Henry's Clinical Diagnosis and Management by Laboratory Methods Twenty-Third Edition 2017

CHAPTER
22 LABORATORY DIAGNOSIS
OF GASTROINTESTINAL AND
PANCREATIC DISORDERS
Haseeb A. Siddiqi,* Martin J. Salwen,* Mohammad F. Shaikh, Wilbur B. Bowne
PANCREATIC DISORDERS, 306 Diarrhea and Malabsorption, 312 Macroscopic Examination, 322
Pancreas in Systemic Disease, 306 Gastrointestinal Tumors, 318 Microscopic Examination, 322
Inflammatory Diseases of the Gastrointestinal Bleeding, 320 SELECTED REFERENCES, 322
Pancreas, 307 Markers for Gastrointestinal
GASTROENTEROLOGIC and Pancreatic Tumors, 321
DISORDERS, 310 STOOL COLLECTION AND
Peptic Ulceration, 310 EXAMINATION, 321
Zollinger-Ellison Syndrome, 311 Collection, 321
Diagnosis of pancreatic and gastrointestinal disease is guided by the

KEY POINTS patient’s history and the significant signs and symptoms. Findings with
• Almost all patients with duodenal ulcers and most with strong negative predictive values exclude some possible causes and focus
chronic gastritis have demonstrable Helicobacter pylori the differential diagnosis. Initially, noninvasive procedures are preferen-
infection. H. pylori stool antigen assays and urea breath tests tially performed. Patient preparation is as important as correct selection
are useful in diagnosis and in monitoring for eradication after of the diagnostic tests or procedures indicated. Endoscopy, when war-
treatment. ranted, can provide direct visualization of the entire gastrointestinal lumen
• Acute pancreatitis presents with abdominal pain and elevated levels and permits biopsy. Imaging-assisted invasive techniques may be required
of serum amylase or lipase. Reversible causes must be excluded in in the critically ill with gastrointestinal bleeding or obstruction. To ensure
patients with recurrent episodes of acute pancreatitis. Routine interpretable endoscopic results and to avoid false-positive and false-
laboratory testing is of limited value in diagnosing chronic negative results, stringent patient preparation is required. Similarly, testing
pancreatitis. requires appropriately collected specimens. Emphasis is given in this
chapter to frequently used diagnostic tests.
• Sweat chloride determination is the necessary initial test in the
workup for cystic fibrosis. Genetic testing can be used to identify the
mutations associated with this disease.
PANCREATIC DISORDERS
• Patients with chronic diarrhea should be evaluated for fecal blood,
fat, leukocytes, and stool pathogens (bacterial culture on routine PANCREAS IN SYSTEMIC DISEASE
media, ova, and parasite examination).
• Clostridium difficile should be considered a cause of diarrhea in Cystic Fibrosis
patients on antibiotic therapy or hospitalized for more than Cystic fibrosis (CF) is characterized by abnormally viscous mucous secre-
3 days. tions from the various exocrine glands of the body, including the pancreas,
salivary glands, and peritracheal, peribronchial, and sweat glands. Involve-
• Diagnostic evaluation of a patient suspected of celiac disease should
ment of the intestinal glands may result in the presence of meconium ileus
be initiated with anti–tissue transglutaminase immunoglobulin A and
total serum immunoglobulin A before placing the patient on a at birth. Two thirds of cases are diagnosed before 1 year of age. Chronic
gluten-free diet. lung disease and malabsorption resulting from pancreatic insufficiency are
the major clinical problems of those who survive beyond infancy, but intel-
• Primary lactose intolerance is common in adults, and secondary
ligence and cognitive functions are unaffected (Cheng et al, 1990).
lactose intolerance may occur in infection and in inflammatory bowel
CF is the most common genetic disorder in Caucasian North Ameri-
disease.
cans. It is an autosomal recessive disease of ion transport affecting the CF
• Positivity of perinuclear antineutrophil cytoplasmic antibody is most transmembrane conductance regulator (CFTR) gene on chromosome 7
often associated with ulcerative colitis and that of anti–Saccharomyces that encodes an epithelial chloride channel protein. Heterozygotes have
cerevisiae antibody with Crohn’s disease. no recognizable clinical symptoms. Homozygotes fully express the syn-
• Endoscopy has replaced gastric acid aspiration for diagnosis. Gastric drome of recurrent pulmonary infection, pancreatic insufficiency, steator-
acid output testing is useful when acid levels are very high or very rhea, and malnutrition. CF is due to defective epithelial chloride transport
low. across membranes, which causes abnormally dehydrated tenacious secre-
tions of all exocrine glands. The viscid inspissated mucous plug ducts cause
• Gastrin, the most powerful gastric acid stimulator, varies inversely
chronic inflammation with atrophy of acini, fibrosis, dilation, and cystic
with gastric acid secretion. Serum gastrin levels are elevated in gastric
atrophy, and gastric acid levels are reduced.
duct changes.
CF is often fatal in childhood, occurring in 1 in 3500 newborns.
• Secretin stimulates gastrin production in patients with Advances in treatment have increased the life span of CF patients; if
a gastrinoma but not in patients with other causes of current mortality rates continue, the average female patient will be
hypergastrinemia. expected to live until 37 years of age, and the average male patient will live
• Intraoperative gastrin measurements are useful in identifying whether until age 40 (MacKenzie et al, 2014). Ninety percent die from pulmonary
the abnormal tissue is completely removed in patients undergoing complications.
surgery for gastrinomas.
• A fecal occult blood test is used to screen for colon cancer.
*Corresponding authors. Each author contributed equally to this chapter.
306
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Overall, the prevalence in the United States is 1 in 3900, with the electrolyte values in adults must be approached with caution (Rosenstein
highest ethnic subgroup being Caucasians (1 in 2500), Ashkenazi Jews (1 & Cutting, 1998; NCCLS, 2000).
in 2300) and Native American tribes (1 in 10,900) (Palomaki et al, 2004). Pancreatic abnormalities occur in more than 80% of cases. The clinical
The Pueblo tribe in particular has been described as having a similar manifestations are varied. Islets of Langerhans are usually spared. No cure
incidence as Caucasians. It is also frequent in Hispanics but is uncommon is available. Persons heterozygous for the R117H mutation may develop
in Asians and blacks. More than 25,000 Americans have CF, and almost pancreatic insufficiency as the result of plugging of ducts, causing idio-
PART 2
1000 new cases are diagnosed each year. The incidence is 1 in 1600 Cau- pathic chronic pancreatitis (Durie, 2000).
casian births and 1 in 17,000 African American births in the United States.
Approximately 1 in every 20 Caucasians is a carrier of one of the alleles. Hemochromatosis
Nearly 2000 mutations of the CFTR gene have been identified. Available Excessive body iron accumulation from any source is directly toxic to cells
probes can be used to test for 70 mutations that account for over 90% of and causes fibrosis. Symptoms include the triad of bronze coloration of
cases of CF. Genetic testing can identify the mutations associated with CF the skin, cirrhosis, and diabetes. Humans have no major iron excretory
(Weiss et al, 2005). pathway. In this disease, the pancreas is slightly enlarged and deep brown
The degree of the defect depends on the nature of the mutation. as the result of accumulated hemosiderin, the iron-containing pigment.
Several characterized mutations lead to a milder form of the disease. The When untreated, progressive fibrosis of the pancreas with atrophy occurs.
classic δ F508 mutation leads to CF when two copies of the gene are Iron is deposited in the acinar and duct cells and in the β cells of the islets.
inherited. Other cells of the islets appear spared. Similar pigments are noted in the
Because of multiple alleles at the cystic fibrosis gene, the demonstration skin. β-cell loss results in bronze diabetes. Hypogonadism with pituitary
of increased chloride in the sweat is a necessary initial test in the diagnosis dysfunction is present in half of cases, and cardiomegaly and osteoarthritis
of CF. Until 1996, sweat chloride testing was employed most often in are present in most cases. Cirrhosis is seen in 70% of cases. Hepatocellular
response to clinical developments or family history. carcinoma (HCC) occurs in 30% of cases
More recently, screens for CF have been developed that involve first Secondary hemochromatosis is typically seen in anemia caused by mul-
an immunoassay for immunoreactive trypsinogen (IRT). Trypsinogen is tiple blood transfusions, hemolytic anemias, or increased oral iron intake,
the inactive, proenzyme form of trypsin secreted by pancreatic acinar cells; which result in excess iron storage.
the active enzyme form is produced by proteolytic cleavage by proteases, Hereditary hemochromatosis (HH) is a human leukocyte antigen
including activated trypsin itself, of an N-terminal peptide segment result- (HLA)–linked autosomal recessive defect in duodenal iron absorption
ing in the active form of this enzyme. There are several forms of trypsino- regulation. As discussed in Chapters 21 and 23, the HFE gene is on the
gen, one of which is IRT; there are two forms of proenzyme: a cationic short arm of chromosome 6. In this common genetic disease, the homo-
form (IRT1) and an anionic form (IRT2). Both forms have been found to zygosity frequency is 1 in 220. When HH is diagnosed, other family
become elevated in a number of different gastrointestinal diseases such as members should be screened; one-quarter of siblings will test positive
CF, meconium ileus, and diseases of the pancreas, including pancreatic (Powell et al, 1996; Bulaj et al, 2000; Beutler et al, 2002). HCC has
steatorrhea and pancreatic carcinoma. ELISA tests have been developed become a chief cause of death in HH (Barton et al, 1998).
for each form (Lindau-Sheppard & Pass, 2010), although most antibodies A number of diagnostic strategies exist (Jensen, 2004). Because the liver
used for the assay recognize both forms. is the major site of the body’s iron storage, liver biopsy remains the gold
With the widespread adoption of newborn screening for CF (e.g., IRT, standard of diagnosis. Given the possibility of complications associated
with or without DNA analysis for known CFTR mutations), sweat chlo- with this invasive procedure, and the potential patient coagulopathy, other
ride testing is now typically performed only when an abnormal result for screening methods are first performed, with biopsy only employed as a
these screens is found (Farrell et al, 2008). confirmatory measure (Powell, 2002; Jensen, 2004). The screening test
Using the long-established Gibson-Cooke method, pilocarpine is consists of transferrin saturation (TS) = serum iron ÷ total iron binding
introduced into the skin by iontophoresis to stimulate locally increased capacity × 100. Results are interpreted as abnormal if greater than 60% in
sweat gland secretion. The resulting sweat is absorbed by filter paper or women and greater than 50% in men (Powell, 2002). Other tests, such as
gauze and is weighed, diluted with water, and analyzed for sodium and serum ferritin, serum ferritin iron, hepcidin, and imaging with MRI are
chloride concentrations. Total body sweating in patients with cystic fibrosis also employed (Jensen, 2004; Konz et al, 2014). In HH, genetic testing for
is hazardous, and a number of deaths from the procedure have been mutations in HFE, transferrin receptors, ferroporitin, and hepcidin can
reported. help with diagnosis.
When performed properly in duplicate, the sweat test has a sensitivity
of 90% to 99%. High rates of incorrect results have been attributed to
problems associated with sweat specimen sample collection and test analy-
INFLAMMATORY DISEASES OF THE PANCREAS
sis (National Committee for Clinical Laboratory Standards [NCCLS], Pancreatitis is an inflammation of the pancreas caused by injury to acinar
2000; LeGrys et al, 2007; Farrell et al, 2008). cells due to activation of digestive enzymes within the pancreatic paren-
More than 99% of children with CF have concentrations of sweat chyma; it is characterized by significant morbidity and mortality. Clinical
chloride greater than 60 mmol/L. The sweat chloride may not be as dra- manifestations of pancreatitis are highly variable.
matically increased in adolescent or adult patients. The test needs to be
performed with care (LeGrys et al, 2007). Acute Pancreatitis
In children, chloride concentrations greater than 60 mmol/L in sweat Acute reversible inflammation is due to enzymatic necrosis. Acute pancre-
on at least two occasions are diagnostic. Levels of between 50 and atitis occurs at any age—usually 30 to 70 years—but is rare in children. Its
60 mmol/L are suggestive in the absence of adrenal insufficiency. Patients diagnosis is based on the presence of two out of the following three condi-
in whom CF is suspected on the basis of indeterminate sweat electrolyte tions: abdominal pain consistent with acute pancreatitis (typically acute
results may undergo confirmatory testing following administration of a onset, epigastric, with other causes ruled out); serum amylase and/or lipase
mineralocorticoid such as fludrocortisone. In those patients with CF, elec- activity greater than triple the upper limit of the normal reference range;
trolyte values would remain unchanged, whereas normal controls would and imaging evidence of acute pancreatitis (Morinville et al, 2012). Clini-
show a decrease in sweat electrolytes. Sodium concentrations in sweat cal suspicion is supported by findings of elevated serum amylase and/or
tend to be slightly lower than those of chloride in patients with CF, but lipase (Table 22-1).
the reverse is true in normal subjects. Sweat chloride concentrations In 30% of patients, the diagnosis of acute pancreatitis was not suspected
greater than 60 mmol/L may be found in some patients with malnutrition, and was made only at autopsy (Wilson et al, 1985). Many causes have been
hyperhidrotic ectodermal dysplasia, nephrogenic diabetes insipidus, renal identified. Gallstones continue to be the leading cause (30% to 60%), and
insufficiency, glucose-6-phosphatase deficiency, hypothyroidism, muco- alcohol is the second most common cause (responsible for 15% to 30% of
polysaccharidosis, and fucosidosis. These disorders usually can be easily cases). Other causes include duct obstruction due to tumors or parasites,
differentiated from CF by their clinical symptoms. False-negative sweat duct anomalies such as pancreas divisum, infections (mumps, coxsackievi-
test results have been seen in patients with CF in the presence of hypo- rus A), blunt trauma or post endoscopic retrograde cholangiopancreatog-
proteinemic edema. raphy (ERCP), many drugs (diuretics, sulfonamides), organophosphates,
Sweat electrolytes in about half of a group of premenopausal adult methyl alcohol, nitrosamines, hypertriglyceridemia, and hypercalcemia.
women were shown to undergo cyclic fluctuation, reaching a peak chloride
concentration most commonly 5 to 10 days before the onset of menses. Amylase
Peak values were slightly less than 65 mmol/L. Men showed random Amylase in serum and urine is stable for 1 week at ambient temperature
fluctuations up to 70 mEq/L. For this reason, interpretation of sweat and for at least 6 months under refrigeration in well-sealed containers.
307
Plasma specimens that have been anticoagulated with citrate or oxalate be 62% and 93%, respectively (Hofmeyr et al, 2014). Serum amylase levels
22 LABORATORY DIAGNOSIS OF GASTROINTESTINAL AND PANCREATIC DISORDERS
should be avoided for amylase determination because amylase is a calcium- do not correlate with cause or severity of pancreatitis. The pancreas con-
containing enzyme. Heparinized plasma specimens do not interfere with tributes 40% of the total serum amylase; the rest comes mostly from the
the amylase assay. salivary glands (Halangk & Lerch, 2005).
Diagnosis is confirmed by detection of elevated serum amylase three- Although a variety of reliable amylase methods are available, care is
fold above normal. It peaks in 20 to 30 hours, often at 10 to 20 times the required in specimen handling. Caution must be exercised to avoid con-
upper reference limit (Papachristou & Whitcomb, 2005). Amylase returns tamination of specimens with saliva, because its amylase content is approxi-
to normal in 48 to 72 hours. Elevated values persisting longer than this mately 700 times that of serum. Red cells contain no amylase, so hemolysis
suggest continuing necrosis or possible pseudocyst formation. Amylase does not affect most methods, except those coupled-enzyme methods in
continues to be a first-line test for acute pancreatitis in current clinical which the released peroxide is determined by a coupled-peroxidase
practice despite certain problematic issues. Serum amylase has poor sen- reaction.
sitivity for pancreatitis; it is not increased in about 20% of patients with The urine amylase activity rises promptly, often within several hours
pancreatitis. Serum amylase increases nonspecifically in many acute of the rise in serum activity, and may remain elevated after the serum level
abdominal conditions. In hyperlipidemic patients with pancreatitis, normal has returned to the normal range. Values greater than 1000 Somogyi units/
serum and urine amylase levels are frequently encountered. The spuriously hour are seen almost exclusively in patients with acute pancreatitis. In a
normal levels are believed to be the result of suppression of amylase activity majority of patients with acute pancreatitis, serum amylase activity is ele-
by triglyceride or by a circulating inhibitor in serum. A recent series found vated, and a concomitant increase in urine amylase activity occurs.
the sensitivity and specificity for serum amylase for acute pancreatitis to Increased renal clearance of amylase can be used in the diagnosis of acute
and relapsing pancreatitis, but the ratio of amylase clearance to creatinine
clearance expressed as a percentage adds little to the diagnosis, because
elevated ratios may be found in unrelated conditions.
Lower than normal serum amylase activity may be found in patients
TABLE 22-1 with chronic pancreatitis and has been seen in such diverse conditions as
Laboratory Tests in Acute Pancreatitis congestive heart failure, pregnancy (during the second and third trimes-
ters), gastrointestinal (GI) cancer, bone fracture, and pleurisy.
Laboratory Test Purpose Usage and Limitations Serum amylase may be elevated in patients with pancreatic carcinoma
but often too late to be diagnostically useful. Serum amylase activity may
Amylase Diagnosis Accurate over 3× the upper normal
also be elevated in patients with cholecystitis, peptic ulcer, renal transplant,
limit; decreased specificity in renal
viral hepatitis, or ruptured ectopic pregnancy, or after a gastrectomy.
failure; elevated in
macroamylasemia;
Increased ascites fluid amylase levels have been seen in patients with
hypertriglyceridemia interferes; pancreatitis, a leaking pancreatic pseudocyst, pancreatic duct rupture, pan-
elevated from other sources such creatic cancer, abdominal tumors that secrete amylase, and perforation of
as salivary glands and/or a hollow viscus. Fractionation of amylase in serum, urine, and other body
intraabdominal inflammation (not fluids can be done by physical means, such as electrophoresis, chromatog-
above 3×); can be normal in raphy, or isoelectric focusing; each isoenzyme is then quantitated by direct
alcohol-induced pancreatitis densitometry.
Lipase Diagnosis Decreased specificity in renal failure;
Macroamylasemia
immune complexes create false
positives; elevated from salivary Macroamylasemia is not a disease, but an acquired benign condition that
glands and intraabdominal is more frequent in men and is usually discovered incidentally in the fifth
inflammation through seventh decades (Remaley & Wilding, 1989). A persistent increase
Trypsinogen 2 Diagnosis Limited use; unclear if superior to in serum amylase is seen without clinical symptoms. Urine amylase is
amylase/lipase normal or low. Macroamylases are heterogeneous complexes of normal
AST/ALT Etiology If greater than 3× upper normal amylase (usually salivary isoenzyme) with immunoglobulin (Ig)G, IgA, or
limit, gallstones present as polysaccharide (Van Deun et al, 1989). Because of their large size, mac-
etiology in 95% of cases. Low roamylases cannot be filtered through the glomerulus and are retained in
sensitivity the plasma; they are not present in urine. Plasma amylase activity is often
Lipase/amylase Etiology >5 is diagnostic for alcohol-induced increased two- to eightfold. Serum lipase is normal. Macroamylasemia is
ratio acute pancreatitis. Low sensitivity found in about 1% of randomly selected patients. Renal function is normal,
and the amylase/creatinine clearance ratio is low (Table 22-2).
CDT Etiology Useful in patients who deny alcohol;
remains elevated for weeks after Lipase
binge drinking; not widely
available The pancreas is the major and primary source of serum lipase. Human
pancreatic lipase is a glycoprotein with a molecular weight of 45 kDa.
Hematocrit Severity >44% on admission, or rising over
Lipase is not present in the salivary glands. Lipases are defined as enzymes
initial 24 hrs; associated with
pancreatic necrosis
that hydrolyze preferentially glycerol esters of long-chain fatty acids at the
carbon 1 and 3 ester bonds, producing 2 moles of fatty acid and 1 mole of
C-reactive protein Severity >150 mg/L associated with
β-monoglyceride per mole of triglyceride. After isomerization, the third
pancreatic inflammation. Useful
fatty acid can be split off at a slower rate. Lipolysis increases in proportion
after first 36-48 hrs
to the surface area of the lipid droplets, and the absence of bile salts in
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; CDT, carbohydrate- duodenal fluid with resultant lack of emulsification renders lipase
deficient transferrin. ineffective.
TABLE 22-2
Differential Diagnosis of Hyperamylasemia and Macroamylasemia
Condition Serum Amylase Serum Lipase Urinary Amylase Cam :Ccr Serum Macroamylase
Pancreatic hyperamylasemia High High High High Absent

Salivary hyperamylasemia High Normal Low or normal Low or normal Absent
Macroamylasemia High Normal Low Low High
Adapted from Kleinman DS & O’Brien JF: Macroamylase, Mayo Clin Proc 61:669–670, 1986.
Cam:Ccr = amylase clearance:creatinine clearance ratio = (urinary amylase/serum amylase) × (serum creatinine/urinary creatinine).
308
Serum lipase has been described as a better first-line test for diagnosis Serum trypsinogen 2 levels rise rapidly, showing a tenfold to twentyfold
of acute pancreatitis than serum amylase. It has a sensitivity and specificity increase. Urinary concentrations are even more steeply elevated. A recent
of 92% and 91%, respectively (Hofmeyr et al, 2014). Serum lipase increases meta-analysis of 18 trials investigating the diagnostic utility of urinary
in 4 to 8 hours and remains elevated for 8 to 14 days. Increased lipase trypsinogen-2 in acute pancreatitis demonstrated a pooled sensitivity and
activity rarely lasts longer than 14 days; prolonged increases suggest a poor specificity of 80% and 92%, respectively. The pooled sensitivity and speci-
prognosis or the presence of a pancreatic cyst. Hyperglycemia and elevated ficity for post-ERCP pancreatitis in this same analysis were 86% and 94%,
PART 2
bilirubin concentrations may be present, and leukocytosis is frequently respectively (Jin et al, 2013). Irrespective of the cause, all origins allow
reported. activation of the inactive proenzyme trypsinogen to trypsin, which then
Pancreatic lipase must be differentiated from lipoprotein lipase, alies- activates most of the other digestive enzymes and produces tissue damage
terase, and arylester hydrolase, which are related but different enzymes. and necrosis of the pancreas, surrounding fat, and adjacent structures.
The activities of these enzymes may be included in the measurement of Other enzymes that have been proposed as diagnostic tools include
lipase activity unless suitable assay conditions for pancreatic lipase are pancreatic isoamylase, phospholipase A, elastase 1, and trypsinogen 2
adapted. Lipase is also present in liver, stomach, intestine, white blood (Forsmark & Baillie, 2007). Other tests (aspartate aminotransferase,
cells, fat cells, and milk. alanine aminotransferase, C-reactive protein [CRP], hematocrit,
Calcium is necessary for maximal lipase activity, but at higher concen- carbohydrate-deficient transferrin [CDT], and trypsinogen activation
trations it has an inhibitory effect. It is speculated that the inhibitory effect peptide [TAP]) have shown low sensitivity for diagnosing acute pancreati-
is due to its interference with the action of bile salts at the water/substrate tis. CDT is a marker for chronic alcoholism. Urinary TAP is a valuable
interface. Similar to serum albumin, bile salts prevent the denaturation of marker for severity of pancreatitis. Markers of inflammatory response (e.g.,
lipase at the interface. Heavy metals and quinine inhibit lipase activity. CRP) peak, following interleukin (IL)-1 and IL-6 increases, on day 3 after
Lipase is filtered by the glomeruli owing to its low molecular weight; onset of abdominal pain; this is useful in predicting the severity of pancre-
it is normally completely reabsorbed by the proximal tubules and is absent atitis (Smotkin & Tenner, 2002).
from normal urine. In patients with failure of renal tubular reabsorption A computed tomography (CT) scan is the most useful test to establish
caused by renal disorders, lipase is found in the urine. Urine lipase activity the diagnosis, with characteristic radiologic findings of enlarged edematous
in the absence of pancreatic disease is inversely related to creatinine and inflamed pancreas with or without surrounding fluid collection, with
clearance. or without necrosis. An ultrasonogram may be useful in showing a diffusely
Serum lipase is stable up to 1 week at room temperature and may be enlarged, hypoechoic pancreas, and may show the presence of gallstones
kept stable longer if it is refrigerated or frozen. The optimal reaction in the gallbladder, indicating a possible cause. A CT severity score (the
temperature is about 40° C. The optimal pH is 8.8, but other values Balthazar score) is based on the degree of necrosis, inflammation, and fluid
ranging from 7.0 to 9.0 have been reported. This difference probably is collection. A 23% mortality rate is associated with any degree of pancreatic
due to the effects of differences in types of substrate, buffer, incubation necrosis, and a strong association has been noted between necrosis and
temperature, and concentrations of reagents used. Serum is the specimen morbidity and mortality. After initial assessment, a CT scan need not be
of choice for blood lipase assays. Icterus, lipemia, and hemolysis do not repeated unless one suspects development of a complication such as pan-
interfere with turbidimetric lipase assays. creatic necrosis. Magnetic resonance imaging (MRI) is being used increas-
Both serum lipase and amylase are useful in ruling out acute pancre- ingly to detect pancreatitis and to characterize the pancreatic necrosis seen
atitis. Although determination of serum lipase has diagnostic advantages on CT into peripancreatic necrotic fluid collection, necrotic pancreatic
over serum amylase for acute pancreatitis, this value is not specific for acute parenchyma, and hemorrhagic foci. MRI can also detect pancreatic duct
pancreatitis. Serum lipase may also be elevated in patients with chronic disruption, seen early in the course of acute pancreatitis.
pancreatitis, obstruction of the pancreatic duct, and nonpancreatic condi- Serum and urine amylase elevations occur in many conditions other
tions, including renal disease, acute cholecystitis, intestinal obstruction or than pancreatitis, such as renal failure, parotitis, and diabetic ketoacidosis.
infarction, duodenal ulcer, and liver disease, as well as alcoholism and Patients with acidemia may have spurious elevations of serum amylase.
diabetic ketoacidosis, and in patients who have undergone ERCP. Patients This explains why patients with diabetic ketoacidosis may have marked
with trauma to the abdomen uniformly have increases in both serum elevations of serum amylase without evidence of acute pancreatitis. No
amylase and lipase. Elevation of serum lipase activity in patients with data indicate that measuring both amylase and lipase adds significant diag-
mumps strongly suggests significant pancreatic involvement by the disease. nostic accuracy. Once the diagnosis is established, daily measurement of
amylase or lipase provides little value in gauging the clinical course or the
Trypsinogen prognosis.
Trypsin is produced in the exocrine pancreas as two proenzymes, known Predictors of severe acute pancreatitis include hematocrit greater than
as trypsinogen 1 and trypsinogen 2. These proenzymes are activated in the 44% with failure to decrease at 24 hours (this is indicative of pancreatic
duodenum by an enterokinase that yields trypsin 1 and trypsin 2, respec- necrosis and is predictive of organ failure) and C-reactive protein greater
tively. Trypsin present within the peripheral circulation is inactivated by than 150 mg/L. Serum creatinine greater than 2.0 mg/dL or marked
complexing with α-2-macroglobulin or α-1-antitrypsin (AAT). Trypsin, hyperglycemia (>150 mg/dL) is predictive of mortality (Lankisch et al,
unlike amylase, is produced solely by the pancreatic acinar cells and there- 2001). A strong association has been found between the extent of blood
fore is a specific indicator of pancreatic damage. Premature activation of urea nitrogen (BUN) increase and mortality at 24 hours. Each increase in
the proenzyme to active trypsin within the pancreatic parenchyma is BUN of 5 mg/dL was associated with a corresponding increase in mortal-
thought to be a key mechanism in the development of acute pancreatitis ity. A reduction in blood urea was associated with significantly improved
(Andersen et al, 2001). Currently, levels of all forms of trypsin are deter- survival (Wu et al, 2009) (Table 22-3). One serum marker of interest is
mined by specific immunoassays. cytokeratin 8, a cytoskeletal protein and marker of apoptosis. Higher
Trypsin assays are currently used to differentiate the cause of an acute cytokeratin 8 levels have been shown to be associated with a milder clinical
episode of pancreatitis. One study demonstrated that trypsinogen 2 and course of acute pancreatitis (Koruk et al, 2012).
trypsin-2-AAT are increased in all forms of acute pancreatitis but are more Hemorrhagic pancreatitis, a severe form of acute pancreatitis, results
elevated in alcohol-associated pancreatitis than in biliary pancreatitis. from necrosis within and around the pancreas with hemorrhage that may
Trypsinogen 1, amylase, and lipase were found to be more elevated in cause shock and death. Initially, necrosis is coagulative, but necrotic cells
patients with biliary pancreatitis. Furthermore, the ratio of serum trypsin- rapidly undergo liquefaction. Biliary tract disease with gallstones or
2-AAT to trypsinogen 1 was determined to be the best discriminator inflammation of the gallbladder or bile ducts, or alcoholism, is present in
between biliary and alcoholic pancreatitis (Andersen et al, 2001). Another about 80% of patients. The male/female ratio is 1 : 3 in acute pancreatitis
study supported the use of trypsin assays for the diagnosis of acute pan- associated with biliary tract disease and 6 : 1 in alcoholism. Pancreatic
creatitis, because the determined time course profile of trypsinogen 2 and microlithiasis may be responsible for many cases.
trypsin-2-AAT is appropriate for diagnostic purposes. These enzymes are The sequence of changes following release of activated intrapancreatic
elevated within hours of onset of the acute episode and therefore are enzymes in acute pancreatitis consists of microvascular leakage causing
already elevated upon admission; this is followed by a rapid rise. Both edema, necrosis of fats, and acute inflammatory reaction. Proteolytic
enzyme levels remain elevated longer than amylase, and the magnitude of destruction of pancreatic tissue and blood vessels causes edema and focal
elevation corresponds to the severity of pancreatic inflammation, which is dilation of acini with variable amounts of hemorrhage. In fat necrosis,
extremely useful for diagnosing acute pancreatitis upon admission, for neutral fats are broken down, glycerol is reabsorbed, and fatty acids
predicting severity of illness, and for monitoring disease progression combine with calcium salts to form soaps (saponification) with a zone of
(Kemppainen et al, 2000). Elevated trypsin-1-ATT has also been demon- acute inflammation around the foci of necrosis. After a few days, secondary
strated in patients with biliary tract cancer (Andersen et al, 2001). infection with suppuration and abscesses may occur.
309
TABLE 22-3 The central enzyme involved in activation of all digestive proenzymes
Laboratory Findings in Acute Pancreatitis is trypsin, which is synthesized and maintained as inactive trypsinogen in
secretory granules in the pancreatic acinar cell. After release into the
At Presentation At 48 Hours pancreatic duct, trypsinogen is cleaved by enterokinase on the brush
border of the duodenum to active trypsin. Trypsin is stabilized in the
Age >55 Hematocrit Fall by >10% pancreatic acini by a serine protease inhibitor, SPINK1. Mutations in
Leukocyte >16,000/mm3 Urea nitrogen Increase by >5 mg/ SPINK1 increase the risk of chronic pancreatitis almost twelvefold by
count dL despite fluids impairing the ability of acinar cells to counteract and inhibit the damaging
Blood glucose >200 mg/dL Serum calcium <8 mg/dL effects of intracellular trypsin (Schneider et al, 2004; DiMagno &
LD 350 U/L pO2 <60 mmHg DiMagno, 2005). PRSS1 mutations involving codons 29 and 122 cause
AST >250 U/L Base deficit >4 mEq/L autosomal dominant forms of hereditary pancreatitis (Whitcomb, 2000;
Fluid sequestration >6000 mL Cohn et al, 2005).
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; LD, lactate dehy-

drogenase; pO2, partial pressure of oxygen.
GASTROENTEROLOGIC DISORDERS
PEPTIC ULCERATION
In 15% to 30% of those with pancreatic necrosis, poorly defined areas Helicobacter pylori has been recognized as the principal cause of duodenitis
of acute fluid collection occur, along with fibrosis. The liquefied areas are and duodenal ulcers, and it has been strongly associated with chronic antral
walled off, and pseudocysts form. Pseudocysts contain pancreatic fluid gastritis, gastric ulcer, nonulcer dyspepsia, gastric carcinoma, and mucosa-
enclosed in fibrous tissue with no epithelial lining; they often communicate associated lymphatic tissue lymphoma (Peterson, 1991; Veldhuyzen van
with a pancreatic duct and continue to increase in mass. Zanten & Sherman, 1994; Thiede et al, 1997; Wotherspoon, 1998). The
use of nonsteroidal anti-inflammatory drugs (NSAIDs) causes or aggra-
Complications of Acute Pancreatitis vates peptic and gastric inflammation and ulceration. Hypersecretory
Hypocalcemia and mild jaundice may appear after 24 hours as the result states are a much rarer cause of peptic ulcer disease. Data gathered by
of biliary obstruction. A sepsis-like syndrome due to digestive enzymes in history and physical examination may initially suggest peptic ulcer disease.
the systemic circulation may cause the release of inflammatory cytokines, Radiologic and/or endoscopic techniques are employed to confirm the
a systemic immune response syndrome with severe systemic complications. diagnoses. Testing for H. pylori and hypersecretory states involves labora-
About 75% of patients with acute pancreatitis have a benign course and tory analysis.
recover rapidly. No treatment has proven to interrupt the inflammatory Because H. pylori has been shown to be the most important cause of
process effectively. peptic ulcer disease and is significantly associated with multiple other types
Idiopathic acute pancreatitis occurs in about 10% to 20% of patients of upper GI pathology, a great deal of research has focused on its detection
with pancreatitis. It is believed that many cases are germline mutations of and treatment and on confirmation of pathogen eradication. Within the
cationic trypsinogen (PRSS1) (see earlier) or serine protease inhibitor, last decade, numerous products used for the detection of this bacterium
kazal type 1 (SPINK1). There is high risk for development of endocrine have become commercially available. The American College of Gastroen-
or exocrine insufficiency and pancreatic adenocarcinoma. These mutations terology recommends H. pylori testing in individuals with peptic ulceration
can cause an autosomal recessive hereditary acute or chronic pancreatitis but leaves the clinician considerable discretion in choosing the diagnostic
with onset in childhood or early adulthood. PRSS1 abrogates the inactiva- modality, because no one test is recognized as the gold standard (Chey
tion of trypsinogen for cleavage of trypsin. SPINK1 mutation inactivates et al., 2007). Although the numbers and types of tests will likely continue
pancreatic secretory trypsin inhibitor (Howes et al, 2005; Schneider, to grow, tissue sampling, breath tests, and fecal antigen detection are cur-
2005). rently the mainstay in the diagnostic armamentarium. The incidental use
Patients with these disorders typically have recurrent acute pancreatitis of proton pump inhibitors (PPIs), antibiotics, or bismuth-containing ant-
sometime between infancy and the fourth decade. Chronic pancreatitis and acids may lead to false-negative tests.
pancreatic cancer develop at a relatively young age. No specific treatment Some diagnostic testing relies on the fact that the organism has urease
is known for the prevention or treatment of hereditary pancreatitis. In activity, which metabolizes urea to bicarbonate and ammonia. The tests
concert with standard pancreatitis laboratory testing and imaging, genetic that employ this key characteristic are rapid urease testing and urea breath
testing for the aforementioned mutations can lead to this diagnosis. Ancil- testing.
lary diagnostic modalities include ERCP with secretin stimulation or Rapid urease testing involves taking a specimen from an antral biopsy
sphincter of Oddi manometry. These tests can help identify sphincter of and placing it on an agar gel or reaction strip with urea and a pH-sensitive
Oddi dysfunction that could contribute to recurrent acute pancreatitis color-changing indicator. A change in color would indicate a change in
(Testoni, 2014). pH, which in turn represents urease activity and thus suggests presence of
H. pylori.
Chronic Pancreatitis The urea breath test also exploits the presence of urease in the H. pylori
It is the irreversible damage and often-progressive inflammation with organism. It has the advantage of not requiring an endoscopically obtained-
irregular fibrosis, duct dilation, and loss of pancreatic parenchyma that tissue sample. Labeled urea is ingested and labeled CO2 is detected and
characterize chronic pancreatitis. This occurs after repeated bouts of acute quantified in expired breath. The label can be either nonradioactive 13C
pancreatitis, obstruction of pancreatic duct by mechanical blockage or or radioactive 14C. Another nonendoscopic urease test works by detecting
congenital defect or by neoplasm, gallstone duct obstruction, or alcohol- labeled bicarbonate in a blood sample (Ahmed et al, 2005).
ism. Early in the course, the pancreas becomes enlarged. Some cases Although not included in the latest guidelines on H. pylori diagnosis,
develop pseudotumor mass lesions. Subsequently, as the result of scarring, we discuss hydrogen breath tests here for historical interest. Radioactive
the gland usually shrinks with loss of acini and still later loss of ductules. and nonradioactive hydrogen breath tests are examples of noninvasive
Preserved or even increased islets are seen in the fibrous scar. Patients seek means for detecting active H. pylori infection. Each is sensitive and specific
medical attention for abdominal pain or maldigestion. before therapy. Hydrogen breath tests may be falsely negative if they are
Maldigestion/malabsorption and steatorrhea are due to pancreatic performed too soon after treatment, before the bacterial load is great
insufficiency with loss of enzymes, glucose intolerance or diabetes, and enough to be detected (Atherton & Spiller, 1994).
islet damage. A low fecal elastase 1 (i.e., concentration of <15 μg/g) has Serum antibodies directed against H. pylori can be used to detect expo-
been associated with pancreatic insufficiency with a sensitivity and specific- sure to H. pylori. Enzyme immunoassay (EIA) tests are available and reli-
ity of 93.3% and 81.5%, respectively, in nonoperated patients (Benini et al, able (Feldman et al, 1995; Feldman & Evans, 1995; van de Wouw et al,
2013). Clinically, recurrent or chronic pain is reported at a lower incidence 1996). Although quantitative levels of these antibodies are not currently
than in acute pancreatitis, but this is now increasing in frequency. The routinely utilized in the clinical setting to determine whether there is
incidence is greater in males than in females, and the average age of onset current or past infection, they have been reported to be highly accurate
is 40 years. It is more prevalent in tropical countries, and the main form (Lerang et al, 1998). At present, serology is generally used to screen for
is chronic calcifying pancreatitis with duct calcifications. In temperate H. pylori, and breath tests are used to confirm eradication after treatment.
areas, chronic alcoholism is reported in more than half of cases. No caus- Alternatively, endoscopy allows collection of tissue for rapid urease testing
ative factor is apparent in 40% of cases. or histologic examination (Megraud, 1997).
310
Office-based serologic quick-test kits are available. The accuracy of respectively. Each form has a different assay sensitivity. All gastrins origi-
these kits has been shown to be dependent on the antibody preparations nate from a single precursor, preprogastrin, which is cleaved by the action
used. IgG preparations perform most consistently. Other test qualities such of trypsin. It is interesting to note that in pathologic cases of increased
as reproducibility, cost, and ease of utilization are factors to be considered gastrin production, as with achlorhydric gastritis or gastrinomas, larger
when reviewing each of the many available brands marketed today (Laheij molecular forms of gastrin and incompletely processed precursors are
et al, 1998). Histologic review of biopsy specimens stained with Warthin- present and are beyond the scope of detection by conventional assays. In
PART 2
Starry or Giemsa stain remains one of the most frequently employed such cases, only little gastrin would be detectable in serum (Goetze &
techniques to detect active infection. Culture of the organism may be Rehfeld, 2003).
inconsistent and usually is not done in routine clinical settings. If endos- Laboratory determination of gastrin levels with radioimmunoassay
copy must be performed for other reasons, a rapid urease test is the least (RIA) or EIA is indicated for the confirmation of suspected gastrin-
expensive means of documenting the presence of H. pylori. secreting tumors—namely, gastrinomas or ZE syndrome. The antibodies
Hypersecretory states are suggested by extensive peptic ulcer disease, present in these assays are specific for the biologically active C-terminal
especially in the absence of H. pylori, and by the use of NSAIDs. Failure of the gastrin molecule, and they have minimal cross-reactivity with cho-
to respond to the usual doses of histamine-2 (H2)-receptor blocking agents lecystokinin (CCK) peptides. Before determination of gastrin levels, a
and PPIs also suggests oversecretion of hydrochloric acid. Care must be patient must be fasting for 12 hours because the concentration of G34
taken to avoid the use of antisecretory medications for the appropriate time doubles and the concentration of G17 quadruples following a meal, alter-
intervals before such testing. H2-receptor blockers should be held for 48 ing the results of the assay. Specimens must be frozen immediately because
hours, and PPIs should be avoided for 7 days. H2-receptor blockers are gastrin is unstable in serum. Because of the action of proteolytic enzymes,
available without a prescription, so patient education is important, and 50% of the specimen’s immunoreactivity may be lost within 48 hours at a
clinicians must remember to review all of the medications utilized by their temperature of 4° C. It is recommended that specimens should be kept in
patients. a freezer at a temperature of –70° C without a self-defrosting cycle if long-
term storage is required. Specimens must be analyzed immediately after
thawing, while avoiding refreezing and thawing.
ZOLLINGER-ELLISON SYNDROME Fasting serum gastrin levels are increased with increasing age, espe-
This syndrome is defined by the triad of peptic ulceration, hyperchlorhy- cially in patients older than 60 years, in part because of gastric mucosal
dria, and non–β islet cell tumors (gastrinomas). Duodenal ulcers do not atrophy. Approximately 15% of individuals older than 60 years may have
occur in achlorhydric individuals but are present in those with extreme gastrin levels between 100 and 800 ng/L (Hill, 2006). Reference intervals
hyperchlorhydria. Gastrinomas may occur in the body or tail of the pan- for infants and children differ from those for adults; interpretation should
creas or in the upper duodenum; they may be multiple and malignant. use age-specific reference ranges. Gastrin concentration greater than
About 25% of Zollinger-Ellison (ZE) patients have multiple endocrine 1000 ng/L with gastric acid hypersecretion (basal acid secretion >15 mmol/
neoplasia (MEN) 1 with hyperparathyroidism (Hung et al, 2003). hour) is diagnostic of gastrinoma. The secretin stimulation test is a pro-
Gastrin levels, with and without secretin stimulation, can be used to vocative biochemical test that can help confirm the diagnosis of ZE
diagnose ZE syndrome. Serum gastrin levels greater than 150 ng/L (refer- in questionable cases. Infused secretin should cause a drop in gastrin
ence, <100 ng/L), especially with simultaneous gastric pH values of less levels in normal individuals. However, in patients with ZE, a dramatic
than 3, are highly suggestive of a gastrinoma. For equivocal results, secre- increase in gastrin level is seen after secretin infusion. The mechanism
tin (2 U/kg in 10 mL 0.9% sodium chloride) can be given intravenously by which secretin stimulates an increase in gastrin levels in these patients
in 30 seconds, and serial gastrin levels can be drawn at 0, 2, 5, 10, 15, 20, is poorly understood; however, it is thought to be due to a direct
and 30 minutes. An increase in gastrin of 200 ng/L or greater within 15 local effect on blood flow to the tumor (Ashley et al, 1999). Limitations
minutes of injection is considered a positive test result. Although these include altered results from conditions that may lead to elevated gastrin
criteria are typically applied, it is important for the clinician to bear in levels, such as gastric ulcer disease, chronic renal failure, hyperparathy-
mind that a nonelevated result does not preclude presence of a gastrinoma. roidism, pyloric obstruction, vagotomy, retained gastric antrum, short
Indeed, there have been reports of gastrinomas with normal serum gastric bowel syndrome, and pernicious anemia. Certain medications, such as
levels. These cases have been attributed to the fact that some tumors antacids, H2-blocking agents, and proton pump inhibitors, can also increase
secrete bioactive gastrin precursors, some of which go undetected by avail- gastrin measurements; all of these agents are commonly used in the treat-
able testing modalities (Rehfeld et al., 2012). Octreotide, a synthetic form ment of patients with peptic ulcer disease. However, the elevations are
of somatostatin, has been used for localization of tumors. Radiolabeled moderate and certainly are not as high as in a patient with a gastrin-
octreotide binds to somatostatin receptors and can be subsequently local- secreting tumor.
ized by scintigraphy (Zimmer et al, 1995). Somatostatin (SST) receptor Intraoperative testing for gastrin is of potential use because gastrinomas
scintigraphy (SRS) is now the imaging modality of choice for these lesions, can be multiple and are often difficult to locate; they can be distributed
with a reported mean sensitivity and specificity of 72% and 86%, respec- widely in the stomach, pancreas, and duodenum or periaortic lymph nodes.
tively (Gibril & Jensent, 2005). The underlying mechanism for the effec- Intraoperative gastrin measurement is of potential use because gastrin has
tiveness of SRS is that neuroendocrine tumors, such as gastrinomas, have a short half-life of approximately 10 minutes. The catabolic breakdown of
increased density of SST receptors (SSTRs), specifically subtypes SSTR2 most peptide hormones follows first-order exponential decay. Therefore,
and SSTR5 (Warner & O’dorisio, 2002). If such tumors are surgically if the entire hormone-secreting tissue is surgically resected, only approxi-
removed, gastrin levels can be used to assess potential success or future mately 12.5% of the baseline concentration would be present in serum
recurrence. after three half-lives. When patients with ZE or gastrinoma were evaluated
Gastrin is a primary GI hormone that is produced mainly by the antral with intraoperative gastrin assays, a drop in gastrin levels to within refer-
G cells; it regulates gastric acid secretion and stimulates growth of the ence values within 20 minutes of resection was indicative of cure (Sokoll
gastric mucosa, among other functions. To a lesser extent, gastrin is pro- et al, 2004). Gastrin and secretin levels remain the most sensitive methods
duced by G cells of the proximal small intestine and δ cells of the pancreas. to detect recurrence (Norton & Jensen, 2007).
Gastrin acts on the parietal cells located in the fundus of the stomach,
stimulating the secretion of gastric acid. Gastrin also increases blood flow Pepsin and Pepsinogen
to the stomach and is responsible for increased gastric and intestinal motil- Pepsinogens are the biologically inactive proenzymes of pepsins that are
ity. Other functions include stimulation of gastric pepsinogens and intrin- produced by chief cells and other cells in the gastric mucosa and are found
sic factor secretion, release of secretin from the small intestine, and in two distinct types: pepsinogen I (PGI), also known as pepsinogen A, and
secretion of pancreatic enzymes as well as bicarbonate (Hill, 2006). This pepsinogen II (PGII), also known as pepsinogen C. Pepsinogen secretion
hormone is secreted from antral distention, mainly after the detection of is stimulated by the vagus nerve, gastrin, secretin, and CCK, and is inhib-
digested protein products. Maximal stimulation of gastrin secretion occurs ited by gastric inhibitory peptide (GIP), anticholinergics, histamine H2-
within a pH range of 5 to 7. An acid environment serves as a negative receptor antagonists, and vagotomy (Hill, 2006). PGI is produced in the
feedback mechanism for the release of gastrin, with 80% reduction in chief cells and mucous cells of oxyntic glands; PGII is produced in mucous
secretion at a pH of 2.5 (Hill, 2006). This serves to protect the stomach cells in oxyntic and pyloric regions and in the duodenum. The ratio of
from overacidification caused by excess stimulation of gastrin. For this concentration of PGI to PGII in the serum or plasma of healthy individuals
reason, individuals on acid suppression therapy for peptic ulcer disease may is approximately 4 : 1 (Samloff, 1982). Pepsinogen is converted to the active
have elevated gastrin levels. form, pepsin, by gastric acid that can activate additional pepsinogen auto-
Three main forms of gastrin are found in human blood and tissues: catalytically. Both groups of pepsinogens are activated at an acid pH below
G34, G17, and G14, known as big gastrin, little gastrin, and mini gastrin, 5 and are destroyed by alkaline pH. Both types can be detected in blood.
311
Only type I pepsinogens are present in the urine. Pepsins are responsible diagnosis and guiding the laboratory evaluation (Table 22-4). The physi-
for the hydrolysis of proteins to polypeptides. The pepsinogen released cal examination, although usually less helpful than the history, must be
from the gastric mucosa constitutes a major component of gastric fluid. comprehensive.
Only approximately 1% gets into the peripheral blood. Active pepsin is Acute diarrheas of less than 4 weeks generally have an infectious origin.
rapidly inactivated in the bloodstream, whereas pepsinogen is stable in the Those with a course of longer than 4 weeks are considered chronic diar-
blood. Pepsinogen is then filtered by the kidneys and is excreted in the rheas (Fine & Schiller, 1999) and are categorized as osmotic, secretory, or
urine, where the slightly acidic pH converts the pepsinogen, now called inflammatory. Hypermotility or shortened gut may reduce the transit time
uropepsinogen, to uropepsin (Hill, 2006). Immunoassay is the method and absorptive surface, resulting in diarrhea and/or some degree of
used to detect serum pepsinogen. However, the PGI isoform is commonly malabsorption.
analyzed in the clinical laboratory because it is the isoform commonly Osmotic diarrhea results from unabsorbable or poorly absorbed solutes.
associated with disease. These include polyethylene glycol in colon-cleansing solutions, magne-
Serum levels of pepsinogen I provide an accurate estimate of parietal sium salts (magnesium citrate in cathartics, magnesium hydroxide in some
cell mass and correlate with the acid-secretory capacity of the stomach. antacids), sorbitol in chewing gum, lactulose in the treatment of hepatic
Increased pepsinogen levels and associated activity are observed in patients encephalopathy, and lactose in lactase-deficient individuals. These osmoti-
with disease states that lead to increased gastric output or with increased cally active substances in the lumen alter the osmotic gradient that nor-
parietal cell mass—namely, gastrinoma, ZE syndrome, duodenal ulcer mally favors Na+ absorption, drawing fluid into the lumen.
disease, and acute and chronic gastritis. Decreased levels of pepsinogen are Fasting or cessation of consumption of the suspected solute stops
associated with decreased parietal cell mass, atrophic gastritis, and gastric osmotic diarrhea. Stool pH values of less than 5.6 are consistent with
carcinoma, as well as with myxedema, Addison’s disease, and hypopituita- carbohydrate malabsorption (Fine & Schiller, 1999). Sodium and potas-
rism (Hill, 2006). The PGI/PGII ratio decreases linearly with worsening sium concentrations in stool water are measured to calculate the fecal
atrophic gastritis. Absence of pepsinogen is noted in patients with achlor- osmotic gap, which estimates the contributions of electrolytes and non-
hydria. PGI levels measured by immunoassay usually range from 20 to electrolytes to water retention in the gut lumen. Osmotic gap is useful in
107 μg/L, and PGII levels usually range from 3 to 19 μg/L. differentiating osmotic from secretory diarrhea; it is best calculated as 290
Pepsinogen assays are being explored for their utility in the noninvasive – 2 × ([Na+] + [K+]), where 290 represents the stool osmolality that approxi-
identification of patients with chronic atrophic gastritis and to obtain an mates plasma osmolality, and a factor of 2 is used to account for associated
estimate of the extent of atrophic gastritis, a known precursor of gastric anions. Osmotic gaps of greater than 125 mOsm/kg characterize osmotic
carcinoma. Severe atrophic body gastritis causes a four- to fivefold increase diarrhea, and those of less than 50 mOsm/kg are seen in secretory diarrhea
in the risk of gastric carcinoma compared with healthy individuals (Miki (Fine, 1999).
et al, 2003). It is hoped that this finding will help to identify a subgroup Stool osmolality must be measured on a freshly collected specimen.
of individuals with chronic atrophic gastritis who would benefit from Because of continued degradation of stool carbohydrates, osmolality of the
endoscopic evaluation for detection of early-stage gastric tumor. These specimen increases over hours. Continued diarrhea during a 48-hour fast
assays are currently utilized in Japan, an area marked by high prevalence is suggestive of a secretory process, although fecal weight may decrease
of gastric cancer, as a potential method for widespread screening of high- because of increasing dehydration (Fordtran, 1967; Fine & Schiller, 1999).
risk individuals (Miki et al, 2003). These authors recommended that cri-
teria for diagnosing chronic atrophic gastritis should include persons with Disaccharidase Deficiency
PGI less than 70 μg/L and a PGI/PGII ratio less than 3.0. In Japan, the Because the small intestinal mucosa is impermeable only to disaccharides,
pepsinogen serum screening test has been demonstrated to detect a higher special enzymes are required for the breakdown of these molecules. Defi-
percentage of early cancers compared with conventional methods, and a ciency leads to malabsorption and thus dietary intolerance manifested in
considerable number of patients have subsequently been candidates for diarrhea. The important enzymes are lactase-phlorizin hydrolase, sucrase-
treatments with endoscopic surgery (Miki et al, 2003). The most sensitive isomaltase, and maltase-glucoamylase (Clinton et al, 2012). Disaccharide
test for fundic atrophic gastritis is considered to be the PGI/II serum ratio, absorption may also be diminished from primary alactasia or primary
with 99% sensitivity and 94% specificity (Hill, 2006), and 64% sensitivity trehalase deficiency, or from secondary disaccharidase deficiencies due to
and 61% specificity for antral and pangastric atrophic gastritis (Lee et al, celiac disease, tropical sprue, acute viral gastroenteritis, or drugs such as
2014). Furthermore, PGII levels may be a useful marker of prognosis, orally administered neomycin, kanamycin, and methotrexate. These sec-
serving as an independent predictor of tumor biology and survival in ondary disaccharidase deficiencies are usually transient and involve more
patients with gastric carcinoma. The absence of PGII production has been than one enzyme. Although the incidence of lactose intolerance due to
associated with aggressive tumor behavior and shorter overall survival in congenital lactase deficiency is low, the prevalence of lactose intolerance
gastric cancer patients (Fernandez et al, 2000). Pepsinogen assays there- in adults is quite high. About 10% of Caucasians, 70% to 80% of African
fore may prove useful as a serum screening method for detection of gastric Americans, and an even greater percentage of Asians manifest some degree
carcinoma among high-risk individuals. of lactose intolerance, even though they were able to digest lactose well as
infants. In these disorders, intestinal bacteria ferment unhydrolyzed and
DIARRHEA AND MALABSORPTION unabsorbed carbohydrates, producing gas, lactic acid, or other organic
acids. Normally, absorption of digested carbohydrates is rapid and fairly
Diarrhea complete in the proximal small intestine. Unhydrolyzed disaccharides or
About 8 to 10 L of fluid enters the duodenum every 24 hours. Much of monosaccharides unabsorbed because of deficiencies in transport are
this fluid is absorbed in the small intestine, and about 1.5 L enters the osmotically active and thus cause secretion of water and electrolytes into
large intestine, but only 100 to 150 mL is voided in stools. Increased fluid the small and large intestines. This can result in protracted diarrhea, as
secretion or decreased fluid absorption in the small or large intestine may well as complaints of bloating and flatulence.
result in diarrhea. One of the most important parameters defining diarrhea Screening tests for disaccharidase deficiencies include oral challenge of
in an individual patient is a change in the usual bowel habit to more fre- suspected disaccharides to reproduce the abdominal symptoms, followed
quent, looser stools. Diarrhea is the passage of three or more loose or by stool analysis. The stools are usually watery, acidic, explosive, and
liquid stools per day, or more frequently than is normal for the individual fermentative. Stool pH of less than 5.5 is suggestive, but the measurement
(World Health Organization [WHO], 2013). A decrease in fecal consis- of pH is not valid if the patient is taking oral antibiotics. High pH does
tency (i.e., increased fluidity) is more important than the number of stools. not exclude the diagnosis. Normal infants between 3 and 7 days of age
However, this property is difficult to measure, so increased stool weight, commonly have high stool pH. Stools can be analyzed for sugars by chro-
frequency, and duration are used in defining diarrhea. matography or by one of the semiquantitative nonspecific tests for urinary
The diagnosis of diarrhea starts with a thorough history to character- sugar adapted for stool analysis. The Clinitest tablet (Bayer Diagnostics,
ize the condition. The WHO guidelines categorize diarrhea into four Australia) is suitable for this purpose. The presence of 0.25 g/dL reducing
clinical umbrellas: acute watery, acute bloody, persistent, and diarrhea substances is considered normal; from 0.25 to 0.5 g/dL is regarded as
with malnutrition. Additional clinical questions to further characterize suspicious; and more than 0.5 g/dL is considered abnormal. In patients
the condition include: Is the diarrhea bland or bloody (dysentery)? Are with intolerance to sugar, the amount of total reducing substance in the
there constitutional symptoms? What is the duration of the illness? Self- stool usually exceeds 0.25 g/dL feces.
limited, acute diarrhea (<2 weeks in duration) without bleeding or con- An oral tolerance test using a specific sugar such as lactose or sucrose
stitutional symptoms rarely requires diagnostic testing. Chronic diarrhea, can be used to establish a specific carbohydrate intolerance. Although
the passage of blood, and constitutional symptoms all suggest the need the oral tolerance test is fairly specific and sensitive, in some instances 23%
for a specific diagnosis. History is the key to developing the differential to 30% false-positive results were noted following administration of
312
TABLE 22-4
Laboratory Tests in the Differential Diagnosis of Diarrhea
Test Method Use
Initial Screening Tests
PART 2
Fecal leukocytes Wright’s stain or methylene blue Identify inflammatory diarrhea
Fecal occult blood test Immunochemical Detect blood
Fecal osmotic gap 290 − 2 × (fecal Na+ + K+) Distinguish secretory vs. osmotic diarrhea
Stool alkalinization Color change after adding NaOH to stool/urine Phenolphthalein laxative ingestion
Infectious Causes
Stool bacterial culture Routine culture and sensitivity Identify Shigella, Salmonella
Stool special culture Specialized culture and serotyping Identify E. coli 0157:H7, Yersinia, Campylobacter
Stool C. difficile toxin assay EIA for toxins A and B Pseudomembranous colitis
HIV serology EIA, Western blot HIV enteritis
Stool rotavirus screen EIA for antigen Rotavirus enteritis
Stool ova and parasites Concentration and stains Enteric parasitic infection
Stool mycobacteria Acid-fast stain, culture and sensitivity, PCR Mycobacterium, antibiotic selection
Stool E. histolytica Ag EIA for antigen Entameoba histolytica
Stool Giardia Ag EIA for antigen Giardia lamblia
Stool Cryptosporidium Ag EIA for antigen Cryptosporidium parvum
Endocrine Causes
Urine 5-HIAA or blood serotonin HPLC Carcinoid syndrome
Serum VIP RIA VIPoma
Serum TSH, free T4 Immunoassay Hyperthyroidism
Serum gastrin RIA Zollinger-Ellison syndrome
Serum calcitonin RIA Hypocalcemia-related diarrhea
Serum somatostatin RIA Somatostatinoma
Malabsorption
Lactose tolerance test See text Lactase deficiency
Stool reducing sugars Clinitest tablets Carbohydrate intolerance
Sweat chloride See text Cystic fibrosis
D-Xylose absorption test See text Evaluate pancreatic and jejunal function
Fecal fat stain Fat stain Lipid malabsorption
Serum carotene Spectrophotometry Lipid malabsorption
14
C-glyceryl trioleate test malabsorption See text Lipid malabsorption
Serum IgA Nephelometry Rule out IgA deficiency
Antitissue transglutaminase antibody EIA Celiac disease
Hydrogen breath test Electrochemical hydrogen Carbohydrate malabsorption
monitorinomatography g
Bacterial colony count Small bowel aspirate and quantitative culture Bacterial overgrowth
Other
Serum ionized calcium Ion-specific electrode Hypocalcemia-related diarrhea
Serum protein and albumin Nephelometry, photometry IBD, protein-losing enteropathy
Stool alpha-1-antitrypsin Nephelometry Protein-losing enteropathy
Quantitative immunoglobulins Nephelometry Agammaglobulinemia
7α-Hydroxy-4-cholestin-3-one HPLC Bile salt malabsorption
Fecal elastase or pancreolauryl test EIA Pancreatic insufficiency
Intestinal biopsy Endoscopic or open biopsy Whipple’s disease, MAI, abetalipoproteinemia, neoplasia,
lymphoma, amyloidosis, eosinophilic gastroenteritis,
agammaglobulinemia, intestinal lymphangiectasia, Crohn’s
disease, tuberculosis, graft-versus-host disease, Giardia, other
parasitic infections, collagenous colitis, microscopic colitis
Extraintestinal causes See text Hyperthyroidism, diabetes, hypoparathyroidism, adrenal
cortical insufficiency, hormone-secreting tumors
5-HIAA, 5-Hydroxyindoleacetic acid; Ab, antibody; Ag, amtigen; EIA, enzyme immunoassay; HIV, human immunodeficiency virus; HPLC, high-performance liquid chroma-
tography; IBD, inflammatory bowel disease; MAI, Mycobacterium avium-intracellulare; PCR, polymerase chain reaction; RIA, radioimmunoassay; TSH, thyroid-stimulating
hormone; VIP, vasoactive intestinal peptide.
lactose—that is, a flat tolerance curve and less than 20 mg/dL (1.1 mmol/L) A recent genetic analysis of infants with congenital sucrose-isomaltase (SI)
increase in blood sugar (Krasilnikoff et al, 1975). Delayed gastric emptying deficiency suggests that genetic testing of saliva or serum for four specific
appears to be the cause of the false-positive result because duodenal instil- mutations in the SI gene could lead to a valid diagnosis in 83% of these
lation of lactose eliminates the flat tolerance curve. infant patients of European extraction (Uhrich et al, 2012).
With our increased understanding of the genetic basis of certain inher- Definitive diagnosis of disaccharidase deficiency depends on the dem-
ited disaccharidase deficiencies, the role of genetic testing has been inves- onstration of low specific enzyme activity in the mucosa of small intestinal
tigated. When testing a saliva or serum sample could avoid sedation and biopsy material. An assay for disaccharidase has been published (Dahlqvist,
instrumentation of an infant (for tissue diagnosis), it should be considered. 1968).
313
presence of an otherwise unexplained high-volume secretory diarrhea and
Lactose Tolerance Test a serum VIP concentration in excess of 75 pg/mL. It is important to

A lactose tolerance test provides a presumptive diagnosis of lactase defi- replace fluid losses in these patients, and octreotide may be used to control
ciency. In patients with alactasia or hypolactasia, whether primary or sec- diarrhea.
ondary to mucosal disease, oral lactose results in an insignificant rise in Patients usually present between 30 and 50 years of age; 90% of cases
blood glucose. Following an overnight fast, a blood sample is drawn, and are primary pancreatic tumors, most commonly arising in the body or tail.
50 g of lactose dissolved in 400 mL of water is orally administered. A 100-g Metastatic spread has already occurred in 60% to 70% at presentation.
lactose dose has been reported to yield more definitive results. Blood Long-acting somatostatin analogs control symptoms in greater than 90%
samples are collected at 30, 60, and 120 minutes after lactose ingestion. of cases (Kapoor et al, 2009).
An optional 5-hour stool specimen can be collected, and its appearance, Vasoactive intestinal peptide, released in response to gut distention, is
consistency, and pH noted. a potent vasodilator and is responsible for the relaxation of vascular and
Patients with lactase deficiency exhibit a peak rise of less than 20 mg/ nonvascular smooth muscle of the intestinal tract. It is also a potent stimu-
dL of reducing substances, expressed as glucose. In individuals with flat lator of water and electrolyte secretion, acting through stimulation of
tolerance curves, the test should be repeated in 2 days and the less abnor- cAMP. Similar to glucagons, VIP stimulates breakdown of glycogen and
mal of the two curves used for interpretation. In patients with lactase lipid stores and inhibits histamine-stimulated acid secretion in the stomach,
deficiency, the nonabsorbed lactose, upon reaching the colon, is degraded resulting in hypochlorhydria or achlorhydria.
to gas and lactic acid, which inhibits salt and water absorption, resulting Laboratory evaluations for determination of VIP levels are clinically
in abdominal discomfort and diarrhea. In children, the oral dose of lactose relevant for diagnosis of VIPomas. These VIP-secreting tumors, most
or other sugars is 2 g/kg body weight. Lactase can also be detected in a commonly of pancreatic origin, account for 10% of neuroendocrine
mucosal biopsy specimen. tumors of the gastrointestinal tract. Approximately 60% of VIPomas are
Secretory diarrhea is evoked by a variety of exogenous and endogenous malignant, and 6% are associated with MEN type 1. This syndrome was
secretagogues. The hypersecretion of isotonic fluid exceeds the absorptive first described in 1958 by Verner and Morrison, and is characterized by
capacity of the colon. Cholera toxin activates mucosal cyclic adenosine WDHA.
monophosphate (cAMP) that results in outpouring of vast quantities of salt VIPomas produce a severe, secretory diarrhea that has been termed
and water in jejunum with normal structure. In Verner-Morrison syn- pancreatic cholera. Diarrhea may be present for several years before the
drome (pancreatic cholera), vasoactive intestinal peptide also activates diagnosis of VIPoma. Patients typically produce more than 3 L of watery
cAMP. Thus secretory diarrhea remains unrelieved despite fasting. stools per day, although volume can be as high as 30 L/day. Diarrhea is
Diarrhea also occurs in hypergastrinemic states (e.g., ZE syndrome). not controlled with fasting, and an average secretion of 300 mmol of potas-
Sustained hypersecretion of acid lowers intestinal pH, denatures pancreatic sium per 24 hours occurs (Vinik, 2004). Stool volume of less than 700 mL/
enzymes (causing steatorrhea), and precipitates bile salts (causing bile salt day excludes the diagnosis of VIPoma. If the diagnosis is missed or delayed,
malabsorption); the latter induces water secretion in the colon. In patients as is often the case, chronic diarrhea results in severe fluid and electrolyte
with mastocytosis, excessive histamine release stimulates acid hypersecre- imbalances that produce a myriad of clinical symptoms, the most severe
tion, but plasma gastrin concentrations remain low or normal. Gastroin- of which is sudden death from cardiac arrhythmias resulting from electro-
testinal dysfunction caused by release of mast cell mediators can be lyte disturbances with potassium depletion and acidosis. The typical meta-
observed in both cutaneous and systemic mastocytosis (Liu et al., 2010). bolic profile seen in these patients is hypokalemia with hyperchloremic
Signs and symptoms include abdominal pain, diarrhea, nausea, vomiting, metabolic acidosis. The diagnosis of VIPoma is made with confirmation
peptic ulcer disease, and GI bleeding. Diarrhea can result from increased of raised fasting VIP levels in association with secretory diarrhea and the
motility induced by prostaglandin D2 secretion or from decreased rectal presence of a lesion, most commonly located in the pancreas and associated
compliance and overactive rectal contractility (Jensen, 2000). with VIP production.
The biochemical assay of VIP is sensitive and specific. The normal
Drug-Induced Diarrhea value for circulating VIP levels is less than 170 pg/mL. For patients with
Prokinetic agents (metoclopramide, domperidone, cisapride), proton functional VIP-secreting tumors, values range from 675 to 965 pg/mL
pump inhibitors, and antibiotics (erythromycin and other macrolides) (Thomas et al, 2003). Appropriate handling of the serum sample is critical
produce loose stools or diarrhea. Erythromycin binds motilin receptors on for the accuracy of the VIP assay because VIP has a half-life of 1 minute.
the GI smooth muscle membranes (motilin agonist). When used as a The serum must be added immediately to aprotinin, a protease inhibitor
prokinetic agent, intravenous administration is more effective than oral that prevents breakdown of VIP. The sample must be separated within 10
dosage, and long-term use downregulates motilin receptors. minutes and frozen to –20° C. Some of the non-VIP products of the
precursor molecule are secreted at higher levels than VIP; however, com-
Other Causes of Diarrhea mercially available assays are not available, and clinical utility has not been
Diarrhea may occur in patients with hypothyroidism and hyperthyroidism, established. False-positive elevations of VIP can be observed in patients
diabetes and adrenal insufficiency, tumors (villous adenoma, small bowel with small bowel ischemia or severe low-flow states resulting from diarrhea
carcinoid), and infiltrative disorders (scleroderma, reactive amyloidosis, and subsequent dehydration not associated with VIP-producing lesions. In
gut lymphoma). Ethanol abuse, ischemic bowel disease, and radiation addition, the serum pancreatic polypeptide level should be determined at
enteritis also produce diarrhea. Heat-labile enterotoxin of Escherichia coli the time of the VIP assay; this value will be elevated if the VIPoma is
and toxins of Staphylococcus aureus and Clostridium perfringens activate bio- located within the pancreas.
chemical events that induce a secretory response. CT scan, MRI, and abdominal ultrasound are useful imaging modali-
ties for VIPoma tumor localization. Angiography can be used to localize
Gut Peptides in Diarrhea smaller tumors. Various nuclear scans have been utilized for localization
In acute infectious diarrheas, the plasma concentrations of glucagon, PYY, of VIPomas, including 123I VIP receptor scintigraphy, which is currently
and motilin may be increased, contributing most likely to altered gut under investigation.
motility and promoting mucosal repair. Patients with Crohn’s disease have
an elevated pancreatic polypeptide, GIP, motilin, and glucagon, and in Antibiotic-Associated Diarrhea
ulcerative colitis, a modest elevation is observed in pancreatic polypeptide, This term is typically reserved for Clostridium difficile, a gram-positive,
GIP, motilin, and gastrin, the last in response to the associated hypochlor- spore-forming anaerobic bacillus that is the most important cause of
hydria. No demonstrable abnormalities in gut peptides account for disor- nosocomial diarrhea in adults; more than 300,000 cases are reported per
dered motility in the irritable bowel syndrome. year in the United States. C. difficile is thought to be associated with
approximately 25% of all antibiotic-associated cases of diarrhea and 50%
Vasoactive Intestinal Peptide to 75% of cases involving antibiotic-associated colitis (Malnick & Zimhony,
VIPomas are rare tumors that secrete vasoactive intestinal polypeptide 2000). It represents a significant clinical burden in the United States, with
(VIP). VIP suppresses gastric acid secretion, resulting in secretory diarrhea recent inquiries of national databases revealing an increase in incidence
with stool volume exceeding 700 mL/day in all patients (even during over the last decade (Halabi et al, 2013; Pant et al, 2015). Halabi and col-
fasting) and 3 L/day in approximately 70%. The stools are tea-colored and leagues queried the Nationwide Inpatient Sample and found over 2.5
odorless, with features of a secretory diarrhea such as persistence with million discharges of C. difficile colitis over the period from 2001 to 2010.
fasting, high sodium concentration, and a low stool osmotic gap. Most Pant and colleagues queried the Nationwide Emergency Room Sample
patients with VIPoma have the watery diarrhea–hypokalemia–hypochlor- and found over half a million ER visits over half that time period, 2006 to
hydria (WDHA) syndrome. The diagnosis of VIPoma is established by the 2010. They also found a 47% and 24% increase in the number of inpatients
314
and emergency room visits, respectively, for this diagnosis over the study TABLE 22-5
periods. Clearly, this is an important problem requiring clinical attention. Laboratory Tests for the Diagnosis of Clostridium difficile–
It may manifest clinically, from a mild, watery diarrhea to life-threatening Associated Diarrhea
pseudomembranous colitis and toxic megacolon. This can lead to colonic
perforation and peritonitis, with a mortality rate as high as 38% (Poutanen Test Advantages Disadvantages
& Simor, 2004). Patients can present with watery diarrhea, lower abdomi-
PART 2
nal pain/cramping, or systemic symptoms such as fever and malaise, or can Clostridium difficile Excellent specificity Decreased diagnostic
have occult gastrointestinal bleeding. The pathogenesis of this disease cytotoxin assay (99% to 100%) sensitivity (80% to
entity usually involves disruption of the normal colonic flora, typically 90%); test results not
available until after
following a course of antibiotic therapy in hospitalized patients, followed
48 hours; requires
by exposure to a toxigenic strain of C. difficile. Broad-spectrum antibiotics
tissue culture facility;
such as penicillin, clindamycin, and cephalosporins have been particularly detects toxin B only
implicated; however, any antibiotic can lead to development of C. difficile
Immunoassay for High negative Toxin assay required
colitis (Malnick & Zimhony, 2000). Clinical suspicion of the disease is
glutamate predictive value because GDA does
confirmed with detection of C. difficile toxin A or B virulence factors in
dehydrogenase without additional not distinguish
stool samples. Toxins A and B lead to increased vascular permeability and antigen (GDA) of C. tests toxigenic and
have the potential to cause hemorrhage. They induce the production of difficile nontoxigenic strains
tumor necrosis factor-α and inflammatory interleukins that are responsible
Immunoassay for Good specificity (95% Reduced sensitivity
for the inflammatory response and pseudomembrane formation (Poutanen
detection of toxin A to 100%); test (65% to 85%) as
& Simor, 2004). or toxins A and B results available compared with
Endoscopic visualization of the colonic mucosa is required for diagno- within 4 hours; cytotoxin assay
sis of pseudomembranous colitis associated with C. difficile. However, technically simple
endoscopy should be avoided in cases of suspected fulminant colitis because
Stool culture to isolate Excellent sensitivity Results not available for
of the risk of perforation. Laboratory methods are available for confirma- C. difficile with (>90%) and at least 72-96 hours;
tion of C. difficile infection. Tissue culture cytotoxicity assays, which take subsequent cytotoxin specificity (>98%); labor-intensive;
at least 48 hours to complete, are considered the gold standard for the assay of isolate enables typing of requires tissue culture
detection of C. difficile cytotoxin B in stool specimens, with a sensitivity strain for outbreak facility
ranging between 94% and 100% and a specificity of approximately 99%. investigation
This tissue culture assay can detect as little as 10 pg of toxin in stool Nucleic acid Excellent sensitivity Useful only in acute
specimens. Rapid EIAs, which can be completed within several hours, have amplification assay (93% to 100%); disease; false
been developed for the detection of toxin A or B from stool specimens. for toxigenic C. useful in positives of concern
However, the sensitivity and specificity of these immunoassays are 65% to difficile confirmation of
85% and 95% to 100%, respectively, compared with cytotoxic assays. The results of GDA or
EIA can detect 100 to 1000 pg of toxin in stool specimens. In hospitalized toxin immunoassays
patients with more than six stools per day, EIA is the optimal diagnostic
test (Malnick & Zimhony, 2000). Stool cultures can also be performed but Adapted from Poutanen SM, Simor AE: Clostridium difficile–associated diarrhea in
adults, Can Med Assoc J 171:51–58, 2004; Fenner L, et al: Rapid and reliable
require up to 96 hours for completion. Polymerase chain reaction (PCR)
diagnostic algorithm for detection of Clostridium difficile, J Clin Microbiol 46:328–
methods for detection of C. difficile toxin A or B are currently being devel- 330, 2008; Surawicz CM, et al: Guidelines for diagnosis, treatment, and preven-
oped with similar sensitivity and specificity profiles compared with cyto- tion of Clostridium difficile infections, Am J Gastroenterol 108:478–498, 2013.
toxic assays (Poutanen & Simor, 2004). Traditional PCR techniques can
still take 3 to 4 hours but have high sensitivities and specificities (83% to
95% and 97% to 99%, respectively) (Putsathit et al, 2015). Even more
recently, automated PCR assays utilizing the Taq Man hybridization probe
for the tcdB gene for Toxin B have cut down processing time to 10 minutes less than 100 cells per microliter are at risk for opportunistic infections
per 10 samples and maintain high sensitivities and specificities (94% to that are typically chronic, such as C. parvum, MAC, cytomegalovirus,
97% and 97% to 99%, respectively) (Putsathit et al, 2015). Isospora belli, or microsporidia.
PCR is unable to distinguish between asymptomatic carriage and symp- An epidemiologic history with a focus on travel history (Entamoeba
tomatic infection. It is currently recommended that these tests be per- histolytica, Giardia lamblia), sexual exposure (history of unprotected anal
formed on diarrheal stools; in most cases, one stool sample is sufficient for intercourse suggesting transmission of herpes simplex virus, Neisseria gon-
the diagnosis of C. difficile infection (Poutanen & Simor, 2004). However, orrhoeae, Chlamydia trachomatis, or, occasionally, E. histolytica), and food
multiple samples may be required for confirmation, and empirical treat- associations (lactose intolerance) should be sought. In patients who are
ment with oral antibiotics may be indicated in patients with clinical evi- taking highly active antiretroviral therapy, medication-induced diarrhea
dence of C. difficile infection. Diarrheic stools can also be screened by an (nelfinavir, ritonavir) should be considered, particularly when diarrhea is
immunoassay for glutamate dehydrogenase antigen, a C. difficile–specific the sole presenting symptom. Clostridium difficile should be considered
antigen, and those positive should be tested for toxins A and B (Fenner because most patients with HIV are given antibiotics for the treatment of
et al, 2008). Refer to Table 22-5 for laboratory tests available for the various infections (Sanchez et al, 2005).
diagnosis of C. difficile–associated diarrhea.
Malabsorption Syndromes
HIV-Related Diarrhea Malabsorption is the pathologic state of impaired nutrient absorption in
Diarrheal disease in human immunodeficiency virus (HIV)–infected indi- the gastrointestinal tract. Normal nutrient absorption occurs in three
viduals is frequently caused by infectious agents but may also be due to steps: luminal and brush border processing, absorption into the intestinal
infiltrative diseases, such as lymphoma or Kaposi’s sarcoma. Common mucosa, and transport into the circulation. Disruption in any one or a
enteric pathogens with sufficient virulence that cause disease in healthy combination of these steps can result in inadequate mucosal absorption of
hosts can also cause diarrheal disease in HIV-infected individuals with carbohydrates, proteins, fats, vitamins, or minerals. Malabsorption can also
intact or compromised immunologic function. Less virulent pathogens result from the presence of substances in the bowel that cannot be absorbed
such as Cryptosporidium parvum, which appear to require some immune (e.g., lactulose, sorbitol). Maldigestion results from an intraluminal defect
compromise to establish disease, are more common in patients with more that leads to the incomplete breakdown of nutrients into their absorbable
advanced HIV infection or acquired immunodeficiency syndrome (AIDS). substrates. This can occur with pancreatic insufficiency and loss of exocrine
Mycobacterium avium-intracellulare complex (MAC) is predominantly function, resulting in increased osmotic load of the colon and diarrhea. In
associated with lung infection in immunocompetent patients. MAC may addition, patients can have selective malabsorption/maldigestion of spe-
also produce disseminated disease with bowel infiltration and malabsorp- cific nutrients, resulting in associated clinical sequelae. Irrespective of the
tion in patients with severe immune compromise and should be considered cause, diarrhea, especially steatorrhea, is the most common feature of
in the differential diagnosis. In these cases, blood should also be obtained malabsorption.
in fungal isolator tubes for culture. Hepatic maldigestion results from interference or obstruction of bile
In patients with HIV, it is important to ascertain the nature and chro- flow. Loss of bile salts interferes with fat emulsification, diminishing the
nicity of symptoms and the CD4 cell count. Patients with CD4 cell counts surface area available for lipolytic action. In addition, bile salt activation
315
of lipase activity is lost. Patients are usually jaundiced, pass dark urine, and
have other signs of liver disease. Hepatic steatorrhea may coexist with Agammaglobulinemia
pancreatic steatorrhea, as in patients with a neoplasm obstructing the X-linked agammaglobulinemia is a primary humoral immunodeficiency
ampulla of Vater. The inability to assimilate fats and proteins due to mal- characterized by recurrent bacterial infection of the respiratory tract and
digestion also occurs in patients with vasculitis, diabetes mellitus, carcinoid increased susceptibility to enteroviral infection. Absence of humoral
syndrome, hypogammaglobulinemia, and relative vitamin B6 or B12 immunity makes the patient susceptible to bacterial gastroenteritis.
deficiency.
Enteric malabsorption comprises a variety of conditions that have in Abetalipoproteinemia
common normal digestion but inadequate net assimilation of nutrients. Abetalipoproteinemia is a rare autosomal recessive disorder that is charac-
This may result from competition by bacteria or altered bacterial flora, as terized by defective assembly and secretion of apolipoprotein B (apoB) and
in the blind loop syndrome or diverticulosis of the small bowel, or from apoB-containing lipoproteins, resulting from mutations in the gene encod-
obstruction to the flow of lymph. It may also result from diseases affecting ing the microsomal triglyceride transfer protein; the serum β lipoprotein
the small bowel mucosa, such as amyloidosis, inflammation following irra- is absent. Abetalipoproteinemia causes defective absorption of lipids.
diation (radiation enteritis), diminished mucosal surface area as in gastro- Patients may have neurologic manifestations, acanthocytes, fat malabsorp-
ileostomy (gastric bypass), or small bowel resection. Depending on the tion, steatorrhea, and associated fat-soluble vitamin deficiencies (Gregg
location within the intestinal tract of such pathology, preferential loss of et al., 1994).
specific substrates may occur. One of the most common clinical scenarios
encountered is regional enteritis localized to the distal ileum, the site Tests for Steatorrhea
of vitamin B12 and bile salt absorption, which will result in vitamin B12 Screening tests for detection of steatorrhea include microscopic examina-
deficiency, as well as a decreased pool of circulating bile salts for tion of feces for fat globules and determination of serum carotenoid.
metabolism. Carotenoids are a group of compounds that are the major precursors of
Steatorrhea is a hallmark finding in patients with malabsorption, result- vitamin A in humans. Absorption of carotenoids in the intestines depends
ing in fluid, semifluid, or soft and pasty, pale, bulky, and foul-smelling on the presence of dietary fat. Because carotenoids are not stored in the
stools. These stools may be foamy because of the high fat content and may body to any appreciable degree, lack of carotenoids in the diet or distur-
float on water. However, the latter may occur with stools from healthy bances in absorption of lipids from the intestine can result in decreasing
individuals and therefore is a nonspecific sign of malabsorption. levels of serum carotenoid. This is a simple and useful screening test for
In patients with steatorrhea, unabsorbed fecal dietary fat is passed in steatorrhea. In addition to steatorrhea and poor dietary intake, liver disease
stools above and beyond the normal 1% to 9%, along with as much as and high fever may cause a low level of serum carotenoid. Elevated serum
40% of ingested fat. The quantity of fecal fat depends on the dietary fat carotenoid levels are seen in patients with hypothyroidism, diabetes,
intake. Thus dietary fat intake must be known for proper interpretation of hyperlipidemia, and excessive intake of carotene.
fecal fat, which is expressed as the percentage of dietary fat, allowing
assessment of variation in an individual patient. Normally, greater than Tests for Malabsorption
93% of dietary fat is absorbed, but diarrhea of any cause may lead to a When a diagnosis of malabsorption is being entertained, it is important to
slight increase in fecal fat content. distinguish pancreatic maldigestion from enteric malabsorption. In chil-
Another clinical presentation of malabsorption is the development of dren, the main cause of pancreatic malabsorption is CF, and the sweat
fat-soluble vitamin (A, D, E, and K) deficiencies. Primary and secondary chloride determination should be used when clinical evidence warrants it.
alterations of the bowel mucosa may also result in deficiencies of water- Screening tests based on absent stool trypsin have also been used. One of
soluble vitamins. Other evidence of nutritional deficiencies, such as hypo- the most valuable differential diagnostic tests, especially in adults, is the
prothrombinemia, glossitis, anemia, edema, ascites, and osteomalacia, may d-xylose absorption test.
be evident in these individuals. These patients may experience significant The cellobiose-mannitol sugar permeability test and the lactulose-
weight loss due to diarrhea, leading to cachexia in severe cases. mannitol test have been used in the diagnosis of celiac disease. Modern
Quantitative fecal fat measurement has many limitations and should be evaluation of this disorder has been described earlier. Isotopic techniques
abandoned (Holmes & Hill, 1988; Hill, 2001). Sample collection is known and the starch tolerance test have been used as alternatives to the d-xylose
to be incomplete (Ditchburn et al, 1971; West et al, 1981). Also, there is test. Quantitative specific fecal trypsin and chymotrypsin assays may be
poor precision in the analytic performance, making interpretation uncer- helpful, as may the Schilling test for vitamin B12 absorption, which tends
tain (Duncan & Hill, 1998). Newer tests provide improved sensitivity and to be abnormal in patients with enteric steatorrhea in whom the abnormal-
specificity for the diagnosis of malabsorption (Hill, 2001): 14C-glycerol ity is not correctable with intrinsic factor. Endoscopy, radiologic studies,
trioleate breath test (Turner et al, 1987) and mixed-chain triglyceride and biopsy have replaced these methods in many cases.
breath test are widely available (Vantrappen et al, 1989; Amarri et al, Fecal Elastase. Elastase-1 is a proteolytic enzyme produced by the
1997). However, these tests have limited reliability in diabetes, obesity, pancreas. Pancreatic elastase survives intestinal transit intact and is five- to
hyperthyroidism and hypothyroidism, and chronic respiratory insuffi- sixfold concentrated in the feces (Lankisch, 2004). Reduced pancreatic
ciency and should not be performed in pregnancy. elastase-1 in feces indicates pancreatic insufficiency in infants older than
The test is based on the measurement of 14CO2 in expired air following 2 weeks of age with CF and in older children with the disorder (Phillips
the ingestion of various 14C-labeled triglycerides (triolein, tripalmitin, and et al, 1999; Cade et al, 2000; Leus et al, 2000).
trioctanoin). Steatorrhea from pancreatic insufficiency or other causes This EIA is unaffected by pancreatic enzyme replacement therapy.
results in decreased absorption of triglycerides. This in turn results in a Although sensitive for detection of severe pancreatic insufficiency, it lacks
decrease in expired carbon dioxide (CO2) derived through the metabolism sensitivity for detection of milder forms. Fecal elastase is better than fecal
of triglyceride fatty acids. chymotrypsin, para-aminobenzoic acid, bentiromide, and pancreolauryl
After an overnight fast, the patient consumes 14C-labeled triglyceride. tests (Lankisch, 2004). Single analysis of a 100-mg stool sample is adequate
Periodically, breath CO2 is collected in a trapping solution containing an for determination of fecal elastase levels. If borderline values are detected,
indicator that changes color when a predetermined amount of CO2 is in a repeat sample may be useful. This test should be performed only on
solution. The radioactivity of the 14CO2 is then measured in a liquid scintil- formed stool. With a cutoff of 200 μg/g stool, the positive predictive value
lation counter, and the results are reported as a percentage of the dose of of fecal elastase determination is estimated to be approximately 50% (Lüth
14
CO2 excreted per hour. et al, 2001).
To distinguish pancreatic insufficiency from other causes of steator- Xylose Absorption Test. The d-xylose absorption test is a valu-
rhea, some investigators have developed a two-stage breath test (Goff, able test for the differential diagnosis of malabsorption. In this proce-
1982). In the first stage of the test, the patient consumes a 14C-labeled dure, a 25-g dose of pentose sugar in water is administered orally, and
triglyceride, and 14CO2 is measured as previously described. The second the amount excreted in urine over a 5-hour period is determined. If the
stage of the test is performed 5 to 7 days later and is the same as the first amount excreted is less than 3 g, the diagnosis is most likely enteroge-
stage, except that the patient is given an oral dose of pancreatic enzymes nous malabsorption, because pancreatic enzymes are not required for
along with the dose of 14C-labeled triglyceride. In patients with steatorrhea absorption of d-xylose. d-Xylose is passively absorbed in the small intes-
due to pancreatic insufficiency, the amount of 14CO2 expired should tine and is not metabolized by the liver, although a portion of an orally
increase relative to the amount of 14CO2 expired in the first stage of the or intravenously administered dose is destroyed. The accuracy of the
test. Patients with steatorrhea from other causes should show no significant method depends not only on the rate of absorption of d-xylose but also
change in the amount of 14CO2 expired following the oral administration on the rate of renal excretion. Therefore, in patients with renal disease,
of pancreatic enzymes. xylose should be quantified in blood 2 hours after its oral administration
316
because urine values are difficult to interpret in the absence of reference TABLE 22-6
values. Biomarkers in the Diagnosis of Celiac Disease and Monitoring
Isotopic techniques and the starch tolerance test have been used as Compliance to Gluten-Free Diet
alternatives to the d-xylose test. Quantitative specific fecal trypsin and
chymotrypsin assays may be helpful, as may the Schilling test, which is Biomarker Method Comments
used to assess the function of the terminal ileum. An oral dose of radioac-
PART 2
tive vitamin B12 is followed by an intramuscular large dose of nonradioac- Antireticulin IFA (rat kidney) Lack optimal sensitivity
tive vitamin B12, and radioactivity in urine is measured. Urinary radioactivity antibodies—IgG/IgA and specificity for
reflects the absorbed amount of vitamin B12. A repeat test to diagnose routine diagnostic use
pernicious anemia or gastric pathology in a patient with steatorrhea Total IgA Quantitative Useful in ruling out IgA
involves coadministration of intrinsic factor and vitamin B12. An abnormal nephelometry deficiency; specific IgG
result indicates ileal disease. antibodies need to be
tested in IgA-deficient
Laxative Abuse individuals
Surreptitious laxative abuse is a frequently overlooked cause of chronic Antigliadin antibodies— Quantitative EIA Low sensitivity and
diarrhea and is the final diagnosis for chronic diarrhea in 15% to 26% of IgG/IgA specificity; useful in
patients at referral centers (Bytzer et al, 1989; Duncan et al, 1992). In monitoring dietary
compliance
Munchausen’s syndrome by proxy, adults administered laxatives surrepti-
tiously to young children (Duncan, 2000). The main prerequisite for Antideaminated gliadin Quantitative EIA Inferior performance
making the diagnosis of surreptitious laxative abuse is clinical suspicion. antibodies—IgG/IgA relative to other
Analysis of urine and fecal samples taken during diarrhea is necessary. diagnostic assays
Phenolphthalein is less frequently found since over-the-counter sales were Antiendomysial IFA (rhesus monkey High sensitivity and
banned. Senna, aloin, and cascara are colonic stimulants that are abused antibodies—IgG/IgA esophagus; specificity in CD;
and can be detected by thin-layer chromatography. human umbilical observer bias limits
cord) usefulness
Celiac Disease Antitissue glutaminase— Quantitative EIA Assays using purified
Celiac disease (gluten-sensitive enteropathy) is a disorder precipitated, in IgG/IgA human or recombinant
genetically predisposed individuals, by the ingestion of gluten, the major human tTG are more
storage protein of wheat and similar grains, characterized by intestinal sensitive than those
using guinea pig tTG;
malabsorption of nutrients due to sensitivity to the alcohol-soluble portion
useful in both diagnosis
of gluten known as gliadin. Wheat, rye, and barley contain this protein
and monitoring dietary
and can induce mucosal damage in the gut, causing nonspecific villous
compliance
atrophy of the small intestinal mucosa. Celiac disease does not develop
HLA-DQ2/HLA-DQ8 PCR-based assays High negative predictive
unless a person has alleles that encode for HLA-DQ2 or HLA-DQ8
value; not affected by
proteins, products of two of the human leukocyte antigen genes. This
dietary gluten; found
genetic predisposition is most common in Caucasians of Northern Euro-
in ≈30% of general
pean descent. The prevalence is not clear but is estimated to be as high as population
1% in some countries, and the condition is being increasingly recognized
(Green & Cellier, 2007; Sabatino & Corazza, 2009).
Some patients remain asymptomatic, but an astute clinician may
suspect this disorder when patients present with thin stature, iron defi-
ciency anemia, weight loss, chronic bloating, and/or diarrhea. In severe are currently detected via immunofluorescence of sections of monkey
cases, one may see malabsorption, steatorrhea, and wasting. Associations esophagus or human umbilical cord and are costly, cumbersome, and
have been noted between celiac disease and type 1 diabetes mellitus, Down subject to interobserver interpretive variability.
syndrome, dermatitis herpetiformis, IgA deficiency, autoimmune thyroid Wheat storage protein, gliadin, is available to be used as an antigen in
disease, and other disorders (Barr & Grehan, 1998). Because of enteropa- an EIA. Although serum IgA and IgG AGA levels are frequently elevated
thy associated with the disorder, multiple hematologic and biochemical in untreated celiac disease, these tests are of only moderate sensitivity and
abnormalities may be found in persons with untreated celiac disease, specificity. IgG AGA testing is particularly useful in the 2% of patients
including deficiencies of iron, folate, or vitamin D. The peripheral blood with celiac disease who appear to be IgA deficient. However, these tests
film may reveal nonspecific target cells, siderocytes, crenated red cells, have largely been replaced by EMA. EMA binds to connective tissue sur-
Howell-Jolly bodies, and Heinz bodies. Similarly, small bowel absorptive rounding smooth muscle cells. Most laboratories use sections of human
testing will be abnormal, including oral d-xylose testing and fecal fat umbilical cord. Serum IgA EMA binds to the endomysium to produce a
evaluation. characteristic staining pattern seen on indirect immunofluorescence. The
The gold standard for diagnosis remains histologic examination of antibody is highly sensitive and specific. However, after treatment, the
multiple biopsies of the affected small bowel mucosa for the identification titers fall quickly to undetectable levels (Volta et al., 1995). The epitope
of villous atrophy and crypt hyperplasia. The lesions may be patchy, and against which EMA is directed has been shown to be tissue transglutamin-
sampling errors can occur (Green & Cellier, 2007; Ensari, 2010). Biopsy ase. Use of IgA anti-tTG assays has been shown to be highly sensitive and
is reserved for patients in whom the diagnosis is suspected on the basis of specific for the diagnosis of celiac disease (Dieterich et al., 1998). An EIA
signs or symptoms of the disease, especially in higher-risk populations with for IgA anti-tTG is widely available, less costly, and easier to perform than
supporting serologic findings. These patients must be maintained on a the older immunofluorescence assays for IgA EMA.
gluten-free diet for the rest of their lives to control symptoms and mitigate Antigliadin antibody serology is best avoided in the diagnosis of celiac
cancer risk (Table 22-6). disease because of frequent false positives. A second generation of antiglia-
In current clinical practice, four serologic studies are used to assist in din antibody test based on the potentiation of toxic gliadin peptides by
the diagnosis of celiac disease. These include testing for antibodies to tTG enzymatic activity is used to monitor dietary compliance. These IgA
gliadin (AGA-IgA and AGA-IgG), endomysium (EMA-IgA), reticulin and IgG deamidated gliadin peptide (DGP) assays appear similar to tTG
(ARA-IgA), and transglutaminase (tTG-IgA), all of which are commer- IgA or IgG in diagnostic accuracy, leading to the belief that strongly posi-
cially available. Results of serologic testing for celiac disease must be tive tTG IgA in conjunction with positive DGP serology may be used as
analyzed with caution because this disease is associated with selective IgA confirmation of celiac disease without the need for biopsy histology.
deficiency that will give rise to false-negative serum IgA antibody tests Although IgG endomysium and IgG tTG antibodies may be suitable
(Thomas et al., 2003). Transient IgA deficiency may be seen in patients on for serologic diagnosis of celiac disease, they cannot be used to monitor
phenytoin, penicillamine, or sulfasalazine. Therefore, total IgA levels the response to dietary modification. Endomysium IgA antibodies disap-
should be checked or specific IgG serology performed if there is a high pear following treatment of celiac sprue with a gluten-free diet.
clinical suspicion of celiac disease. The sensitivity and specificity of these The HLA-DQ2 allele is identified in 90% to 95% of patients with
tests are extremely high when compared with a gold standard of flattened celiac disease and HLA-DQ8 in most of the remaining patients. These
small bowel villi responding to dietary changes (Farrell & Kelly, 2001). alleles occur in 30% to 40% of the general population, and the absence of
Endomysial antibodies have the best sensitivity and specificity, but they these alleles is important for its high negative predictive value. Thus the
317
presence of HLA-DQ2 and HLA-DQ8 is important for determining tute 85% of all pancreatic tumors and are the fourth most frequent cause
which family members should be screened with serologic testing (Kauki- of death from cancer. They originate in small ducts and progress from
nen et al, 2002). Uncontrolled celiac disease appears to predispose patients noninvasive pancreatic intraepithelial lesions to invasive cancers.
to intestinal carcinomas and lymphomas (Nehra, 1998). Precursor lesions for pancreatic adenocarcinoma include intraepithelial
pancreatic mucinous neoplasms (IPMNs) and pancreatic intraepithelial
Whipple’s Disease neoplasia (PanIN) (Hruban et al, 2005; Distler et al, 2014). PanIN is the
Whipple’s disease is a rare multisystem disease that often presents with most common of these precursor lesions. First described in 1998, PanIN
arthralgias, diarrhea, malabsorption, and weight loss. It is predominantly are a series of histological descriptions of lesions initially found in close
found in males, and about 15% of patients do not present with classical proximity to invasive adenocarcinoma (Brat et al, 1998). This series traces
signs and symptoms of this disease (Fenollar et al, 2007). It is caused by the progression and development of exocrine pancreatic ductal adenocar-
Tropheryma whipplei, a bacillus that does not stain well with Gram stain, cinoma from normal pancreatic ductal epithelium through PanIN grades
although it is classified with gram-positive bacteria based on 16S rRNA 1-A, 1-B, 2, 3, and then to infiltrating pancreatic ductal adenocarcinoma
sequencing (Marth & Raoult, 2003). This disorder can affect the central (Recavarren et al, 2011). Histologically, this is manifested by changes from
nervous system and cause endocarditis. Demonstration of periodic acid– low-columnar or cuboidal epithelium with normal nuclei to papillary and
Schiff (PAS)–positive material in the lamina propria and villous atrophy of micropapillary architecture with nuclear irregularities, abnormal mitoses,
the small intestine are diagnostic. A prothrombin time should be checked and luminal necrosis. Ki-67 staining also increases with PanIN grade
before biopsy because of the frequent occurrence of vitamin K (Klein et al, 2002).
malabsorption. Little change in their incidence or survival rate has been seen in the
T. whipplei has been cultured from the stools of a patient with Whipple’s past 20 years; 5-year survival is less than 5%. A slight male predominance
disease, using a specific axenic medium and specific techniques (Raoult has been noted, especially in younger age groups. This is a disease mostly
et al., 2006). PCR testing of infected tissue or cerebrospinal fluid has been of late life; 80% of patients are 60 to 80 years of age, although cases in the
used to confirm the diagnosis and monitor treatment (von Herbay et al, third decade are not uncommon. This cancer is more common in African
1997). Biopsy of the duodenum with PAS staining had been considered Americans and Native Americans. A two- to threefold greater risk has been
pathognomonic for Whipple’s disease. It is now recognized that PAS- reported among cigarette smokers. Patients with chronic pancreatitis and
positive macrophages may be seen in AIDS patients with Mycobacterium diabetes mellitus are at increased risk. High intake of meat and fat appears
avium-intracellulare complex. Thus PCR has gained even more importance to be a risk factor, as well as intake of nitrosamines and polycyclic hydro-
in the management of this entity. Long-term antibiotic therapy with carbons. The neoplastic mechanism remains obscure.
central nervous system penetration is used to treat patients with Whipple’s Clinical presentation depends largely on the location of the tumor:
disease (Ramzan et al, 1997; Singer, 1998). 60% arise in the head, often with painless jaundice; 10% in the body and
10% in the tail are often silent until quite large or widely disseminated;
Inflammatory Bowel Disease 20% are diffuse at presentation. Familial clusters have been reported, but
Immunologic mechanisms within the colon are involved in the pathogen- no distinct genetic abnormality has been described.
esis of inflammatory bowel disease. The underlying antigenic challenge to The ampullary region is invaded by carcinomas of the head of the
the immunologic response is not clearly understood. Over the past decade, pancreas, causing bile duct obstruction. Acute painless dilation of the
two antibody tests have become available that assist in the laboratory evalu- gallbladder (Courvoisier’s sign) and jaundice occur as the result of common
ation of patients with inflammatory bowel disease (Rutgeerts & Vermeire, bile duct obstruction by tumor in most cases. Carcinomas of the body and
2000). The combination of clinical findings, endoscopy, radiologic imaging, tail do not impinge on the biliary tract. Migratory thrombophlebitis
and blood work may help differentiate the subtypes of inflammatory bowel (Trousseau’s sign) develops in 10% of patients with pancreatic cancer,
disease. Perinuclear-antineutrophil cytoplasmic antibody (p-ANCA) and especially those with tumors of the body and tail, probably because of
anti–Saccharomyces cerevisiae antibody (ASCA) can be used to help distin- platelet-aggregating factors and procoagulants from the tumor. Anorexia,
guish abdominal pain seen in irritable bowel syndrome from inflammatory conspicuous weight loss, and gnawing epigastric pain that radiates to the
bowel disease and can help distinguish ulcerative colitis from Crohn’s back are frequent clinical features.
disease (Sendid et al., 1998; Shanahan, 1994) (Table 22-7). These tests Early diagnosis of pancreatic carcinoma is unusual. These tumors are
have limitations, and interpretation requires careful understanding of the typically silent until they impinge on a vital structure or on the posterior
tests. Although few normal persons with irritable bowel syndrome will wall of the abdomen and then cause severe pain. Pain is usually the first
have ANCA, 70% of persons with ulcerative colitis and 20% of persons symptom. Less than 20% of the tumors are resectable at the time of
with Crohn’s disease will have significant titers. Among patients with presentation.
inflammatory bowel disease, 65% of those with Crohn’s disease will have No morphologic difference is known between carcinomas of the head
ASCA, whereas only 20% of patients with ulcerative colitis will have sig- of the pancreas and those of the body and tail. These tumors are usually
nificant titers. Given their low sensitivity and specificity, use of these tests moderately or poorly differentiated mucin-producing adenocarcinomas.
should be dependent on the clinical circumstance. For example, a person They have abortive tubular structures and dense stromal fibrosis and
with diarrhea and equivocal biopsy findings found to have a positive ANCA aggressive infiltrative growth, often with perineural invasion. Tumor cells
is more likely to have inflammatory bowel disease than irritable bowel are cuboidal or columnar and are usually poorly differentiated. The adja-
syndrome. Likewise, if a person with what appears to be ulcerative colitis cent pancreatic parenchyma often demonstrates foci of ductal dysplasia and
is found to have a positive ASCA, Crohn’s colitis may be present. intraductal tumor growth.
Point mutations in KRAS and in p16 are found in more than 90% of
GASTROINTESTINAL TUMORS cases, and mutations in p53 cause inactivation in 50% to 70% of cases.
Both carcinoembryonic antigen (CEA) and CA 19-9 (tumor marker for
Pancreatic Adenocarcinoma pancreatic cancer) are elevated in some pancreatic adenocarcinomas.
Ductal adenocarcinomas of the exocrine pancreas are malignant epithelial According to the most recent guidelines from the American Society of
tumors composed of mucin-producing glandular structures. They consti- Clinical Oncology, clinicians are advised to use these tumor markers very
cautiously (Locker et al, 2006). CA 19-9 is not recommended as a marker
for screening for pancreatic cancer, nor for determination of operability.
Routine use of CA 19-9 is not recommended for monitoring treatment
TABLE 22-7 response. However, it can be measured at the initiation of treatment and
Markers for Inflammatory Bowel Disease then every 1 to 3 months thereafter. An elevation should prompt investiga-
tion for advanced metastatic disease. However, their increases can be used
FREQUENCY (%) to monitor for recurrence (Table 22-8).
p-ANCA ASCA Neuroendocrine Tumors
Irritable bowel syndrome (normal patients) <5 <5 Gastroenteropathic neuroendocrine tumors (GEP-NET) are relatively
Ulcerative colitis 70 15 rare neoplasms with varied clinical manifestations. Abdominal pain and
diarrhea are two of the more common clinical symptoms. Carcinoid tumor
Crohn’s disease 20 65
was the term chosen, more than 100 years ago, to distinguish these tumors
ASCA, Anti–Saccharomyces cerevisiae antibody; p-ANCA, perinuclear antineutrophil from carcinomas of the GI tract. Because these tumors are rare, they were
cytoplasmic antibody. lumped together. Recently, with greater knowledge of their development
318
TABLE 22-8
Pancreatic Cancer–Associated Genetic Syndromes
Genetic Syndrome Gene(s) Pancreatic Cancer Risk Increase Histopathologic Features
Hereditary breast and ovarian cancer BRCA2 3.5- to 10-fold Ductal adenocarcinoma
syndrome BRCA1 2-fold
PART 2
Peutz-Jeghers syndrome STK11/LKB1 132-fold Intraductal papillary mucinous neoplasm
Familial adenomatous polyposis APC Up to 4-fold Ductal adenocarcinoma, intraductal papillary
neoplasm, pancreatoblastoma
Familial atypical multiple melanoma CDKN2A 13- to 22-fold Ductal adenocarcinoma
Hereditary nonpolyposis colorectal cancer Mismatch repair genes Increased Medullary carcinoma
syndrome
Hereditary pancreatitis PRSS1 53-fold Ductal adenocarcinoma
SPINK1
Familial pancreatic cancer Unknown 9- to 32-fold
From Shi C, Hruban RH, Klein AP: Familial pancreatic cancer, Arch Pathol Lab Med 133:365–374, 2009.
and biological behavior, the World Health Organization classification of may secrete various normal hormones that are not ordinarily produced in
GEP-NET was published in 2000. Specific markers of normal and neo- the pancreas, including adrenocorticotropic hormone (ACTH), parathy-
plastic neuroendocrine cells are the hormones that occur in the GEP roid hormone, calcitonin, and vasopressin.
system. The organ in which a certain hormone-producing tumor develops
appears to make a difference (e.g., the differing malignant potential of Insulinoma
duodenal compared with pancreatic gastrinoma) (Klöppel et al., 2004). Insulinomas are derived from β cells and produce insulin that induces
These tumors exhibit amine precursor uptake and decarboxylation (APUD) clinically significant hypoglycemia. Factitious disease due to exogenous
and are therefore known as APUDomas. Cells of the GEP-NET belong insulin is part of the differential diagnosis. Insulinomas are usually found
to the system of disseminated neuroendocrine cells called APUD cells. in the pancreas and are typically small and solitary and often contain
These cells are scattered throughout the mucosa of the GI tract and the amyloid; 10% are malignant. Diagnosis is made by demonstrating elevated
islets of the pancreas. Insulinomas and gastrinomas are the most common plasma insulin associated with hypoglycemia and measurement of
pancreatic endocrine tumors. Glucagonomas are rare and make up 2% to C-peptide. C-peptide is equimolar to insulin and is needed to exclude
5% of series. Other, even rarer types, such as somatostatinomas and increases in insulin from exogenous sources.
VIPomas, have been identified (Perr & Vinik, 1996). Chemical measure-
ment of the secretagogues of these tumors generally suggests the diagnosis Gastrinoma
in the right clinical setting. Gastrinomas are gastrin-secreting non–β cell pancreatic tumors that cause
Localizing these tumors can be challenging. Ultrasonography, CT a syndrome of intractable peptic ulcer disease and gastric acid hypersecre-
scanning, MRI, endoscopy, angiography, and octreotide scanning all have tion. Gastrin binds cholecystokinin-B receptors on parietal cells of the
significant technical limitations. With the exception of ultrasonography stomach to stimulate acid secretion and also has a trophic effect on gastric
and MRI, potential morbidity can result from the testing as well. Soma- mucosal parietal and enterochromaffin-like cells, causing mucosal hyper-
tostatin receptor scintigraphy (SRS) is widely used in the evaluation of trophy (McIntyre et al, 2002). The mean age at onset is 50 years, with
GEP-NETs (Warner & O’dorisio, 2002) and is a useful tool in the arma- male preponderance. At the time of diagnosis, 70% to 90% of the tumors
mentarium of the diagnostician. The underlying basis of this imaging are malignant with metastases or local invasion. Up to 60% of gastrinomas
modality is that NETs have a greater density of SSTRs on the cell surface. are associated with MEN 1, and about one-half of MEN 1 patients develop
As such, this diagnostic modality is value-added in utility because it can gastrinomas. Most gastrinomas arise in the gastrinoma triangle: duode-
identify those patients who would be susceptible to therapy with SST num, pancreatic head, and hepatoduodenal ligament.
analogs. The SST analogs used in SRS typically have high affinity for Gastrin is not usually detected in the adult pancreas but is present in
receptor subtypes SSTR2 and SSTR5, low affinity for SSTR3, and no the fetal pancreas. Gastrinomas induce peptic ulcer disease refractory to
affinity for SSTR1 and SSTR4 (Sclafani et al, 2011). These tumors are treatment, esophagitis, and diarrhea. High levels of plasma gastrin are
often small, frequently are multifocal, and can be located in a variety of noted with high basal gastric acid secretion. Increased gastrin levels
organs. They can be malignant or benign. They are similar on histologic are also caused by gastric atrophy and by acid antisecretory drugs such as
examination, so histologic staining is used to distinguish the types (Perry H2 blockers. Some gastrinoma patients are hypercalcemic because of
& Vinik, 1996). A recent retrospective analysis comparing SRS positivity PTH-related protein production or because patients with MEN 1 may
with IHC analysis of SSTR2 and SSTR5 expression discovered a high develop hyperparathyroidism. About 50% of patients with gastrinomas
concordance rate (70%) but a nonnegligible (50%) number of SRS- have metastases, mainly to the liver and nodes. The 5-year survival is
negative tumors that stained positively for SSTR2. This subpopulation of 20% with liver metastases, and without metastases, 80% will survive for
patients is important because they may be susceptible to radiopharamaceu- 5 years.
ticals (Sclafani et al, 2011). These findings highlight the fact that, as with Gastrinomas can cause high-volume diarrhea through an increased rate
all neoplastic lesions, biopsy is essential to confirm the diagnosis. of gastric acid secretion, resulting in a volume that cannot be fully reab-
GEP-NETs make up about 10% of pancreatic neoplasms and are clas- sorbed. The acid exceeds the neutralizing capacity of the pancreatic bicar-
sified as functioning or nonfunctioning tumors. These tumors are single bonate and inactivates the pancreatic digestive enzymes; this interferes
or multiple, and benign or malignant. They are often solitary, circum- with the emulsification of fat by bile salts, resulting in steatorrhea. A secre-
scribed lesions, amenable to surgical resection. Immunohistochemistry is tory component to the diarrhea has also been observed. Diagnosis is
needed for demonstration of endocrine activity. Hormone assays are useful established by measuring serum gastrin levels; a level greater than 1000
for the diagnosis of pancreatic endocrine tumors (Modlin & Tang, 1997; pg/mL is virtually diagnostic. The secretin stimulation test can differenti-
Eriksson et al, 2000; Barakat et al, 2004). ate patients with gastrinomas from those with the many other causes of
Cytologic criteria are unreliable in diagnosis. The diagnosis of malig- hypergastrinemia; this test should be performed in every patient suspected
nancy requires demonstration of metastases and vascular or tissue invasion. to have the ZE syndrome who has a nondiagnostic fasting serum gastrin
These tumors are often slow growing. Functioning tumors cause recogniz- concentration (Berna et al, 2006).
able clinical syndromes due to excess peptide hormone secretion. Non-
functioning tumors have a worse prognosis and typically present with Glucagonoma
metastases or local symptoms. This is a rare tumor, mostly of pancreatic origin, that secretes glucagon (α
GI endocrine tumors may be part of the syndrome of MEN 1 with cells), which induces glycogenolysis and gluconeogenesis in the liver and
parathyroid disease and pituitary and pancreatic tumors. Islet cell tumors raises blood glucose levels. It causes a syndrome of mild diabetes,
319
necrotizing migratory erythematous rash, anemia, and venous thrombosis, of blood proteins in the small intestine and absorption of nitrogenous
and it is associated with severe infection. Onset occurs at 40 to 70 years products may be the cause.
of age, with slight female predominance (Bloom & Polak, 1987). These
are large, locally invasive tumors that histologically resemble trabecular Fecal Occult Blood Testing
and solid patterns of insulinomas; two thirds are malignant. Plasma gluca- The fecal occult blood test (FOBT) depends on the peroxidase activity of
gon levels are elevated up to 30 times above normal. hemoglobin. Reagents used include guaiac (Hemoccult), benzidine (mar-
keting restricted by federal regulation because of its carcinogenicity),
Somatostatinoma orthotoluidine (Hematest), and ortho-dianisidine. The reagents differ in
These usually solitary tumors are derived from δ cells that produce soma- sensitivity, although all are associated with frequent false-positive and
tostatin, which inhibits pituitary release of growth hormone and secretion false-negative results, mostly due to the specimen tested. Specimens col-
by α, β, and δ cells. This peptide also regulates glucose homeostasis and lected by digital rectal examination have a high frequency of false positives
causes a syndrome of mild diabetes, gallstones, steatorrhea, and hypochlor- caused by injury to the rectal mucosa.
hydria, due to the inhibitory effect of somatostatin on the other islet and The normal person loses 0.5 to 1.5 mL of blood into the GI tract daily
gastrointestinal neuroendocrine cells (Krejs et al., 1979). Somatostatin in association with the normal shedding of epithelial cells. Commercial
measurement in a fasting serum specimen may aid diagnosis; patients with tests are designed to turn positive with blood loss greater than 5 to 10 mL
somatostatinomas may have 1000-fold elevated concentrations. These per day. This corresponds to 5 to 10 mg of hemoglobin/gram of feces,
tumors may also secrete calcitonin or ACTH, and most are malignant with assuming a blood hemoglobin of 15 g/dL and an average daily 150-g stool.
metastases at diagnosis. In addition to sample handling and testing, diet is very important in
compromising these tests. The high rate of false positives is due to the lack
VIPoma of specificity of the reagents and the presence of peroxidase activity in
These tumors are presented in the previous section on diarrhea and other fecal constituents, as well as the sensitivity of the different chromo-
malabsorption. gens to peroxidase activity. The myoglobin and hemoglobin of ingested
meat and fish have peroxidase activity that may falsely indicate the presence
Carcinoid Syndrome of occult blood. Bacteria in the bowel, as well as ingested vegetables and
Pancreatic carcinoids are rare malignant neoplasms resembling intestinal fruits, such as horseradish, turnips, bananas, black grapes, pears, and
carcinoids. They synthesize serotonin and motilin. When confined to the plums, have peroxidase and can falsely elevate fecal peroxidase activity.
pancreas, these tumors may induce an atypical carcinoid syndrome that False-negative tests occur in the presence of large amounts of vitamin C
consists of facial flush, hypotension, periorbital edema, and lacrimation. and other antioxidants.
Cases with liver metastases cause a classical carcinoid syndrome. Diagnosis Patient preparation and specimen collection are important in ensuring
is aided by demonstration of increased 5-hydroxyindoleacetic acid valid test results. For 72 hours prior, patients should be on a diet free of
(5-HIAA) levels in 24-hour urine specimens. exogenous peroxide activity (meat, fish, turnips, horseradish), GI irritants
(aspirin, NSAIDs), and vitamin C. Variations in testing technique produce
Amyloidosis errors due to stool consistency, the application of large aliquots of stool,
GI amyloidosis is mainly of the reactive type (secondary or amyloid- and, particularly, inaccurate timing of the reaction.
associated [AA] amyloidosis) and results from mucosal or neuromuscular Immunochemical tests for hemoglobin are more sensitive and specific
infiltration. It may result in GI bleeding from vascular friability. The and yield fewer false negatives. They are not affected by diet, animal
patient may also have diarrhea from a combination of altered intestinal hemoglobin, or human myoglobin. Dietary peroxidases do not affect
motility, bacterial overgrowth, and protein-losing enteropathy. Liver immunochemical test results. They are useful only for screening blood of
involvement can be seen in primary (amyloid light chain) or AA amyloi- the lower intestinal tract and are insensitive to upper GI bleeding because
dosis. Common symptoms include involuntary weight loss, fatigue, and globin is destroyed in the small intestine.
abdominal pain. Common physical findings consist of hepatomegaly, Colon cancer is a leading cause of cancer-related deaths in the United
ascites, purpura, and splenomegaly. The most common laboratory abnor- States, accounting for approximately 55,000 deaths annually. According to
mality is an elevated alkaline phosphatase. The diagnosis of multiple recent cancer statistics, approximately 150,000 new colon cancer cases
myeloma should be confirmed by tissue biopsy of duodenal or colorectal were diagnosed in 2003. Evidence has demonstrated the clinical usefulness
mucosa. Although GI complications can result in significant morbidity, of FOBT to detect these cancers at an earlier stage, potentially resulting
they usually are not the cause of death, which is most often due to renal in decreased mortality. Because of the generally favorable clinical biology
failure, restrictive cardiomyopathy, or ischemic heart disease (Ebert & of these tumors when detected earlier (with an 80% to 90% survival rate
Nagar, 2008). with local confined disease) (Helm et al, 2003) and the relatively inexpen-
sive, noninvasive nature of FOBT, this may serve as a useful screening
technique. Several professional organizations recommend annual or bien-
GASTROINTESTINAL BLEEDING nial FOBT, but universally accepted screening protocols have not been
Throughout most of the GI tract, the lumen of the gut is separated from established. The American Cancer Society guidelines for colorectal cancer
the capillary blood supply by only a single layer of epithelial cells. Thus screening, the most widely utilized, recommend annual FOBT and flexible
even minor injury to the epithelial lining may result in GI bleeding. Occult sigmoidoscopy every 3 to 5 years, beginning at age 50, in asymptomatic,
GI bleeding is bleeding unknown to the patient. Iron deficiency anemia average-risk individuals (Marshall, 1996). Limitations of this testing
should be considered to be the result of GI bleeding until excluded include the high numbers of false-positive and false-negative results. The
(Rockey, 2010). sensitivity of FOBT has been estimated at between 30% and 50%. The
Hemoglobin and hematocrit are usually low, and their levels may have true sensitivity of FOBT is difficult to determine because individuals who
some relation to blood loss. A low mean cell volume (MCV) may indicate test negative do not undergo further colonoscopic evaluation to determine
that the patient is iron deficient and that chronic blood loss has occurred. whether the FOBT is a true negative. Only approximately 5% to 10% of
An elevated MCV may indicate a folate or vitamin B12 deficiency with positive reactions prove to be caused by an occult malignancy (Simon,
macrocytosis and raises the possibility of ethanol abuse, chronic liver 1998). However, following a stepwise approach to colon cancer screening
disease, gastric cancer in association with pernicious anemia, or regional should minimize the clinical effects of limited sensitivity and specificity
enteritis involving the terminal ileum. and offer valuable information.
If a clotting defect exists, prompt correction of the deficiency is crucial. Occult blood can be detected by chemical (guaiac), hemoporphyrin, or
Extensive transfusion dilutes platelets and clotting factors, particularly immunologic methods. Occult blood may arise anywhere along the intes-
factors V and VII. Also, a high proportion of patients who bleed while tinal tract and is often the first warning sign of GI malignancy. Other
taking therapeutic anticoagulants do so from a clinically significant lesion. potential sources of occult blood may arise from bleeding esophageal
It is important to evaluate these patients for a GI pathologic condition and varices, polyps, esophageal or gastric inflammation, hemorrhoids or fis-
to correct their clotting status. Leukocytosis may accompany acute GI sures, inflammatory bowel disease, peptic ulcer disease, or angiodysplasias
bleeding, but it is usually not in excess of 15,000 white blood cells/mm3. of the colon. Laboratory diagnosis of the presence of fecal occult blood
Leukocytosis should not be attributed to acute blood loss without comple- generally involves a guaiac-smear test (Hemoccult, Seracult, Coloscreen),
tion of a search for sources of infection. the most commonly used method at present. Guaiac is a naturally occur-
Elevated BUN in a patient whose BUN was recently normal, or whose ring phenolic compound that is oxidized to quinone by hydrogen peroxi-
serum creatinine concentration is normal, suggests an upper GI bleed. The dase, resulting in a detectable color change. These tests detect the
BUN rise may be due to the hypovolemia of acute blood loss, but digestion pseudoperoxidase activity of heme as intact hemoglobin or as free heme
320
(Allison et al, 1996). These tests are not specific for human hemoglobin, type or the specific organ involved. Lactate dehydrogenase, a glycolytic
and hemoglobin from red meat, peroxidase from fruits and vegetables, and pathway enzyme, is released as a result of cell damage, and its elevation in
certain medications can lead to false-positive results. The presence of more malignancy is nonspecific (Schwartz, 1982). Neuron-specific enolase
than 5 to 10 mL/day of blood in the stool results in a positive guaiac smear. (NSE) is found in neural tissue and in cells of the diffuse neuroendocrine
Stool specimens should be received from three consecutive stools. Two system. NSE is found in association with tumors of neuroendocrine origin,
slides should be prepared for each stool sample. Slides should not be and its serum levels are of prognostic significance (Zeltzer et al, 1986).
PART 2
rehydrated and should be developed within 7 days of collection. To ensure Urokinase-plasminogen activator, a serine protease system, is a prognostic
quality testing, some medical institutions now require that stool samples marker in colorectal cancer (Duffy et al, 1999). Tumor-associated trypsin
be sent to the laboratory for guaiac testing, rather than having residents inhibitor (TATI) is identical to pancreatic secretory trypsin inhibitor, also
or nurses perform tests on the ward. In addition, the test must be per- known as the kazal inhibitor. It is strongly expressed in pancreatic cells and
formed under appropriate conditions that serve to limit its sensitivity. in low concentrations in normal GI and urogenital tissues. TATI is a useful
Factors that can cause inaccuracies in the results include the presence of marker for GI, urologic, and pancreatic cancers (Stenman, 2002).
bleeding gums, for example, or ingestion of large amounts of red meat
before testing. In addition, patients may be using certain medications that Hormones
will influence the results of FOBT. For example, drugs that can cause GI Hormones are normally produced in endocrine organs but may also be
irritation and subsequent bleeding, such as anticoagulants, aspirin, produced in nonendocrine tissue. They are assayed by EIA using mono-
NSAIDs, or colchicines, may lead to false-positive results. Other drugs clonal antibodies or by RIA. Multiple endocrine neoplasia (MEN 2A and
that have been implicated include reserpine and oxidizing drugs such as MEN 2B) syndromes synthesize several polypeptide hormones such as
iodine. Ingestion of large amounts of vitamin C can cause false-negative ACTH, calcitonin, gastrin, glucagon, and insulin. Vasoactive intestinal
results. Patients should avoid such medications or food products before peptide is produced by some endocrine tumors (Perry, 1996).
FOBT. A positive FOBT prompts further evaluation for a GI lesion. ACTH may be the result of pituitary or ectopic production. Elevated
Additional evaluations usually include sigmoidoscopy with barium enema ACTH levels have been reported from pancreatic, gastric, and colonic
or full colonoscopy, the latter being the preferred modality. A negative carcinomas. Patients with serotonin-producing carcinoid tumors often
FOBT, however, cannot definitely rule out the presence of colonic neo- have marked tenfold increases in urinary 5-HIAA excretion. Ingestion of
plasia. If a patient is presenting with signs and symptoms suggestive of serotonin-rich foods, such as bananas, chocolate, plums, or walnuts, or
colon cancer, further evaluation is warranted, even in the presence of nega- medications containing guaifenesin may produce false-positive elevations
tive FOBT. (Kema et al, 1992).
Fecal DNA testing is a promising technique for colorectal cancer
screening. This test involves the collection of a single stool specimen, Other Protein Markers
which is then screened for DNA markers. PCR is used to amplify the fecal Oncofetal antigens are proteins produced in fetal life that decrease to low
DNA. These tests are useful because DNA is shed continuously and levels or disappear after birth but reappear in cancer patients. The discov-
remains stable in stool, and minute amounts are detectable. Clinical studies eries of α-fetoprotein (AFP) and carcinoembryonic antigen (CEA) in the
have shown that fecal DNA testing has high specificity and sensitivity for 1960s had a profound effect on the use of tumor markers. AFP is a marker
cancer detection, considerably more than chemical guaiac testing. Several for hepatocellular and germ cell (nonseminomatous) carcinomas. CEA, a
markers have been investigated; however, further evaluation and improved glycoprotein, is a marker for colorectal, GI, lung, and breast carcinomas.
specificity and sensitivity are needed for their widespread use (Itzkowitz CEA testing may be useful as an adjunct to clinical staging (Sikorska et al,
et al, 2008; Lieberman, 2009; Mandel, 2008). 1992). Amplification of Her2/neu, a tyrosine kinase receptor of the epi-
dermal growth factor family, is seen in GI, breast, and ovarian tumors.
bcl-2, a protein known to inhibit apoptosis, appears early in colorectal
Blood in Newborn Feces (Apt Test for cancer. C-peptide is a marker for insulin production.
Swallowed Blood)
When blood is found in the GI tract or stool of neonates, usually on the Blood Group Antigens
second or third day of life, a determination must be made of whether it is Some of the blood group carbohydrates are tumor markers with elevated
swallowed blood of maternal origin or is secondary to disease in the levels in specific types of cancer. CA 19-9, a sialylated Lewis antigen, is
newborn (Guritzky & Rudnitsky, 1996). The Apt test is a qualitative test elevated in patients with colorectal and pancreatic carcinomas (Lamerz,
that is used to make this determination in grossly bloody stools or vomitus 1992). Its levels are elevated in benign conditions such as Mirizzi’s syn-
(hematemesis) from a newborn. Infants may ingest maternal blood during drome (Robertson & Davidson, 2007). It is absent in individuals with
birth or from a fissured or bleeding nipple. The sample first is mixed with pancreatic tumors who are Lewis negative. Another related Lewis antigen,
water and then is centrifuged. The supernatant, which should be pink, is C50, is used as a pancreatic tumor marker but is considered less sensitive
then mixed with 1% sodium hydroxide in a 5 : 1 ratio. If the blood is of than CA 19-9. CA 242 and CA 72-4 are markers for GI and pancreatic
maternal origin, the mixture turns yellow-brown after several minutes. tumors, but CA 72-4 is considered of greater prognostic value in pancreatic
Fetal blood remains pink because fetal hemoglobin is more resistant to cancer (Louhimo et al, 2004).
alkali denaturation than adult hemoglobin. The test has relatively low
sensitivity, and the result must be interpreted with caution (McRury & Genetic Markers
Barry, 1994). Two classes of genes are implicated in cancer: cell activator genes and cell
suppressor genes. Most oncogenes code for proteins that activate cell
MARKERS FOR GASTROINTESTINAL AND proliferation. Mutated K-ras is present in 95% of pancreatic cancers, in
40% of colon cancers, and in lower percentages of other tumors (Chan et
PANCREATIC TUMORS al, 2006). Mutations of ras oncogenes have been detected in the stools of
Tumor markers are substances produced by tumor cells or other body cells 9 of 15 patients with curable colorectal tumors (Sidransky et al, 1992).
in response to neoplastic or certain nonneoplastic conditions; they are Any genetic testing requires that the physician clearly understand how
found in tissues or body fluids. Different tumor markers are found in dif- to interpret the results and how the results may affect patient management;
ferent types of cancers, and the same tumor marker may be found in more patients and their family members must be counseled appropriately (Grody
than one type of cancer. Tumor markers are not expressed in all people et al, 2001; LeGrys et al, 2007).
with cancer, and some are expressed in patients with benign conditions.
Identification or measurement of tumor markers is used in the detection, Tumor Suppressor Genes
diagnosis, or management of some types of cancer. Although an abnormal Oncogenicity derives from loss of the gene, rather than its activation, as
tumor marker level may suggest cancer or limited efficacy of therapy, this with the p53 gene. Three-fourths of colon carcinomas show deletion in
alone is not enough to establish diagnosis and is usually combined with one p53 allele and a point mutation in the other allele.
other tests, such as biopsy (Bigbee & Herberman, 2003; Chan et al, 2006;
Locker et al, 2006).
STOOL COLLECTION AND EXAMINATION
Enzymes
Enzymes were one of the first groups of tumor markers identified, and
COLLECTION
their elevated levels were linked with cancer. Most changes in enzyme Uninstructed patients sometimes exhibit considerable ingenuity in collect-
levels are not specific or sensitive enough to be used to identify the cancer ing stool specimens, but a few simple instructions are likely to produce
321
more satisfactory specimens. A scoured, well-rinsed bedpan is a convenient MICROSCOPIC EXAMINATION
collection container. If the patient does not own one, a carefully cleaned,
rinsed, and boiled glass jar of suitable size is a satisfactory alternative. Fat
Patients should be warned against passing urine at the same time into the The simplest technique is microscopic examination using one of the Sudan
bedpan or container because, among other things, urine has a harmful stains. This procedure has been widely employed for screening because of
effect on protozoa. Tongue depressors or pieces of cardboard are reason- its simplicity. In our experience, results have correlated well with quantita-
ably convenient instruments for transferring the stool from bedpan to tive measurements when aliquots of the same homogenized stool have
transport vessel, for which plastic, cardboard, and glass containers are been analyzed. For this purpose, a small aliquot of stool suspension is
available. We prefer to use two 2-ounce ointment jars with screw caps for placed on a slide and is mixed with two drops of 95% ethanol; then two
small stool samples because they are odor free, leakproof, and easy to drops of saturated ethanolic solution of Sudan III are added, with further
transport. Patients should be instructed not to contaminate the outside of mixing. A coverslip is applied. Under these conditions, fatty acids are
the container and not to overfill the container. Gas, which frequently present as lightly stained flakes or as needle-like crystals that do not stain
accumulates, should be released gradually by carefully loosening the cap. and therefore may be missed. Soaps also do not stain but appear as well-
Failure to observe this simple precaution, especially in the case of an defined amorphous flakes or as rounded masses or coarse crystals. Neutral
overfilled container, can result in an explosive release of contents. Fecal fats, however, appear as large orange or red droplets. When 60 or more
specimen collection at home is by no means simple and easy unless the stained droplets of neutral fats per high-power field are seen, one may be
patient has been instructed properly. reasonably certain that the patient has steatorrhea. Caution is advisable in
interpretation, however, because mineral oil or castor oil may mimic
neutral fat. The procedure is then repeated by adding several drops of 36%
MACROSCOPIC EXAMINATION (v/v) acetic acid to the stool mixture and warming the slide several times
The quantity, form, consistency, and color of the stool should be noted. over a flame until slight boiling occurs. This converts neutral fats and soaps
Normally, 100 to 200 g of stool is passed per day. Diarrheic stool is to fatty acids and melts the fatty acids, causing them to form droplets that
watery. Passage of large amounts of mushy, foul-smelling, gray stool that stain strongly with Sudan III. The slide is then examined while warm. After
floats on the water is characteristic of steatorrhea. Constipation may be this procedure has been performed, the presence of up to 100 stained
associated with passage of small, firm, spherical masses of stool (scybala). droplets per high-power field is considered normal. Patients with steator-
Clay color suggests diminution or absence of bile or the presence of rhea of pancreatic origin are likely to have greater increases in fatty acids
barium sulfate. Blood, especially blood originating from the lower gut, may and soaps.
cause the stool to be red; beets in the diet may mimic this. Bleeding from
the upper GI tract is more likely to cause the stool to be black and have a Meat Fiber
tarry consistency. Bismuth, iron, and charcoal may also cause a black color. The technique for sampling is identical to that used for Sudan preparations
Stool that is allowed to stand in the air for a time may darken on the for detection of fecal fat. The stool is mixed thoroughly on a slide with a
surface. solution of eosin in 10% ethanol; it is then allowed to stain for 3 minutes
and is examined for muscle fibers. The entire area under the coverslip is
Mucus examined, and only rectangular fibers with clearly evident cross-striations
The presence of recognizable mucus in a stool specimen is abnormal and are counted. More than 10 fibers per high-power field suggests maldiges-
should be reported. Translucent gelatinous mucus clinging to the surface tion and/or hypermotility. It appears that examination for meat fibers
of the formed stool suggests spastic constipation or mucous colitis. It is correlates well with chemical determination of fat excretion (Moore et al,
seen in stools of emotionally disturbed patients and may result from exces- 1971).
sive straining. Bloody mucus clinging to the fecal mass suggests neoplasm
or inflammatory processes of the rectal canal. Mucus associated with pus Leukocytes
and blood is found in stools of patients with ulcerative colitis, bacillary A small fleck of mucus or a drop of liquid stool is placed on a glass micro-
dysentery, ulcerating diverticulitis, and intestinal tuberculosis. Patients scopic slide with a wooden applicator stick. Two drops of methylene blue
with villous adenoma of the colon may pass copious quantities of mucus, are added and mixed thoroughly and carefully. A coverslip is placed on the
amounting to 3 to 4 L in 24 hours. They frequently develop severe dehy- mixture, which is allowed to stand for 2 to 3 minutes for good nuclear
dration and electrolyte disturbances, especially hypokalemia. staining. Using low-power scanning, rough quantitative counts are made
by approximating the average numbers of leukocytes and erythrocytes. All
Pus differential counts should be made under high power, counting 200 cells
Patients with chronic ulcerative colitis and chronic bacillary dysentery when possible. Only those cells clearly identified as either mononuclear or
frequently pass large quantities of pus with the stool, the recognition of polymorphonuclear are included in the differential count. Macrophages
which requires microscopic examination. This also occurs in patients with and epithelial cells that cannot be clearly identified are ignored. The initial
localized abscesses or fistulas communicating with the sigmoid colon, cell counts should be performed at the time of presentation of the
rectum, or anus. Large amounts of pus seldom accompany the stools of specimen.
patients with amebic colitis, and its presence is evidence against this diag-
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CHAPTER

Diagnosis of pancreatic and gastrointestinal disease is guided by the

Pancreatic hyperamylasemia High High High High Absent

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; LD, lactate dehy-

Initial Screening Tests

Lactose Tolerance Test a serum VIP concentration in excess of 75 pg/mL. It is important to

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