronic loop

Gitelman syndrome

Reabsorptive defect of NaCl in DCT. Leads to hypokalemia, hypomagnesemia, metabolic


alkalosis, hvpocalciuria. Similar to using lifelong thiazide diuretics. Autosomal recessive. Less
severe than Bartter syndrome]

Liddle syndrome

Gain of function mutation


t Na+ reabsorption in collecting tubules ( t activity of epithelial Na+
channel ). Presents like hyperaldosteronism , but aldosterone is nearly undetectable.
Autosomal dominant . Results in hypertension , hypokalemia , metabolic alkalosis, i aldosterone.

diuretic use. Autosomal recessive

Treatment: Amiloride.
Syndrome of
Apparent
Mineralocorticoid
Excess

Hereditary deficiency of HP-hydroxysteroid dehydrogenase, which normally converts cortisol (can


activate mineralocorticoid receptors) to cortisone (inactive on mineralocorticoid receptors ) in cells
containing mineralocorticoid receptors. Excess cortisol in these cells from enzyme deficiency
t mineralocorticoid receptor activity -* hypertension, hypokalemia , metabolic alkalosis. Low
serum aldosterone levels. Can acquire disorder from glycvrrhetinic acid ( present in licorice),
which blocks activity of llp-hydroxysteroid dehydrogenase.
Treatment: corticosteroids (exogenous corticosteroids 1 endogenous cortisol production
1 mineralocorticoid receptor activation ).
Cortisol tries to be the SAME as aldosterone.

558

SECTION III

Potassium shifts

RENAL

RENAL

PHYSIOLOGY

SHIFTS K + OUT OF CELL (CAUSING HYPERKALEMIA )

SHIFTS

Digitalis ( blocks Na + / K+ ATPase)


HyperOsmolarity
Lysis of cells (eg, crush injury, rhabdomyolysis,
tumor lysis syndrome)
Acidosis
P-blocker

r INTO CELL (CAUSING HYPOKALEMIA )

Hypo-osmolarity

Alkalosis

p-adrenergic agonist ( t Na+/K+ ATPase)

Patient with hyperkalemia? DO LApSj

Insulin ( t Na+ / K+ ATPase)


Insulin shifts K+ into cells

ELECTROLYTE

LOW SERUM CONCENTRATION

HIGH SERUM CONCENTRATION

Na +

Nausea and malaise, stupor, coma , seizures

Irritability, stupor, coma

K*

U waves and flattened T waves on ECG ,


arrhythmias, muscle cramps, spasm , weakness

Wide QRS and peaked T waves on ECG,


arrhythmias, muscle weakness

Ca 2+

Tetany, seizures, QT prolongation , twitching


(Chvostek sign ), spasm ( Trousseau sign )

Stones (renal ), bones ( pain ), groans (abdominal


pain), thrones ( t urinary frequency), psychiatric
overtones (anxiety, altered mental status), but
not necessarily calciuria

Mg2+

Tetanv, torsades de pointes, hypokalemia ,


hypocalcemia (when [ Mg 1 < 1.2 mg/dLi
Bone loss, osteomalacia (adults), rickets
(children )

1 DTRs, lethargy, bradycardia, hypotension ,


cardiac arrest , hypocalcemia

High blood Sugar ( insulin deficiency)

Electrolyte disturbances

43-

PO

Renal stones, metastatic calcifications,

hypocalcemia

Features of renal disorders


CONDITION

BLOOD PRESSURE

PLASMA RENIN

ALDOSTERONE

SERUM Mg2+

URINE Ca 2+

Bartter syndrome
Gitelman syndrome

t
t

t
t

Liddle syndrome

SIADH

Primary
hyperaldosteronism
(Conn syndrome)

Ji

II

Renin secreting tumor

562

SECTION III

Nephritic syndrome

RENAL

RENAL PATHOLOGY

Nephritic syndrome = Inflammatory process. When it involves glomeruli, it leads to hematuria


and RBC casts in urine. Associated with azotemia, oliguria, hypertension (due to salt retention),
proteinuria.

Acute
poststreptococcal
glomerulonephritis

LM glomeruli enlarged and hypercellular Q.


IF (starry sky) granular appearance
( lumpy-bumpy) due to IgG, IgM, and C 3
deposition along GBM and mesangium.
EM subepithelial immune complex (IC )
humps.

Most frequently seen in children. Occurs


~ 2-4 weeks after group A streptococcal
infection of pharynx or skin. Resolves
spontaneously. Type III hypersensitivityreaction.
Presents with peripheral and periorbital edema,
cola-colored urine, hypertension.
Positive strep titers/serologies, i complement
levels (C3) due to consumption

Rapidly progressive
(crescentic)
glomerulonephritis

LM and IF crescent moon shape Q. Crescents


consist of fibrin and plasma proteins (eg, C 3b)
with glomerular parietal cells, monocytes,
macrophages.
Several disease processes may result in this
pattern, in particular:
u
Goodpasture syndrome type II
hypersensitivity reactioij antibodies to
GBM and alveolar basement membrane

Poor prognosis. Rapidly deteriorating renal


function (days to weeks).

JinearjF

Granulomatosis with polyangiitis (Wegener)


Microscopic ijplyangiitis

Diffuse proliferative

glomerulonephritis

IgA nephropathy
(Berger disease)

Hematuria/hemoptysis.
Treatment: emergent plasmapheresis.

PR 3-ANCA/c-ANCA. Pauci-immune (no Ig/C3


deposition).
MPO-ANCA /p-ANCA. Pauci-immune (no Ig/C3
deposition).

Due to SLE or membranoproliferative


glomerulonephr itis.
LM wire looping of capillaries.
EM subendothelial and sometimes
intramembranous IgG-based ICs often with
C3 deposition.
IF granular.

A common cause of death in SLE (think wire


lupus ). DPGN and MPGN often present as
nephrotic syndrome and nephritic syndrome

LM mesangial proliferation.
EM mesangial IC deposits.
IF IgA-based IC deposits in mesangium.
Renal pathology of Henoeh-Schonlein purpura.

Episodic gross hematuria that occurs


concurrently with respiratory or GI tract
infections (IgA is secreted by mucosal linings).
Not to be confused with Buerger disease
(thromboangiitis obliterans).

concurrently.

562

SECTION III

Nephritic syndrome

RENAL

RENAL PATHOLOGY

Nephritic syndrome = Inflammatory process. When it involves glomeruli, it leads to hematuria


and RBC casts in urine. Associated with azotemia, oliguria, hypertension (due to salt retention),
proteinuria.

Acute
poststreptococcal
glomerulonephritis

LM glomeruli enlarged and hypercellular Q.


IF (starry sky) granular appearance
( lumpy-bumpy) due to IgG, IgM, and C 3
deposition along GBM and mesangium.
EM subepithelial immune complex (IC )
humps.

Most frequently seen in children. Occurs


~ 2-4 weeks after group A streptococcal
infection of pharynx or skin. Resolves
spontaneously. Type III hypersensitivityreaction.
Presents with peripheral and periorbital edema,
cola-colored urine, hypertension.
Positive strep titers/serologies, i complement
levels (C3) due to consumption

Rapidly progressive
(crescentic)
glomerulonephritis

LM and IF crescent moon shape Q. Crescents


consist of fibrin and plasma proteins (eg, C 3b)
with glomerular parietal cells, monocytes,
macrophages.
Several disease processes may result in this
pattern, in particular:
u
Goodpasture syndrome type II
hypersensitivity reactioij antibodies to
GBM and alveolar basement membrane

Poor prognosis. Rapidly deteriorating renal


function (days to weeks).

JinearjF

Granulomatosis with polyangiitis (Wegener)


Microscopic ijplyangiitis

Diffuse proliferative

glomerulonephritis

IgA nephropathy
(Berger disease)

Hematuria/hemoptysis.
Treatment: emergent plasmapheresis.

PR 3-ANCA/c-ANCA. Pauci-immune (no Ig/C3


deposition).
MPO-ANCA /p-ANCA. Pauci-immune (no Ig/C3
deposition).

Due to SLE or membranoproliferative


glomerulonephr itis.
LM wire looping of capillaries.
EM subendothelial and sometimes
intramembranous IgG-based ICs often with
C3 deposition.
IF granular.

A common cause of death in SLE (think wire


lupus ). DPGN and MPGN often present as
nephrotic syndrome and nephritic syndrome

LM mesangial proliferation.
EM mesangial IC deposits.
IF IgA-based IC deposits in mesangium.
Renal pathology of Henoeh-Schonlein purpura.

Episodic gross hematuria that occurs


concurrently with respiratory or GI tract
infections (IgA is secreted by mucosal linings).
Not to be confused with Buerger disease
(thromboangiitis obliterans).

concurrently.

564

SECTION III

Nephrotic syndrome

RENAL

RENAL PATHOLOGY

NephrOtic syndrome massive prOteinuria (> 3.5 g/day) with hypoalbuminemia , resulting
edema , hyperlipidemia. Frothy urine with fatty casts. Due to podocyte damage disrupting
glomerular filtration charge barrier. May be 1 (eg, direct sclerosis of podocytes) or 2 (systemic
process [eg, diabetes) secondarily damages podocytes). Associated with hypercoagulable state (eg,
thromboembolism ) due to antithrombin ( AT) III loss in urine and t risk of infection (due to loss of
immunoglobulins in urine and soft tissue compromise by edema ).
Severe nephritic syndrome may present with nephrotic syndrome features (nephritic-nephrotic
syndrome) if damage to GBM is severe enough to damage charge barrier.

Minimal change
disease ( lipoid
nephrosis)

LM normal glomeruli ( lipid may be seen in


PCT cells).
IF .
EM effacement of foot processes Q.

Focal segmental
glomerulosclerosis

Most common cause of nephrotic syndrome in


LM segmental sclerosis and hvalinosis Q.
IF often , but may be for nonspecific focal African Americans and Hispanics. Can be 1
deposits of IgM, C3, Cl
( idiopathic ) or 2 to other conditions (eg, HIV7
infection, sickle cell disease, heroin abuse,
EM effacement of foot process similar to
massive obesity, interferon treatment , chronic
minimal change disease.
kidney disease due to congenital malformations).
1 disease has inconsistent response to steroids.
May progress to chronic renal disease.
LM diffuse capillary and GBM thickening Q. Most common cause of 1 nephrotic syndrome
IF granular as a result of immune complex
in Caucasian adults. Can be 1 (eg, antibodies
to phospholipase A7 receptor) or 2 to drugs
deposition. Nephrotic presentation of SLE .
(eg, NSAIDs, penicillamine, gold ), infections
EM spike and dome appearance with
(eg, HBV, I ICV, syphilis SLE , or solid tumors.
subepithelial deposits.
1 disease has poor response to steroids. May
progress to chronic renal disease.
Kidney is the most commonly involved organ
LM Congo red stain shows apple-green
(systemic amyloidosis). Associated with
birefringence under polarized light due to
chronic conditions that predispose to amyloid
amyloid deposition in the mesangium .
deposition (eg, AL amyloid , AA amyloid ).
LM mesangial expansion , GBM thickening, Nonenzyinatic glycosylation of GBM
- t permeability, thickening.
eosinophilic nodular glomerulosclerosis
( Kimmelstiel -Wilson lesions, arrows in Q).
Nonenzyinatic glycosylation of efferent arterioles
( hyaline arteriosclerosis )
t GFR mesangial
expansion .
Most common cause of end -stage renal disease in
the United States.

Membranous
nephropathy
( membranous
glomerulonephritis)

Most common cause of nephrotic syndrome


in children . Often 1 (idiopathic) and may be
triggered by recent infection , immunization,
immune stimulus. Rarely, may be 2 to
lymphoma (eg, cytokine-mediated damage). 1
disease has excellent response to corticosteroids.

Amyloidosis

Diabetic glomerulo nephropathy

rv

JI
r-

V:

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&

Vr

nmmssmiife:<
*.

v4 ,

jtw

566

SECTION III

Hydronephrosis

Renal cell carcinoma

RENAL

RENAL PATHOLOGY

Distention/dilation of renal pelvis and calyces Q. Usually caused by urinary tract obstruction (eg,
renal stones, BPH, cervical cancer, injury to ureter); other causes include retroperitoneal fibrosis,
vesicoureteral reflux. Dilation occurs proximal to site of pathology. Serum creatinine becomes
elevated only if obstruction is bilateral or if patient has only one kidney. Leads to compression and
possible atrophy of renal cortex and medulla.

Originates from PCT cells polygonal clear


cells Q filled with accumulated lipids and
carbohydrates. Often golden-yellow [] due to
t lipid content. Most common in men 50-70
years old. t incidence with smoking and
obesity. Manifests clinically with hematuria,
palpable mass, 2 polycythemia, flank pain,
fever, weight loss. Invades renal vein (may
develop varicocele if left sided ) then IVCjand
spreads hematogenouslv; metastasizes to lung
and bone.
Treatment: resection if localized disease.
Immunotherapy (eg, aldesleukin) or targeted
therapy for advanced/metastatic disease.
Resistant to chemotherapy and radiation
therapy.

Most common 1 renal malignancy Q.


Associated with gene deletion on chromosome
5 (sporadic or inherited as von Hippel-Lindau
syndrome). RCC = 3 letters = chromosome 3.
Associated with paraneoplastic syndromes (eg,
ectopic EPO, ACTH, PTHrP, renin).
Silent cancer because commonly presents as a
metastatic neoplasm.

:
*

SS;a
Renal oncocytoma

P5

M
J

Benign epithelial cell tumor arising from


collecting ducts (arrows in Q point to wellcircumscribed mass with central scar).
Large eosinophilic cells with abundant
mitochondria without perinuclear clearing
O (vs chromophobe renal cell carcinoma).
Presents with painless hematuria, flank pain,

abdominal mass.
Often resected to exclude malignancy (eg, renal
cell carcinoma).

m- n

RENAL

Nephroblastoma
( Wilms tumor ) j

>r .

RENAL

PATHOLOGY

SECTION III

567

Most common renal malignancy of early childhood (ages 2-4). Contains embryonic glomerular
structures. Presents with large, palpable, unilateral flank mass Q and/or hematuria.
Loss of function mutations of tumor suppressor genes WTl or WT2 on chromosome 11 .
May be a part of several syndromes:
WAGR complex: Wilms tumor, Aniridia (absence of iris), Genitourinary malformations, mental
Retardation /intellectual disability (WTl deletion )
* Denys-Drash : Wilms tumor, early- onset nephrotic syndrome, male pseudohermaphroditism
( WTl mutation )
Beckwith Wiedemann: Wilms tumor, macroglossia , organomegaly, hemihyperplasiaj ( WT2
mutation)

Transitional cell
carcinoma

Most common tumor of urinary tract system


(can occur in renal calyces, renal pelvis,
ureters, and bladder) Q EDI Painless hematuria
( no casts) suggests bladder cancer.
Associated with problems in your Pee SAC:
Phenacetin , Smoking, Aniline dyes, and
Cyclophosphamide.

m
Squamous cell
carcinoma of the

bladder

pillary turn
\ .* # ' * <&

i in

: ** *

mm

S.'J*

tic urothelium ..

Chronic irritation of urinary bladder - squamous metaplasia dysplasia and squamous cell
carcinoma.
Risk factors include Schistosoma haematobium infection ( Middle East), chronic cystitis, smoking,
chronic nephrolithiasis. Presents with painless hematuria .

Urinary incontinence

Stress incontinence

Outlet incompetence ( urethral hypermobility or intrinsic sphincteric deficiency) - leak with


t intra-abdominal pressure (eg, sneezing, lifting) t risk with obesity, vaginal delivery, prostate
surgery. bladder stress test (directly observed leakage from urethra upon coughing or Valsalva
maneuver). Treatment: pelvic floor muscle strengthening ( Kegel ) exercises, weight loss, pessaries.
Overactive bladder (detrusor instability) -* leak with urge to void immediately. Treatment: Kegel
exercises, bladder training (timed voiding, distraction or relaxation techniques), antimuscarinics
(eg, oxybutynin).
Features of both stress and urgency incontinence.
,

Urgency incontinence

Mixed incontinence

Overflow
incontinence

Incomplete emptying (detrusor underactivity or outlet obstruction ) -* leak with overfilling t post
void residual ( urinary retention ) on catheterization or ultrasound. Treatment: catheterization,
relieve obstruction (eg, a-blockers for BPH ).
,

568

SECTION III

Urinary tract infection


(acute bacterial
cystitis)

RENAL PATHOLOGY

RENAL

Inflammation of urinary bladder. Presents as suprapubic pain, dysuria , urinary frequency, urgency,
Systemic signs (eg, high fever, chills) are usually absent .
Risk factors include female gender (short urethra ), sexual intercourse ( honeymoon cystitis ),
indwelling catheter, diabetes mellitus, impaired bladder emptying.
Causes:

E coli ( most common ).


Staphylococcus saprophyticus seen in sexually active young women (E coli is still more
common in this group ).

Klebsiella.
Proteus mirabilis urine has ammonia scent .
Lab findings: leukocyte esterase. nitrites (indicate gram organisms, especially E coli ). Sterile
pyuria and urine cultures suggest urethritis by Neisseria gotiorrhoeae or Chlamydia trachomatis .

Pyelonephritis
Acute pyelonephritis

Neutrophils infiltrate renal interstitium Q. Affects cortex with relative sparing of glomeruli /vessels.
Presents with fevers, flank pain (costovertebral angle tenderness), nausea /vomiting, chills.
Causes include ascending UTI ( E coli is most common ), hematogenous spread to kidney. Presents
with WBCs in urine +/ WBC casts. CT would show striated parenchymal enhancement QJ.
Risk factors include indwelling urinary catheter, urinary tract obstruction , vesicoureteral reflux,
diabetes mellitus, pregnancy.
Complications include chronic pyelonephritis, renal papillary necrosis, perinephric abscess,

urosepsis.
Treatment: antibiotics.
Chronic

pyelonephritis

The result of recurrent episodes of acute pyelonephritis. Typically requires predisposition to


infection such as vesicoureteral reflux or chronically obstructing kidney stones.
Coarse, asymmetric corticomedullary scarring, blunted calyx. 7ubules can contain eosinophilic
casts resembling thyroid tissue Q (thyroidization of kidney).
Xanthogranulomatous pyelonephritis rare; grossly orange nodules that can mimic tumor
nodules, characterized b\lwidespread kidney damage due to granulomatous tissue containing
foamy macrophages.

iV \

>

>

>
it

1
Diffuse cortical
necrosis

-5

Acute generalized cortical infarction of both


kidneys. Likely due to a combination of
vasospasm and DIC.

Z
Associated with obstetric catastrophes (eg,
abruptio placentae), septic shock ,

570

SECTION III

Acute interstitial
nephritis
( tubulointerstitial
nephritis)

Acute tubular necrosis

RENAL

RENAL PATHOLOGY

Acute interstitial renal inflammation. Pyuria


(classically eosinophils) and azotemia
occurring after administration of drugs that
act as haptens, inducing hypersensitivity (eg,
diuretics, penicillin derivatives, proton pump
inhibitors, sulfonamides, rifampin, NSAIDs).
Less commonly may be 2 to other processes
such as systemic infections (eg, mycoplasma)
autoimmune diseases (eg, Sjogren syndrome,
SLE, sarcoidosis).

Associated with fever, rash, hematuria, and


costovertebral angle tenderness, but can be
asymptomatic.
Remember these Ps:
Pee (diuretics)
u
Pain-free (NSAIDs)
Penicillins and cephalosporins
Proton pump inhibitors

RifamPin

Most common cause of acute kidney injury- in hospitalized patients. Spontaneously resolves in
many cases. Can be fatal, especially during initial oliguric phase t FENa.
Key finding: granular (muddy brown ) casts Q.
3 stages:
,

;
. H
\
A In

1. Inciting event
2. Maintenance phase oliguric; lasts 1-3 weeks; risk of hyperkalemia, metabolic acidosis,
uremia
3. Recovery phase polvuric; BUN and serum creatinine fall; risk of hypokalemia
Can be caused by ischemic or nephrotoxic injury:
Ischemic 2 to i renal blood flow (eg, hypotension, shock, sepsis, hemorrhage, HF). Results
in death of tubular cells that may slough into tubular lumen []] (PCT and thick ascending limb
are highly susceptible to injury).
Nephrotoxic 2 to injury resulting from toxic substances (eg, aminoglycosides, radiocontrast
agents, lead, cisplatin, ethylene glycot. crush injury (myoglobinuria), hemoglobinuria. PCT is
particularly susceptible to injury.

' iiMr \m 0 TTI i


Renal papillary
necrosis

m
i

Sloughing of necrotic renal papillae Q gross


hematuria and proteinuria. May be triggered
by recent infection or immune stimulus.
Associated with sickle cell disease or trait,
acute pyelonephritis, NSAIDs, diabetes
mellitus.

SAAD papa with papillary necrosis:


Sickle cell disease or trait
Acute pyelonephritis
Analgesics (NSAIDs)
Diabetes mellitus

RENAL PATHOLOGY

RENAL

571

SECTION III

Renal cyst disorders

Autosomal dominant
polycystic kidney
disease

Numerous cysts in cortex and medulla Q causing bilateral enlarged kidneys ultimately destroy
kidney parenchyma. Presents with flank pain, hematuria, hypertension, urinary infection,
progressive renal failure in ~ 50% of individuals.
Mutation in PKD1 ( 85% of cases, chromosome 16 ) or PKD2 ( 15% of cases, chromosome 4). Death
from complications of chronic kidney disease or hypertension (caused by t renin production).
Associated with berry aneurysms, mitral valve prolapse, benign hepatic cysts, diverticulosij
Treatment: ACE inhibitors or ARBs.

Autosomal recessive
polycystic kidney
disease

Cystic dilation of collecting ducts Q. Often presents in infancy. Associated with congenital
hepatic fibrosis. Significant oliguric renal failure in utero can lead to Potter sequence. Concerns
beyond neonatal period include systemic hypertension, progressive renal insufficiency, and portal
hypertension from congenital hepatic fibrosis.

Medullary cystic
disease

Inherited disease causing tubulointerstitial fibrosis and progressive renal insufficiency with inability
to concentrate urine. Medullar}' cysts usually not visualized; shrunken kidneys on ultrasound.
Poor prognosis.

Simple vs complex
renal cysts

Simple cysts are filled with ultrafiltrate (anechoic on ultrasound Q). Very common and account for
majority of all renal masses. Found incidentally and typically asymptomatic.
Complex cysts, including those that are septated, enhanced, or have solid components on imaging
require follow-up or removal due to risk of renal cell carcinoma.

P'f

,4.c.

ra

-L

RENAL

RENAL PHARMACOLOGY

573

SECTION III

Mannitol
MECHANISM

CLINICAL USE

ADVERSE EFFECTS

Osmotic diuretic, t tubular fluid osmolarity


-* t urine flow, I intracranial /intraocular

pressure.
Drug overdose, elevated intracranial /intraocular
pressure.
Pulmonary edema , dehydration .
Contraindicated in anuria , HF.

Acetazolamide
MECHANISM

Carbonic anhydrase inhibitor. Causes self


limited NaHCO, diuresis and i total body
HCO - stores.

CLINICAL USE

ADVERSE EFFECTS

Glaucoma , urinary alkalinization, metabolic


alkalosis, altitude sickness, pseudotumor
cerebri .
Proximal renal tubular acidosis, paresthesias,
NFL toxicity, sulfa allergy; hypokalemial

ACID azolamide causes ACIDosis.

Loop diuretics

Furosemide, bumetanide, torsemide


MECHANISM

Sulfonamide loop diuretics. Inhibit cotransport


system ( Na + / K+ /2C1-) of thick ascending limb
of loop of Henle. Abolish hvpertonicity of
medulla , preventing concentration of urine.
Stimulate PGE release (vasodilatory effect
on afferent arteriole ); inhibited by NSAIDs.
t Ca 2+ excretion . Loops Lose Ca +.

CLINICAL USE

Edematous states ( HF, cirrhosis, nephrotic


syndrome, pulmonary edema), hypertension ,

ADVERSE EFFECTS

Ototoxicity , Hypokalemia , Hy pomagnesemia,

hypercalcemia.

m
OHH DANG!

ft

r -J

Dehydration , Allergy (sulfa ) /metabolic


Alkalosis, Nephritis (interstitial ), Gout .
Ethacrynic acid
MECHANISM

CLINICAL USE
ADVERSE EFFECTS

Nonsulfonamide inhibitor of cotransport system


( Na +/ K+ /2C1 ~ ) of thick ascending limb of loop
of Henle.
Diuresis in patients allergic to sulfa drugs.
Similar to furosemide, but more ototoxic.

V
Loop earrings hurt your ears.

RENAL PHARMACOLOGY

RENAL

Angiotensin
converting enzyme
inhibitors

SECTION III

Captopril, enalapril, lisinopril, ramipril.

MECHANISM

Inhibit ACE i AT II i GFR by preventing


constriction of efferent arterioles, t renin due
to loss of negative feedback. Inhibition of ACE
also prevents inactivation of bradvkinin, a
potent vasodilator.

CLINICAL USE

Hypertension, HF (i mortality), proteinuria,


diabetic nephropathy. Prevent unfavorable
heart remodeling as a result of chronic
hypertension.

In diabetic nephropathy, i intraglomerular


pressure, slowing CBM thickening

Cough, Angioedema (due to t bradvkinin;


contraindicated in Cl esterase inhibitor
deficiency), Teratogen (fetal renal
malformations), t Creatinine (1 GFR),
Hyperkalemia, and Hypotension. Used with
caution in bilateral renal artery stenosi
because ACE inhibitors will further 1 GFR

Captopril's CATCHH.

ADVERSE EFFECTS

Angiotensin II receptor
blockers

renal failure.

Losartan, candesartan, valsartan.

MECHANISM

Selectively block binding of angiotensin II to ATj receptor. Effects similar to ACE inhibitors, but
ARBs do not increase bradvkinin.

CLINICAL USE

Hypertension, HF, proteinuria, or diabetic nephropathy with intolerance to ACE inhibitors (eg,
cough, angioedema).

ADVERSE EFFECTS

Hyperkalemia, i GFR, hypotension; teratogen.

Aliskiren
MECHANISM

Direct renin inhibitor, blocks conversion of angiotensinogen to angiotensin I.

CLINICAL USE

Hypertension.

ADVERSE EFFECTS

Hyperkalemia, i GFR, hypotension, angioedema Relatively contraindicated in patients already


taking ACE inhibitors or ARBs.

575

HIGH - YIELD SYSTEMS

Reproductive

Artificial insemination is when the farmer does it to the cow instead of the
bull.

Student essay

Whoever called it necking was a poor judge of anatomy."

Groucho Marx
See , the problem is that Cod gives men a brain and a penis, and only
enough blood to run one at a time.
Robin Williams

Embryology

578

Anatomy

589

Physiology

593

Pathology

601

Pharmacology

616

I think you can say that life is a system in which proteins and nucleic
acids interact in ways that allow the structure to grow and reproduce. It s
that growth and reproduction , the ability to make more of yourself , thats
important.
Andrew H . Knolli

577

578

SECTION III

REPRODUCTIVE

REPRODUCTIVE

REPRODUCTIVE

EMBRYOLOGY

EMBRYOLOGY

Important genes of embryogenesis

Sonic hedgehog gene

Produced at base of limbs in zone of polarizing activity. Involved in patterning along


anteroposterior axis and CNS development; mutation can cause holoprosencephaly.

Wnt -7 gene

Produced at apical ectodermal ridge (thickened ectoderm at distal end of each developing limb ).
Necessary for proper organization along dorsal-ventral axis.

FGF gene

Produced at apical ectodermal ridge. Stimulates mitosis of underlying mesoderm, providing for
lengthening of limbs.

Homeobox ( Hox )
genes

Involved in segmental organization of embryo in a craniocaudal direction . Code for transcription


factors. Hox mutations appendages in wrong locations.

Early fetal development

Early embryonic
development
DAY 1

Faun ' i

mo

,
.

DAY 4
Morula

Degenerated
DMoping corpus litojm
follicle v

DAY 5
Blastocyst

*
2 oocyte

En kxneb uni

Within week 1

hCG secretion begins around the time of

Blastocyst sticks at day 6:

Within week 2

implantation of blastocyst.
Bilaminar disc (epiblast , hypoblast).

2 weeks = 2 layers.

Within week 3

Gastrulation forms trilaminar embryonic disc.


Cells from epiblast invaginate -* primitive
streak -* endoderm , mesoderm , ectoderm.
Notochord arises from midline mesoderm ;
overlying ectoderm becomes neural plate.

3 weeks = 3 layers.

Weeks 3-8
(embryonic period )

Neural tube formed by neuroectoderm and


closes by week 4.

Extremely susceptible to teratogens.

Organogenesis.
Week 4
Week 6
Week 8

Week 10

Heart begins to beat .


Upper and lower limb buds begin to form .
Fetal cardiac activity visible by transvaginal
ultrasound .
Fetal movements start .
Genitalia have male /female characteristics.

4 weeks = 4 limbs and 4 heart chambers.

Gait at week 8.

TENitalia

REPRODUCTIVE

REPRODUCTIVE

EMBRYOLOGY

SECTION III

579

Embryologic derivatives

External /outer layer

Ectoderm

Surface ectoderm

Epidermis; adenohypophysis (from Rathke


pouch); lens of eye; epithelial linings of oral
cavity, sensor}- organs of ear, and olfactory
epithelium;final canal below the pectinate line;
parotid , sweat, mammary glands.

Neural tubel

Brain ( neurohypophysis, CNS neurons, oligo-

Neural crest

Craniopharyngioma benign Rathke pouch


tumor with cholesterol crystals, calcifications.

Neuroectoderm think CNS.


dendrocytes, astrocytes, ependymal cells, pineal
gland ), retina, spinal cord.
PNS (dorsal root ganglia , cranial nerves
Neural crest think PNS and non-neural
structures nearby.
autonomic ganglia , Schwann cells),
melanocytes, chromaffin cells of adrenal
medulla , parafollicular (C ) cells of thyroid,
pia and arachnoid , bones of the skull ,
odontoblasts, aorticopulmonary septum ,
endocardial cushions, myenteric (Auerbach )

plexuj
Mesoderm

Muscle, bone, connective tissue, serous


linings of body cavities (eg, peritoneum ),
spleen (derived from foregut mesentery),
cardiovascular structures, lymphatics, blood
wall of gut tube, upper vagina , kidneys,
adrenal cortex, dermis, testes, ovaries.
Notochord induces ectoderm to form
neuroectoderm ( neural plate). Its only
postnatal derivative is the nucleus pulposus of
the intervertebral disc.

MiddleAneat layer.
Mesodermal defects = VACTERL:

Gut tube epithelium ( including anal canal


above the pectinate line), most of urethra and
lower vagina (derived from urogenital sinus),
luminal epithelial derivatives (eg, lungs,
liver, gallbladder, pancreas, eustachian tube,
thymus, parathyroid, thyroid follicular cells).

Enter nal layer.

Endoderm

Vertebral defects

Anal atresia
Cardiac defects
Tracheo-Esophageal fistula

Renal defects
Limb defects ( bone and muscle)

Types of errors in organ morphogenesis

Agenesis

Absent organ due to absent primordial tissue.

Aplasia

Absent organ despite presence of primordial tissue.

Hypoplasia

Incomplete organ development; primordial tissue present.


2 breakdown of previously normal tissue or structure (eg, amniotic band syndrome).
Extrinsic disruption ; occurs after embryonic period .

Disruption

Deformation
Malformation

Sequence

Intrinsic disruption ; occurs during embryonic period (weeks 3-8).


Abnormalities result from a single 1 embryologic event (eg, oligohydramnios

Potter sequence).

580

SECTION III

Teratogens

TERATOGEN

REPRODUCTIVE

REPRODUCTIVE EMBRYOLOGY

Most susceptible in 3rd 8th weeks (embryonic period organogenesis) of pregnancy. Before week
3, all-or-none effects. After week 8, growth and function affected.
EFFECTS ON FETUS

NOTES

Medications
ACE inhibitors

Renal damage

Alkylating agents

Absence of digits, multiple anomalies

Aminoglycosides

Ototoxicity
Neural tube defects, cardiac defects, cleft
palate, skeletal abnormalities (eg, phalanx/nail
hypoplasia, facial dysmorphism)

Antiepileptic drugs

Diethylstilbestrol

Folate antagonists

Vaginal clear cell adenocarcinoma, congenital


Mullerian anomalies
Neural tube defects

Lithium

Multiple severe birth defects


Ebstein anomaly (apical displacement of
tricuspid valve)

Isotretinoin

A mean guy hit the baby in the ear.

High-dose folate supplementation


recommended. Most commonly valproate,
carbamazepine, phenytoin, phenobarbital.

Includes trimethoprim, methotrexate,


antiepileptic drugs.
Contraception mandatory. IsoTERATinoin.

Methimazole

Aplasia cutis congenita

Tetracyclines

Discolored teeth, inhibited bone growth

Teethracyclines.

Thalidomide

Limb defects (phocomelia, micromelia


flipper limbs)

Limb defects with tha-limb-domide.

Warfarin

Bone deformities, fetal hemorrhage, abortion,

Do not wage warfare on the baby; keep it heppy


with heparin (does not cross placenta).

ophthalmologic abnormalities
Substance abuse
Alcohol
Cocaine

Smoking
(nicotine, CO)

Common cause of birth defects and intellectual

disability; fetal alcohol syndrome


Low birth weight, preterm birth, IUGR,
placental abruption
Low birth weight (leading cause in developed
countries), preterm labor, placental problems,
IUGR, SIDS

Cocaine - vasoconstriction.

Nicotine - vasoconstriction.
CO -* impaired 02 delivery.

Other
Iodine ( lack or excess)

Maternal diabetes

Congenital goiter or hypothyroidism (cretinism)


Caudal regression syndrome (anal atresia
to sirenomelia), congenital heart defects,
neural tube defects, macrosomia, neonatal

hypoglycemia
Methylmercury

Neurotoxicity

Vitamin A excess

Extremely high risk for spontaneous abortions


and birth defects (cleft palate, cardiac)
Microcephaly, intellectual disability

X- rays

Highest in swordfish, shark, tilefish, king


mackerel.

Minimized by lead shielding.

REPRODUCTIVE EMBRYOLOGY

REPRODUCTIVE

SECTION III

Fetal alcohol
syndrome

Leading cause of intellectual disability in the US. Newborns of alcohol-consuming mothers


have t incidence of congenital abnormalities, including pre- and postnatal developmental
retardation, microcephaly, facial abnormalities (eg, smooth philtrum, thin Vermillion border
[upper lip], small palpebral fissures), limb dislocation, heart defects. Heart-lung fistulas and
holoprosencephalv in most severe form. Mechanism is failure of cell migration.

Twinning

Dizygotic ( fraternal ) twins arise from 2 eggs that are separately fertilized by 2 different sperm
(always 2 zygotes) and will have 2 separate amniotic sacs and 2 separate placentas (chorions).
Monozygotic ( identical) twins arise from 1 fertilized egg ( 1 egg + 1 sperm) that splits in early
pregnancy. The timing of cleavage determines chorionicitv (number of chorions) and amnionicity
(number of amnions).
Dizygotic ( fraternal) [- tys)

Note

581

Monozygotic (identical) [~ tyj]

No twinning

spelling
change to
Dizygotic

O'

2 egjs

1egg, 1sperm

2 sperm

<D

2-cell stage

2- cell stage

iRevised

I Figure l

2-cell stage
0-4 days

0>*

Cleavage

2-cell stage

Morula

Blastocyst

Dichorionic
diamniotic 125%)

Moi J a

Moruta

Monochonomc

4- 8 days

diamniotic (75%)

3 astocysl

Cleavage

8 12 days

Monochonomc
IMM DammotK

rare
Chonomc

.Q

cavity -

armed

Amniotic

cavity

Fort ed
embryonic disc

embryonic disc

> 13 days

Cleavage or
axis duplication

Lhorion
o utei

Ammon

Dichorionic
diamniotic

Endometrium
No twinning if
no cleavage

Monodvononk
monoammatK
[conjoined rarel

582

SECTION III

REPRODUCTIVE

REPRODUCTIVE

EMBRYOLOGY

1 site of nutrient and gas exchange between mother and fetus.

Placenta
Fetal component

Cytotrophoblast

Inner layer of chorionic villi .

Syncytiotrophoblast

Outer layer of chorionic villi ; synthesizes and


secretes hormones, eg, hCG (structurally
similar to LH; stimulates corpus luteum to
secrete progesterone during first trimester).

Cytotrophoblast makes Cells.


Syncytiotrophoblast synthesizes hormones.
Lacks MHC-I expression 1 chance of attack
by maternal immune system.

Maternal component

Derived from endometrium . Maternal blood in


lacunae.

Decidua basalis

Branch villus

Umbilical vein
( rich)
02
Umbilical arteries ^
(02 poor ) \

Endometrial vein

Endometrial artery

Maternal
circulation

Maternal circulation

9
Hormones

laG
Drugs

Fetal circulation
H20
Urea, waste products
Hormones

Syncytium
Cytotrophoblast

endothelial cell

Amnion

Chorionic plate
Maternal blood

Decidua basalis

REPRODUCTIVE

REPRODUCTIVE

EMBRYOLOGY

587

SECTION III

Genital embryology

Default development . Mesonephric duct


degenerates and paramesonephric duct

Female

develops.

Indifferent gonad

SRY gene on Y chromosome produces testis


determining factor -* testes development.
Sertoli cells secrete Mullerian inhibitoryfactor ( MIF ) that suppresses development of
paramesonephric ducts.
Leydig cells secrete androgens that stimulate
development of mesonephric ducts.

Male

Develops into female internal structures


fallopian tubes, uterus, upper portion of vagina
( lower portion from urogenital sinus). Male

Paramesonephric
( Mullerian ) duct

Paramesonephric duct

Urogenital sinus

-Gubernaculum

Testis-devetoping factor
Androgens

No androgens

MIF
Epididymis

remnant is appendix testis.


Mullerian agenesis ( Mayer- RokitanskyKuster- Hauser syndrome) may present
as 1 amenorrhea (due to a lack of uterine
development ) in females with fully developed
2 sexual characteristics (functional ovaries).

ddra ,

Develops into male internal structures (except


prostate) Seminal vesicles, Epididymis,
Ejaculatory duct, Ductus deferens (SEED ).

Mesonephric
( Wolffian ) duct

JV d id

Unnary
bladder
Degenerated
mesonephric

Degenerated
paramesonephric duct

duel

- Uterus
- Vagina

Vas deferens /

In females, remnant of mesonephric duct


-* Gartner duct.

EJ

SRYgene

O No Sertoli cells or lack of Mullerian inhibitory-

SRI'gene on V chromosome

I
Testis-determining factor
. Testes

Leydig cell

Sertoli cell

~t~

| Mullerian inhibitory factor |


Testosterone
Degeneration of
paramesonephric ( Mullerian)
duct (female internal
genitalia)

Genital tubercle,
urogenital sinus

-0

(i

Wolffian duct

Male internal genitalia


( except prostate)

DHT
Male external genitalia,
prostate

factor develop both male and female


internal genitalia and male external genitalia
5a-reductase deficiency inability to convert
testosterone into DHT male internal
genitalia , ambiguous external genitalia until
puberty (when t testosterone levels cause
masculinization)
Sertoli Shuts down female developmental

pathway.
Leydig Leads to male developmental pathway.

588

SECTION I I I

REPRODUCTIVE EMBRYOLOGY

REPRODUCTIVE

Uterine ( Mullerian duct ) anomalies

Septate uterus

Common anomaly vs normaluterusJQ. Incomplete resorption of septum Q. 1 fertility. Treat with


septoplasty.

Bicornuate uterus

Incomplete fusion of Mullerian ducts Q. t risk of complicated pregnancy.


Complete failure of fusion - double uterus, cervix, and vaginalEl. Pregnancy possible.

Uterus didelphys

Normal

Didelphys

Bicornuate

Septate

Male/female genital homologs


Male

Female

Undifferentiated
Gians penis

Genital

Genital groove

Penile urethra

tubercle

Urogenital
fold

Labioscrotal
swelling

Urogenital

Clitoris

Labia
minora

Opening of
urethra

sinus
Scrotum

Labia
majora

Opening of
vagina

Anus

*
Urachus

Urinary
bladder

Allantois

Testis

Gians
penis

part

Genital
tubercle

Pehric
part

Ureter

Spongy
urethra

Ductus
deferens

Prostate gland

Ventral shaft of penis


(penile urethra)
Scrotum

.
-^

Urinary
bladder

Clitoris

"\

part

Kidney

^
^

Dihydrotestosterone
Gians penis
Corpus cavernosum
and spongiosum
Bulbourethral glands
(of Cowper)

Urogenital
sinus

Phallic
Rectum

Uterine
tube

Urachus

vesica

Kidney

Estrogen
Genital tubercle
Genital tubercle

Urogenital sinus

Ovary

Uterus

Vagina

Gians clitoris

Vestibular bulbs

Greater vestibular glands

(of Bartholin)

Urogenital sinus

Urethral and paraurethral


glands (of Skene)

Urogenital folds

Labia minora

Labioscrotal swelling

Labia majora

REPRODUCTIVE ANATOMY

REPRODUCTIVE

591

SECTION III

Male reproductive anatomy


Ureter
Bladder

ieir

naI vesicle

Apulia

Vas deferens

Bulbourethral

'

Corpus cavernosa

Efferent ductule

Prostate

.e

Jrethi i

Head of epididymis

Ejaculatory duct

Js

Symphysis pubis

gland (Cowper )

Epididymis

Sem nlferous
iubules

\>r

Rete testis

Vas deferens

Prepuce
Tunica
albuginea

Q ans

Testis

Scrotum

Tail of epididymis -

na

Pathway of sperm during ejaculation


SEVEN UP:

Seminiferous tubules
Epididymis
Vas deferens
Ejaculatory ducts
(Nothing)
Urethra
Penis

Urethral injury

Suspect if blood seen at urethral meatus. Urethral characterization contraindicated


Posterior urethra membranous urethra prone to injury from pelvic fracture. Injury can cause urine
to leak into retropubic space.
Anterior urethra bulbar Jarethra at risk of damage due to perineal straddle injury. Can cause urine
to leak beneath deep fascia of Buck. If fascia is torn, urine escapes into superficial perineal space.

Autonomic
innervation of the
male sexual response

Erection Parasympathetic nervous system


(pelvic nerve):
NO -* t cGMP smooth muscle
relaxation -* vasodilation proerectile.
Norepinephrine t [Ca-+]in -* smooth
muscle contraction vasoconstriction
D

-* antierectile.

Emission Sympathetic nervous system


( hypogastric nerve).
Ejaculation visceral and Somatic nerves
(pudendal nerve).

Point, Squeeze, and Shoot.


PDE-5 inhibitors (eg, sildenafil) 1 cGMP
breakdown.

REPRODUCTIVE

REPRODUCTIVE PATHOLOGY

601

SECTION III

REPRODUCTIVE PATHOLOGY
Sex chromosome
disorders

Klinefelter syndrome
[male] (47,XXY )

Turner syndrome
[female] (45,XO)

l.

Aneuploidy most commonly due to meiotic nondisjunction.


Testicular atrophy, eunuchoid body shape,
Dysgenesis of seminiferous tubules
tall, long extremities, gynecomastia, female
t FSH.
1 inhibin B
Abnormal Leydig cell function 1 testosterone
hair distribution Q. May present with
t LH t estrogen.
developmental delay. Presence of inactivated
X chromosome (Barr body). Common cause of
hypogonadism seen in infertility work-up.

Short stature (if untreated), ovarian dysgenesis


(streak ovary), shield chest, bicuspid aortic
valve, coarctation (femoral < brachial pulse),
lymphatic defects (result in webbed neck or
cystic hygroma; lymphedema in feet, hands),

horseshoe kidney Q.
Most common cause of 1 amenorrhea. No Barr
body.

Double Y males ( XYY )

Phenotypically normal (usually undiagnosed),


very tall. Normal fertility. May be associated
with severe acne, learning disability, autism

Ovotesticular disorder
of sex development

46,XX > 46,XY.


Both ovarian and testicular tissue present
(ovotestis); ambiguous genitalia. Previously
called true hermaphroditism.

spectrum disorders.

Menopause before inenarche.


1 estrogen leads to t LH, FSH .

Sometimes due to mitotic error mosaicism (eg,


45,XO/46,XX).
Pregnancy is possible in some cases (IVF,
exogenous estradiol-17P and progesterone).
Can use growth hormone to achieve normal
height .

602

SECTION III

Diagnosing disorders
of sex hormones

Other disorders of sex


development

REPRODUCTIVE

REPRODUCTIVE PATHOLOGY

Testosterone

LH

Diagnosis

Defective androgen receptor

Testosterone-secreting tumor, exogenous


steroids

Hvperqonadotrophic hypogonadism (1)l

Hypogonadotropic hypogonadism (2)

Disagreement between the phenotypic (external genitalia) and gonadal (testes vs ovaries) sex.
Include terms pseudohermaphrodite, hermaphrodite, and intersex.

46,XX DSD

Ovaries present, but external genitalia are virilized or ambiguous. Due to excessive and
inappropriate exposure to androgenic steroids during early gestation (eg, congenital adrenal
hyperplasia or exogenous administration of androgens during pregnancy).

46,XY DSD

Testes present, but external genitalia are female or ambiguous. Most common form is androgen
insensitivity syndrome ( testicular feminization).

Placental aromatase
deficiency

Inability to synthesize estrogens from androgens. Masculinization of female (46,XX ) infants


(ambiguous genitalia), t serum testosterone and androstenedione. Can present with maternal
virilization during pregnancy (fetal androgens cross the placenta).

Androgen insensitivity
syndrome (46,XY )

Defect in androgen receptor resulting in normal-appearing female; female external genitalia with
scant sexual hair, rudimentary vagina; uterus and fallopian tubes absent. Patients develop normal
functioning testes (often found in labia majora; surgically removed to prevent malignancy),
t testosterone, estrogen, LH (vs sex chromosome disorders).

5a- reductase
deficiency

Autosomal recessive; sex limited to genetic males (46,XY ). Inability to convert testosterone to DHT.
Ambiguous genitalia until puberty, when t testosterone causes masculinization/t growth of
external genitalia. Testosterone/estrogen levels are normal; LII is normal or t . Internal genitalia
are normal.

Kallmann syndrome

Failure to complete puberty; a form of hypogonadotropic hypogonadism. Defective migration of


GnRH cells and formation of olfactory bulb; i synthesis of GnRH in the hypothalamus; anosmia;
1 GnRH, FSH, LH, testosterone. Infertility (low sperm count in males; amenorrhea in females).

REPRODUCTIVE

REPRODUCTIVE PATHOLOGY

SECTION III

605

Pregnancy complications (continued )

Vasa previa

Fetal vessels run over, or in close proximity


to, cervical os. May result in vessel rupture,
exsanguination, fetal death. Presents with
triad of membrane rupture, painless vaginal
bleeding, fetal bradycardia (< 110 beats/min).
Emergency C-section usually indicated.
Frequently associated with velamentous
umbilical cord insertion (cord inserts in
chorioamniotic membrane rather than
placenta fetal vessels travel to placenta
unprotected by Wharton jelly).

Placenta

Placenta
I succenturiate

lobe)

Postpartum
hemorrhage

Due to 4 Ts: Tone (uterine atony; most


common), Trauma (lacerations, incisions,
uterine rupture) Thrombin (coagulopathy),
Tissue (retained products of conception).

Ectopic pregnancy

Most often in ampulla of fallopian tube


( shows 10-mm embryo in oviduct at 7
weeks of gestation). Suspect with history of
amenorrhea, lower-than-expected rise in hCG
based on dates, and sudden lower abdominal
pain; confirm with ultrasound. Often
clinically mistaken for appendicitis.

C
I

New

Asherman syndrome

I Fact 1

Pain +/ bleeding.
Risk factors:
Prior ectopic pregnancy
History of infertility
Salpingitis ( PID)
Ruptured appendix
Prior tubal surgery
5

Condition characterized by adhesions and/or fibrosis of the endometrium, often associated with
dilation and curettage of the intrauterine cavity.

Amniotic fluid abnormalities

Polyhydramnios

Too much amniotic fluid; associated with fetal malformations (eg, esophageal /duodenal atresia,
anencephaly; both result in inability to swallow amniotic fluid), maternal diabetes, fetal anemia,

Oligohydramnios

Too little amniotic fluid; associated with placental insufficiency, bilateral renal agenesis, posterior
urethral valves (in males) and resultant inability to excrete urine. Any profound oligohydramnios
can cause Potter sequence.

multiple gestations.

REPRODUCTIVE

REPRODUCTIVE PATHOLOGY

SECTION III

607

Vaginal tumors

Squamous cell
carcinoma

Usually 2 to cervical SCC; 1 vaginal carcinoma rare.

Clear cell

Affects women who had exposure to DES in utero.

adenocarcinoma
Sarcoma botryoides|

Embryonal rhabdomyosarcoma variant.

Affects girls < 4 years old; spindle-shaped cells; desmin .


Presents with clear, grape-like, polypoid mass emerging from vagina.

Cervical pathology

Dysplasia and
carcinoma in situ

Disordered epithelial growth; begins at basal layer of squamocolumnar junction (transformation


zone) and extends outward. Classified as CIN 1, CIN 2, or CIN 3 (severe dysplasia or carcinoma
in situ), depending on extent of dysplasia. Associated with HPV 16 and HPV 18, which
produce both the E6 gene product (inhibits pS 3 suppressor gene) and E7 gene product (inhibits
RB suppressor gene). May progress slowly to invasive carcinoma if left untreated. Typically
asymptomatic (detected with Pap smear) or presents as abnormal vaginal bleeding (often

postcoital).

'

Risk factors: multiple sexual partners (#1), smoking, starting sexual intercourse at young age, HIV

V
Invasive carcinoma

Premature ovarian

failure

Most common causes

of anovulation

Polycystic ovarian
syndrome ( SteinLeventhal syndrome )

infection.
Often squamous cell carcinoma. Pap smear can detect!cervical dysplasia (koilocytes Q) before it
progresses to invasive carcinoma. Diagnose via colposcopy and biopsy. Lateral invasion can block
ureters -* renal failure.

Premature atresia of ovarian follicles in women


of reproductive age. Patients present with signs
of menopause after puberty but before age 40.

i estrogen, t LH, t FSH.

Pregnancy, polycystic ovarian syndrome, obesity, HPO axis abnormalities, premature ovarian
failure, hyperprolactinemia, thyroid disorders, eating disorders, competitive athletics, Cushing
syndrome, adrenal insufficiency.

Hvperinsulinemia and/or insulin resistance hypothesized to alter hypothalamic hormonal feedback


response t LH:FSH, t androgens (eg, testosterone) from theca interna cells, 1 rate of follicular
maturation unruptured follicles (cysts) + anovulation. Common cause of subfertility in women.
Enlarged, bilateral cystic ovaries Q; presents with amenorrhea /oligomenorrhea, hirsutism, acne,
i fertility. Associated with obesity, t risk of endometrial cancer 2 to unopposed estrogen from
repeated anovulatory cycles.
Treatment: cycle control weight reduction ( 1 peripheral estrone formation), OCPs ( prevent
endometrial hyperplasia due to unopposed estrogen); infertility cloniiphene, metformin (induce
ovulation); hirsutism spironolactone ( androgen receptor inhibitor ), OCPs, ketoconazolej

REPRODUCTIVE

REPRODUCTIVE

PATHOLOGY

SECTION III

609

Ovarian neoplasms ( continued )

Malignant ovarian neoplasms


Granulosa cell tumor

Most common malignant stromal tumor. Predominantly women in their 50s. Often produces
estrogen and/or progesterone and presents with postmenopausal bleeding, sexual precocity
( in pre-adolescents), breast tenderness. Histology shows Call-Exner bodies 0 ( granulosa cells
arranged haphazardly around collections of eosinophilic fluid , resembling primordial follicles).

Serous
cystadenocarcinoma

Most common malignant ovarian neoplasm , frequently bilateral. Psammoma bodies,

Mucinous

Pseudomyxoma peritonei-intraperitoneal accumulation of mucinous material from ovarian or


appendiceal tumor.
Aggressive, contains fetal tissue, neuroectoderm . Commonly diagnosed before age 2Qt Typicallyrepresented by immature/embryonic-like neural tissue.

cystadenocarcinoma

Immature teratoma
Dysgerminoma

Most common in adolescents. Equivalent to male seminoma but rarer. 1% of all ovarian tumors;
30% of germ cell tumors. Sheets of uniform fried egg cells Q. hCG, LDH = tumor markers.

Yolk sac (endodermal


sinus) tumor

Aggressive, in ovaries or tested and sacrococcygeal area in young children . Most common tumor in
male infants. Yellow, friable ( hemorrhagic), solid mass. 50% have Schiller Duval bodies ( resemble
glomeruli ) Q. AFP = tumor marker.

Krukenberg tumor

GI malignancy that metastasizes to ovaries -* mucin-secreting signet cell adenocarcinoma.

I*

as

HR

m
m

SSMI

r-

ssfcsi

7k

610

SECTION III

REPRODUCTIVE

REPRODUCTIVE

PATHOLOGY

Endometrial conditions

Polyp

Well-circumscribed collection of endometrial tissue within uterine wall. May contain smooth
muscle cells. Can extend into endometrial cavity in the form of a polyp. May be asymptomatic or
present with painless abnormal uterine bleeding.

Adenomyosis

Extension of endometrial tissue ( glandular) into uterine myometrium . Caused by hyperplasia of


basal layer of endometrium . Presents with dysmenorrhea , menorrhagia , uniformly enlarged , soft,
globular uterus.
Treatment: GnRH agonists, hysterectomy.

Leiomyoma (fibroid )

Most common tumor in females. Often presents with multiple discrete tumors Q. t incidence in
African Americans. Benign smooth muscle tumor; malignant transformation to leiomyosarcoma is
rare. Estrogen sensitive tumor size t with pregnancy and i with menopause. Peak occurrence at
20-40 years old . May be asymptomatic, cause abnormal uterine bleeding, or result in miscarriage.
Severe bleeding may lead to iron deficiency anemia. Whorled pattern of smooth muscle bundles
with well-demarcated borders Q.

Endometrial
hyperplasia

Endometrial
carcinoma

Endometritis

Endometriosis

Abnormal endometrial gland proliferation Q usually caused by excess estrogen stimulation t risk for
endometrial carcinoma ; nuclear atypia is greater risk factor than complex (vs simple) architecture.
Presents as postmenopausal vaginal bleeding. Risk factors include anovulatory cycles, hormone
replacement therapy, polycystic ovarian syndrome, granulosa cell tumor.
Most common gynecologic malignancy Q. Peak occurrence at 55-65 years old. Presents with
vaginal bleeding. Typically preceded by endometrial hyperplasia. Risk factors include prolonged
use of estrogen without progestins, obesity, diabetes, hypertension , nulliparity, late menopause,
early menarchej Lynch syndrome.
Inflammation of endometrium Q associated with retained products of conception following
delivery, miscarriage, abortion, or with foreign body (eg, IUD). Retained material in uterus
promotes infection by bacterial flora from vagina or intestinal tract.
Treatment: gentamicin + clindamycin +/ ampicillin.
Non-neoplastic endometrial glands/stroma outside endometrial cavity Q- Can be found anywhere;
most common sites are ovary (frequently bilateral ), pelvis, peritoneum . In ovary, appears as
endometrioma ( blood-filled chocolate cyst ). May be due to retrograde flow, metaplastic
transformation of multipotent cells, transportation of endometrial tissue via lymphatic system .
Characterized by cyclic pelvic pain , bleeding, dysmenorrhea , dyspareunia, dyschezia ( pain with
defecation ), infertility; normal-sized uterus.
Treatment: NSAIDs, OCPs, progestins, GnRH agonists, danazol , laparoscopic removal .
,

v
; t.
/

<

m:

mamr- -wmm
r -:

sw

*1

ti m11
1i|
isssb* r

K
*

,t.

'

'

612

SECTION III

REPRODUCTIVE

REPRODUCTIVE

PATHOLOGY

Commonly

Risk factors: t estrogen exposure, t total number


of menstrual cycles, older age at 1st live birth,
obesity ( t estrogen exposure as adipose tissue
converts androstenedione to estrone), BRCA1
oi[ BRCA2 gene mutations, African American
ethnicity ( t risk for triple breast cancer).

CHARACTERISTICS

NOTES

Ductal carcinoma in
situ

Fills ductal lumen ( black arrow in Q indicates


neoplastic cells in duct ; blue arrow shows
engorged blood vessel ). Arises from ductal
atvpia. Often seen early as microcalcifications
on mammography.

Early malignancy without basement membrane


penetration .

Comedocarcinoma

Ductal , central necrosis (arrow in Q). Subtype


ofDCIS.
Results from underlying DCIS or invasive breast
cancer. Eczematous patches on nipple Q.
Paget cells = intraepithelial adenocarcinoma
cells.

Malignant breast
tumors

TYPE

postmenopausal . Usually arise from


terminal duct lobular unit. Overexpression
of estrogen / progesterone receptors or c-erbB2
( HER-2 , an EGF receptor) is common; triple
negative ( ER 0, PR , and Her2/ Neu ) more
aggressive; type affects therapy and prognosis.
Axillary lymph node involvement indicating
metastasis is the most important prognostic
factor in early-stage disease. Most often located
in upper-outer quadrant of breast.

Noninvasive

Paget disease

Invasive
Invasive ductal
carcinoma

Firm , fibrous, rock-hard mass with sharp


margins and small , glandular, duct-like
cells 0. Can have dimpling of breast due to
deformation of suspensory ligaments by tumor.
Grossly see classic stellate infiltration .

Most common (~ 75% of all breast cancers).

Invasive lobular
carcinoma

Orderly row of cells ( single!file

Medullary carcinoma

Fleshy, cellular, lymphocytic infiltrate.


Dermal lymphatic invasion by breast
carcinoma. Peau d orange ( breast skin
resembles orange peel Q); neoplastic cells
block lymphatic drainage.

Often bilateral with multiple lesions in the same


location.
Lines of cells = Lobular.
Good prognosis.
Poor prognosis ( 50% survival at 5 years).
Often mistaken for mastitis or Paget disease.

Inflammatory breast

cancer

i E-cadherin expression .

0), due to

REPRODUCTIVE

REPRODUCTIVE PATHOLOGY

SECTION III

613

Malignant breast tumors (continued )

m*

m
u

mmm
.

S';

urn

m
mm
Penile pathology

Peyronie disease

Ischemic priapism

New
Fact

&T

Abnormal curvature of penis due to fibrous plaque within tunica albuginea. Associated with
erectile dysfunction. Can cause pain, anxiety. Consider surgical repair once curvature stabilizes.
Distinct from penile fracture (rupture of corpora cavernosa due to forced bending).
Painful sustained erection lasting > 4 hours. Associated with sickle cell disease (sickled RBCs
? ), medications (eg, sildenafil,
block venous drainage of corpus cavernosum vascular channel!
trazodone). Treat immediately with corporal aspiration, intracavernosal phenylephrine, or surgical
decompression to prevent ischemia.

Squamous cell
carcinoma

More common in Asia, Africa, South America. Precursor in situ lesions: Bowen disease (in
penile shaft, presents as leukoplakia), erythroplasia of Quevrat (cancer of glans, presents as
erythroplakia), Bowenoid papulosis (carcinoma in situ of unclear malignant potential, presenting
as reddish papules). Associated with HPV and lack of circumcision.

Cryptorchidism

Undescended testis (one or both); impaired spermatogenesis (since sperm develop best at
temperatures < 37C ); can have normal testosterone levels (Leydig cells are mostly unaffected
by temperature); associated with t risk of germ cell tumors. Prematurity t risk of cryptorchidism.
1 inhibin B, t FSH, t LH; testosterone 1 in bilateral cryptorchidism, normal in unilateral.

Testicular torsion

Rotation of testicle around spermatic cord and vascular pedicle.


Commonly presents 12-18 years of age. Characterized by acute, severe pain, high riding testis, and
absent cremasteric reflex .
Treatment: surgical correction (orchiopexy) within 6 hours, manual detorsion if surgical option
unavailable in timeframe. If testis is not viable, orchiectomy. Bilateral orchiopexy must always be
performed, contralateral testis at risk for subsequent torsion.

614

SECTION III

Varicocele

REPRODUCTIVE

REPRODUCTIVE PATHOLOGY

Dilated veins in pampiniform plexus due to t venous pressure; most common cause of scrotal
enlargement in adult males; most often on left side because of t resistance to flow from left
gonadal vein drainage into left renal vein; can cause infertility because of t temperature;
diagnosed by standing clinical exam (distension on inspection and bag of worms on palpation)
or ultrasound with Doppler Q; does not transilluminate.
Treatment: varicocelectomy, embolization.

Extragonadal germ cell Arise in midline locations. In adults, most commonly in retroperitoneum, mediastinum, pineal, and
suprasellar regions. In infants and young children, sacrococcygeal teratomas are most common.

tumors

Scrotal masses

Benign scrotal lesions present as testicular masses that can be transilluminated (vs solid testicular

tumors)

Congenital hydrocele

Common cause of scrotal swelling in infants,


due to incomplete obliteration of processus
vaginalis. Most spontaneously resolve by 1 year
of a gej

Acquired hydrocele

Scrotal fluid collection usually 2 to infection,


hematocele.
trauma, tumor. If bloody

Spermatocele

Cyst due to dilated epididymal duct or rete


testis.

Testicular germ cell


tumors

Seminoma

Transilluminating swelling,

Paratesticular fluctuant nodule,

testicular tumors. Most often occur in young men. Risk factors: cryptorchidism,
Klinefelter syndrome. Can present as a mixed germ cell tumor. Testicular mass that does not
transilluminate.

~ 95% of all

Malignant; painless, homogenous testicular enlargement; most common testicular tumor. Does
not occur in infancy. Large cells in lobules with watery cytoplasm and fried egg appearance
t placental ALP. Radiosensitive. Late metastasis, excellent prognosis.
Yellow, mucinous. Aggressive malignancy of testes, analogous to ovarian yolk sac tumor. SchillerDuval bodies resemble primitive glomeruli t AFP is highly characteristic. Most common
testicular tumor in boys < 3 years old.
,

Yolk sac (endodermal


sinus) tumor
Choriocarcinoma

Teratoma

Embryonal carcinoma

Malignant, t hCG. Disordered syncytiotrophoblastic and cytotrophoblastic elements.


Hematogenous metastases to lungs and brain. May produce gynecomastia, symptoms of
hyperthyroidism (hCG is structurally similar to LH, FSII, TSH).
Unlike in females, mature teratoma in adult males may be malignant. Benign in children .
Malignant, hemorrhagic mass with necrosis; painful; worse prognosis than seminoma. Often
glandular /papillary morphology. Pure" embryonal carcinoma is rare; most commonly mixed
with other tumor types. May be associated with t hCG and normal AFP levels when pure ( t AFP
when mixed).

REPRODUCTIVE

Testicular non germ


cell tumors
Leydig cell

Sertoli cell

Testicular lymphoma

Benign prostatic
hyperplasia

REPRODUCTIVE

PATHOLOGY

615

SECTION III

5% of all testicular tumors. Mostly benign .

Golden brown color; contains Reinke crystals (eosinophilic cytoplasmic inclusions). Produce
androgens or estrogens -* gynecomastia in men, precocious puberty in boys.
Androblastoma from sex cord stroma .
Most common testicular cancer in older men. Not a 1 cancer; arises from metastatic lymphoma to
testes. Aggressive.

Common in men > 50 years old . Characterized


by smooth, elastic, firm nodular enlargement
( hyperplasia not hypertrophy) of periurethral
( lateral and middle) lobes, which compress the
urethra into a vertical slit. Not premalignant .
Often presents with t frequency of urination ,
nocturia , difficulty starting and stopping urine
stream, dvsuria. May lead to distention and
hypertrophy of bladder, hydronephrosis, UTIs.
t free prostate-specific antigen ( PSA).
Treatment: (Xj-antagonists ( terazosin ,
tamsulosin ), which cause relaxation of
smooth muscle; 5a-reductase inhibitors (eg,
finasteride); PDE-5 inhibitors (eg, tadalafil j

Benign
prostatic
hyperplasia

Anterior lobe

Urethra

Middle lobe
m

Posterior
ior lobe

K\

Lateral lobe

____

I
m

Prostate
Pf ostai cancer

Prostatitis

Dvsuria , frequency, urgency, low back pain . Warm , tender, enlarged prostate. Acute bacterialmost common cause is E coli in older men , young males consider C trachomatis, N gonorr /ioec/e;
chronic bacterial or abacterial

Prostatic
adenocarcinoma

Common in men > 50 years old . Arises most often from posterior lobe ( peripheral zone) of prostate
gland and is most frequently diagnosed by t PSA and subsequent needle core biopsies. Prostatic
acid phosphatase ( PAP) and PSA are useful tumor markers ( t total PSA, with i fraction of free
PSA) . Osteoblastic metastases in bone may develop in late stages, as indicated by lower back pain
and t serum ALP and PSA.

REPRODUCTIVE

REPRODUCTIVE PHARMACOLOGY

SECTION III

619

Testosterone, methyltestosterone
MECHANISM

Agonists at androgen receptors.

CLINICAL USE

Treat hypogonadism and promote development of 2 sex characteristics; stimulate anabolism to


promote recovery after burn or injur)'.

ADVERSE EFFECTS

Mbsculinization in females; 1 intratesticular testosterone in males by inhibiting release of LH (via


negative feedback)

Antiandrogens

gonadal atrophy. Premature closure of epiphyseal plates, t LDL, 1 HDL.

Finasteride

Testosterone ^-reductase f)HT (more potent).


Sex-reductase inhibitor (i conversion of
testosterone to DHT). Used for BPH and malepattern baldness.

Flutamide

Nonsteroidal competitive inhibitor at androgen


receptors. Used for prostate carcinoma.

Ketoconazole

Inhibits steroid synthesis (inhibits 17,20


desmolase/17a-hvdroxylasd).

Spironolactone

Inhibits steroid binding, 17,20 desmolase / 17a-

hydroxylase

Used for polycystic ovarian syndrome to reduce


androgenic symptoms. Both have side effects of
gynecomastia and amenorrhea.

used to treat BPH by inhibiting smooth muscle contraction. Selective for <XjA D
receptors (found on prostate) vs vascular ajB receptors.

Tamsulosin

OC ]-antagonist

Phosphodiesterase
type 5 inhibitors

Sildenafil, vardenafil, tadalafil.

MECHANISM

Sildenafil, vardenafil, and tadalafil fill the


Inhibit PDE- 5 -* t cGMP -* prolonged
penis.
smooth muscle relaxation in response to NO
-* t blood flow in corpus cavernosum of penis,
1 pulmonary vascular resistance.

CLINICAL USE

Erectile dysfunction, pulmonary hypertension,


BPH (tadalafil only).

ADVERSE EFFECTS

Headache, flushing, dyspepsia, cyanopia


( blue-tinted vision). Risk of life-threatening
hypotension in patients taking nitrates.

Hot and sweaty but then Headache,


Heartburn, Hypotension.

Minoxidil
MECHANISM

Direct arteriolar vasodilator.

CLINICAL USE

Androgenetic alopecia; severe refractory hypertension.

HIGH - YI E LD SYSTEMS

Respiratory

Theres so much pollution in the air now that if it werent for our lungs,
there 'd he no place to put it all.

Robert Orben
Mars is essentially in the same orbit. Somewhat the same distance from
the Sun , which is very important. We have seen pictures where there are
canals, we believe, and water. If there is water, that means there is oxygen.
If there is oxygen, that means we can breathe.

Former Vice President Dan Quayle


Whenever I feel blue , I start breathing again.

Embryology

622

Anatomy

624

Physiology

626

Pathology

632

Pharmacology

643

L. Frank Baum

Life is not the amount of breaths you take; its the moments that take
your breath away."

Hitch

621

622

SECTION III

RESPIRATORY

RESPIRATORY

RESPIRATORY

EMBRYOLOGY

EMBRYOLOGY

Lung development

Occurs in five periods. Initial development includes development of lung bud from distal end of
.
respiratory diverticulum during week 4|

STAGE

IMPORTANT TERMS

Embryonic
( weeks 4-7 )

Lung bud -* trachea bronchial buds!


mainstem bronchi secondary ( lobar)
bronchi -* tertiary (segmental ) bronchi .

Errors at this stage can lead to TE fistula.

Pseudoglandular
( weeks 5-1

Endodermal tubules terminal bronchioles.


Surrounded by modest capillary network .

Respiration impossible, incompatible with life.

Canalicular
( weeks 16-2

Terminal bronchioles respiratory bronchioles


-* alveolar ducts. Surrounded by prominent
capillary network .
Alveolar ducts terminal sacs. Terminal sacs
separated by 1 septae. Pneumocytes develop.

Airways increase in diameter.


Respiration capable at 25 weeks.

Terminal sacs adult alveoli (due to 2


septation ).
In utero, breathing occurs via aspiration
and expulsion of amniotic fluid -* t vascular
resistance through gestation.
At birth , fluid gets replaced with air A in
pulmonary vascular resistance.

At birth: 20-70 million alveoli.


By 8 years: 300-400 million alveoli .

Saccular
( weel

426-birth)

Alveolar
( weel

436j-8 years)

NOTES

Embyronic

Fetal

Postnatal
Alveolar
Saccular

Canalicular

BIRTH

Pseudoglandular
Embryonic

Surfactant

10 12 14 16

18

20

22

24

26 28 50

52 54 56

58 40

<

2 4 6
Weeks Years *

<D

X
Congenital lung malformations

bronchial tree with abnormal histology. Associated with congenital diaphragmatic


hernia ( usually left-sided ), bilateral renal agenesis ( Potter sequence [syndrome!1

Pulmonary hypoplasia

Poorly developed

Bronchogenic cysts

Caused by abnormal budding of the foregut and dilation of terminal or large bronchi . Discrete,
round , sharply defined and fluid-filled densities on CXR ( air-filled if infected!Generally
asymptomatic but can drain poorly causing airway compression and /or recurrent respiratory
infection

RESPIRATORY

RESPIRATORY EMBRYOLOGY

SECTION III

623

Pneumocytes

97% of alveolar surfaces. Line the alveoli.

Type I cells

Squamous; thin for optimal gas diffusion.

Type II cells
Type II pneumocyte

u*%*

Secrete pulmonary surfactant I alveolar


surface tension, prevents alveolar collapse,
1 lung recoil, and t compliance. Cuboidal and
clustered Q. Also serve as precursors to type
I cells and other type II cells. Type II cells

proliferate during lung damage.

Collapsing pressure ( r ) =

2 (surface tension)
radius

Alveoli have t tendency to collapse on expiration


as radius 1 (law of Laplace).
Pulmonary surfactant is a complex mix of
lecithins, the most important of which is
dipahnitoylphosphatidvicholine ( DPPCj
Surfactant synthesis begins around week 26 of
gestation, but mature levels are not achieved
until around week 35.

Nonciliated; low-colunmar /cuboidal with


secretory granules. Secrete component of
surfactant; degrade toxins; act as reserve cells.

Club cells

Neonatal respiratory
distress syndrome

:o

Surfactant deficiency t surface tension


alveolar collapse (ground-glass appearance
of lung fields) Q. j
Risk factors: prematurity, maternal diabetes ( due
to t fetal insulin), C-section delivery ( 4 release
of fetal glucocorticoids; less stressful than
vaginal delivery!
Complications: fDA, necrotizing enterocolitis.
Treatment: maternal steroids before birth;
exogenoujsurfactant for infant.
Therapeutic supplemental 0-> can result in
Retinopathy of prematurity, Intraventricular
hemorrhage, Bronchopulmonary dysplasia

(RIB).

Screening tests for fetal lung maturity: lecithinsphingomyelin ( L /S ) ratio in amniotic fluid
(> 2 is healthy; < 1.5 predictive of NRDS ), foam
stability index test, surfactant-albumin ratio.
Persistently low Q-, tension
risk of PDA.

r-

Mature

'

15-

Transitional

10 -

us *22
i

26

Immature
i

30

35

Gestational age (wk )

40

HEMATOLOGY AND ONCOLOGY PHYSIOLOGY

HEMATOLOGY AND ONCOLOGY

Plasma cell

!<
'

387

SECTION III

Multiple myeloma is a plasma cell cancer,

Produces large amounts of antibody specific to


a particular antigen. Clock-face chromatin
distribution and eccentric nucleus, abundant
RER, and well-developed Golgi apparatus
(yellow arrows in Q). Found in bone marrow
and normally do not circulate in peripheral
blood.

HEMATOLOGY AND ONCOLOGY PHYSIOLOGY


Fetal erythropoiesis

Hemoglobin

development

Young Liver Synthesizes Blood.

Fetal erythropoiesis occurs in:


Yolk sac ( 3-8 weeks)
Liver ( 6 weeks-birth)
Spleen ( 10-28 weeks)
Bone marrow ( 18 weeks to adult)
Embryonic globins: and e.
Fetal hemoglobin (HbF) = CX2Y2 Adult hemoglobin (HbAj) = a2P2.
HbF has higher affinity for O? due to less avid
binding of 2,3-BPG, allow ing HbF to extract
02 from maternal hemoglobin (HbAj and
HbA2) across the placenta. HbA -? ( ObS? ) is a
minor form of adult hemoglobin present in
small amounts.

From fetal to adult hemoglobin:


Alpha Always; Gamma Goes, Becomes Beta.

BIRTH
Site of
erythropoiesis

Yolk

sac

L vc 1

0.1

Bone marrow

crn

'

40

Fetal (HbF )

Adult (HbAj)

If

% of total 30
globin synthesis

20
tmbryomc globins

10
Weeks: 6

12

18

FETUS (weeks)

24

50

12

18

POSTNATAL (months)

24

40

40

L
ADULT
0

RESPIRATORY

RESPIRATORY

Right lung has 3 lobes; Left has Less Lobes (2)


and Lingula ( homolog of right middle lobe).
Right lung is more common site for inhaled
foreign body because the right main stem
bronchus is wider and more vertical than
the left.

Lung relations

ANATOMY

625

SECTION III

Instead of a middle lobe, the left lung has a


space occupied by the heart.
The relation of the pulmonary artery to the
bronchus at each lung hilum is described by
RALS Right Anterior; Left Superior.

If you aspirate a peanut:


While upright enters inferior segment of
right lowed lobe.
While supine enters posterior segments of
right upper lobe or superior segment of right
lower lobcj

Trachea

Upper lobe
HON:: r t
1

fissure
Oblique
Assure

Middle lobe
Oblique fissure

Inferior lobe
Right
bronchus

Diaphragm structures
Central tendon
Inferior vena cava (T8)

Esophagus (T10)

< 10

Aorta CT12 )
Vertebrae
Inferior view
'

Lingula

Left
bronchus

Structures perforating diaphragm :


At T8: IVC , right phrenic nervel
At T10: esophagus, vagus (CN 10; 2 trunks)
* At T12: aorta ( red ), thoracic duct (white ),
azygos vein ( blue) ( At T-l-2 it's the red ,
white, and blue )
Diaphragm is innervated by C3, 4, and 5
( phrenic nerve). Pain from diaphragm
irritation (eg, air, blood , or pus in peritoneal
cavity) can be referred to shoulder (C 5 ) and
trapezius ridge (C3, 4).

*
R

Lower

Lowei

lobe
L

Anterior view

Posterior view

Number of letters = T level :


T8: vena cava
T10: oesophagus
T12: aortic hiatus

I ( IVC ) ate (8) ten ( 10) eggs (esophagus) at


(aorta ) twelve ( 12 ).
C 3, 4, 5 keeps the diaphragm alive.
Other bifurcations:
The common carotid bifourcates at C 4.
The trachea bifourcates at T4.

The abdominal aorta bifourcates at L4.

Revised
Figure

626

SECTION III

RESPIRATORY

RESPIRATORY

RESPIRATORY

PHYSIOLOGY

PHYSIOLOGY

Lung volumes

Inspiratory reserve
volume

Air that can still be breathed in after normal


inspiration

Tidal volume

Air that moves into lung with each quiet


inspiration, typically 500 mL

Expiratory reserve
volume

Air that can still be breathed out after normal


expiration
Air in lung after maximal expiration ; any lung
volume or capacity that includes RV cannot be
measured by spirometnj

Residual volume

Inspiratory capacity

Functional residual
capacity

IRV + TV
RV + ERV
Volume of gas in lungs after normal expiration ;
includes RV, cannot be measured bv

Lung volumes (LITER ):

6.0

Volume
(L)

IRV

TV

1C

VC

TLC

2.7

AAA)

2.2

ERV

1.2

RV

FRC

RV

A capacity is a sum of > 2 physiologic volumes.

spirometry!

Vital capacity

TV + 1RV + ERV
Maximum volume of gas that can be expired
after a maximal inspiration

Total lung capacity

IRV + TV + ERV + RV
Volume of gas present in lungs after a maximal
inspiration; includes RV, cannot be measured
by spirometry

Determination of
physiologic dead
space

,, . Paco2 - Pi .co:
V d ~ V t *.
VD = physiologic dead space = anatomic dead
w

space of conducting airways plus alveolar


dead space; apex of healthy lung is largest
contributor of alveolar dead space. Volume
of inspired air that does not take part in gas
exchange.
V j = tidal volume .
Paco2 = arterial Pco? .
PECO? = expired air Pco?.
Ventilation

Minute ventilation

< VE)
Alveolar ventilation
(VA

>

^ VEJLVD

Taco, Paco, PECO, Paco (refers to order of


variables in equation )
Physiologic dead space approximately
equivalent to anatomic dead space in normal
lungs. May be greater than anatomic dead
space in lung diseases with V/Q defects.
Pathologic dead space when part of the
respiratory zone becomes unable to perform
gas exchange. Ventilated but not perfused .

Total volume of gas entering lungs per minute


VE = VT x RR
Volume of gas per unit time that reaches alveoli

VA = ( VT - VD) x RR

Normal values:
Respiratory rate ( RR) = 12-20 breaths/min
VT = 500 mL/breath
VQ = 150 mL/breath

RESPIRATORY PHYSIOLOGY

RESPIRATORY

Lung and chest wall

Elastic recoil tendency for lungs to collapse


inward and chest wall to spring outward.
At FRC, inward pull of lung is balanced by
outward pull of chest wall, and system pressure
is atmospheric.
Elastic properties of both chest wall and lungs
determine their combined volume.
At FRC, airway and alveolar pressures are 0,
and intrapleural pressure is negative (prevents
atelectasij). PVR is at minimum.
Compliance change in lung volume for a
change in pressure; expressed as AV/AP and is
inversely proportional to wall stiffness. High
compliance = lung easier to fill (emphysema,
normal aging!lower compliance = lung
harder to fill ( pulmonary fibrosis, pneumonia,
NRDS, pulmonary edema!(Surfactant
increases compliance.
Hysteresis lung inflation curve follows a
different curve than the lung deflation curve

SECTION III

627

Chest wall

'

LC

Lung -chest
wall system

7
S

vT
FRC

Lung

-20

-10

30
0
10
20
Transorgan static pressure (cmH20)

40

Compliant lungs comply (cooperate) and fill


easily with air.

due to need to overcome surface tension forces


in inflation.

Hemoglobin ( Hb) is composed of 4 polypeptide


subunits ( 2 a and 2 (3) and exists in 2 forms:
T (taut; deoxvgenated) form has low affinity
for 02, thus promoting release /unloading of

Hemoglobin

07.
Heme

Fetal Hb ( 2a and 2y subunits) has a higher


affinity for 07 than adult Hb, driving diffusion
of oxygen across the placenta from mother to
fetus t 07 affinity results from i affinity of
HbF for 2,3-BPG.
Taut in Tissues.
Relaxed in Respiratory area.
,

R (relaxed; oxygenated) form has high


affinity for 07 ( 300x). Hb exhibits positive
cooperativitv and negative allostery
t Cl-, 11+, C07, 2,3 -BPG, and temperature favor
taut form over relaxed form (shifts dissociation Hemoglobin acts as buffer for H+ ions.
t 07 unloading).
curve right
,

628

SECTION III

Hemoglobin
modifications

Methemoglobin

RESPIRATORY PHYSIOLOGY

RESPIRATORY

Lead to tissue hypoxia from 1 07 saturation and i 07 content.

Oxidized form of Hb (ferric, Fe +) that does


not bind 07 as readily, but has t affinity for

cyanide.
Iron in Hb is normally in a reduced state
(ferrous, Fe2+).
Methemoglobinemia may present with cyanosis
and chocolate-colored blood.
Induced methemoglobinemia (using nitrites,
followed by thiosulfate) may be used to treat

Methemoglobinemia can be treated with


methylene blue and vitamin C.
Nitrites (eg, from dietary intake or polluted/high
altitude water source j) and benzocaine cause
poisoning by oxidizing Fe2+ to Fe+.
Fe2+ binds 07.

cyanide poisoning.
Carboxyhemoglobin

Form of Hb bound to CO in place of 07.


Causes l oxygen-binding capacity with left
shift in oxygen-hemoglobin dissociation curve.
i 07 unloading in tissues.
CO binds competitively to Hb and with 200x
greater affinity than 07.
Presents with headaches, dizziness, and cherry
red skin. May be caused by fires, car exhaust,
or gas heaters.
Treat with 100% 07 and hyperbaric 07.

-'

'
''' Nor

nal|100% Ibl

50% COHb

/i

4
0

^ 50% Hb

anemia)

20

40

60

80

100

Po ? (mm Hg)

Oxygen-hemoglobin dissociation curve

Sigmoidal shape due to positive cooperativitv


(ie, tetrameric Hb molecule can bind 4 07
molecules and has higher affinity for each
subsequent 07 molecule bound). Myoglobin
is monomeric and thus does not show

positive cooperativitv; curve lacks sigmoidal


appearance.
When curve shifts to the right, 1 affinity of Hb
for 07 (facilitates unloading of 07 to tissue).
An t in all factors (including H+) causes a shift
of the curve to the right.
A I in all factors (including H+) causes a left
shift 1 07 unloading -* renal hypoxia
t EPO synthesis compensatory
erythrocytosis. Lower = Left.
Fetal Hb has higher affinity for O-, than adult
Hb (due to low affinity for 23-BPG j so its
dissociation curve is shifted left.

Right shift ACE BATs right handed:


Acid

co7
Exercise
2,3-BPG

Altitude
Temperature
Myoglobin

Hemoglobin

Oxygenated blood
leaving the lungs

25

C
25

75
50
Po2 (mm Hg)

100

RESPIRATORY PHYSIOLOGY

RESPIRATORY

Oxygen content of
blood

SECTION III

629

O, content = (134 x Hb x Sao7) + (0.003 x Pao?)


Hb = hemoglobin level
Sao7 = arterial 07 saturation
Pao7 = partial pressure of Q,- in arterial blood

Normally 1 g Hb can bind 134 mL O,- ; normal Hb amount in blood is 15 g/dL.


07 binding capacity * 20.1 mL 07 /dL blood.
With 1 Hb there is 1 O-, content of arterial blood, but no change in 07 saturation and Pao7 .
07 deliver}' to tissues = cardiac output x O, content of blood.

CO poisoning

Hb concentration % 02 sat of Hb

Dissolved 02
(Pao2)

Normal

Normal

1 (CO competes

Total 02 content

with 07)

Pulmonary circulation

Anemia

Normal

Normal

Polycythemia

Normal

Normal

Normally a low-resistance, high-compliance


system. Po7 and Pco, exert opposite effects
on pulmonary and systemic circulation. A
i in PAO7 causes a hypoxic vasoconstriction
that shifts blood away from poorly ventilated
regions of lung to well-ventilated regions of
lung.
Perfusion limited Oz (normal health), CO,- ,
N70. Gas equilibrates early along the length of
the capillary. Diffusion can be t only if blood
flow t.
Diffusion limited 07 (emphysema, fibrosis),
CO. Gas does not equilibrate by the time
blood reaches the end of the capillary.

Perfusion limited (eg, C02, N20)

Diffusion limited (eg CO)

Equilibration

Length along pulmonary capillary

A consequence of pulmonary hypertension is cor


pulmonale and subsequent right ventricular
failure ( jugular venous distention, edema,

hepatomegaly).
Diffusion: Vgas = A x Dk x

hzh where

blood!
Oxygen

Normal

Partial pressure
difference between
alveolar air and
pulmonary capillary
blood

Length along pulmonary capillary

Pa = partial pressure of gas in pulmonary capillary blood


PA = partial pressure of gas in alveolar air

A = area, T = alveolar wall thickness,


Dj.(Pj P7) = difference in partial pressures:
A 1 in emphysema.
T t in pulmonary fibrosis.
D rn is the extent to which CO, a surrogate
tor oxygen, passes from air sacs of lungs into

*
^ *

Exercise

----

Fibrosis

Length along pulmonary capillary

632

SECTION III

RESPIRATORY

RESPIRATORY

RESPIRATORY

PATHOLOGY

Rhinosinusitis

PATHOLOGY

Obstruction of sinus drainage into nasal cavity inflammation and pain over affected area
( typically maxillary sinuses , which drain into the middle meatus, in adults).
Most common acute cause is viral URI; may cause superimposed bacterial infection, most
commonly S pneumoniae, H influenzae, M catarrhalis.

Epistaxis

Nose bleed. Most commonly occurs in anterior segment of nostril ( Kiesselbach plexus). Lifethreatening hemorrhages occur in posterior segment (sphenopalatine artery, a branch of maxillary
artery ). Common causes include foreign body, trauma , allergic rhinitis, and nasal angiofibroma

Head and neck cancer

Deep venous
thrombosis

Mostly squamous cell carcinoma . Risk factors include tobacco, alcohol , HPV-16 (oropharyngeal ),
EBV ( nasopharyngeal ). Field cancerization : carcinogen damages wide mucosal area multiple
tumors that develop independently after exposure

Blood clot within a deep vein swelling,


redness Q, warmth , pain. Predisposed by
Virchow triad (SHE ):
Stasis (eg, post-op, long drive /flight )
Hypercoagulability (eg, defect in
coagulation cascade proteins, such as
factor V Leiden )
Endothelial damage (exposed collagen
triggers clotting cascade)
D-dimer lab test used clinically to rule out DVT
( high sensitivity, low specificity).

Most pulmonary emboli arise from proximal


deep veins of lower extremity.
Homan sign forced dorsiflexionjof foot -* calf
pain .
Use unfractionated heparin or low-molecularweight heparins (eg, enoxaparin) for
prophylaxis and acute management .
Use oral anticoagulants (eg, warfarin,
rivaroxaban ) for treatment ( long-term
prevention ).
Imaging test of choice is compression ultrasound
with Doppleij

RESPIRATORY

Pulmonary emboli

RESPIRATORY PATHOLOGY

V/Q mismatch -* hypoxemia -* respiratory


alkalosis. Sudden-onset dyspnea, pleuritic
chesjl pain, tachypnea, tachycardia. Large
emboli or saddle embolus Q may cause
sudden death.
Lines of Zahn are interdigitating areas of pink
( platelets, fibrin) and red ( RBCs) found only in
thrombi formed before death; help distinguish
pre- and postmortem thrombi Q.
Types: Fat, Air, Thrombus, Bacteria, Amniotic
fluid, Tumor.
Fat emboli associated with long bone fractures
and liposuction; classic triad of hypoxemia,
neurologic abnormalities, petechial rash.
Amniotic fluid emboli can lead to D1C,
especially postpartum.
Air emboli nitrogen bubbles precipitate
in ascending divers (caisson disease,
decompression sickness); treat with hyperbaric
O-,; or, can be iatrogenic 2 to invasive
procedures (eg, central line placement).

SXZE
Nr

SECTION III

CT pulmonary angiography is imaging test of


choice for PE ( look for filling defects) Q.

An embolus moves like a FAT BAT.

633

634

SECTION III

RESPIRATORY PATHOLOGY

RESPIRATORY

LONG PAGE Please edit to lose lines.

Obstructive lung
diseases

Obstruction of air flow resulting in air trapping in lungs. Airways close prematurely at high lung
volumes t RV and T FRC, t TLC. PFTs: U FEVj, 1 FVC iFEV /FVC ratio ( hallmark),
V/Q mismatch. Chronic, hypoxic pulmonary vasoconstriction can lead to cor pulmonale. Digital
clubbing can be caused by bronchiectasis, but not COPD or asthmai

TYPE

PATHOLOGY

OTHER

Chronic bronchitis
("blue bloater " )

Hypertrophy and hvperplasiajof mucus-

Productive cough for > 3 months in a yea jfor


consecutive years.
Findings: wheezing, crackles, cyanosis (earlyonset hypoxemia due to shunting), late-onset
dyspnea, CO-, retention 2 polycythemia.
Chronic complications: pulmonary
hypertension, cor pulmonale.

secreting glands in bronchi - Reid index


(thickness of mucosal gland layer to thickness
of w all between epithelium and cartilage)

>po%.

Emphysema ("pink
puffer ")

Enlargement of air spaces, 1 recoil,


t compliance, 1 JQiresulting from
destruction of alveolar walls (arrow in Q). Tw o
types:
e
Centriacinar associated with
smoking Q Q. Frequently in upper lobes.
Panacinar associated w ith oq-antitrypsin

t elastase activity -* loss of elastic fibers


-* t lung compliance.
Exhalation through pursed lips to t airway
pressure and prevent airway collapse
Barrel-shaped chest 0. X-ray shows t AP
diameter, flattened diaphragm, t lung field

lucency.

deficiency. Frequently in lower lobes.


Asthma

Bronchial hyperresponsiveness causes reversible


bronchoconstriction. Smooth muscle hyper
trophy, Curschmann spirals Q (shed epithelium
forms whorled mucus plugs), and CharcotLeyden crystals (eosinophilic, hexagonal,
double-pointed, needle-like crystals formed
from breakdown of eosinophils in sputum).

Can be triggered by viral URIs, allergens, stress.


Aspirin-induced asthma: COX inhibition
leukotrienc overproduction airway
constriction. Associated with nasal polvpsj

Chronic necrotizing infection of bronchi

Associated with bronchial obstruction, poor


ciliary motility (eg, smoking, Kartagener
syndrome), cystic fibrosis 0, allergic

Bronchiectasis

permanently dilated airways, purulent


sputum, recurrent infections, hemoptysis,
-*

digital clubbing.

Clinical diagnosis can be supported by


spirometry and methacholine challenge.
Findings: cough, wheezing, tachypnea,
dyspnea, hypoxemia, l inspiratory/expiratory
ratio, pulsus paradoxus, mucus plugging Q.
Peribronchial cuffing on CXR .

bronchopulmonary aspergillosis.

U
\

&

A
->

7
*

RESPIRATORY PATHOLOGY

RESPIRATORY

SECTION III

635

Restricted lung expansion causes i lung volumes (I FVC and TLC). PFTs: FEVj /FVC ratio > 80%.
Patient presents with short, shallow breaths.

Restrictive lung
diseases

Types:
Poor breathing mechanics (extrapuhnonarv, peripheral hypoventilation, normal A-a gradient):
Poor muscular effort polio, myasthenia gravis, Guillain-Barre syndrome
Poor structural apparatus scoliosis, morbid obesity
Interstitial lung diseases ( pulmonary 1 diffusing capacity, t A-a gradient):
* Acute respiratory distress syndrome ( ARDS)
Neonatal respiratorv distress syndrome (NRDS; hyaline membrane disease)
Pneumoconioses (eg, coal workers pneumoconiosis silicosis, asbestosis)
Sarcoidosis: bilateral hilar lymphadenopathy, noncaseating granuloma; t ACE and Ca-+
Idiopathic pulmonary fibrosis Q (repeated cycles of lung injury and wound healing with
t collagen deposition, honeycomb lung appearance and digital clubbing)
pranulomatosis with polyangiitis ( Wegener)
H

W
T

Pulmonary Langerhans cell histiocytosis (eosinophilic granuloma)


Hypersensitivity pneumonitis
Drug toxicity (bleomycin, busulfan, amiodarone, methotrexate)_
Hypersensitivity pneumonitis mixed type III/IV hypersensitivity reaction to environmental
antigen. Causes dyspnea, cough, chest tightness, headache. Often seen in farmers and those
exposed to birds.

Obstructive lung volumes > normal ( t TLC, t FRC, t RV ); restrictive lung volumes < normal. In
obstructive, FEV| is more dramatically reduced compared with FVC
decreased FEVj /FVC
ratio. In restrictive, FVC is more reduced or close to same compared with FEV )
increased or
normal FEVi /FVC raticj

Flow volume loops

NORMAL

OBSTRUCTIVE

RESTRICTIVE

Loop shifts to the left

A
V /

vV

Loop shifts to the right

i; o

>

I
8

8.

\v_y7w
TLC-

0
4

Volume (L)

636

SECTION III

Pneumoconioses

Asbestosis

RESPIRATORY

RESPIRATORY

PATHOLOGY

Coal workers pneumoconiosis, silicosis, and


asbestosis t risk of cor pulmonale, cancer,
and Caplan syndrome ( rheumatoid arthritis
and pneumoconioses with intrapulmonary
)
nodules!
Associated with shipbuilding, roofing,
plumbing. Ivory white, calcified ,
supradiaphragmatic!El and pleural Q
plaques arej pathognomonic of asbestosis.

Risk of bronchogenic carcinoma > risk of


mesothelioma.
Berylliosis

Associated with exposure to beryllium in


aerospace and manufacturing industries.
Granulomatous on histology and therefore
occasionally responsive to steroids.

Coal workers'
pneumoconiosis

Prolonged coal dust exposure macrophages


laden with carbon -* inflammation and
fibrosis.
Also known as black lung disease.
Associated with foundries, sandblasting,
mines. Macrophages respond to silica
and release fibrogenic factors, leading to
fibrosis. It is thought that silica may disrupt
phagolysosomes and impair macrophages,
increasing susceptibility to I B .

Silicosis

'P,

Asbestos is from the roof (was common in


insulation ), but affects the base ( lower lobes ).
Silica and coal are from the base ( earth ), but
affect the roof ( upper lobes ).

Affects lower lobes.


Asbestos (ferruginous) bodies are golden-brown
fusiform rods resembling dumbbells 0,
found in alveolar sputum sample!visualized
using Prussian blue stain , often obtained by
bronchoalveolar lavage,
t risk of pleural effusions.
Affects upper lobes.

Affects upper lobes.


Anthracosis asymptomatic condition found in
many urban dwellers exposed to sooty air.
Affects upper lobes.
Chest x-rav shows eggshell calcification of
hilar lymph nodeil

:: i f

r?

<

RESPIRATORY

RESPIRATORY

Acute respiratory
distress syndrome

Diagnosis of exclusion characterized by


respiratory failure w ithin 1 week of alveolar
insult, bilateral lung opacities, I PaCVFIO-,
( hypoxemia due to t intrapulmonary shunfmg
and diffusion abnormalities ), no evidence
of HF/fluid overload . Caused by sepsis,
pancreatitis, pneumonia , aspiration , trauma ,
"

or shock . Endothelialdamage -*

PATHOLOGY

637

?
>

t alveolar

capillar}- permeability -* protein-rich leakage


into alveoli diffuse alveolar damage and
noncardiogenic pulmonary edema ( normal
PCWP) Q- Results in formation of intraalveolar hyaline membranes Q. Initial damage

SECTION III

rr r:

WL

'

due to release of neutrophilic substances


toxic to alveolar wall and pulmonary capillary
endothelial cells, activation offcoagulation
cascade, and oxygen-derived free radicals.
Management: mechanical ventilation with low
tidal volumes, address underlying cause.

Sleep apnea

Obstructive sleep

apnea

Repeated cessation of breathing > 10 seconds during sleep disrupted sleep -* daytime
somnolence. Normal Pao? during the day.
Nocturnal hypoxia systemic/pulmonary hypertension , arrhythmias (atrial fibrillation /flutter),
sudden death .
Hypoxia t EPO release t erythropoiesis.
Respiratory effort against airway obstruction . Associated with obesity, loud snoring. Caused by
excess parapharyngeal tissue in adults, adenotonsillar hypertrophy in children . Treatment: weight
loss, CPAP, surgery.

Central sleep apnea

No respiratory effort due to CNS injurv/toxicitv, HF, opioids. May be associated with CheyneStokes respiration . Treat with bilevel positive airway pressure (cm H -,Oi

Obesity
hypoventilation
syndrome

Obesity ( BMI

> 30 kg /m ~ ) hypoventilation t PaCO-, during waking hours ( retention ); 1 PaOi


and t PaCOo during sleep]

638

SECTION III

Pulmonary
hypertension

RESPIRATORY

RESPIRATORY PATHOLOGY

Normal mean pulmonary artery pressure = 10-14 mm Hg; pulmonary hypertension > 25 mm I Ig at
rest. Results in arteriosclerosis, medial hypertrophy, intimal fibrosis of pulmonary arteries. Course:
death from decompensated cor pulmonale.
severe respiratory distress cyanosis and RVH

ETIOLOGIES

Pulmonary arterial
hypertension

Idiopathic PAH.
Heritable PAH often due to an inactivating mutation in BMPR2 gene (normally inhibits vascular
smooth muscle proliferation); poor prognosis.
Other causes include drugs (eg, amphetamines, cocaine), connective tissue disease, HIV infection,
portal hypertension, congenital heart disease, schistosomiasis.

Left heart disease

Causes include systolic /diastolic dysfunction and valvular disease (eg, mitral lung).

Lung diseases or
hypoxia

Destruction of lung parenchyma (eg, COPD), lung inflammation/fibrosis ( eg, interstitial lung
diseases), hypoxemic!vasoconstriction (eg, obstructive sleep apnea, living in high altitude).

Chronic

Recurrent microthrombi -* 1 cross-sectional area of pulmonary vascular bed.

thromboembolic
Multifactorial

Causes include hematologic, systemic, and metabolic disorders.

Lung physical findings


ABNORMALITY

BREATH SOUNDS

PERCUSSION

FREMITUS

TRACHEAL DEVIATION

Pleural effusion

Dull

or away from side of


lesion (if large)

Atelectasis ( bronchial
obstruction)

Dull

Toward side of lesion

Simple pneumothorax

Hyperresonant

Tension
pneumothorax

Hyperresonant

Away from side of lesion

Consolidation
( lobar pneumonia,
pulmonary edema )

Bronchial breath
sounds; late inspiratory
crackles, egophonv,

Dull

bronchophonv,
whispered pectoriloqu\|

RESPIRATORY

Pleural effusions

RESPIRATORY PATHOLOGY

639

SECTION III

Excess accumulation of fluid between pleural layers Q -* restricted lung expansion during
inspiration. Can be treated with thoracentesis to remove fluid Q.

Transudate

1 protein content. Due to t hydrostatic pressure (eg, CHFj) or 1 oncotic pressure (eg, nephrotic
syndrome, cirrhosis).

Exudate

t protein content, cloudy. Due to malignancy, pneumonia, collagen vascular disease, trauma
(occurs in states of t vascular permeability). Must be drained due to risk of infection.

Lymphatic

Also known as chylothorax. Due to thoracic duct injury from trauma or malignancy. Milkyappearing fluid; t triglycerides.

Gf)
V
Pneumothorax

Pretreatment

Accumulation of air in pleural space Q. Dyspnea, uneven chest expansion. Chest pain, 1 tactile
fremitus, hvperesonace, and diminished breath sounds, all on the affected sidej

Primary spontaneous
pneumothorax

Due to rupture of apical subpleural bleb or cysts. Occurs most frequently in tall, thin, young males.

Secondary

Due to diseased lung (eg, bullae in emphysema, infections), mechanical ventilation with use of
high pressures barotrauma.

spontaneous

pneumothorax
Traumatic

Caused by blunt (eg, rib fracture) or penetrating (eg, gunshot) trauma.

pneumothorax
Tension

pneumothorax

Can be any of the above. Air enters pleural space but cannot exit. Increasing trapped air
pneumothorax. Trachea deviates away from affected lung Q. Needs immediate needle
decompression and chest tube placement.

r
r''

.
4

m.

tension

640

SECTION III

RESPIRATORY

RESPIRATORY

PATHOLOGY

Pneumonia
TYPE

TYPICAL ORGANISMS

Lobar

S pneumoniae most frequently, also

CHARACTERISTICS

Legionella,

Klebsiella
Bronchopneumonia

S pneumoniae, S aureus, H influenzae,

Klebsiella
Interstitial (atypical )
pneumonia

Mycoplasma , Chlamydophila pneumoniae


Chlamydia psittaci Legionella , viruses ( RSV,
CMV, influenza , adenovirus)

Bronchiolitis
obliterans organizing

Intra-alveolar exudate

consolidation Q; may
involve entire lobe Q or lung.
Acute inflammatory infiltrates H from
bronchioles into adjacent alveoli; patchy
distribution involving > 1 lobe 0.
Diffuse patchy inflammation localized to
interstitial areas at alveolar walls; diffuse
distribution involving > 1 lobe Q. Generally
follows a more indolent course ( walking
pneumonia ).
Noninfectious pneumonia characterized bv
inflammation of bronchioles and surrounding
structures. Caused bv chronic inflammatory

pneumonia

diseases (eg, rheumatoid arthritis ) or medication


side effects ( eg, amiodarone ). Negative sputum
and blood cultures, no response to antibiotics.

Lung abscess

1
*

Localized collection of pus within


parenchyma Q. Caused by aspiration of
oropharyngeal contents (especially in patients
predisposed to loss of consciousness [eg,
alcoholics, epileptics] ) or bronchial obstruction
(eg, cancer).
Treatment: clindamycin .

Air-fluid levels Q often seen on CXR. Fluid


levels common in cavities; presence suggests
cavitation . Due to anaerobes (eg, Bacteroides ,
Fusobacterium, Peptostreptococcus ) or S aureus.
Lung abscess 2 to aspiration is most often found
in right lung. Location depends on patient's
position during aspiration :
Upright inferio segments of right lower
5

lobe
Supine posterior segments of right upper
lobe or superior segment of right lower lobe

RESPIRATORY

RESPIRATORY PATHOLOGY

SECTION III

Mesothelioma

Malignancy of the pleura associated with


asbestosis. May result in hemorrhagic pleural
effusion (exudative), pleural thickening.

Pancoast tumor
( superior sulcus
tumor )

Carcinoma that occurs in the apex of lung Q may cause Pancoast syndrome by invading cervical

Psammoma bodies seen on histology.


Cytokeratin and calretinin in almost all
mesotheliomas, in most carcinomas.
Smoking not a risk factor.

sympathetic chain.
Compression of locoregional structures may cause array of findings:
Recurrent laryngeal nerve hoarseness
Stellate ganglion!- Horner syndrome (ipsilateral ptosis, miosis, anhidrosis)
s
Superior vena cava -* SVC syndrome_
Brachiocephalic vein brachiocephalic syndrome (unilateral symptoms)
Brachial plexus - sensorimotor deficit!

Superior vena cava


syndrome

An obstruction of the SVC that impairs blood


drainage from the head ( facial plethora;
note blanching after fingertip pressure in Q),
neck ( jugular venous distention), and upper
extremities (edema). Commonly caused by
malignancy ( eg, mediastinal mass, Pancoast
tumod) and thrombosis from indwelling
catheters Q. Medical emergency. Can raise
intracranial pressure (if obstruction is severe)
headaches, dizziness, t risk of aneurysm/
rupture of intracranial arteries.

MfU

LV

641

642

SECTION III

RESPIRATORY PATHOLOGY

RESPIRATORY

Leading cause of cancer death.


Presentation: cough, hemoptysis, bronchial
obstruction, wheezing, pneumonic coin
lesion on CXR or noncalcified nodule on CT.
Sites of metastases from lung cancer:
adrenals, brain, bone (pathologic fracture),
liver ( jaundice, hepatomegaly).
In the lung, metastases (usually multiple
lesions) are more common than 1
neoplasms. Most often from breast, colon,
prostate, and bladder cancer.

Lung cancer

TYPE

Superior vena cava syndrome


Pancoast tumor
Horner syndrome
Endocrine (paraneoplastic)
Recurrent laryngeal nerve compression
(hoarseness)
Effusions ( pleural or pericardial)
Risk factors include smoking, secondhand smoke,
radon, asbestos, family history.
Squamous and Small cell carcinomas are Sentral
(central) and often caused by Smoking.

LOCATION

CHARACTERISTICS

Central

Undifferentiated very aggressive.


Neoplasm of
neuroendocrine
May produce ACTH (Cushing syndrome), SI ADII, or
Antibodies against presynaptic Ca 2+ channels (LambertKulchitsky cells - small
dark blue cells CJ.
Eaton myasthenic syndrome) or neurons (paraneoplastic
myelitis, encephalitis, subacute cerebellar degeneration). Chromogranin A ,
neuron-specific
Amplification of myc oncogenes common. Managed
enolase .
with chemotherapy +/- radiation.

Peripheral

Most common lung cancer in nonsmokers and overall


(except for metastases). Activating mutations include
KRAS , EGFR , and ALK . Associated with hypertrophic
osteoarthropathy (clubbing).
Bronchioloalveolar subtype ( adenocarcinoma in situ):
CXR often shows hazy infiltrates similar to pneumonia;
better prognosis.
Bronchial carcinoid and bronchioloalveolar cell
carcinoma have lesser association with smoking.

Glandular pattern on
histology, often stains
mucin Q.
Bronchioloalveolar subtype:
grows along alveolar septa
apparent thickening
of alveolar walls. Tall,
columnar cells containing
Keratin pearls 0 and

Small cell
Small cell (oat cell )
carcinoma

SPHERE of complications:

HISTOLOGY

Non- small cell


Adenocarcinoma

Squamous cell
carcinoma

Central

Hilar mass arising from bronchus Q; Cavitation;


Cigarettes; hyperCalcemia (produces PTHrP).

Large cell
carcinoma

Peripheral

Highly anaplastic undifferentiated tumor; poor prognosis.


Less responsive to chemotherapy; removed surgically.
Strong association with smoking

Bronchial carcinoid
tumor

Excellent prognosis; metastasis rare.


Symptoms due to mass effect or carcinoid syndrome
(flushing, diarrhea, wheezing).

mucus.

intercellular bridges.
Pleomorphic giant
cells Ql
Nests of neuroendocrine
cells; chromogranin A .

Wm

m1& .
H

<

Is

ilti

nr,

0 '

1 V

RESPIRATORY

RESPIRATORY PHARMACOLOGY

SECTION III

643

RESPIRATORY PHARMACOLOGY
Antihistamines

Reversible inhibitors of Hj histamine receptors.

First generation

Diphenhydramine, dimenhydrinate,
chlorpheniramine.

CLINICAL USES

Allergy, motion sickness, sleep aid.

ADVERSE EFFECTS

Sedation, antimuscarinic, anti-a-adrenergic.

Second generation

Loratadine, fexofenadine, desloratadine,


cetirizine.

CLINICAL USES

Allergy.
Far less sedating than 1st generation because of

ADVERSE EFFECTS

Names contain -en /-ine or -en/-ate.

Names usually end in -adine.

i entry into CNS.

Guaifenesin

Expectorant thins respiratory secretions; does not suppress cough reflex.

!V-acetylcysteine

Mucolytic liquifies mucous in chronic bronchopulmonary diseases (eg, COPD, CF) by disrupting
disulfide bonds. Also used as an antidote for acetaminophen overdose.

Dextromethorphan

Antitussive (antagonizes NMDA glutamate receptors). Synthetic codeine analog. Has mild opioid
effect when used in excess. Naloxone can be given for overdose. Mild abuse potential. May cause
serotonin syndrome if combined with other serotonergic agents.

Pseudoephedrine, phenylephrine

-adrenergic agonists, used as nasal decongestants.

MECHANISM

(X

CLINICAL USE

Reduce hyperemia, edema, nasal congestion; open obstructed eustachian tubes. Pseudoephedrine
also illicitly used to make methamphetamine.

ADVERSE EFFECTS

Hypertension. Can also cause CNS stimulation/anxiety ( pseudoephedrine).

Pulmonary hypertension drugs


DRUG

MECHANISM

CLINICAL NOTES

BosENtan

Competitively antagonizes ENdothelin-1


receptors 1 pulmonary vascular resistance.

Hepatotoxic (monitor LFTs).

Sildenafil

Inhibits PDE-5 which t cGMP, thereby


prolonging vasodilatorv effect of nitric oxidej

Also used to treat erectile dysfunction

Epoprostenol, iloprost

PGI? (prostacyclin) with direct vasodilator)'


effects on pulmonary and systemic arterial
vascular beds. Inhibits platelet aggregation.

Side effects: flushing, jaw pain,

644

SECTION III

Bronchoconstriction is mediated by (1) inflammatory processes and ( 2) parasympathetic tone;


therapy is directed at these 2 pathways.

Asthma drugs

RESPIRATORY PHARMACOLOGY

RESPIRATORY

Albuterol relaxes bronchial smooth muscle (short acting ( -agonist) Used during acute
exacerbation.

agonists

Salmeterol, formoterol long-acting agents for prophylaxis. Adverse effects are tremor and

arrhythmia.
Inhaled
corticosteroids

Fluticasone, budesonide inhibit the synthesis of virtually all cytokines. Inactivate NF-KB, the
transcription factor that induces production of TNF-a and other inflammatory agents, lst-line
therapy for chronic asthma. May cause oral thrusht

Muscarinic
antagonists

Tiotropium, ipratropiumj competitively blocks muscarinic receptors, preventing


bronchoconstriction. Also used for COPD. Tiotropium is long acting.

Antileukotrienes

Montelukast, zafirlukast block leukotriene


receptors (CvsLTl ). Especially good for
aspirin-induced and exercise-induced asthmqj
Zileuton 5 -lipoxygenase pathway inhibitor.
Blocks conversion of arachidonic acid to
leukotrienes Hepatotoxic.

Exposure to antigen
(dust, pollen, etc)

I (3)

Avoidance

Antigen and IgE [-{3) Omalizumab


on mast cells

Omalizumab binds mostly unbound serum


IgE and blocks binding to FceRI. Used in
allergic asthma with t IgE levels resistant to
inhaled steroids and long-acting [ -agonists.

Anti- lgE monoclonal


therapy

I (3} Steroids

Theophylline likely causes bronchodilation


by inhibiting phosphodiesterase t cAMP
levels due to i cAMP hydrolysis. Usage is
limited because of narrow therapeutic index
(cardiotoxicity, neurotoxicity); metabolized
by cytochrome P- 450. Blocks actions of
adenosine.

Methylxanthines

Mediators
(leukotrienes, histamine, etc)

p -agonists
Theophylline
Muscarinic
antagonists

-GH

Steroids

H5>- Antileukotrienes

ATP

( )

AC | <

Bronchodilation

Q
ACh

Bronchial tone

0-agonists

Early response:
bronchoconstriction

Late response:
inflammation

cAMP

I PDEji

O
AMP

Adenosine

Muscarinic
antagonists

Theophylline

Symptoms

Bronchial
hyperreactivity

Theophylline

Bronchoconstriction

Methacholine

Muscarinic receptor (MJ agonist. Used in bronchial challenge test to help diagnose asthma.

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