McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods, 21st ed.

Copyright © 2006 W. B. Saunders Company CHAPTER 22 – Laboratory Diagnosis of Gastrointestinal and Pancreatic Disorders Martin H. Bluth, MD PhD Rosemarie E. Hardin, MD Scott Tenner, MD Michael E. Zenilman, MD Gregory A. Threatte, MD KEY POINTS • Helicobacter pylori is recognized as the principal cause of gastrointestinal ulcers and gastritis. Serology tests are used to screen for H. pylori and noninvasive breath tests or endoscopic biopsy are used to confirm eradication after treatment. • Serum amylase is the analyte of choice to diagnose acute pancreatitis. Other markers, including lipase, trypsinogen (and metabolites), AST and ALT, can aid in determining etiology and/or diagnosis. Routine laboratory testing is of little value in identifying patients with chronic pancreatitis. Diagnosis relies on imaging techniques (ERCP). Laboratory screening for cystic fibrosis should be limited to sweat chloride testing. Genetic analysis should be used as a confirmatory test in specific cases. Chronic diarrhea can often be classified as inflammatory, osmotic or secretory in origin or the result of altered bowel motility. Initial stool tests for blood, microbes, fat and leukocytes help determine subsequent testing algorithms. IgA deficiency should be considered in patients suspected of having celiac sprue and incorporated in the interpretation of anti-gliadin, anti-endomysium, anti-reticulin, or anti-transglutaminase antibody results. Lactose intolerance increases with age. Screening tests for true disaccharidase deficiencies include oral challenge of suspected disaccharides to reproduce the abdominal symptomatology followed by stool analysis. Definitive diagnosis of disaccharidase deficiencies depends on the demonstration of low specific enzyme activity in the mucosa of small intestinal biopsy material. p-ANCA and ASCA can be used to distinguish abdominal pain seen in irritable bowel syndrome from inflammatory bowel disease. Carcinoid tumor is the most common type of neuroendocrine tumor of the gastrointestinal tract. Intraoperative gastrin measurements are useful in identifying whether the abnormal tissue is completely removed in patients undergoing surgery for gastrinomas. Screening with fecal occult blood testing can decrease mortality from colon cancer by 15-35%. A variety of factors can create false-positive or false-negative results.

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Over the past two decades the practice of gastroenterology has evolved tremendously. Increased expertise with endoscopic techniques has allowed direct visualization and biopsy of pathological lesions, facilitating confirmation of suspected clinical diagnoses such as gastric

and duodenal ulcer disease. Although these endoscopic evaluations are invaluable diagnostic modalities, they are expensive, invasive and require the specialized skill of a gastroenterologist. In recent years, clinical practices have continued to evolve with the advent of new laboratory evaluations for noninvasive diagnosis of gastrointestinal and pancreatic disorders. Examples include fecal immunochemical and DNA testing for detection of colon cancer and various serum antibody testing to aid diagnosis of inflammatory bowel disease. The latter gives one the ability to differentiate Crohn's disease from ulcerative colitis, which was previously impossible using the available routine laboratory testing. Furthermore, new laboratory tests with enhanced sensitivity and specificity are replacing older, previously established tests for diagnosis of diseases. One such example is the replacement of fecal chymotrypsin with fecal elastase levels to detect pancreatic insufficiency. Knowledge of these tests, their sensitivity and specificity profiles as well as awareness of false positives and negatives of these tests is crucial to the interpretation of the results, especially to the clinician responsible for appropriate disease management. New noninvasive serum tests are also being explored for clinical utility as screening methods, such as pepsinogen tests for detection of atrophic gastritis and early gastric carcinoma. In this chapter we will present clinically relevant disorders and discuss the utility of laboratory methods in confirming disease, guiding therapeutic interventions, predicting prognosis and monitoring therapy. In this edition, we have chosen to adapt laboratory evaluations to those that most closely reflect common clinical practice in the era of endoscopy and with the advent of the newer diagnostic tests. Email to Colleague Print Version Copyright © 2007 Elsevier Inc. All rights reserved. -

McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods, 21st ed.
Copyright © 2006 W. B. Saunders Company Common Gastroenterological Disorders
Gastric Disorders Peptic Acid Disease

The practical approach to peptic acid disease requires the integration of data supplied by the clinician, endoscopist, radiologist, clinical pathologist, and surgical pathologist. Helicobacter pylori has been recognized as the principal cause of duodenitis and duodenal ulcers, as well as being strongly associated with type B chronic antral gastritis, gastric ulcers, nonulcer dyspepsia, gastric carcinoma, and MALTomas ( Veldhuyzen van Zanten, 1994 ; Wotherspoon, 1998 ; Peterson, 1991 ; Thiede, 1997 ). The use of nonsteroidal antiinflammatory drugs (NSAIDs) causes or aggravates peptic and gastric inflammation and ulceration. Hypersecretory states are a much rarer cause of acid peptic disease. Data gathered by history and physical examination may initially suggest peptic acid disease. Radiologic and/or endoscopic techniques are employed to confirm the diagnoses. Testing for H. pylori and hypersecretory states involves laboratory analysis. (For more information see Ch. 56 .) Since H. pylori has been shown to be the most important causative agent for peptic ulcer disease, and is significantly associated with multiple other types of upper gastrointestinal (GI) pathology, there has been tremendous research involving its detection and treatment, and the confirmation of pathogen eradication. Within the last decade there have been numerous Food and Drug Administration (FDA)-approved and commercially available products for the detection of this bacterium. A cogent argument has been made that all patients found to harbor this organism should be treated ( Graham, 1997 ). Although the numbers and types of tests will likely continue to grow, tissue sampling, breath tests, and serology are currently the mainstay in the diagnostic armamentarium. Testing for H. pylori often utilizes the organism's ability to produce urease. Radioactive and nonradioactive breath hydrogen tests are examples of noninvasive means for detecting active H. pylori infection. Each is sensitive and specific prior to therapy. The incidental use of proton pump inhibitors, antibiotics, or bismuth-containing antacids may lead to false-negative tests. Treatment of H. pylori may not lead to complete eradication of the organism. Hydrogen breath tests may be falsely negative if they are performed too soon after treatment, before the bacterial load is great enough to be detected ( Atherton, 1994 ). Serum antibodies directed against H. pylori can be used to detect exposure to H. pylori. Enzyme-linked immunosorbent assay (ELISA) tests are available and reliable (Feldman, 1995a, b [19] [20]; van de Wouw, 1996 ). Although quantitative levels of these antibodies are not currently routinely utilized in the clinical setting to determine whether there is current or past infection, they have been reported to be highly accurate ( Lerang, 1998 ). At present, serology is generally utilized to screen for H. pylori and breath tests are used to confirm

eradication after treatment unless endoscopy allows collection of tissue for rapid urease testing or histologic review ( Megraud, 1997 ). Urease-based chemical tests are routinely used to detect H. pylori in biopsy specimens obtained via endoscopy. Fresh biopsy specimens obtained via endoscopy are placed into fluids or gels containing urea. The bacterial urease splits the urea, producing ammonia. The change in pH affects a color indicator, thus providing the basis for the detection. Bacterial load will determine the amount of urease present and can affect the rapidity of response. If the load is too low, the test can be falsely negative ( Xia, 1994 ). The test is inexpensive and easy to perform, but it requires endoscopy with its expense and potential risks. Office-based serologic quick-test kits are available. The accuracy of these kits has been shown to be dependent on the antibody preparations used. Immunoglobulin G (IgG) preparations perform most consistently. Other test qualities such as reproducibility, cost, and ease of utilization are factors to be considered when reviewing each of the many available brands marketed today ( Laheij, 1998 ). Histologic review of biopsy specimens stained with Warthin–Starry or Giemsa's stain remains one of the most frequently employed techniques to determine active infection. Culture of the organism may be inconsistent and is usually not done in routine clinical settings. Stool studies employing antigen enzyme assays and polymerase chain reaction (PCR) methodologies are also commercially available, but efficacy remains controversial ( Makristathis, 1998 ). Hypersecretory states are suggested by extensive peptic acid disease, especially in the absence of H. pylori, and the use of NSAIDs. Failure to respond to the usual doses of histamine-2 (H2)-receptor blocking agents and proton pump inhibitors also suggests oversecretion of hydrochloric acid. Although gastric analysis remains the „gold standard‟ with regard to the amount of acid secreted, it is invasive and used much less frequently. Care must be taken to avoid the use of antisecretory medications for the appropriate time intervals before such testing. H2-receptor blockers should be held for 48 hours and proton pump inhibitors should be avoided for 7 days. H2-receptor blockers are available without prescriptions, so patient education is important and clinicians must remember to review all of the medications their patients utilize. Gastrin levels, with and without secretin stimulation, can be used to diagnose Zollinger– Ellison syndrome, in many cases sparing the patient gastric analysis. Serum gastrin levels greater than 150 ng/L (normal < 100 ng/L), especially with simultaneous gastric pH values of < 3, are highly suggestive of a gastrinoma. For equivocal results, secretin can be given (2 U/kg) intravenously and serial gastrin levels can be drawn at 2, 5, 10, 15, and 20 minutes. An increase in gastrin of more than 100 ng/L (normal increase < 50 ng/L or 50%) is considered a positive test. Octreotide, a synthetic form of somatostatin, has been used for localization of the tumor(s). Radioactive-labeled octreotide binds to somatostatin receptors and can be subsequently localized by scintigraphy. If such tumors are surgically removed, gastrin levels can be used to assess potential success or future recurrence.
Pancreatic disorders Macroamylasemia

Macroamylasemia is the term used to describe a condition of persistently elevated serum amylase activity with no apparent clinical symptoms of a pancreatic disorder. It is attributed to the presence of an amylase–macromolecule complex whose larger size precludes its

excretion into urine, prolonging its half-life. Macroamylase is a circulating complex of normal amylase linked to an immunoglobulin in most cases and to a polysaccharide in others. The immunoglobulins involved are IgA and IgG. The composition of macroamylases is heterogeneous. Analysis of the complex after acid dissociation revealed that P-type and Stype isoamylases were present in variable proportions. The molecular weight has been estimated at 150 000 to more than 1 million. Macroamylasemia may also occur in hyperamylasemic patients with undiminished urine amylase and in patients with normal serum and urine amylase activity. Serum lipase may also form a complex with circulating immunoglobulins, resulting in macrolipasemia ( Zaman, 1994 ). Table 22-1 shows the distinguishing features of different types of hyperamylasemia.

Table 22-1 -- Differential Diagnosis of Hyperamylasemia and Macroamylasemia Condition Serum Serum Urinary Cam: Ccr Serum amylase lipase amylase macroamylase Pancreatic hyperamylasemia Salivary hyperamylasemia Macroamylasemia type 1 Macroamylasemia type 2 Macroamylasemia type 3 High High High High Normal High Normal Normal Normal Normal High Low or normal Low Low or normal Normal High Low or normal Very low Low Low or normal Absent Absent High Moderate Trace

Cam : Ccr = amylase clearance : creatinine clearance ratio = (urinary amylase/serum amylase) × (serum creatinine/urinary creatinine). After Kleinman DS, O'Brien JF: Macroamylase. Mayo Clin Proc 1986, 61:69, with permission.

Macroamylasemia can occur with a frequency of 1.05% in randomly selected patients, 2.56% among persons with hyperamylasemia, and 0.98% in persons with normal serum amylase ( Klonoff, 1980 ). Macroamylasemia per se is not a disease entity because no clinical symptoms consistently accompany it. It is an acquired and benign condition that may occur in apparently healthy individuals and is found more frequently in men than in women. The age at the time of discovery in most patients is in the fifth through seventh decades. The occurrence of macroamylasemia may be an early sign of disease, either as a marker or as a nonspecific disease-induced dysproteinemia with amylase-binding capability, and it may be regarded as one of the immunoglobulin-complexed enzyme disorders. Clinically, it is important to differentiate macroamylasemia from other conditions associated with hyperamylasemia. A patient with hyperamylasemia, a very low (< 1%) amylase/creatinine clearance ratio, and normal renal function should be considered for the possibility of having macroamylasemia. Definitive identification of macroamylasemia,

A detection method using chromatography has been in use for many years and a rapid and simple assay based on selective precipitation of macroamylase in a polyethylene glycol solution has also been reported ( Levitt. the utility of serum lipase in acute pancreatitis has been shown to vary due to discrepancies in measurement method. 4-8 hours after the onset of acute pancreatitis. 2002 ). 1993 ). Derived from pancreatic acinar cells. „boring‟ epigastric pain radiating to back or flanks associated with nausea and vomiting. 1929 ). patients with hypertriglyceridemia. The sensitivity is limited in patients with hypertriglyceridemia and alcoholism. Regardless. For these reasons. The serum lipase also lasts longer in the serum. and peaks earlier. Due to the additional cost and lack of benefit in the majority of patients. decreased clearance can lead to falsely elevated levels in patients with renal insufficiency and normal persons who harbor proteins or polypeptides that are not associated with disease ( Smotkin. peaks at 48 hours and returns to normal within 3-5 days ( Zieve. the serum amylase level rises over the first 2-12 hours after the onset of acute pancreatitis. However. The use of a serum lipase in the diagnosis of acute pancreatitis should be reserved to patients with clinical symptoms consistent with the disease and an amylase that is suspected to be falsely low. requires direct demonstration of the existence of macroamylase molecules by ultracentrifugation. Although serum lipase is derived from pancreatic acinar cells. 1985 ). serum lipase is more sensitive and specific than the serum amylase. In the appropriate clinical setting marked by new-onset sharp. urinary dipstick testing for . 1964 ). or other physical techniques. 8-14 days. utilizing serum lipase in conjunction with serum amylase as a routine process in the laboratory evaluation of suspected acute pancreatitis should be considered inappropriate. such as in alcoholics. the serum amylase helps to confirm the suspected diagnosis of acute pancreatitis with a positive predictive value approaching 100%. 1999 ). 1996 ). serum amylase has remained the universal laboratory diagnostic test in the determination of acute pancreatitis ( Elman. parotid and submandibular salivary gland inflammation. Others feel that pancreatic isoamylase determination is the most cost-effective method ( Sternby. patient selection. it is difficult to calculate sensitivity and specificity for these enzymes precisely. There is no additional clinical benefit in the determination of serum lipase in a patient with the clinical symptoms of acute pancreatitis and a serum amylase greater than three times the upper limit of normal. Thus. there are certain clinical situations where the clinician must entertain a degree of skepticism and be aware of the assay's limitations. chromatography. the serum amylase is accurate in the appropriate clinical setting. 1993 ). Recently. 1985 ). Due to a lack of a readily available gold standard measurement for the diagnosis of acute pancreatitis and variability of chemical methods. Also. The specificity is limited by elevations in amylase from inflammatory intra-abdominal processes. Using a cutoff of greater than three times the upper limit of normal will lead to an increased specificity ( Steinberg. and cutoff point ( Tietz. it rises slightly earlier than amylase. Acute Pancreatitis Since the first description in 1929. It is recognized that amylase and lipase may both arise from sources other than the pancreas ( Frank. Despite high positive and negative predictive values. utilizing both assays may optimize accuracy ( Corsetti. at 24 hours ( Steinberg. or presenting late with the disease. 1982 ).however.

Plasma calcitonin precursors have been demonstrated to rise significantly with the onset of severe infection and systemic inflammation. this rise occurs in a predictable stepwise fashion allowing this serum assay to potentially serve as a marker for disease severity. the lipase/amylase ratio appears to predict alcoholinduced pancreatitis ( Tenner. the alkaline phosphatase remains elevated for weeks beyond an acute event involving the biliary tree. It is an ideal marker in a patient suspected of being an alcoholic. who denies alcohol use when the alcohol level is normal ( Le Moine. One in four patients with alcohol-induced acute pancreatitis present with a normal amylase ( Spechler. Although a considerable number of other enzymes have been examined for their potential clinical role in the diagnosis and prognosis of acute pancreatitis. it appears that the bilirubin and alkaline phosphatase have a limited role in the diagnosis of gallstone acute pancreatitis. A sensitive assay that detects plasma calcitonin precursors is another method that is currently being investigated for the determination of severity of an acute episode of pancreatitis. 1977 ). 1992 ). persistent elevations of the serum bilirubin may signal the presence of a persistent common bile duct stone warranting endoscopic retrograde cholangiopancreatography (ERCP) and stone extraction. For this reason. the lipase is not as affected. the disease is different. This may provide a rapid screening test under the correct clinical circumstance. usually within hours after the onset of abdominal pain ( Ammori. The gland becomes „burned out. Laboratory testing can help distinguish the etiology in patients with acute pancreatitis. Furthermore. urinary amylase offers no advantage over serum testing and urinary clearance of amylase is not specific ( Lankisch. Due to a combination of low sensitivity and low specificity. There appears to be four to five times more lipase in the pancreas than amylase ( Tietz.trypsinogen-2 was shown to have a sensitivity of 94% and a specificity of 95% as compared to serum amylase with a sensitivity of 85% and a specificity of 91% with 300 U/L as the upper limit ( Kemppainen. Unlike the normal pancreas that becomes inflamed in patients with gallstone pancreatitis. However. 1994 ). in a patient with gallstone pancreatitis. 1993 ). a ratio of greater than 3 is predictive. carbohydrate deficient transferrin (CDT) appears useful in the determination of alcoholism. Abnormal levels can be detected upon admission. while greater than 5 is diagnostic for acute alcohol-induced acute pancreatitis. A person who consumes large amounts of alcohol will have a CDT elevation regardless of whether they have been consuming alcohol during the past several days. 2003 ). the pancreas in a patient with alcohol-induced acute pancreatitis has been damaged over years of alcohol consumption. . Because of decreased clearance.‟ Although the amylase is affected. Management decisions to prevent a recurrence of disease depend on the ability to determine the etiology. none has gained widespread clinical use. The gland itself typically has altered architecture. only half of the patients with gallstone pancreatitis demonstrated a significantly elevated AST/ALT ( Tenner. Despite the high specificity. as occurs with acute pancreatitis. In addition to the lipase/amylase ratio. Thus. 1994 ). The ducts have been altered by the deposition of proteinaceous plugs. Using multiples of the upper limit of normal. 1997 ). A meta-analysis showed that an alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) of more than 150 IU/dL (a threefold elevation) had a positive predictive value of 95% in predicting gallstones as the underlying cause. 1983 ). Additionally.

A TAP greater than 30 mmol/L has been shown to be associated with severe disease. immune complex creates false positives. In patients with acute pancreatitis. difficulty in the early determination of severity complicates the management of a significant proportion of patients. Table 22-2 -. 1986 ). Despite intense study. A new ELISA is available from Biotrin (Dublin. Multiple laboratory tests have been studied in an attempt to define severity early in the course of the disease. or rising over initial 24 hours associated with pancreatic necrosis Lipase Trypsinogen 2 AST/ALT Lipase/amylase ratio Carbohydrate deficient transferrin (CDT) Trypsinogen Severity activation peptide (TAP) Hematocrit Severity . elevated from salivary gland and intraabdominal inflammation Diagnosis Limited use. Low sensitivity Useful in patients who deny alcohol. normally elevated in macroamylasemia. trypsinogen activation peptide (TAP) and hematocrit appear to be useful early in the course of the disease. A hematocrit above 44 or rising over the first 24 hours has been shown to be associated with pancreatic necrosis ( Baillargeon. unclear if superior to amylase/lipase Etiology Etiology Etiology If greater than three times upper limit of normal.In the management of acute pancreatitis. Ireland) that can assist in the determination of severity through the use of urine samples. 1998 ). remains elevated for weeks after binge drinking Greater than 30 mmol/L in 12-hour urine. This protein product is typically not seen at significant levels in the blood or urine. Low sensitivity Greater than 5 is diagnostic for alcohol acute pancreatitis. can be normal in alcohol-induced acute pancreatitis Diagnosis Decreased specificity in renal failure. gallstones present as etiology in 95% of cases. only two tests. 100% negative predictive value Greater than 44 on admission. Inappropriate early activation of trypsin in the acini of the pancreas leads to the release of trypsinogen activation peptide. 1997 ).Laboratory Tests in Acute Pancreatitis Laboratory test Purpose Usage and limitations Amylase Diagnosis Accurate over three times the upper limit of normal. and poor intravenous hydration. TAP levels rise. with a negative predictive value of 100% ( Tenner. fluid sequestration. A serum C-reactive protein is useful later (after 36-48 hours after the onset of symptoms) in determining the presence of pancreatic necrosis ( Buchler. decreased specificity in renal failure. This is likely related to hemoconcentration from a combination of severe third space losses. test interference in hypertriglyceridemia. Refer to Table 22-2 for a summary of laboratory tests used in the evaluation of acute pancreatitis. elevated from other sources such as salivary gland and/or intra-abdominal inflammation (not above 3×).

Approximately 1 in every 20 Caucasians is a carrier. many clinicians will attempt an empiric course of exogenous pancreatic enzymes. Chronic pancreatitis is suspected in the correct clinical setting and presents as mild glucose intolerance to frank diabetes mellitus. the anatomy of the gland is reviewed radiographically and insulin and exocrine pancreatic enzymes are replaced as necessary. Routine laboratory testing is of little value in patients suspected as having chronic pancreatitis. Hyperglycemia may result from disease progression with subsequent pancreatic endocrine dysfunction. Serum trypsinogen assays are available and may have a diagnostic utility when values are below 20 ng/mL but the levels are only found to be low in patients with advanced disease (typically when steatorrhea is already present) ( Jacobsen. a low level of pancreatic elastase in the stool can be used in the diagnosis of chronic pancreatitis. 1996 ). If this works. A novel ELISA for fecal elastase. If symptoms suggest this disorder. including the pancreas. Useful after first 36–48 hours C-reactive protein Severity Chronic Pancreatitis Chronic pancreatitis is marked by progressive destruction of islet cells and acinar tissue. peribronchial. maldigestion of fat occurs after 90% of pancreatic lipase secretory capacity is lost. has been developed and marketed and appears to be very sensitive for chronic pancreatitis ( Loser. Because of inadequate delivery of fecal elastase to the duodenum. Cystic fibrosis is characterized by abnormal secretion from the various exocrine glands of the body. peritracheal. The simplest method of functional testing of the pancreas is assessing the presence of fat in the stool. and/or maldigestion/malabsorption. more novel tests have shown that the test is accurate in the evaluation of less advanced disease. Cystic Fibrosis Cystic fibrosis (mucoviscidosis) of the pancreas is an autosomal recessive disease with an incidence of 1 in 1600 Caucasian births and 1 in 17 000 African American births in the United States. When pancreatic maldigestion is suspected as the cause for diarrhea. As malnutrition progresses. There is little clinical need to estimate the percentage of exocrine or endocrine function. typically ERCP. the absence of these enzyme elevations in the serum does not rule out an attack of pain from chronic pancreatitis. 100% and 100% for patients with mild. Although initial studies suggested that the test could not detect chronic pancreatitis in the absence of steatorrhea. the serum albumin may fall. Unfortunately. A serum beta-carotene may be found to be low as malabsorption for lipids develops. One clinical study found sensitivities of 63%. the latter responsible for the maldigestion associated with this disease. the diagnosis is likely in the appropriate clinical setting.Laboratory test Purpose Usage and limitations Values over 200 IU/L associated with pancreatic necrosis. Although the amylase and lipase may be elevated in acute exacerbations. salivary glands. lacrimal . chronic abdominal pain. a pancreas-specific enzyme that is not degraded during intestinal transport and reaches concentration in fecal matter five to six times that found in duodenal juice. moderate and severe pancreatic insufficiency respectively. due to loss of enzyme secretion responsible for digestion of foodstuffs within the small intestine. and peribronchiolar glands. The clinical diagnosis of chronic pancreatitis depends on the finding of structural abnormalities in ductal anatomy found on imaging. 1984 ).

glands. For this reason. Levels of between 50-60 mmol/L are suggestive in the absence of adrenal insufficiency. but the reverse is true in normal subjects. hyperhidrotic ectodermal dysplasia. Laboratory testing begins with randomly collected stool specimens submitted for blood. Chronic lung disease and malabsorption resulting from pancreatic involvement are the major clinical problems of those who survive beyond infancy. fat and microbes (ova and parasites). Unfortunately. interpretation of sweat electrolyte values in adults must be approached with caution. mucosal glands of the small bowel. Detection of fecal leukocytes with Wright's stain on microscopy is also of importance. it probably is the least reliable test and has a high proportion of false-positive and false-negative results. and fucosidosis. Involvement of the intestinal glands may result in the presence of meconium ileus at birth. whereas normal controls would show a decrease in sweat electrolytes. These disorders are usually easily differentiated from cystic fibrosis by their clinical symptoms. renal insufficiency. Sodium concentrations in sweat tend to be slightly lower than those of chloride in patients with cystic fibrosis. Crohn's disease. ischemic colitis. Approximately 90% of the water that enters the colon is removed during transit. Using a definition of chronic diarrhea as excessive stool frequency without associated abdominal pain. However. 69 ). glucose-6-phosphatase deficiency. a newer method utilizing lactoferrin may be more accurate in the identification of leukocytes and appears to be more sensitive ( Guerrant. In children. reaching a peak chloride concentration most commonly 5-10 days prior to the onset of menses. and resolves quickly. laboratory diagnosis still depends largely on the demonstration of increased sodium and chloride in the sweat. In addition. sweat glands. The definition of chronic diarrhea is greater than three loose stools per day for more than 4 weeks' duration and/or daily stool weight greater than 200 g/day ( Thomas. Chronic diarrhea is a common complaint of patients presenting to physicians. Men showed random fluctuations up to 70 mEq/L. 1992 ). the electrolyte values would remain unchanged. 2003 ). Patients in whom cystic fibrosis is suspected on the basis of indeterminate sweat electrolyte results may undergo confirmatory testing by having the sweat electrolytes test repeated following administration of a mineralocorticoid such as fludrocortisone. Sweat chloride concentrations of more than 60 mmol/L may be found in some patients with malnutrition. hypothyroidism. nephrogenic diabetes insipidus. Intestinal Disorders Chronic Diarrhea Acute diarrhea is self-limited. the prevalence of this disorder in western population is estimated to be approximately 4-5% ( Thomas. The differential diagnosis is complex and a variety of laboratory tests can be found to be useful. unless the sweat test is correctly performed. detecting the presence of leukocytes in the stool is of importance in determining whether the diarrhea is inflammatory in nature (ulcerative colitis. False-negative sweat test results have been seen in patients with cystic fibrosis in the presence of hypoproteinemic edema. 2003 ). typically viral. Sweat electrolytes in about half of a group of premenopausal adult women were shown to undergo cyclic fluctuation. mucopolysaccharidosis. The principal function of the colon is to absorb water from the fecal stream. In these patients. and bile ducts. chloride concentrations of over 60 mmol/L of sweat on at least two occasions are diagnostic. The rectosigmoid colon also . Peak values were slightly under 65 mmol/L. invasive microbes). Because of the multiple alleles at the cystic fibrosis gene (see Ch.

Analysis of laxatives should be done early in the evaluation. such as sodium phosphate (Fleet phosphosoda). . Inflammatory or exudative diarrhea is often bloody. It can also result from irritation or inflammation of the colon. Although multiple drugs and other therapies induce diarrhea as an unwanted side effect. altered motility. Classification via pathogenesis remains controversial. The overlap of the pathogenic types of diarrhea is thus demonstrated. while histologic review of biopsy specimens demonstrates inflammation. The atypical inflammatory bowel diseases such as microscopic colitis or collagenous colitis do not produce exudative diarrhea. Diarrhea may precipitate incontinence in someone who can control defecation with formed stool. it is most reasonable to determine whether blood or fecal leukocytes are present in the stool of a patient with diarrhea. invasive infectious organisms. or some combination thereof. The causes of diarrhea are often divided into four major pathogenic groups. Similarly. The osmotic gap is calculated from electrolyte concentrations in stool water by the following formula: 290 . Crohn's disease. the mechanism by which they do so involves inflammation. and more than one diarrheal etiology can be present in a single patient simultaneously. If findings suggest secretory diarrhea.[2 × (Sodium + Potassium)]. and radiation-induced colitis are common causes of inflammatory diarrhea. Rectal incontinence is often incorrectly reported as diarrhea. An absent or significantly abbreviated colon ensures large volume and loose stools. secretion. but it does not have to be. osmotic gap > 125 mOsm/kg. which interferes with the colon's ability to store feces. A frankly exudative process classic for inflammatory diarrhea is not present in these cases. and the diarrheas that result from altered bowel motility.stores stool until it is possible to defecate in a socially acceptable fashion. iatrogenic diarrhea is not a separate pathogenic category. the method or methods employed by the patient involve one of the four aforementioned types. Semantic arguments aside. The sum of the sodium and potassium concentrations is multiplied by a factor of two to account for associated anions. so it is important to distinguish between the two. The management of incontinence may be quite different from the management of diarrhea. A brief mention of factitious diarrhea is warranted because it is not uncommon. Their presence suggests that inflammation is playing a role in the patient's diarrhea. the mucosa of the bowel appears grossly normal. Hypersecretion or lessened absorption of water may be the means by which these entities produce diarrhea. the secretory diarrheas. the osmotic diarrheas. osmotic gap less than 50. In some cases of inflammatory diarrhea. Stool water should be analyzed for osmolality and electrolytes. osmotic load. magnesium laxatives (Maalox) should be suspected. These major groups are the inflammatory diarrheas. Specific causes of diarrhea may do so by more than one pathogenic means. ulcerative colitis. If stool electrolyte analysis suggests osmotic diarrhea. the patient may have ingested a laxative causing a secretory diarrhea. Diarrhea occurs when the amount of water in the colonic lumen (which is the sum of the water reaching it from the small bowel and the water secreted by the colonic mucosa) exceeds the amount of water capable of being absorbed by the colonic mucosa. The osmolality of the stool within the distal intestine is estimated to be 290 mOsm/kg (equilibrates with plasma osmolality). The presence of fecal leukocytes on microscopic evaluation may be the only clue to inflammation. Although many clinicians use the category „factitious‟ as a fifth pathogenic classification for those who self-induce diarrhea. ischemic colitis.

and constitutional symptoms all suggest the need for making a specific diagnosis. Whether the diarrhea is bland or bloody. In fact. Unless there are obvious structural defects. the conditions continue to generate diarrhea even when the patient invokes a strict fast. However. Short gut syndromes (e. . postsurgical) reduce the amount of absorptive colon and can result in diarrhea. The diagnosis of diarrhea starts with a very thorough history. One can calculate a stool osmotic gap by first measuring stool osmolality. In developed countries. the presence or absence of constitutional symptoms and the duration of the illness are major points in determining the subsequent evaluation. the tests should be submitted for analysis. carcinoid syndrome. The history is the key to narrowing down the potential diagnosis.. Such diarrheas can cause dehydration. Unlike osmotic diarrheas. Chronic diarrhea.g. the passage of blood. A variety of hormonal causes such as gastrinoma (Zollinger–Ellison syndrome). Analysis of the urine for 5-hydroxyindoleacetic acid for carcinoid syndrome. Secretory diarrheas result from the active secretion of water into the fecal stream that overwhelms the absorptive process. electrolyte depletion. and villous adenoma of the rectosigmoid colon have been identified. the most difficult to characterize and quantify. Multiple toxins. alter motility. or the diagnosis of irritable syndrome is clear. Most current diagnostic methodologies alter the colonic milieu and. must still be very comprehensive. Motility disorders are. motility disorders are often suspected by exclusion. acute diarrhea (less than 2 weeks in duration) without bleeding or constitutional symptoms rarely requires diagnostic testing. and even death. The physical examination. sodium.Osmotic diarrhea occurs when the osmotic load of the fecal stream favors excess water loss. medications are probably the most common cause of secretory diarrhea. A value of greater than 100 mmol/L suggests the presence of a large number of unmeasured osmotic particles causing fluid to be drawn into the colonic lumen. Barium studies or the ingestion of radiopaque markers may assist in estimating colonic transit time. mastocytosis.. The classic secretory diarrhea is cholera. Irritable bowel syndrome may involve excessive neural stimulation with resultant decreased stool transit times. In other words. Self-limited. and medications can cause an active secretion of water and electrolytes in the colonic lumen. Such patients may have to be observed during the fast. the osmotic gradient drives water into the colonic lumen creating looser. Uncooperative patients or patients with „factitious diarrhea‟ who continue to ingest osmotically active substances will continue to have diarrhea. but consensus normal values are lacking. vasoactive intestinal polypeptide (VIP)-producing tumors (e. and potassium.g. hormones. Fecal bacteria continue to produce osmotic particles as a result of digestion while the specimen awaits processing. The most practical way of determining that the diarrhea is osmotic in the cooperative patient is to fast the patient. A strict fast causes osmotic diarrhea to subside. more voluminous stools. these patients can dehydrate quickly without continued fluid intake. medullary thyroid carcinoma. The stool specimen from which these measurements are derived must be very fresh. vanillylmandelic acid for pheochromocytoma and histamine for mastocytosis is rarely helpful. although usually less helpful than the history. presumably. These bacterial breakdown products can falsely elevate the fecal osmotic load. and such fasting should be under observation when secretory diarrhea is suspected. VIPoma syndrome). Motility disorders can hurry the fecal stream and thwart complete water absorption. by far. if the clinical suspicion exists.

enzymes for rotavirus and giardiasis. Stool culture. and the like. Patients with diarrhea must be queried about their medications. Constitutional symptoms such as fever.Laboratory Tests in the Differential Diagnosis of Diarrhea Test Method Use Initial screening tests Fecal leukocytes Hemoccult test Fecal osmotic gap Wright's stain or methylene blue Peroxidase reaction for hemoglobin FOG = fecal osmolality – 2 × (fecal Na + K) Color change after adding NaOH to stool Routine culture and sensitivity Identify inflammatory diarrhea Identify hemorrhagic diarrhea Distinguish secretory vs. Table 22-3 shows recommended tests that can be used in the evaluation strategy. radiation. coli 0157:H7. In patients with similar diarrheal illnesses occurring over the same time period. In patients with the acquired immunodeficiency syndrome (AIDS). a common infectious source should be considered (see Ch. arthralgias/arthritis. Table 22-3 -. stool frequency. or who have been significantly immunosuppressed. stool consistency. Antibiotic usage. recent surgery. In any patient with chronic diarrhea it is wise to consider establishing human immunodeficiency virus (HIV) status. and water supply.A critical aspect in the evaluation of diarrhea revolves around immunocompetence. 61 ). rashes. If the patient is among others who develop diarrhea simultaneously. diet. may give strong clues as to the diarrheal etiology. Infectious agents may be sought. Travel histories. sexual practices. Duration of symptoms. and stool volume should be estimated. Campylobacter Identify E. 56 ). an infectious cause or common toxin can be suspected. osmotic diarrhea Stool alkalinization Phenolphthalein laxative ingestion Infectious causes Stool bacterial culture Identify Shigella. or chemotherapy. and ova and parasite examinations should be done in the appropriate clinical setting (see Ch. Yersinia. incontinence. difficile toxin assay HIV serology Stool rotavirus Tissue culture cytotoxicity ELISA Antigen enzyme . urgency. and any change in a patient's usual regimen may shed light on the situation. and family histories may be useful. Vibrio Pseudomembranous colitis HIV enteritis Rotavirus enteritis Stool special culture Specialized culture and serotyping Stool C. The clinician should always inquire about potential similar episodes in the past and determine if the diarrhea is recurrent. It helps to know if there are outbreaks of diarrheal illnesses in the community. the diagnostic evaluation must consider unusual infections. daily stool patterns. Salmonella. weight loss.

Test screen Stool ova and parasites Stool mycobacteria Stool protozoans E. tuberculosis. MAI Cryptosporidium. PCR Iodine or modified acid-fast stain Serology Enzyme immunoassay HPLC HPLC RIA Immunoassay RIA RIA RIA See text See text Clinitest tablets Use Enteric parasitic infection M. Isospora belli Entameoba histolytica Giardia lamblia Carcinoid syndrome Carcinoid syndrome VIPoma Hyperthyroidism Zollinger–Ellison syndrome Hypocalcemia-related diarrhea Somatostatinoma Lactase deficiency Pancreatic insufficiency Cystic fibrosis Carbohydrate intolerance D-Xylose absorption See text test 72-Hour fecal fat content Fecal fat stain Serum carotene 14 Evaluate surface area of intestinal mucosa Lipid malabsorption Lipid malabsorption Lipid malabsorption Saponification and titration Sudan stain Spectrophotometry CO2 breath test as a test for lipid (fat) malabsorption See text Endomysial Serology Lipid malabsorption Celiac disease . free T4 Serum gastrin Serum calcitonin Serum somatostatin Maldigestion Lactose tolerance test Sweat chloride Stool reducing sugars Malabsorption Method immunoassay Wet mount Acid-fast stain and culture. histolytica Ab titers Stool Giardia antigen Endocrine causes Urine 5-HIAA Blood serotonin Serum VIP Serum TSH.

abetalipoproteinemia. 5-HIAA = 5-hydroxyindoleacetic acid. leukocytes. collagenous colitis Whipple's disease. sorbitol) may be. IBD = inflammatory bowel disease. microscopic colitis Other and miscellaneous Serum ionized calcium Serum protein and albumin Stool alpha-1antitrypsin Quantitative immunoglobulins Colon biopsy Intestinal biopsy PCR = polymerase chain reaction. Any diarrheagenic medication that can be stopped should be. especially if it was started or the dosage was increased around the time that the diarrhea began. MAI = Mycobacterium aviumintracellulare. Infectious agents may be sought via enzymatic testing. Ab= antibody. Stool can be tested for blood. MAI. HIV = human immunodeficiency virus. Giardia. eosinophilic gastroenteritis. or direct microscopic evaluation. collagenous colitis. amyloidosis. graft-versus-host disease. lymphoma.g. ELISA = enzyme-linked immunoabsorbent assay. agammaglobulinemia. Fecal fat testing is . but that the carrier substance (e. anionic dyes See text Nephelometry Endoscopic biopsy Endoscopic or open biopsy IBD. tuberculosis. electrolytes. It should be remembered that the „active‟ drug may not be responsible for the diarrhea. other parasitic infections. and should be considered under the right clinical conditions. culture.. and osmolality. intestinal lymphangiectasia.Test antibody Gliadin antibody H2 breath test Bacterial colony count Method Serology Expired H2 by gas chromatography Use Celiac disease Carbohydrate malabsorption Small bowel aspirate Bacterial overgrowth and quantitative culture Ion-specific electrode Hypocalcemia-related diarrhea Biuret reaction. It must be remembered that many readily available substances can cause diarrhea. HPLC = high-performance liquid chromatography. protein-losing enteropathy Protein-losing enteropathy Agammaglobulinemia Neoplasia. RIA = radioimmunoassay. Crohn's disease. It is simple and inexpensive. although widely written about. lymphocytic colitis. Stools may be alkalinized to test for phenolphthalein if surreptitious laxative use is suspected. is often of little practical value. however. and stool alkalinization.

in all patients with chronic diarrhea. HIV-Related Diarrhea The actual causes of diarrhea in the patient with HIV are related to the aforementioned pathophysiologic mechanisms. abdominal bloating and pain. Both toxin A and B lead to increased vascular permeability and have potential to cause hemorrhage. systemic symptoms such as fever and malaise. however. this test has been largely abandoned. 2004 ). Broad-spectrum antibiotics such as penicillin. The most frequent tests for lactase insufficiency rely on the ingestion of 25 g of lactose. Sensitivity varies based on the level of observer skill and experience. Laboratory . A fast may be very helpful. a Gram-positive. if it has not become evident already. This method correlates well with quantitative fat output as measured using the van de Kamer method ( Sugal. An alternative method of assessing fecal fat is semiquantitative. typically following a course of antibiotic therapy in hospitalized patients. It is thought to be associated with approximately 25% of all antibiotic-associated cases of diarrhea and 50-75% of cases involving antibiotic-associated colitis ( Malnick. 2004 ). However. However. Clinical suspicion of the disease is confirmed with detection of C. Complicated and expensive diagnostic evaluations for secretory diarrhea should generally not be undertaken unless other more likely causes have been ruled out or unless signs and symptoms are suggestive. The exact methodology depends on the sugar studied and the sensitivity and specificity desired. Patients can present with watery diarrhea. Once these data have been collected it is usually possible to classify the diarrhea and begin to find the specific diagnosis. Nosocomial Diarrhea Clostridium difficile. lower abdominal pain/cramping. Direct visualization of the colonic mucosa with the aid of endoscopy is required for diagnosis of pseudomembranous colitis associated with C. is the most important cause of nosocomial diarrhea in adults with greater than 300 000 cases per year in the US ( Malnick. spore-forming anaerobic bacillus. or can have occult GI bleeding. 1994 ). it is prudent to consider the possibility of AIDS. the steatocrit. It may present clinically. followed by exposure to a toxigenic strain of C. 2000 ). for practical considerations. 2000 ). difficile toxin A or B virulence factors in stool samples. Breath testing assists in the evaluation of a person's difficulty in metabolizing lactose. Although 48. clindamycin and cephalosporins have been particularly implicated. The most common tests use a probe for carbon-14 or a nonradioactive fermentable sugar. the specific etiologic agents (especially the infectious ones) often differ greatly from those in the immunocompetent patient. with a mortality rate as high as 38% ( Poutanen. 2000 ). difficile. from a mild watery diarrhea to lifethreatening pseudomembranous colitis and toxic megacolon. endoscopy should be avoided in cases of suspected fulminant colitis because of the risk of perforation. 72-hour quantitative testing of stool for fecal fat remains the gold standard.also relatively simple. The pathogenesis of this disease entity usually involves disruption of the normal colonic flora. difficile colitis ( Malnick. any antibiotic can lead to development of C. sucrose and glucose (secondary to bacterial overgrowth). They induce the production of tumor necrosis factor alpha and inflammatory interleukins that are responsible for the inflammatory response and pseudomembrane formation ( Poutanen. This can lead to colonic perforation and peritonitis. The standard method for detecting fat in the stool is using Sudan stain. Breath testing is becoming increasingly utilized for the evaluation of chronic diarrhea. Thus.

Stool cultures can also be performed but require up to 96 hours for completion. 65-85% and 95-100% respectively. ELISA is the optimal diagnostic test ( Malnick. However. 2000 ). can also be performed but has much lower sensitivity and specificity compared to other available tests. multiple samples may be required for confirmation. difficile toxin A or B are currently being developed with similar sensitivity and specificity profiles compared to cytotoxic assays ( Poutanen. 2004 ). limiting its clinical utility. Rapid enzyme immunoassays. Table 22-4 -. compared with cytotoxic assays. 2004 ). which can be completed within several hours. difficile infection. difficile with subsequent cytotoxin assay of isolate Excellent sensitivity (> 90%) Results not available for at and specificity (> 98%) least 72–96 h Enables typing of strain Labor-intensive for outbreak Requires tissue culture investigation facility . difficile-associated diarrhea. PCR methods for detection of C. difficile cytotoxin B in stool specimens are considered the „gold standard. difficile cytotoxin assay Excellent specificity (99– 100%) Decreased diagnostic sensitivity (80–90%) Test results not available until after 48 h Requires tissue culture facility Detects only toxin B Immunoassay for detection of toxin A or toxins A and B Good specificity (95–100%) Reduced sensitivity (65– 85%) as compared with Test results available cytotoxin assay within 4 h Technically simple Stool culture to isolate C. However.‟ with a sensitivity ranging between 94-100% and specificity of approximately 99% ( Malnick. 2000 ). This tissue culture assay can detect as little as 10 pg of toxin in stool specimens ( Malnick. difficile infection. In hospitalized patients with greater than six stools per day. However.methods are available for confirmation of C. have been developed for the detection of toxin A or B from stool specimens.Laboratory Tests Available for the Diagnosis of Clostridium DifficileAssociated Diarrhea Test Advantages Disadvantages C. difficile infection ( Poutanen. 2000 ). Latex agglutination tests that detect glutamate dehydrogenase. It is currently recommended that these tests be performed on diarrheal stool specimens. in most cases one stool sample is sufficient for diagnosis of C. a common clostridial protein. for detecting C. the sensitivity and specificity of these immunoassays are decreased. 2000 ). PCR is unable to distinguish between asymptomatic carriage and symptomatic infection. Tissue culture cytotoxicity assays. which take at least 48 hours to complete. and empiric treatment with oral antibiotics may be indicated in patients with clinical evidence of C. The ELISA can detect 100-1000 pg of toxin in stool specimens ( Malnick. Refer to Table 22-4 for laboratory tests available for the diagnosis of C.

steatorrhea is a hallmark finding in patients with malabsorption. proteins. which will result in vitamin B12 deficiency as well as a decreased pool of circulating bile acids for metabolism. In addition. cannot occur. such as amyloidosis. These stools may be foamy due to the high fat content and may tend to float on water. diabetes mellitus. pale. The classic malabsorption syndromes. diminished mucosal surface area as in gastroileostomy (gastric bypass). Normal absorption. Enteric malabsorption comprises a variety of conditions that have in common normal digestion but inadequate net assimilation of foodstuffs. © 2004 CMA Media Inc. as in lymphoma. carcinoid syndrome. therefore. This may result from competition by bacteria or altered bacterial flora. for example nonabsorbable sugars such as lactulose and sorbitol. Hepatic maldigestion results from interference or obstruction of bile flow. These conditions may result in increased osmotic load of the colon. In addition. bile salt activation of lipase activity is lost. “Clostridium difficile-Associated diarrhea in adults” – Malabsorption Syndromes Malabsorption results from either inadequate mucosal absorption of carbohydrates. bulky and foul smelling stools. Loss of bile salts interferes with fat emulsification. the clinical presentation may be specific to the malabsorbed substrate such as with lactase deficiency causing lactose intolerance. Malassimilation or the inability to assimilate fats and proteins due to maldigestion also occurs in patients with vasculitis. inflammation following irradiation (radiation enteritis). the site of vitamin B12 and bile acid absorption. Maldigestion results from an intraluminal defect that leads to the incomplete breakdown of nutrients into their absorbable substrates. preferential loss of specific substrates may occur. Pages 51–58 by permission of the publisher. as in the blind loop syndrome or diverticulosis of the small bowel. or may be a general consequence of the increased osmotic load to the colon. the latter may occur with stools from healthy individuals and is therefore. or soft and pasty. and from obstruction to the flow of lymph. However. If symptoms arise. Normal individuals with a normal fat intake excrete up to 5 g of lipid daily. resulting in diarrhea. Depending on the location within the intestinal tract of such pathology. and have other signs of liver disease. pass dark urine. semifluid. as in patients with a neoplasm obstructing the ampulla of Vater. One of the most common clinical scenarios encountered is regional enteritis localized to the distal ileum. It may also result from diseases affecting the small bowel mucosa. resulting in fluid. fats vitamins or minerals or from the presence of substances in the bowel that cannot be absorbed. Patients are usually jaundiced. 171(1). patients can have selective malabsorption/maldigestion of specific nutrients resulting in associated clinical sequelae. or small bowel resection. diminishing the surface area available for lipolytic action. Patients with malabsorption syndromes may remain symptomatic. are described below. Hepatic steatorrhea may coexist with pancreatic steatorrhea. a nonspecific sign of malabsorption. hypogammaglobulinemia. celiac disease and Whipple's disease. For example. and relative vitamin B6 or B12 deficiency. This can occur with pancreatic insufficiency and loss of exocrine function.Reprinted from CMAJ 06-Jul-04. Steatorrhea may be defined as the presence of more than 5 g of lipid .

Most patients with celiac sprue are asymptomatic.93 g) plus 2. Another clinical presentation of malabsorption is the development of fat-soluble vitamin (A. pancreatic enzymes and bile acids. the 72-hour fecal stool fat measurement is an accurate diagnostic test for identification of maldigestion/malabsorption with high sensitivity and specificity. IgA deficiency. The low sensitivity of this test limits its clinical application. glossitis. A false-negative rate as high as 25% may result with use of the qualitative Sudan III fat staining if steatorrhea is less than 10 g per 24 hours ( Romano. Other evidence of nutritional deficiencies. The diagnosis is often made by an astute clinician that notes a patient with thin stature. rye. Celiac Sprue Celiac sprue is a disorder characterized by intestinal malabsorption of nutrients due to sensitivity to the alcohol-soluble portion of gluten known as gliadin. Although diet has some effect on it. and bacterial metabolism also contribute. it may prompt further evaluation with a 72-hour stool collection ( Romano. paraffins. On a fat-free diet. Classic fat malabsorption is diagnosed by revealing excessive fecal fat. such as hypoprothrombinemia. dermatitis herpetiformis. E. barley and. the pattern of lipids excreted may be very different from the lipids ingested in the diet.(measured as fatty acids) in feces per 24 hours. Spot stool specimens can be stained with Sudan stain for detection of fecal fat. remains quantifying the amount of fecal fat per 24 hours in a 72-hour stool collection after consumption of a high-fat diet. Normal fat absorption requires normal mucosa. These patients are also liable to experience significant weight loss due to diarrhea-induced. This disease has variable clinical manifestations and can lead to severe symptoms such as profound malabsorption. D. Uncontrolled celiac sprue . iron deficiency anemia. The prevalence is not clear but estimated to be between 1:300 and 1:1000 (Catassi. 1994. to a lesser extent. edema. and others ( Barr. Therefore. However. oats contain this protein substance and can induce mucosal damage in the gut causing nonspecific villous atrophy of the small intestine mucosa. chronic bloating and/or diarrhea. fecal lipid is equal to a constant (2. other diagnostic tests include determination of levels of carotenoid. However. large caloric losses leading to cachexia in severe cases. weight loss. and osteomalacia may be evident in these individuals. and the d-xylose test for differentiation of pancreatic malabsorption from enteric malabsorption. including higher alcohols. cellular desquamation. and the quantity of fat ingested by a normal individual has a relatively small effect on the total output of fat. Intraluminal defects as occur with maldigestion or mucosal abnormalities will result in abnormal fat excretion. 1998 ). Down syndrome. 1989 ). The gold standard however. gastrointestinal excretions. the output of fat normally varies from 1–4 g/day. autoimmune thyroid disease. There are associations between celiac sprue and type 1 diabetes mellitus. which requires the normal absorption of dietary fat for proper absorption. Not.1% of the dietary fat intake. lipoids are present. Wheat. and wasting. Lipids are normally present as soaps and triglycerides. These tests are described in full detail in the latter part of this chapter. ascites. and K) deficiencies. According to one study. In addition. The evaluation of stool for fecal fat content remains the definitive test for steatorrhea. and vegetable carotenoids. detectable in the stool specimen. as well as the breath test and titrimetric methods for detection of malabsorption. an indicator of malabsorption. steatorrhea. anemia. Although the source of fecal lipid is largely dietary. if positive. the main precursor of vitamin A in humans. 1998 ). 1989 ). Primary and secondary alterations of the bowel mucosa may also result in deficiencies of water-soluble vitamins.

Clin Lab Med 1997. Owing to the fact that these patients must utilize a gluten-free diet for the rest of their lives in order to control symptoms and mitigate cancer risk. is available to be used as an antigen in an ELISA. The peripheral blood film may reveal nonspecific target cells. The IgG AGA testing is particularly useful in . These include testing for antibodies to gliadin (AGA-IgA and AGA-IgG). 17:452. these tests are of only moderate sensitivity and specificity. Similarly. and subject to interobserver interpretive variability. with permission. small bowel absorptive testing will be abnormal.appears to predispose patients to gut carcinomas and lymphomas ( Nehra. There is a genetic predisposition and it is most common in Caucasians of Northern European descent. 1998 ). and sampling errors can occur. In current clinical practice. endomysium (EMA-IgA). The sensitivity and specificity of these tests are extremely high when compared to a gold standard of flattened small bowel villi responding to dietary changes ( Farrell. Howell–Jolly bodies. Therefore. Wheat storage protein. Biopsy is reserved for patients in whom the diagnosis is suspected based on signs or symptoms of the disease. histologic diagnosis is very important. including iron deficiency. Due to the enteropathy associated with the disorder. and transglutaminase (tTG-IgA). Results of serological testing for celiac disease must be analyzed with caution because this disease is associated with selective IgA deficiency that will give rise to false-negative serum IgA antibody tests ( Thomas. multiple hematologic and biochemical abnormalities may be found in persons with untreated celiac sprue. 2003 ). siderocytes. IgG serology or total IgA levels should be checked if there is a high clinical suspicion of celiac disease. cumbersome. The gold standard for diagnosis remains biopsy of the small bowel mucosa and identification of classic histologic changes ( Trier. gliadin. reticulin (ARA-IgA). The lesions may be patchy. folate deficiency. Although serum IgA and IgG AGA levels are frequently elevated in untreated celiac sprue. Table 22-5 -. 1998 ). and Heinz bodies. and vitamin D deficiency. all of which are commercially available. Endomysial antibodies have the best sensitivity and specificity. but they are currently detected via immunofluorescence of sections of monkey esophagus or human umbilical cord and are costly.Ranges of Sensitivities and Specificities for Commercially Available Serologic Tests for Celiac Sprue Adults Children Sensitivity (%) Specificity (%) Sensitivity (%) Specificity (%) AGA-IgA 31–100 AGA-IgG 46–95 EMA-IgA 89–100 85–100 87–98 95–100 90–100 91–100 100–100 86–100 67–100 100–100 ARA-IgA 41–92 95–100 29–100 98–100 From Murray JA: Serodiagnosis of celiac disease. This is done via endoscopy. 2001 ). crenated red cells. there are four serologic studies used to assist in the diagnosis of celiac sprue ( Table 22-5 ). especially in higher-risk populations. including oral d-xylose testing and fecal fat evaluation.

these tests have largely been replaced by EMA. an organism yet to be cultured. primary alactasia. lactic acid or other organic acids. 1998 ). EMA binds to connective tissue surrounding smooth muscle cells. acute viral gastroenteritis. Disaccharide absorption is diminished either from primary disaccharidase deficiencies such as sucrase–isomaltase deficiency. This can result in protracted diarrhea as well as complaints of bloating and flatulence. 1997 ). As this disease can be treated and is no longer uniformly fatal. intestinal bacteria ferment unhydrolyzed and unabsorbed carbohydrates. The . Ramzan. Serum IgA EMA binds to the endomysium to produce a characteristic staining pattern seen on indirect immunofluorescence.the 2% of patients with celiac disease who appear to be IgA deficient. Unhydrolyzed disaccharides or monosaccharides unabsorbed because of deficiencies in transport are osmotically active and hence cause secretion of water and electrolytes into the small and large intestines. or secondary disaccharidase deficiencies due to celiac disease. Thus. However. It is caused by the Gram-positive rod Tropheryma whippelii. producing gas. About 10% of Caucasians. Most laboratories use sections of human umbilical cord. Disaccharidase Deficiency Many of the previously listed conditions causing malabsorption may also be associated with intolerance to disaccharides. Although the incidence of lactose intolerance due to congenital lactase deficiency is low. tropical sprue. PCR testing of infected tissue or cerebrospinal fluid (CSF) is the optimal way to confirm the diagnosis and monitor treatment ( von Herbay. Biopsy of the duodenum with periodic acid–Schiff (PAS) staining had been considered pathognomonic for Whipple's disease. Normally. 1995 ). they cannot be used to monitor the response to dietary modification. primary trehalase deficiency. or drugs such as orally administered neomycin. 1998 . Although IgG endomysium and IgG tTG antibodies may be suitable for serological diagnosis of celiac disease. 70-80% of African Americans. less costly and easier to perform than the older immunofluorescence assay for IgA EMA. It is now recognized that PAS-positive macrophages may be seen in AIDS patients with Mycobacterium avium complex. Use of IgA anti-tTG assays has been shown to be highly sensitive and specific for the diagnosis of celiac sprue ( Dieterich. absorption of digested carbohydrates is rapid and fairly complete in the proximal small intestine. An ELISA for IgA anti-tTG is widely available. and methotrexate. The epitope against which EMA is directed has been shown to be tissue transglutaminase. kanamycin. and weight loss. after treatment the titers fall quickly to undetectable levels ( Volta. These secondary disaccharidase deficiencies are usually transient and involve more than one enzyme. 1997 ). Screening tests for disaccharidase deficiencies include oral challenge of suspected disaccharides to reproduce the abdominal symptomatology. However. the prevalence of lactose intolerance in adults is quite high. In these disorders. lactase deficiency. and an even greater percentage of Asian people manifest some degree of lactose intolerance even though they were able to digest lactose well as infants. The antibody is very sensitive and specific. it is important to make the diagnosis. Whipple's Disease Whipple's disease is a very rare multisystem disease that often presents with arthralgias. PCR has gained even more importance in the management of this entity. diarrhea. followed by stool analysis. Long-term antibiotic therapy with central nervous system (CNS) penetration is used to treat patients with Whipple's disease ( Singer. Endomysium IgA antibodies disappear following treatment of celiac sprue with a gluten-free diet.

whereas only 20% of patients with ulcerative colitis will have significant titers. the use of these tests should be dependent upon the clinical circumstance. a flat tolerance curve and less than a 20 mg/dL (1.Markers for Inflammatory Bowel Disease Percent frequency p-ANCA ASCA Irritable bowel syndrome (normal patients) < 5 <5 . Whereas few normal persons with irritable bowel syndrome will have ANCA. The presence of 0. and fermentative.5 is suggestive.25-0. the amount of total reducing substances in the stool usually exceeds 0. a person with diarrhea and equivocal biopsy findings found to have a positive ANCA is more likely to have inflammatory bowel disease than irritable bowel syndrome. acidic. An oral tolerance test using a specific sugar such as lactose or sucrose can be used to establish a specific carbohydrate intolerance. Shanahan. An assay for disaccharidase has been published ( Dahlqvist. Likewise. 1975 ). in some instances. explosive. Although the oral tolerance test is fairly specific and sensitive. 1968 ). The Clinitest tablet (Bayer Diagnostics. 70% of persons with ulcerative colitis and 20% of persons with Crohn's disease will have significant titers. two antibody tests have become available that assist in the laboratory evaluation of patients with inflammatory bowel disease. Stool pH of less than 5. The underlying antigenic challenge to the immunologic response is not clearly understood. if a person with what appears to be ulcerative colitis is found to have a positive ASCA. Table 22-6 -. In patients with inflammatory bowel disease. Delayed gastric emptying appears to be the cause of the false-positive result. Normal infants between 3-7 days of age commonly have high stool pH. 23-30% false-positive results were noted following administration of lactose – that is.5 g/dL is regarded as suspicious. Crohn's colitis may be present.1 mmol/L) increase in blood sugar ( Krasilnikoff. Perinuclear-antineutrophil cytoplasmic antibody (p-ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) can be used to distinguish abdominal pain seen in irritable bowel syndrome from inflammatory bowel disease.25 g/dL reducing substances is considered normal. 65% of patients with Crohn's disease will have ASCA. Over the last decade. more than 0. 1994 ) (see Table 22-6 ). from 0. Inflammatory Bowel Disease Immunologic mechanisms within the colon are involved in the pathogenesis of inflammatory bowel disease. and interpretation requires careful understanding of the tests.25 g/dL feces. For example. In patients with intolerance to sugar. but the measurement of pH is not valid if the patient is taking oral antibiotics. These tests have limitations. Definitive diagnosis of disaccharidase deficiencies depends on the demonstration of low specific enzyme activity in the mucosa of small intestinal biopsy material.stools are usually watery. Stools can be analyzed for sugars by chromatography or by one of the semiquantitative nonspecific tests for urinary sugar adapted for stool analysis. and subtype inflammatory bowel disease as either ulcerative colitis or Crohn's disease ( Sendid. High pH does not exclude the diagnosis. 1998 . Australia) is suitable for this purpose. Given the low sensitivity and specificity.5 g/dL is considered abnormal. because duodenal instillation of lactose eliminates the flat tolerance curve.

there can be potential morbidity from the testing as well. hypokalemia. They can be malignant or benign. CT scanning. hypochlorhydria Somatostatinoma Somatostatin . As in all neoplastic lesions. have been identified ( Perry. diarrhea. depression. Gastrinomas comprise 25% of the APUDomas. ASCA: anti-Saccharomyces cerevisiae antibody. Although it was initially hoped that octreotide scanning would replace other modes of localization. such as somatostatinomas. The most common of these tumors are the carcinoid tumors. Abdominal pain and diarrhea are two of the commoner clinical symptoms. recent data suggest that it is useful in determining the extent of carcinoids and gastrinomas. biopsy is essential to confirm the diagnosis. Localizing the tumors can be quite challenging. asthma. The chemical measurement of the secretagogues of these tumors generally suggests the diagnosis in the right clinical setting. while 15% are insulinomas and 6% are VIPomas. endoscopy. These tumors are often small. diabetes. Ultrasonography. while of little use in finding insulinomas or nonfunctional tumors ( Kisker. Neuroendocrine Tumors Neuroendocrine tumors of the gastrointestinal tract are relatively rare neoplastic lesions with protean clinical manifestations ( Table 22-7 ). Other even rarer types. edema Ulcers. weight loss. hypochlorhydria Necrolytic migratory erythema. 1996 ). Table 22-7 -. diabetes. magnetic resonance imaging (MRI) operative exploration. With the exception of ultrasonography and MRI. Glucagonomas are quite rare and make up 2-5% of series. diarrhea Hypoglycemia Diarrhea. so histologic staining is employed to distinguish the types ( Perry. and octreotide scanning all have significant technical limitations.Neuroendocrine Tumors APUDoma Hormones Clinical sequelae Carcinoid Gastrinoma Insulinoma VIPomas Glucagonoma Serotonin (many others possible) Gastrin Insulin Vasoactive intestinal polypeptide Glucagon Abdominal pain. constituting 50% of the total. 1996 ). deep venous thromboses Gallstones. diarrhea. Table 22-7 shows the distinguishing features of the various APUDomas. They are similar on histologic examination. angiography. and can be located in a variety of organs.Percent frequency p-ANCA ASCA Ulcerative colitis Crohn's disease 70 20 15 65 p-ANCA = perinuclear antineutrophil cytoplasmic antibody. flushing. Due to the fact that they exhibit amine precursor uptake and decarboxylation (APUD) they are also known as APUDomas. acidosis. frequently multifocal. 1997 ).

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Values of over 600 Somogyi units/dL. False-negative results are often seen when the urine specimen is taken too soon or too late or in patients with fulminating necrosis in which the production of amylase is decreased or has ceased. Elevated values persisting longer than this suggest continuing necrosis or possible pseudocyst formation. While there are a variety of amylase methods available. but is not proportional to the severity of the disease. and falsely low enzyme activities are obtained from such specimens. caution must be exercised to avoid contamination of specimens with saliva. often within several hours of the rise in serum activity. or both. In serum and urine it is stable for 1 week at room temperature and for at least 6 months under refrigeration in well-sealed containers. Plasma specimens that have been anticoagulated with citrate or oxalate should be avoided for amylase determination because amylase is a calcium-containing enzyme. Methods and Clinical Applications Amylase (Total Serum and Urine) Amylase is a stable enzyme. so hemolysis generally presents no problem with most of the methods except those coupledenzyme methods in which the released peroxide is determined by a coupled-peroxidase reaction. It may be kept in the frozen state much longer without appreciable loss of activity. regardless of the method chosen. There may be instances. Most of the elevations of serum amylase are due to increased rates of amylase entry into the bloodstream. The urine amylase activity rises promptly. In a majority of patients with acute pancreatitis. Saunders Company Common Tests. or over four times the upper limit of normal. because its amylase content is approximately 700 times that of serum. Copyright © 2006 W. Interpretation Elevations of serum and urine amylase are observed in a wide variety of disorders. Activity usually returns to normal in 3-5 days in patients with the milder edematous forms of the disease. and may remain elevated after the serum activity has returned to the normal range. serum amylase activity is elevated and there is a concomitant increase in urine amylase activity. Red cells contain no amylase.McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods. 21st ed. . Serum amylase activity rises within 6-48 hours of the onset of acute pancreatitis in about 80% of patients. decreased rates of clearance. Values of over 1000 Somogyi units/h are seen almost exclusively in patients with acute pancreatitis. in which the elevated urine amylase is not accompanied by a concomitant increase in serum amylase. however. B. Heparinized plasma specimens do not interfere with the amylase assay. are highly suggestive of the diagnosis.

and elevated ratios may be found in patients with burns. normal serum and urine amylase levels are frequently encountered. gastrointestinal cancer. but too late to be diagnostically useful. This ratio (Cam/Ccr) can be calculated by the following formula: The normal ratio averages 1-4%. or ruptured ectopic pregnancy. the ratio adds little to the diagnostic armamentarium.Increased renal clearance of amylase can be used in the diagnosis of acute and relapsing pancreatitis. the third fatty acid can be split off at a slower rate. which is present in both the pancreas and the salivary glands. as well as following thoracic surgery. Human pancreatic lipase is a glycoprotein with a molecular weight of 45 000 Da. whereas that for patients with pancreatitis usually exceeds 4% and is often in the range of 7-15%. it is usually salivary rather than pancreatic amylase that is elevated. heart disease. Unfortunately. or following gastric resection. In hyperlipemic patients with pancreatitis. Fewer hyperamylasemic patients may be found to have intestinal obstruction. Approximately 20% of patients with pancreatitis have normal or near-normal amylase activity. Serum amylase activity may also be elevated in patients with cholecystitis or peptic ulcer. lipase is not present in the salivary glands. and the ratio of amylase clearance to creatinine clearance expressed as a percentage has been used diagnostically. renal transplant. After isomerization. Very high activity has been reported in patients with carcinoma of the lung. Lipolysis increases in proportion to the surface area of the lipid droplets. mesenteric thrombosis. In others. In contrast to amylase. Lipase The pancreas is the major and primary source of serum lipase. renal insufficiency. producing 2 mol of fatty acid and 1 mol of βmonoglyceride per mole of triglyceride. The spuriously normal levels are believed to be the result of suppression of amylase activity by triglyceride or by a circulating inhibitor in serum. a leaking pancreatic pseudocyst. Thus. pancreatic duct rupture. Serum amylase may be elevated in patients with pancreatic carcinoma. ketoacidosis. Increased ascites fluid amylase levels have been seen in patients with pancreatitis. viral hepatitis. abdominal tumors that secrete amylase. Polyacrylamide gel electrophoresis has demonstrated that in this condition. . about one-third of patients with pancreatitis have normal ratios. there may be inflammation involving the pancreas. and perforation of a hollow viscus. and peritonitis. In some of these patients. Lower than normal serum amylase activity may be found in patients with chronic pancreatitis and has also been seen in such diverse and unexpected conditions as congestive heart failure. pancreatic secretions find their way into the peritoneal cavity and are absorbed into the bloodstream. bone fractures. pancreatic cancer. and pleurisy. Lipases are defined as enzymes that hydrolyze preferentially glycerol esters of long chain fatty acids at the carbon 1 and 3 ester bonds. and duodenal perforation. It is also elevated frequently (in over 60% of cases) in patients with diabetic ketoacidosis. pregnancy (during the second and third trimesters).

but at a concentration higher than 5×10-3M. Pancreatic lipase must be differentiated from lipoprotein lipase. if not earlier than. Proteins. and milk. intestinal obstruction or infarction. duodenal ulcer.and the absence of bile salts in duodenal fluid with a resultant lack of emulsification renders lipase ineffective. and prolonged increases suggest a poor prognosis or the presence of a cyst. white blood cells. various abdominal diseases such as acute cholecystitis. These enzymes' activities may be included in the measurement of lipase activity unless the suitable assay conditions for „pancreatic‟ lipase are adapted. To determine accurately and fully the pancreatic lipase activity in patients with pancreatitis it is essential to add colipase to the reagent pack. Like serum albumin. and liver disease. bile salts prevent the denaturation of lipase at the interface. and nonpancreatic conditions including renal diseases. Increased lipase activity rarely lasts longer than 14 days. the elevation of serum amylase. and phospholipids inhibit serum lipase. lipase is found in the urine. Serum is the specimen of choice for blood lipase assays. It is speculated that the inhibitory effect is due to its interference with the action of bile salts at the water–substrate interface. fat cells. The presence of colipase and bile salt is required for full catalytic activity and the greatest specificity of the pancreatic lipase. Urine lipase activity in the absence of pancreatic disease is inversely related to the creatinine clearance. buffer. Colipase is present in the blood of patients with pancreatitis but in variable concentrations and usually below normal and below the amount needed to activate pancreatic lipase fully. which are related but different enzymes. This difference probably is due to the effect of the difference in types of substrate. Both lipase and colipase are secreted by the pancreas and are. it is not specific for acute pancreatitis. obstruction of the pancreatic duct. In acute pancreatitis serum lipase activity tends to become elevated at about the same time as. aliesterase. Lipase is also present in liver. it is normally completely reabsorbed by the proximal tubules and is absent from normal urine. Serum lipase is stable up to 1 week at room temperature and may be kept stable longer if it is refrigerated or frozen. as well as alcoholism. present in the serum. The optimal reaction temperature is about 40°C. Although determination of serum lipase has diagnostic advantages over serum amylase for acute pancreatitis. and diabetic ketoacidosis. and concentrations of reagents used. therefore. but other values ranging from 7. and arylester hydrolase.0-9. and hemolysis do not interfere with turbidimetric lipase assays. The combined use of serum lipase and serum amylase is effective in ruling out acute pancreatitis. Calcium is necessary for maximal lipase activity. In patients with failure of renal tubular reabsorption caused by renal disorders. Heavy metals and quinine inhibit lipase activity. Serum lipase may also be elevated in patients with chronic pancreatitis. The optimal pH is 8. and in patients who have undergone endoscopic retrograde cholangiopancreatography. intestine. Lipase is filtered by the glomeruli owing to its low molecular weight. and it remains elevated for about 7-10 days. Patients with trauma to the abdomen uniformly have increases in both serum amylase and lipase. whereas those with primarily head injury or . lipemia. bile acids. it has an inhibitory effect. colipase reverses this inhibition. Icterus.8. incubation temperature. stomach.0 have been reported.

acceptable analytical precision. P-type amylase is invariably elevated in both serum and urine. common duct narrowing. urine. A simplified.9-7. pancreatic insufficiency.8 for S-type isoamylases. The pH optimum for salivary amylase varies with the anion used as activator. The S-type isoenzyme. Because of its simplicity. and duodenal . The P-type isoenzyme is also elevated in chronic relapsing pancreatitis. Serum lipase and amylase tests have been and continue to be widely used in the diagnosis of acute pancreatitis. chromatographic method has been described by Fridhandler (1980) . chromatography.4 and 5. They have the same amino acid composition and yield similar but not identical peptide maps. however. and 6. chronic renal failure. is decreased to 0-15% of the total activity of serum hyperamylasemia in patients with acute pancreatitis. urine. and good correlation with the electrophoretic isoamylase method. Pancreatic amylase has a molecular weight of 54 000. but have organ-specific variations. and each isoenzyme is then quantitated either by direct densitometry or by amyloclastic or saccharogenic techniques. The pH for optimal activity ranges from 6. S-type amylase is increased in the serum of patients with chronic pancreatitis. These two types of amylase are closely related enzymes. fast. and glomerulonephritis.manipulation of the parotid gland during surgery have a significant increase in serum amylase only. and suitable for emergency situations. acute gastroenteritis. An immunoinhibition method using a monoclonal antibody to inhibit the salivary amylase and subsequently quantitate the remaining pancreatic amylase has been reported ( Mifflin. Each appears to consist of a single polypeptide chain without subunits. and the activation is allosteric. isoamylase). Amylase of pancreatic and salivary origin is abbreviated to P-type and Stype amylase (isoenzyme. and with other cancer-associated hyperamylasemias. acute respiratory insufficiency. mumps. 1985 ). and to near zero in those with carcinoma of the head of the pancreas.6 and 7. readily adaptable. Both serum amylase and serum lipase are elevated in many patients who have inflammatory or other disorders of organs in the abdominal cavity but no evidence of pancreatitis. of which chloride is the most important.2 for P-type. It is concluded that the pancreas is exquisitely sensitive to inflammatory or metabolic disturbances in the peritoneum and nearby organs. A great number of reports have supported the finding that in acute pancreatitis. Optimal chloride concentration is 10 mmol/L. Both amylases contain sulfhydryl groups. lung cancer. Sjögren's syndrome. such as electrophoresis. Isoenzyme studies on serum. this method should be further investigated for clinical application. The fractionation of amylase in serum. Higher molecular weights have been reported for salivary amylase. hypoparathyroidism. or other body fluids may be achieved by physical means. The chemical inhibition of isoamylase determination is simple. cholelithiasis.0. The isoelectric points (pI) have been reported to be 7. Elevation of serum lipase activity in patients with mumps strongly suggests significant pancreatic as well as salivary gland involvement by the disease. A chemical inhibition assay employing a salivary amylasespecific protein inhibitor is also being used for isoenzyme determinations and is commercially available. and isoelectric focusing. Bromide and iodide ions also activate amylase. whenever such a distinction is needed. Isoamylases The amylase present in blood and urine of normal individuals is predominantly of pancreatic and salivary origin. they require this metal for their catalytic activities. to 12-25% in those with chronic relapsing pancreatitis. Amylases are metalloenzymes containing at least one atom of calcium per molecule. alcohol ingestion. respectively.

gastrin is produced by the G cells of the proximal small intestine and delta cells of the pancreas. In several cases. 50% of the . normal serum. The mean ratios of P2/P1 and P3/P1 in fresh pancreatic juice. altering the results of the assay. The relative activity of P-type isoamylase has been reported to be highly useful as a diagnostic index of pancreatic pseudocysts ( Warshaw. All gastrins originate from a single precursor.5 ( Henderson. and pancreatic cancer serum were always less than 0. 1999 ). This ratio was elevated in about 90% of sera from patients with proven pseudocysts but not from others. known as big gastrin. Other functions include stimulation of gastric pepsinogens and intrinsic factor secretion.25 and less than 0. 1994 ). For this reason. Due to the action of proteolytic enzymes. Preprogastrin yields progastrin. preprogastrin that is cleaved by the action of trypsin. individuals on acid suppression therapy for peptic ulcer disease may have elevated gastrin levels. that regulates gastric acid secretion and stimulates growth of the gastric mucosa among other functions.fluid from patients with cystic fibrosis revealed that two-thirds of the patients had no or little pancreatic amylase. this isoamylase analysis ruled out a pseudocyst correctly. larger molecular forms of gastrin and incompletely processed precursors are present and are beyond the scope of detection by conventional assays. Interestingly. chronic pancreatitis serum. An acid environment serves as a negative-feedback mechanism for the release of gastrin with 80% reduction in secretion at a pH of 2. namely. 1994 ). This hormone is secreted mainly after the detection of digested protein products as well as from antral distention. acute pancreatitis serum. Gastrin acts on the parietal cells located in the fundus of the stomach.04. Laboratory determination of gastrin levels with available RIA or ELISA assays is indicated for the confirmation of suspected diagnosis of gastrin-secreting tumors. The antibodies present in these assays are specific for the biologically active C-terminal of the gastrin molecule and they have minimal cross-reactivity with CCK peptides. This serves to protect the stomach from overacidification from excess stimulation of gastrin. Three main forms of gastrin exist in human blood and tissues: G34. To a lesser extent. a patient must be fasting for 12 hours because the concentration of G34 doubles and the concentration of G17 quadruples following a meal. Maximal stimulation of gastrin secretion occurs within a pH range of 5-7. produced mainly by the antral G cells. The P1 isoamylase (the slowest migrating or least anodic) normally accounts for 80-90% of total amylase activity: P2 and P3 account for 0-4% in both serum and pancreatic juice. as with achlorhydric gastritis or gastrinomas. stimulating the secretion of gastric acid. and G14. respectively. in pathologic cases of increased gastrin production. Prior to determination of gastrin levels. which is subsequently processed to yield glycine-extended gastrin (G34 Gly and G17 Gly) before conversion to the amidated forms G34 and G17 ( Wang. Specimens must be frozen immediately because gastrin is unstable in serum. gastrinomas or Zollinger–Ellison syndrome. Gastrin Gastrin is a primary gastrointestinal hormone. release of secretin from the small intestine and secretion of pancreatic enzymes as well as bicarbonate ( Henderson. G17. whereas ultrasound or CT scan erroneously indicated the presence of a pseudocyst. little gastrin and mini gastrin respectively. Gastrin also increases blood flow to the stomach and is responsible for increased gastric and intestinal motility. 2003 ). In such cases only little gastrin would be detectable in serum ( Goetze. 1980 ).

Approximately 15% of individuals older than 60 years may have gastrin levels between 100800 ng/L ( Henderson. Gastrin concentration greater than 1000 ng/L with gastric acid hypersecretion (basal acid secretion > 15 mmol/h) is diagnostic of gastrinomas. Normal reference gastrin levels for fasting individual range up to 100 ng/L. Assays have traditionally been used to detect elevated gastrin levels associated with diseases such as ZE or gastrinoma. it should be noted that fasting serum gastrin levels are increased with increasing age. as occurs in normal patients. in part due to unrecognized gastric mucosal atrophy. approximately 10 minutes. especially in patients older than 60 years. in patients with ZE. patients with ZE or gastrinomas were evaluated with intraoperative gastrin assays. if long-term storage is required. It is recommended that specimens should be kept in a freezer at a temperature of -70°C without a self-defrosting cycle. only approximately 12. among for example. if the entire hormone-secreting tissue is surgically resected. The sensitivity for intraoperative gastrin assays has been estimated to be 88%. Infused secretin should cause a drop in gastrin levels. In one clinical study. The secretin stimulation test is a provocative biochemical test that can help confirm the diagnosis of ZE in questionable cases. pyloric obstruction. However. It should also be noted that reference intervals for infants and children differ from those for adults. there is a dramatic increase in gastrin level. a procedure not advocated on all patients because of associated morbidity and mortality ( Sokoll. hyperparathyroidism. pancreas. However. 1999 ). The catabolic breakdown of most peptide hormones follows first-order exponential decay. so that changes can be detected shortly after resection of hypersecreting tissue. and a drop of gastrin levels to within reference values within 20 minutes of resection was indicative of cure. H2blocking agents and proton pump inhibitors. However. it is thought to be due to a direct local effect on the blood flow to the tumor ( Ashley. Gastrin is an appropriate hormone for rapid intraoperative testing because it has a short analyte half-life. and duodenum or periaortic lymph nodes.5% of the baseline concentration would be present in serum after three half-lives ( Sokoll. retained gastric antrum. vagotomy. Limitations include altered results from conditions that may lead to elevated gastrin levels such as gastric ulcer disease. all commonly used in the treatment of patients with peptic ulcer disease. Certain medication can also increase gastrin measurements such as antacids. and pernicious anemia. the clearly established benefit of rapid intraoperative PTH assays (see Ch. 15 ) has prompted similar interest in gastrin as an intraoperative guide for therapeutic management. 2004 ). 1994 ). rapid analysis that can be completed within the time frame of the operative procedure. however. This test may help to identify patients who may benefit from more extensive dissections or operative procedures such as duodenopancreatectomy. However. avoiding refreezing and thawing. Specimens must be analyzed immediately after thawing. The mechanism by which secretin stimulates an increase in gastrin levels in these patients is poorly understood. so values should be compared to an age-specific reference range for accuracy. 2004 ). 2004 ). and a positive clinical utility ( Sokoll. Therefore. stomach. However. short bowel syndrome. chronic renal failure. up to 2000 times the normal gastrin level. gastrin assays intraoperatively may help to identify patients who . In patients with Zollinger–Ellison syndrome (ZE) there is usually a marked elevation. confirming the diagnosis. these elevations are moderate and certainly not as high as in a patient with a gastrin-secreting tumor. Intraoperative testing is of potential use because gastrinomas can be multiple and are often difficult to locate because they can be distributed widely. either to confirm adequate removal of gastrin-secreting tissue or to prompt further dissection and possibly more elaborate procedures.specimen's immunoreactivity may be lost within 48 hours at a temperature of 4°C.

Decreased levels of pepsinogen are associated with disease states marked by decreased parietal cell mass. Both groups of pepsinogen are activated at an acid pH below 5 and destroyed by alkaline pH. duodenal ulcer disease and acute and chronic gastritis ( Henderson. PGII is produced in mucous cells in oxyntic and pyloric regions and the duodenum. the PGI isoform is commonly analyzed in the clinical laboratory since it is the isoform commonly associated with disease. gastrinomas. also known as pepsinogen A. The pepsinogen released from the gastric mucosa is predominantly secreted and constitutes a major component of gastric fluid. All patients fitting these . histamine H2receptor antagonists and vagotomy ( Henderson. by gastric acid that can activate additional pepsinogen autocatalytically. Active pepsin is rapidly inactivated in the bloodstream. secretin and fivefold increase in the risk of gastric carcinoma compared to healthy individuals ( Sanduleanu. 2003 ). and pepsinogen II (PGII). an area marked by high prevalence of gastric cancer. Absence of pepsinogen is noted in patients with achlorhydria. Pepsin and Pepsinogen Pepsinogens are the biologically inactive proenzymes of pepsins that are produced by the chief cells and other cells in the gastric mucosa and are found in two distinct types. 1994 ). 1982 ). Both types can be detected in blood. also known as pepsinogen C. Miki recommended that criteria for diagnosing chronic atrophic gastritis be persons with PGI < 70 μg/liter and PGI/PGII ratio < 3. Pepsinogen secretion is stimulated by the vagus nerve.would benefit from this surgical intervention. Addison's disease and hypopituitarism ( Henderson. Pepsinogen I levels measured by immunoassay usually range from 20-107 and pepsinogen II levels usually range from 3-19 μg/L. 1994 ). namely atrophic gastritis and gastric carcinoma as well as in patients with myxedema. 2003 ). possibly limiting clinical utility of this serum assay. and type II is present in semen ( Henderson. Zollinger–Ellison syndrome. PGI is produced in the chief cells and mucous cells of oxyntic glands. now called uropepsinogen to uropepsin ( Henderson. 1994 ). This must be kept in mind when analyzing serum pepsinogen levels. These assays are currently utilized in Japan. Only type I pepsinogens are present in the urine. Serum levels of pepsinogen I are an accurate estimate of parietal cell mass and correlate with acid-secretory capacity of the stomach. 1994 ). a remarkable advancement in the management of patients with gastrinomas. anticholinergics. namely. pepsin. The ratio of concentration of pepsinogen I to pepsinogen II in serum or plasma of healthy individuals is approximately 4:1 ( Samloff. The PGI/PGII ratio decreases linearly with worsening atrophic gastritis. Pepsins are responsible for the hydrolysis of proteins to polypeptides. where the slightly acidic pH converts the pepsinogen. Severe atrophic body gastritis causes a four. Immunoassay is the method used to detect serum pepsinogen. Increased pepsinogen levels and associated activity is observed in patients with disease states that lead to increased gastric output or with increased parietal cell mass. Only approximately 1% gets into the peripheral blood. as a potential method for widespread screening of high-risk individuals ( Miki. whereas pepsinogen is stable in the blood. gastrin. Pepsinogen assays are being explored for their utility in the noninvasive identification of patients with chronic atrophic gastritis as well as to provide an estimate of the extent of atrophic gastritis. 1994 ). pepsinogen I (PGI). This will hopefully identify a sub group of individuals with chronic atrophic gastritis that would benefit from endoscopic evaluations for detection of early-stage gastric tumors. Pepsinogen is converted to the active form. Pepsinogen is then filtered by the kidneys and is excreted in the urine. and is inhibited by gastric inhibitory peptide (GIP). However.0. a known precursor of gastric carcinoma.

However.criteria should then be referred to a gastroenterologist for further endoscopic evaluations. Trypsinogen Trypsin is produced in the exocrine pancreas as two proenzymes. discussed in detail in the previous section. Pepsinogen assays may therefore prove to be a useful serum screening method for detection of gastric carcinoma among highrisk individuals. unlike amylase. the pepsinogen serum screening test has been demonstrated to detect a higher percentage of early cancers compared to conventional methods. resulting from gallstones. and therefore already elevated upon admission. to avoid a recurrent episode of a potentially fatal disease. 2001 ). The differentiation between these two etiologies is aided by careful history and imaging studies. The most sensitive test for fundic atrophic gastritis is considered to be the PGI/II serum ratio. However. Trypsin. and a considerable number of patients have subsequently been candidates for treatments with endoscopic surgery ( Mikki. Furthermore. the ratio of serum trypsin-2–AAT to trypsinogen 1 was determined to be the best discriminator between biliary and alcoholic pancreatitis ( Andersen. amylase. Therefore. may benefit from surgical intervention. and are sometimes suggestive of one etiology versus the other. In Japan. This is important. Trypsinogen 1. with 99% sensitivity and 94% specificity ( Henderson. is solely produced by the pancreatic acinar cells and is therefore a specific indicator of pancreatic damage. The proenzymes are activated in the duodenum by an enterokinase that yields trypsin 1 and trypsin 2 respectively. Interestingly. in particular ultrasonography. The absence of PGII production has been associated with aggressive tumor behavior and shorter overall survival in gastric cancer patients ( Fernandez. in approximately 5-10% of acute pancreatitis cases. Alanine aminotransferase (ALT). followed by a rapid rise. biochemical markers to differentiate the etiologies would be clinically invaluable. Pancreatitis. Trypsin present within the peripheral circulation is inactivated by complexing with either alpha-2-macroglobulin or alpha-1-antitrypsin (AAT). a specific etiology is never determined. serving as an independent predictor of tumor biology and survival in patients with gastric carcinoma. Furthermore. 2000 ). Premature activation of the proenzyme to active trypsin within the pancreatic parenchyma is thought to be a key mechanism in the development of acute pancreatitis ( Andersen. 2001 ). Trypsin assays have found clinical utility in the diagnosis of acute pancreatitis. Both enzyme levels remain elevated longer than amylase and the magnitude of elevation . amylase and lipase were found to be more elevated in patients with biliary pancreatitis. Currently. patients with biliary pancreatitis. levels of all forms of trypsin are determined by specific immunoassays. is frequently the result of either excessive alcohol consumption or a sequela of gallstone disease. known as trypsinogen 1 and trypsinogen 2. One study demonstrated that trypsinogen 2 and trypsin-2–AAT are increased in all forms of acute pancreatitis but were more elevated in alcoholic-associated pancreatitis than in biliary pancreatitis. These enzymes are elevated within hours of the onset of the acute episode. aspartate aminotransferase (AST). Elective cholecystectomy should be performed in these patients after the pancreatitis resolves. trypsin assays are currently being utilized for the purpose of differentiating the cause of an acute episode of pancreatitis. 2003 ). another study supported the use of trypsin assays for diagnosis of acute pancreatitis because the determined time course profile of trypsinogen 2 and trypsin-2–AAT is appropriate for diagnostic purposes. pepsinogen II levels may be a useful marker of prognosis. because although the initial management and resuscitation of a patient with pancreatitis follows the same management logarithm for both etiologies. and lipase levels are useful in diagnosing acute pancreatitis. 1994 ).

characterized by watery diarrhea. we will focus on the GI manifestations of VIPomas. VIP levels should be obtained during a bout of diarrhea when active secretion of VIP can be detected. 2004 ). predicting severity of illness and for monitoring disease progression ( Kemppainen. accounting for 10% of neuroendocrine tumors of the gastrointestinal tract. VIPomas produce a severe. extremely useful for diagnosing acute pancreatitis upon admission. delaying the diagnosis. If the diagnosis is missed or delayed. 2003 ). Patients with functional VIP-secreting tumors have ranges from 675- . the chronic diarrhea results in severe fluid and electrolyte imbalances that produce a myriad of clinical symptoms. hyperchloremic metabolic acidosis. In this section. resulting in hypochlorhydria or achlorhydria. Under these circumstances. Approximately 60% of VIPomas are malignant and 6% are associated with multiple endocrine neoplasia (MEN) type I. common in the early stage of tumor growth. If patients have mild or intermittent symptoms. random VIP levels may be normal. acting through stimulation of cyclic AMP (cAMP). Diarrhea may be present for several years prior to the diagnosis of VIPoma. Vasoactive Intestinal Peptide (VIP) Vasoactive intestinal peptide (VIP).2/million per year. as is often the case. 2003 ). consists of 28 amino acids and is a member of the secretin–glucagon family ( Radebold. Elevated trypsin-1–ATT has also been demonstrated in patients with biliary tract cancer ( Andersen. The normal value for circulating VIP levels is less than 170 pg/mL. The metabolic profile present in these patients is typically hypokalemic. It is also a potent stimulator of water and electrolyte secretion. 2000 ). VIP-secreting tumors. Most of these tumors are sporadic and may also occur in the adrenal glands. This syndrome was first described in 1958 by Verner and Morrison. and was later discovered to be caused by tumors secreting large amounts of vasoactive intestinal peptide hormone ( Radebold. lung and jejunum. is modified to yield the 28-amino-acid VIP ( Vinik. secretory diarrhea that has been termed pancreatic cholera.corresponds to the severity of pancreatic inflammation. retroperitoneum. released in response to gut distention. Diagnostic laboratory evaluations for determination of VIP levels are clinically relevant for diagnosis of VIPomas. Diarrhea does not improve with fasting and an average secretion of 300 mmol of potassium per 24 hours occurs ( Vinik. Vasoactive intestinal peptide.05-0. which post-translationally. most commonly of pancreatic origin. The diagnosis of VIPomas is made with confirmation of raised fasting VIP levels in association with secretory diarrhea and the presence of a lesion. Similar to glucagons. mediastinum. VIP stimulates breakdown of glycogen and lipid stores and inhibits histamine-stimulated acid secretion in the stomach. Stool volume of less than 700 mL/day excludes the diagnosis of VIPoma. most commonly located in the pancreas associated with VIP production. 2004 ). Confirming the biochemical diagnosis of VIPoma involves a highly sensitive and specific radioimmunoassay to detect raised VIP levels. It is initially synthesized as a 170-amino-acid precursor pre-pro-VIP. hypokalemia and achlorhydria (WDHA). is a potent vasodilator and is responsible for the relaxation of vascular and nonvascular smooth muscle of the intestinal tract. has a molecular weight of 3381. the most severe of which is sudden death from cardiac arrhythmias resulting from electrolyte disturbances. Patients typically produce more than 3 L of watery stools per day though volume can be as high as 30 L/day. a neuropeptide. 2001 ). The incidence of the tumors is estimated to be between 0. namely potassium depletion and acidosis.

the sample must be separated within 10 minutes and frozen to -20°C. this value will be elevated if the VIPoma is located within the pancreas. The method is painless and reliable if performed properly. which is currently under investigation. Angiography can be used to localize smaller tumors. CT scan. including 123I VIP receptor scintigraphy. Total body sweating in patients with cystic fibrosis is hazardous. MA). qualitative measurements of sweat chloride and sodium. inadequate and inappropriate collection of sweat. 1994 ). It is important to note that appropriate handling of the serum sample is critical to the accuracy of the VIP radioimmunoassay because VIP has a half-life of 1 minute. developed by the National Committee for Clinical Laboratory Standards (NCCLS) (Villanova. serum pancreatic polypeptide level should be determined at the time of the VIP RIA. This NCCLS document includes a discussion of sweat stimulation. Ltd. 1994 ). To provide the best possible quality of sweat testing. Apt Test for Neonatal Bleeding When blood is found in the gastrointestinal tract or stool of neonates. 1994 ). Various nuclear scans have been utilized for localization of VIPomas. 1993). The CAP and the Cystic Fibrosis Foundation have jointly developed the External Proficiency Testing Survey for Sweat Test Analysis (Set SW) for laboratories to further improve the quality of the sweat test. East Walpole. False-positive elevations of VIP can be observed in patients with small bowel ischemia or severe low-flow states resulting from diarrhea and subsequent dehydration not associated with VIP-producing lesions ( Vinik. This reduction of steps in the procedure leads to greater reproducibility. 2004 ). lack of appropriate quality controls. MRI and abdominal ultrasound are useful imaging modalities for VIPoma tumor localization. Methodologic unreliability. UT). Unacceptably high rates of incorrect results have been attributed to problems associated with sweat specimen sample collection and test analysis. In addition. The Cystic Fibrosis Foundation recommends that laboratories that perform few sweat tests per year should refer patients to a cystic fibrosis center ( LeGrys. diluted with water.. weighed. PA) to improve the performance of the sweat test for the diagnosis of cystic fibrosis ( LeGrys. and a number of deaths from the procedure have been recorded. When performed properly in duplicate. The serum must be immediately added to aprotinin. and analyzed for sodium and chloride concentrations. volumes of sweat up to 100 μL can be obtained and the chloride can be measured directly using 20 μL samples with a chloride analyzer such as the Corning 925 (Chiron Diagnostics. Sweat Chloride Pilocarpine is introduced into the skin by iontophoresis to stimulate locally increased sweat gland secretion. 2003 ). and quality control issues. The resulting sweat is absorbed by filter paper or gauze. technical errors.. laboratories are referred to the document „Sweat Testing: Sample Collection and Qualitative Analysis: Proposed Guidelines‟ (document C34-P. Logan. and misinterpretation of test results were found to be sources of errors ( LeGrys. In addition.965 pg/mL ( Thomas. Some of the non-VIP products of the precursor molecule are secreted at higher levels than VIP. the sweat test has a sensitivity of 90-99%. however. commercially available assays are not available and clinical utility has not been established. Using the Wescor Macroduct Sweat collection system (Wescor Inc. a determination of whether the blood is swallowed blood of maternal origin or secondary to disease in the . inexperience of laboratory workers. a protease inhibitor that prevents breakdown of VIP.

newborn must be made ( Guritzky. hyperlipidemia. The Apt test is a qualitative test that is used to make this determination in grossly bloody stools or hematemesis from a newborn. To distinguish pancreatic insufficiency from other causes of steatorrhea some investigators have developed a two-stage breath test ( Goff. based on the fact that HbF is more resistant to alkali denaturation than adult hemoglobin. if there is nipple cracking or bleeding. In addition to steatorrhea and poor dietary intake. 1996 ). liver disease and high fever may also cause a low level of serum carotenoid. lack of carotenoids in the diet or disturbances in absorption of lipids from the intestine can result in decreasing levels of serum carotenoid. Procedure. If the blood is of maternal origin. 1994 ). tripalmitin. This in turn results in a decrease in expired CO2 derived from metabolism of triglyceride fatty acids. and trioctanoin). The supernatant. Breath Test. Tests for Steatorrhea Screening Tests Screening tests for detection of steatorrhea include microscopic examination of feces for fat globules and determination of serum carotenoid. as well. Nursing infants may ingest maternal blood. 1982 ). is then mixed with 1% sodium hydroxide in a ratio of 5:1. Steatorrhea from either pancreatic insufficiency or other causes results in a decreased absorption of triglycerides by the digestive system. Because carotenoids are not stored in the body to any appreciable degree. The radioactivity of the 14CO2 is then measured in a liquid scintillation counter. The sample is first mixed with water and centrifuged. In patients with steatorrhea due to pancreatic insufficiency the amount of 14CO2 expired should increase relative to the amount of 14CO2 expired in the first stage of the test. . The test is based on the measurement of 14CO2 in expired air following the ingestion of various 14C-labeled triglycerides (triolein. and the 14CO2 is measured as previously described. This is a simple and useful screening test for steatorrhea. has a relatively low sensitivity and the result must be interpreted with caution ( McRury. the mixture turns yellow-brown after several minutes. Patients with steatorrhea from other causes should show no significant change in the amount of 14CO2 expired following the oral administration of pancreatic enzymes. Fetal blood remains pink. Periodically. and the results are reported as a percentage of the dose of 14 CO2 excreted per hour. After an overnight fast the patient consumes 14C-labeled triglyceride. In the first stage of the test the patient consumes a 14C-labeled triglyceride. which should be pink. Absorption of carotenoid in the intestines depends on the presence of dietary fat and its normal absorption. diabetes. Elevated serum carotenoid levels are seen in patients with hypothyroidism. Comment. Carotenoids are a group of compounds that are the major precursors of vitamin A in humans. and excessive intake of carotene. breath CO2 is collected in a trapping solution containing an indicator that changes color when a predetermined amount of CO2 is in solution. The second stage of the test is performed 5-7 days later and is the same as the first stage except that the patient is given an oral dose of pancreatic enzymes along with the dose of 14C-labeled triglyceride. This test.

yielding a solution that contains soaps derived from neutral fats and fatty acids and soaps originally present in the stool. The amount of fat in feces may be determined and expressed as a percentage by weight of wet stool. and neutral fats. Because of wide variations in water content of stool. In these tests the specific radioactivity of 14 CO2 is measured after the ingestion of a test meal containing carbon-14 (14C)-labeled triglycerides. for whom the standard 100-g diet cannot be used. is the most reliable measurement. Total output of fat per 24 hours. excess hydrochloric acid is added to convert soaps to fatty acids. „percent coefficient of fat retention‟ is a more useful expression. Fractionation of total lipids into free fatty acids and neutral fats was thought formerly to aid in assessment of the exocrine functions of the pancreas. with higher alcohols. After cooling. In infants and children. The titrimetric method has been the most widely used procedure for the quantitation of fecal fats. taken up in neutral alcohol. The titrimetric method serves as the laboratory procedure for the definitive diagnosis of steatorrhea. Breath tests represent a more recent approach to the diagnosis of fat malabsorption. owing to the presence of bacterial lipase and the spontaneous hydrolysis of neutral fats. Titrimetric methods quantitate various chemical forms of fatty acids. the coefficient of fat retention can be improved by substituting medium-chain fatty acids for long-chain fatty acids in the diet. fatty acid salts (soaps). based on chemical analysis of at least a 3-day stool collection. a percentage of ingested fat retained (absorbed). a percentage by weight of dry stool. paraffins. An improved recovery of medium-chain fatty acids from feces can be obtained by slightly modifying the titrimetric . In this method fats and fatty acids are converted to soap (saponified) by boiling feces with alcoholic potassium hydroxide. or a chemically determined amount of fat per 24-hour stool collection. wet weight concentration is the least informative. and titrated with sodium hydroxide. whereas gravimetric and microscopic procedures evaluate total fecal fat. An aliquot is evaporated. the patient is placed on a standard diet containing 100 g fat per day. Titrimetric Method. The normal fat content of feces consists primarily of fatty acids. This is the difference between fecal fat and ingested fat expressed as a percentage of the ingested fat: The coefficient of fat retention in normal children and adults is 95% or higher. fractionation of total lipids provides no additional information about the cause of steatorrhea. sterols. These are extracted with petroleum ether. and vegetable carotenoids present in significantly smaller amounts. Several laboratory procedures are available for the evaluation of fat malabsorption. Dry weight concentration is only slightly less variable because of the effect of diet on bulk. Fats are calculated as fatty acids. A low value otherwise is indicative of steatorrhea. However. The titrimetric method does not quantitatively recover medium-chain fatty acids. For this purpose. although in premature infants it may be much lower than this. In some cases of malabsorption.Definitive Test for Steatorrhea The definitive test for steatorrhea is the fecal fat determination.

well-rinsed bedpan is a convenient collection container. In this procedure a 25-g dose of pentose sugar in water is administered orally. d-Xylose is passively absorbed in the small intestine and is not metabolized by the liver. Testing and Examination of Feces Collection Uninstructed patients sometimes exhibit considerable ingenuity in collecting stool specimens. Quantitative specific fecal trypsin and chymotrypsin assays may be helpful. Because reference values in this situation are not available. D-Xylose Test The d-xylose absorption test is a valuable test for the differential diagnosis of malabsorption. especially in adults. and the sweat chloride determination should be used when clinical evidence warrants it. the main cause of pancreatic malabsorption is cystic fibrosis. The cellobiose–mannitol sugar permeability test and lactulose–mannitol test have been used in the diagnosis of celiac disease. among other things. although a portion of an orally or intravenously administered dose is destroyed. The amount of water used during saponification can be reduced and the excess alcohol distilled prior to extraction. as may be the Schilling test for vitamin B12 absorption. is the dxylose absorption test. Tests for Malabsorption When a diagnosis of malabsorption is being entertained. Isotopic techniques and the starch tolerance test have been used as alternatives to the d-xylose test. for which plastic. If the amount excreted is less than 3 g. leak proof.procedure. and boiled glass jar of suitable size is a satisfactory alternative. Patients should be instructed not to contaminate . radiologic studies. rinsed. Screening tests based on absent stool trypsin have also been used. urine has a harmful effect on protozoa. resulting in complete recovery of medium-chain and long-chain fatty acids. which tends to be abnormal in patients with enteric steatorrhea and in which the abnormality is not correctable with intrinsic factor. Tongue depressors or pieces of cardboard are reasonably convenient instruments for transferring the stool from bedpan to transport vessel. the test is better avoided in patients with renal disease. the diagnosis is mostly likely enterogenous malabsorption because pancreatic enzymes are not required for absorption of d-xylose. a carefully cleaned. However. cardboard. In children. blood values should also be assayed. One of the most valuable differential diagnostic tests. Patients should be warned against passing urine at the same time into the bedpan or container because. and the amount excreted over a 5-hour period in the urine is determined. High blood values coupled with low urine values are expected in renal disease. The modern evaluation of this disorder has been described above. A scoured. making the test difficult to interpret in patients with renal disease. and biopsy have replaced these methods in many cases. If the patient does not own one. It is therefore advisable in patients with renal disease to collect a blood sample for xylose quantitation 2 hours after the administration of xylose. and easy to transport. it becomes important to distinguish pancreatic maldigestion from enteric malabsorption. If the test is performed in these circumstances. and glass containers are available. The accuracy of the method depends not only on the rate of absorption of d-xylose but also on the rate of excretion by the kidneys. Endoscopy. We prefer two 2-oz ointment jars with screw caps for small stool samples because they are odor-free. but a few simple instructions are likely to produce more satisfactory specimens. poor kidney function may also result in low excretion.

ulcerative colitis. form. consistency. 100-200 g of stool is passed per day. Passage of large amounts of mushy. however. as currently used. obstructive jaundice. Fecal matter left on the physician's gloved finger at the time of a rectal examination may be transferred to a piece of filter paper for inspection and testing for occult blood. are too time-consuming for routine determinations. which is lubricated by dipping into water and then inserted into the young child's rectum. Fecal specimen sample collection at home is by no means simple and easy unless the patient has been instructed properly.3 g) at the beginning and charcoal (1 g) at the end of a collecting period. can result in an explosive release of contents. chromium sesquioxide (Cr2O3) has been used. For this purpose. Therefore. firm. In about two-thirds of cases.the outside of the container and not to overfill the container. rectosigmoidal obstruction. and its concentration in the feces is determined chemically. foul-smelling. and acceptability to patients and laboratory staff. but these methods. Constipation may be associated with passage of small. The accuracy of this method can be enhanced somewhat by having the patient ingest carmine dye (0. spherical masses of . should be released gradually by carefully loosening of the cap. When diarrhea is present the stool is watery. However. which frequently accumulates. cannot be emptied completely at will. Macroscopic Examination of Feces Inspection of the feces is important because it may lead to a diagnosis of parasitic infestation. For determining the 24-hour fecal excretion of any substance. Gas. For collection of timed urine specimens. The gastrointestinal tract. Another method of signaling the collection period involves the use of inert. Salmonella cubana outbreaks in Massachusetts and California were traced to carmine dye. Because of wide variation in bowel habits. absence of requirements for special equipment. diarrhea. or gastrointestinal tract bleeding. malabsorption. A pediatric method described by Jelliffe (1973) includes the use of a thick-walled glass tube. dysentery. stool should be collected over a period of at least 3 days. gray stool that floats on the water is characteristic of steatorrhea. The concentration of the material found in the stool specimen is then used to determine the quantity of stool containing 1 day's ingestion of the material as an indication of the 24-hour output. which can be poked out with an applicator stick into the container. Hoffman (1973) has described a collection method that has the advantages of ease of transportation and storage. and bulk of stool. The quantity. intestinal transit time. especially in the case of an overfilled container. and color of the stool should be noted. Normally. These are taken in divided uniform doses for several days prior to the beginning of the collection. special consideration must be given to methods of timed stool collection. a core of feces can be obtained. Failure to observe this simple precaution. the amount of stool collected in a 24-hour period usually correlates very poorly with the amount of food ingested during a similar period of time. and collecting the stools from the beginning of the appearance of the dye to the beginning of the appearance of the charcoal. continuing through the collection period. nonabsorbable stool markers. The substitution of radioactive chromium or zirconium isotope has made it possible to determine concentration by measuring the radioactivity of the stool. and calculations should be based on the entire specimen divided by the number of days of collection. the urinary bladder can be emptied before and at the end of the collection period.

It is seen in stools of emotionally disturbed patients and may result from excessive straining. Pus. No inflammatory exudate is seen in the watery stools of patients with viral gastroenteritis. They frequently develop severe dehydration and electrolyte disturbances. and charcoal may also cause a black color. Under these conditions fatty acids are present as lightly stained flakes or as needlelike crystals that do not stain and therefore may be missed. Bloody mucus clinging to the fecal mass suggests neoplasm or inflammatory processes of the rectal canal. a small aliquot of stool suspension is placed on a slide and mixed with two drops of 95% ethanol. repeated tests for occult blood are called for to detect more serious organic problems such as carcinoma. the recognition of which requires microscopic examination. however. Parasites are considered in Chapter 61 . especially hypokalemia. seen in patients taking antibiotics orally. iron. which may also afflict those patients. In our experience. beets in the diet may mimic this. In such patients. and intestinal tuberculosis. rectum. For this purpose. Mucus associated with pus and blood is found in stools of patients with ulcerative colitis. Large amounts of pus seldom accompany the stools of patients with amebic colitis and its presence is evidence against this diagnosis. Bismuth. Sudan IV. Patients with chronic ulcerative colitis and chronic bacillary dysentery frequently pass large quantities of pus with the stool. Clay color suggests diminution or absence of bile or the presence of barium sulfate.stool (scybala). Microscopic Examination of Feces Fat. Caution is advisable in interpretation. or anus. It is not unusual to see seeds and vegetable skins. Stool that is allowed to stand in the air for a time may darken on the surface. This also occurs in patients with localized abscesses or fistulas communicating with the sigmoid colon. Blood. amounting to 3–4 L in 24 hours. When 60 or more stained droplets of neutral fats per high-power field (hpf) are seen. ulcerating diverticulitis. Green stools may result from ingestion of spinach and other green vegetables or calomel. then two drops of saturated ethanolic solution of Sudan III are added. however. The presence of recognizable mucus in a stool specimen is abnormal and should be reported. with further mixing. Soaps also do not stain but appear as well-defined amorphous flakes or as rounded masses or coarse crystals. A narrow. or Oil Red O stain. Patients with villous adenoma of the colon may pass copious quantities of mucus. A coverslip is then applied. bacillary dysentery. because mineral oil or castor oil . Neutral fats. especially blood originating from the lower gut. one may be reasonably certain that the patient has steatorrhea. or it may result from the presence of biliverdin. Bleeding from the upper gastrointestinal tract is more likely to cause the stool to be black and have a tarry consistency. may cause the stool to be red. The crudest technique is microscopic examination using Sudan III. Translucent gelatinous mucus clinging to the surface of the formed stool suggests spastic constipation or mucous colitis. Constipation most often results from the irritable colon syndrome in patients with anxiety or from overuse of laxatives. Mucus. results have correlated well with quantitative measurements when aliquots of the same homogenized stool have been analyzed. The procedure has been widely employed for screening because of its simplicity. appear as large orange or red droplets. ribbon-like stool suggests the possibility of spastic bowel or rectal narrowing or stricture.

causing them to form droplets that stain strongly with Sudan III. The procedure is then repeated. this may serve as a useful screening technique. potentially resulting in decreased mortality. which is allowed to stand for 2-3 minutes for good nuclear staining. The sensitivity of FOBT has been estimated between .may mimic neutral fat. Leukocytes. counting 200 cells when possible. Macrophages and epithelial cells that cannot be clearly identified are ignored. and only rectangular fibers with clearly evident cross-striation are counted. The technique for sampling is identical to that used for Sudan preparations for detection of fecal fat. After this procedure. Only those cells clearly identified as either mononuclear or polymorphonuclear are included in the differential count. 2003 ) and the relatively inexpensive. Evidence has demonstrated the clinical usefulness of fecal occult blood testing (FOBT) to detect these cancers at an earlier stage. Due to the generally favorable clinical biology of these tumors when detected earlier. A small fleck of mucus or a drop of liquid stool is placed on a glass microscopic slide with a wooden applicator stick. The College of American Pathologists Laboratory Testing Strategy Task Force also recommends annual stool blood screening as a standard of practice. Meat Fiber. adding several drops of 36% (v/v) acetic acid to the stool mixture and warming the slide several times over a flame until slight boiling occurs. with an 80-90% survival rate with local confined disease ( Helm. According to recent cancer statistics. Patients with steatorrhea of pancreatic origin are likely to have greater increases in fatty acids and soaps. the most widely utilized. noninvasive nature of FOBT. The slide is then examined while warm. The entire area under the coverslip is examined. 1996 ). A coverslip is placed on the mixture. rough quantitative counts are made by approximating the average number of leukocytes and erythrocytes. The limitations of this testing include the high number of false-positive and false-negative results. the presence of up to 100 stained droplets per high-power field is considered normal. The American Cancer Society (ACS) guidelines for colorectal cancer screening. allowed to stain for 3 minutes. approximately 150 000 new colon cancer cases were diagnosed in 2003. Several professional organizations recommend annual of biennial FOBT but universal accepted screening protocols have not been established. accounting for approximately 55 000 deaths annually. recommend annual FOBT and flexible sigmoidoscopy every 3-5 years beginning at age 50 in asymptomatic. and then examined for muscle fibers. All differential counts should be made under high power. Fecal Occult Blood Testing Colon cancer is a leading cause of cancer-related deaths in the US. Two drops of Loffler methylene blue are added and mixed thoroughly and carefully. The stool is mixed thoroughly on a slide with a 10% alcohol solution of eosin. The initial cell counts should be performed at the time of presentation of the specimen. It appears that examination for meat fibers yields results that correlate well with chemical determination of fat excretion. controlled trials have demonstrated that FOBT decreases mortality from colon cancer by 15-35% ( Clinical Guideline. This converts neutral fats and soaps to fatty acids and melts the fatty acids. Some have advocated using Oil Red O because it permits substitution of isopropanol for ethanol. 1997 ). Using low-power scanning. Three randomized. average-risk individuals ( Marshall.

These tests detect the pseudoperoxidase activity of heme. Dukes A or B colon cancer ( Clinical Guideline. FOBT should then be interpreted with caution. A middle-aged patient determined to have a positive FOBT. The presence of greater than 20 mL/day of blood in the stool results in a positive guiac smear. NSAIDs. Other drugs that have been implicated include reserpine and oxidizing drugs such as iodine. Most guiac tests performed by residents are completed after a single digital rectal examination. aspirin. if not clinically feasible. maximizing the sensitivity of the screening procedure. to ensure compliance with this protocol. Other potential sources of occult blood may arise from bleeding esophageal varices. A negative FOBT. esophageal or gastric inflammation. In addition. For example. Occult blood may arise anywhere along the intestinal tract and is often the first warning sign of GI malignancy. drugs that can cause GI irritation and subsequent bleeding such as anticoagulants. Guiac is a naturally occurring phenolic compound that is oxidized to quinone by hydrogen peroxidase. 1997 ). cannot definitely rule out the presence of . 1996). resulting in a detectable color change. polyps. Therefore. Further evaluations usually include either sigmoidoscopy with barium enema or full colonoscopy. Interestingly. Two slides should be prepared for each stool sample. Coloscreen). the latter being the preferred modality. the most commonly used method at present. making screening impractical. Laboratory diagnosis of the presence of fecal occult blood generally involves a guiac-smear test (Hemoccult. or avoided altogether as a screening modality in these patients. or ingestion of large amounts of red meat prior to testing. Searcult. This prompts further unnecessary invasive and expensive colonoscopic evaluations. ingestion of large amounts of vitamin C can lead to a falsenegative result. Factors that can cause inaccuracies in the results include the presence of bleeding gums for example. without slide rehydration. A positive FOBT then prompts further evaluation for suspected colonic neoplasia. A positive result on FOBT should be defined as positivity in one or more slide windows. Rehydration increases test sensitivity for detection of colorectal cancer but decreases specificity. however. resulting in a 10% or greater increase in false-positive results. and hemoglobin from red meat. either as intact hemoglobin or as free heme (Allison. Stool specimens should be received from three consecutive stools. Occult blood can be detected by chemical (guiac). peroxidase from fruits and vegetables and certain medications can lead to false-positive results. hemoporphyrin or immunological methods. The true sensitivity of FOBT is difficult to determine because individuals who test negative. However. has an estimated 7-14% probability of having an early stage. the test must be performed under appropriate conditions that serve to limit the sensitivity of this test. patients must be informed of these effects and ideally should avoid such medications or food products prior to FOBT. 1998 ).30-50%. following a stepwise approach to colon cancer screening should minimize the clinical effects of limited sensitivity and specificity and offer valuable information nonetheless. This is a standard protocol for FOBT. These tests are not specific for human hemoglobin. recommended by randomized clinical trials. On the contrary. patients may be using certain medications that will influence the result of FOBT. Only approximately 5-10% of positive reactions prove to be caused by an occult malignancy ( Simon. PUD or angiodysplasias of the colon. In addition. colchicines or iron supplements may lead to falsepositive results. IBD. Studies have shown that slides should not be rehydrated and should be developed within 7 days of collection. do not undergo further colonoscopic evaluation to determine if the FOBT is a true negative. hemorrhoids or fissures. medical institutions are now requiring that stool samples be sent to the laboratory for guiac testing rather than having residents perform the test on the wards.

APC and p53 are examples of genes serving as DNA markers in stool testing because they control colorectal cell growth and are often affected by colonic neoplasia. widespread use is not current practice. Fecal DNA testing is a promising technique for detection of occult blood. . ranging from 93-100% and sensitivity ranging from 71-91% for detection of cancer. promising improved laboratory diagnosis of colorectal malignancy. These tests do not react with nonhuman hemoglobin or peroxidase. such as HemeSelect or InSure. 2003 ). considerably more than chemical guiac testing. Immunochemical InSure tests target the globin portion of hemoglobin. has been developed to improve the sensitivity and specificity of guiac testing to detect colonic neoplasia. however. This test involves collection of a single stool specimen which is then screened for DNA markers originating from cells of cancers present in the gastrointestinal tract that are shed into the stool ( Helm. 1996). these tests are more specific for lower gastrointestinal. whereas the cells shed from normal epithelium are degraded by enzymes as part of normal cell death ( Helm. Fecal immunochemical testing for human hemoglobin. which does not survive passage through the upper GI tract.colonic neoplasia. If a patient is presenting with signs and symptoms suggestive of colon cancer. PCR is used to amplify the fecal DNA to yield an extremely sensitive assay. so food restrictions are not necessary. Clinical studies have shown that fecal DNA testing has increased specificity. 2003 ). Therefore. This is a useful test because neoplastic DNA remains stable in stool. further evaluation is warranted. even in the presence of negative FOBT. HemeSelect testing is based on an antigen–antibody reaction involving fixed chicken red blood cells coated with anti-human-hemoglobin antibody (Allison. Refer to Figure 22-1 for an algorithm for fecal occult blood testing for early detection of colon cancer. colonic bleeding (Quest Diagnostics). Samples demonstrating agglutination are interpreted as positive for occult human blood. InSure is a test which uses monoclonal mouse antihuman hemoglobin antibody with subsequent colorimetric detection and is sensitive enough to detect 50 μgHb/g feces (Quest Diagnostics).

2004 ). Fecal Elastase Elastase 1 is a proteolytic enzyme. more so than serum amylase ( Henderson. In addition. 1994 ). therefore. 2004 ). produced by the pancreas. Pancreatic elastase survives intestinal transit intact and is concentrated in the feces. Fecal elastase 1 determination is a novel fecal enzyme test. with a molecular weight of sixfold the concentration present in pancreatic juice ( Lankisch. five. may be more specific . elevation of elastase 1 persists longer than serum amylase levels and.Figure 22-1 Screening for occult colorectal malignancy with fecal occult blood testing (FOBT). Interestingly. It was initially isolated in 1975 and called protease E ( Lankisch. This test may replace fecal chymotrypsin levels. used for indirect assessment of pancreatic function to aid diagnosis of exocrine pancreatic insufficiency. elastase 1 is increased in acute and relapsing chronic pancreatitis. and represents approximately 6% of pancreatic enzyme secretions.

unaffected by pancreatic enzyme replacement therapy. the fecal elastase enzyme test is estimated to be 57-90% specific. caution is warranted in interpretation of results. Based on previous testing. This test should only be performed on formed stool. values ranging from 100-200 μgPE-1/g indicate mild to moderate pancreatic insufficiency and values below 100 indicate severe insufficiency ( Lankisch. The test is highly sensitive for detection of severe pancreatic insufficiency. Sensitivity of this test is based on severity of pancreatic insufficiency. 2001 ).for detection of pancreatitis and more accurately follow the clinical course of the disease ( Henderson. Table 22-8 -. para-aminobenzoic acid (PABA) bentiromide test and pancreolauryl test ( Lankisch. until then. Fecal elastase has diagnostic superiority over fecal chymotrypsin levels as well as older test of exocrine pancreatic function. ERCP) Interpretation of fecal elastase-1 estimation[*] Normal Abnormal Normal Normal Severe exocrine pancreatic insufficiency excluded. the positive predictive value of fecal elastase determination is estimated to be approximately 50% ( Luth. Using these cutoff estimations. A single analysis of a 100-mg stool sample is adequate for determination of fecal elastase levels. Fecal elastase determination may be more useful than fecal chymotrypsin levels for diagnosis of pancreatic insufficiency. a problem common to indirect tests of pancreatic function. it lacks sensitivity for detecting mild to moderate disease and cannot diagnose chronic pancreatitis with certainty. This test is estimated to be 100% sensitive for detection of severe disease. In addition it is unable to differentiate between pancreatic and nonpancreatic steatorrhea. test not helpful. and thus pancreatic enzyme substitution-requiring insufficiency. namely. Continued investigation will likely define appropriate utility for fecal elastase analysis in particular clinical settings. making it a useful diagnostic test. It is therefore. 2004 ). then a repeat sample may be useful. values greater than 200 μgPE-1/g are considered normal. it lacks high sensitivity for detection of milder forms. 2004 ). However. This ELISA test uses monoclonal antibodies that react with human pancreatic elastase (PE) ( Lankisch. If borderline values are detected. important in specimen collection and processing. however. 2004 ). limiting its clinical utility. CT. especially in differentiating steatorrhea/diarrhea Test confirms chronic pancreatitis but does not indicate whether steatorrhea. Using a cutoff of 200 μg/g stool. 1994 ). is present Abnormal Abnormal . estimation EUS.Value of Fecal Elastase-1 Estimation in Diagnosing Chronic Pancreatitis and Exocrine Pancreatic Insufficiency Fecal Morphologic elastase-1 procedures (US. Refer to Table 22-8 for summary of the clinical application of fecal elastase-1 estimation for diagnosing chronic pancreatitis and exocrine pancreatic insufficiency. mild to moderate impairment possible Exocrine pancreatic insufficiency may or may not be present. this decreases to between 33-89% for moderate disease and between 0-65% for mild pancreatic insufficiency as per current preliminary studies. However.

consistency. In children. Genetic Markers for Gastrointestinal Disease The molecular defect underlying cystic fibrosis results in alterations in epithelial cell electrolyte transport. using 25 g glucose and 25 g galactose if the lactose test indicates malabsorption. Trypsin is synthesized and maintained as inactive trypsinogen in secretory granules in the pancreatic . The classic delta F508 mutation leads to cystic fibrosis when two copies of the gene are inherited. US = ultrasound. A control test may be performed. The defect is an autosomal recessive mutation in the CFTR gene located on chromosome 7. but mild to moderate exocrine pancreatic insufficiency was not detected. Patients with lactase deficiency exhibit a peak rise of less than 20 mg/dL in reducing substances expressed as glucose.Fecal elastase-1 estimation Normal Morphologic procedures (US. and 120 minutes after ingestion as for a glucose tolerance test. which has been reported by some to yield more definitive results. and pH. It may cause symptoms in patients with mild lactase deficiency. fecal elastase-1 estimation falsely normal The abnormal morphologic examination is due to scars following acute pancreatitis. administer orally 50 g of lactose dissolved in 400 mL of water. Some investigators use a 100-g dose. Lactose Tolerance Test Following an overnight fast. EUS. 60. the test should be repeated within 2 days and the less abnormal of the two curves used for interpretation. In all persons with flat tolerance curves. ERCP = endoscopic retrograde cholangiopancreatography. Draw fasting blood and blood samples at 30. ERCP) Abnormal Interpretation of fecal elastase-1 estimation[*] Two interpretations possible: The patient has chronic pancreatitis on the basis of morphological procedures. An optional 5-hour stool specimen can be collected. The central enzyme involved in activation of all the digestive proenzymes is trypsin. fecal elastase1 estimation is correctly normal CT = computed tomography. Persons heterozygous for the R117H mutation may develop pancreatic insufficiency. These persons may present as idiopathic chronic pancreatitis ( Durie. the dose of lactose or other sugars is 2 g/kg body weight. with permission. examining and recording the appearance. EUS = endoscopic ultrasound. * Interpretation based on suggestion that diagnosis of chronic pancreatitis should be made on a combination of abnormal results of morphologic examinations and abnormal exocrine pancreatic functions tests. The degree of the defect depends on the nature of the mutation. 2000 ). 6:126–131. should clinicians start using it? Curr Gastroenterol Rep 2004. After Lankisch PG: Now that fecal elastase is available in the United States. There are several characterized mutations that lead to a milder form of the disease. CT.

com . leading to decreased ability to prevent inactivation. as the native form leads to stabilization of trypsin. There are regulations developed by the Food and Drug Administration for such testing. Mutations in the SPINK1 molecule lead to a similar problem. After release into the pancreatic duct. Although many other markers are currently being evaluated. and the type of mutation appears to alter the protein. Cationic trypsinogen (PRSS1) mutations involving codon 29 and 122 cause autosomal dominant forms of hereditary pancreatitis ( Whitcomb. Clinical testing is available for the disorders described ( Etemad. Chronic pancreatitis and pancreatic cancer develop at a relatively young age. . trypsinogen is cleaved by enterokinase on the brush border of the duodenum to active trypsin.mdconsult. Thus a series of events leading to active intra-acinar trypsin occurs. SPINK1. Trypsin is stabilized in the pancreatic acini by a serine protease inhibitor. 2001 ).www. The number of mutations is limited. none has achieved widespread use at this time. Ordering genetic testing requires that the physician clearly understand how to interpret the results and anticipate how the results will affect patient management. A more extensive discussion of tumor markers is found in Chapter 74 . All rights reserved. Several mutations in trypsin and SPINK1 exist that have recently gained importance in the evaluation of pancreatitis and pancreatic cancer. The presence of increased acinar trypsin leads to activation of proenzymes and thus pancreatitis. Mutations have been described (N34S) that decrease the ability to promote trypsin degradation. Patients with these disorders typically have recurrent acute pancreatitis sometime between infancy and the 4th decade. 2000 ). Email to Colleague Print Version Copyright © 2007 Elsevier Inc.acinar cell. No specific treatment exists for the prevention or treatment of hereditary pancreatitis.

1994. 47:231-236. specificity. 126(10):808-810. Tekawa I. 1998. et al: Autoantibodies to tissue transglutaminase as predictors of celiac disease. Schulz TJ. Barr GD. Baillargeon JD. N Engl J Med 2004. Ammori BJ. Principles of Surgery. Spencer FC. 1998. Corsetti et al. Malfertheiner P. et al: Hemoconcentration as an early risk factor for necrotizing pancreatitis. 39:2495-2499. Diagnosis. Kemmpainen E. Etemad B. Arvan DA: Combined serum amylase and lipase determinations for diagnosis of suspected acute pancreatitis. Clinical Guideline : Part 1: Suggested technique for fecal occult blood testing and interpretation in colorectal cancer screening. 2001. Becker KL. Arch Surgery 1929. Med Clin North Am 2000. 1999:1195-1196.McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods. Anal Biochem 1968. Ashley et al. Ramagopal V. 84:609-620. Saunders Company References Allison et al. et al ed. 1929. Laag E. Baillargeon et al. and new genetic developments. Atherton and Spiller. Atherton JC. Etemad and Whitcomb.Guidelines address the technique of screening by using fecal occult blood tests. . 169:109114. Ammori et al. 1:227-235. 1986. Med J Aust 1998. with emphasis on the interpretation of positive and negative test results and the subsequent work-up of persons with positive results. Ashley SW. Clinical Guideline. 1997. Clin Chem 2001. Br J Surg 2003. 1968. Schopper H.. Dieterich et al. In: Schwartz SI. B. Gastroenterology 2001. 1993. Daly JM: Stomach. 19:943-948. 1999. Orav J.. and predictive value related to colonoscopy and biopsy findings. et al: The ratio of trypsin2-alpha1-antitrypsin to trypsinogen-1 discriminates biliary and alcohol-induced acute pancreatitis. Andersen et al. 90(2):197-204. Copyright © 2006 W... 35:723-725.. 83:2130-2136. Graham EA: Value of blood amylase estimations in the diagnosis of pancreatic diseases. Schoetensack C. 115:1317-1324. New York: McGraw Hill. Whitcomb DC: Chronic pancreatitis. Dahlqvist. Grehan MJ: Coeliac disease.. 2001. Dieterich W. Durie PR: Pancreatic aspects of cystic fibrosis and other inherited causes of pancreatic dysfunction. Results of a prospective clinical study. 22:99107. et al: A comparison of fecal occult blood tests for colorectal cancer screening. 2004. Buchler MW. Dahlqvist A: Assay of intestinal disaccharides. Gut 1994. Clin Chem 1993.. Am J Gastroenterol 1998. Ransom LJ.. Shires GT. Andersen JM. Ann Intern Med 1997. Evoy D. Kite P: Calcitonin precursors in the prediction of severity of acute pancreatitis on the day of admission. pylori. Hedstrom J. Spiller RC: The urea breath test for H.. 334:155-159. Int J Pancreatol 1986. et al: Sensitivity of antiprotease and complement factors and C reactive protein in detecting pancreatic necrosis. Allison J. Durie. Elman R. Barr and Grehan. 2000.Evaluation of three commonly used screening tests for fecal occult blood with regard to sensitivity. 1998. Elman et al. Gastroenterology 1998. 21st ed. 2003. classification. Arneson I. Cox C. Corsetti JP. Buchler et al. 120:682-707.

184:487-492. Textbook of Clinical Chemistry. et al: Rapid measurement of urinary trypsinogen-2 as a screening test for acute pancreatitis. Feldman RA.. Kemppainen EA. 336:1788-1793. J Clin Microbiol 1992. Jelliffe DB. Henderson et al. Kemppainen E. Goetze and Rehfeld. Klonoff. Frank and Gottlieb. 27:662-664. Puolakkainen P. 113:S113-S117. Gudman-Hoyer E. Goff. Kisker et al. 94:463469. pancreatic and intestinal function. 1995a. Bartsch D. J Am Coll Surg 1997. N Engl J Med 1984.. Acta Paediatr Scand 1975. Ann Surg Oncol 2000. 49(2):333-334. Hoffman et al. 310:1307-1312. et al: The value of somatostatin-receptor scintigraphy in newly diagnosed endocrine gastroenteropancreatic tumors. 133:392-407. Philadelphia: WB Saunders Co. 1994:1576-1644. Guerrant et al. Tietz NW. LaRusso NF. Gastroenterology 1997. N Engl J Med 1997. 64:693-698. ed.. et al: Measurement of fecal lactoferrin as a marker of fecal leukocytes. 1984. 2000. lipase elevated: is it pancreatitis? A case series and review of the literature. Klonoff DC: Macroamylasemia and other immunoglobulin-complexes enzyme disorders. Goff JS: Two-stage triolein breath test differentiates pancreatic insufficiency from other causes of malabsorption. 2:618.. 1980. Feldman et al. Kemppainen et al. 83:44-46. In: Burtis CA. Currington C.. Henderson AR. Krasilnikoff PA. . 1980.. et al: Current and evolving strategies for colorectal cancer screening. Rehfeld JF: Impact of assay epitope specificity in gastrinoma diagnosis. 96:3237-3246. Feldman and Evans. Rinker AD: Gastric. Araujo V. 1:1422. Cancer Control 2003.. Farrell RJ. Evans SJW: Accuracy of diagnostic methods used for epidemiological studies of Helicobacter pylori. Am J Gastroenterol 1999. Deeks JJ. 1975. Toskes PP: Trypsin like immunoreactivity as a test for pancreatic insufficiency. Krasilnikoff et al. Guerrant RL.. Ann Emerg Med 1996. 35(11):1216-1220. Kelly CP: Diagnosis of celiac sprue. 2001. 1997.Farrell and Kelly. Feldman RA.. 10(3):193-204. Clin Chem Acta 1980. Scand J Gastroenterol 2000. Moltke HH: Diagnostic value of disaccharide tolerance tests in children. Lancet 1973. 14:428-433. Evans SJW. 1997. Graham. 2003. Guritzky and Rudnitsky. 1982. 1997. 9(Suppl 2):21-31. Helm et al. Weinel RJ. Aliment Pharmacol Ther 1995. Fridhandler and Berk.. Gottlieb K: Amylase normal. 1994. 2003. Graham DY: Can therapy ever be denied for Helicobacter pylori infection? (editorial). et al: Time course profile of serum trypsinogen-2 and trypsin-2-alpha 1-antitrypsin in patients with acute pancreatitis. 2000. Choi J. Hietaranta A. Jelliffe and Jelliffe. 7(7):508-514. 1999. Puolakkainen PA. Kisker O. Fridhandler L. Vizoso F. Rodriguez JC: Expression and prognostic significance of pepsinogen C in gastric carcinoma. Frank B. Gastroenterology 1982. Jelliffe EFD: Collection of a stool sample. Sutphen R. Guritzky RP. Eur J Clin Microbiol Infect Dis 1995. Goetze JP. Soares E. Berk JE: Simplified chromatographic method for isoamylase analysis. et al: Multi-laboratory comparison of eight commercially available Helicobacter pylori serology kits. 1992. Kemppainen et al. 1973. 30:1238-1242. Connery K. 1973. Lancet 1973... 1995b. Fernandez R. 101:135-138. Rudnitsky G: Bloody neonatal diaper. Jacobsen et al. Hedstrom JI. 1996.. Hoffman AF: An improved method for fecal collection: The field-kit. West J Med 1980. Am J Gastroenterol 2001. Fernandez et al. Jacobsen DG. Clin Chem 2003. Helm J. Hoffman NE. Ashwood ER.

Ellis C: A rapid and simple assay to determine if macroamylase is the cause of hyperamylasemia. Gastroenterology 1997. Benjamin DC. 10(3):189-191. et al: Trypsin activity. Levitt and Ellis. et al: Celiac disease risk in the USA. 1998.Laheij et al.. Digestion 1977. Verbeek ALM: Evaluation of commercially available Helicobacter pylori serology kits: A review. 10(4):248. Mollgaard A.. Mifflin et al. et al: Accuracy of IgG serology and other tests in confirming Helicobacter eradication. Scand J Gastroenterol 1998. Murray JA: Serodiagnosis of celiac disease. Makristathis A. Schutze K. Teyssen S. Gastroenterology 1982. Gut 1996. 36:2803-2809. 33:710-715. Marshall. Folsch UR: Fecal elastase 1: a novel highly sensitive and specific tubeless pancreatic function test. Lerang et al. 2000. 39:580-586. et al: Usefulness of gastric cancer screening using the serum pepsinogen test method. 1997. Deviere .. 1996. Pasching E. 1982.. Le Moine et al. 1998. Lankisch PG: Now that fecal elastase is available in the United States. Mifflin TE. 1977.Erratum in: Pediatr Emerg Care 1994. 1985. 118:865-867. et al: Detection of Helicobacter pylori in stool specimens by PCR and antigen enzyme immunoassay. Perry RR. 17:445-464.. Otto J. McRury and Barry. Loser C. Not et al. 99(3):253-264. Jansen JBMJ. 1994. Malnick and Zimhony. Scand J Gastroenterol 1998. Lankisch PG. Devaster JM. 83:378-382... Clin Lab Med 1997. 98(4):735739. Marshall JB: Colorectal cancer screening: present strategies and future prospects. Forssmann K. Not T. Arch Pathol Lab Med 1994. Makristathis et al. 39:2634-2638. 2001. Horvath K. Laheij RJF. J Clin Microbiol 1998. Scand J Gastroenterol 2001. 6:126-131. 1994. Loser et al. Lerang F. Peterson WL: Helicobacter pylori and peptic ulcer disease. Miki K. 1996. Dig Dis Sci 1994. Koop H. et al: Fecal elastase-1 determination: „gold standard' of indirect pancreatic function tests?. Huag JB. 36(10):1092-1099. Curr Gastroenterol Rep 2004. Levitt MD. Gastroenterol Clin North Am 1998. N Engl J Med 1991.. J Clin Microbiol 1998. 47:57-68. 31:1283-1288. LeGrys VA. Luth S. 27:453-465. Lankisch et al. et al: Specificity of increased amylase to creatinine clearance ratio in acute pancreatitis. 494:33-39. Moum B. Miki et al. McRury JM. 1996. Le Moine O.. Straatman H. 113:S93S98. Peterson. 36:2772-2774. Nehra. Malnick S. Hill ID. 1994. 1998. Pediatr Emerg Care 1994. 324:1043-1048. 1991. Lankisch. Clin Chem 1985. 2004. Bruns DE: Rapid quantitative. 1998. Results of the College of American Pathologists Needs Assessment Survey. 16:160-164. specific measurement of pancreatic amylase with the use of a monoclonal antibody. Postgrad Med 1996. Ann Pharmacother 2000. LeGrys and Burnett. Nehra V: New clinical issues in celiac disease. Megraud F: Diagnosis and candidates for treatment of Helicobacter pylori infection: How should Helicobacter pylori be diagnosed?. 1997. Luth et al. Zimhony O: Treatment of Clostridium difficileassociated diarrhea. Perry and Vinik. Morita M. Murray. 36:1767-1775. Megraud. 2003. A new marker of acute alcoholic pancreatitis. . Barry RC: A modified Apt test: a new look at an old test. 1998. Annu Rev Med 1996. should clinicians start using it?.. Am J Gastroenterol 2003. Burnett RW: Current status of sweat testing in North America. Vinik AI: Endocrine tumors of the gastrointestinal tract. Sasajima M.

82:26-33. 2003. Gastroenterology 1982.. 1989. 1997.. 1998. Singer R: Diagnosis and treatment of Whipple's disease. Biemond I. A new index that distinguishes acute episodes of alcoholic from non-alcoholic pancreatitis. 50(7):1126-1135. Romano and Dobbins. Sugal et al. 126:520-527. Int J Pancreatol 1997. Drugs 1998. DiMagno EP: What is the best biochemical test to diagnose acute pancreatitis? A prospective clinical study. Smotkin and Tenner. Gastroenterology 1994. Smotkin J. 1994. Robins AH. 1997. Dalton JW. Sokoll et al. et al: Steatocrit: a reliable semiquantitative method for detection of steatorrhea. Sanduleanu S. 1982. 1983. Tenner et al..emedicine. et al: Guidelines for the investigation of chronic diarrhea. Mayo Clin Proc 1996. et al: Ratio between serum IL-8 and pepsinogen A/C: a marker for atrophic body gastritis. 87:755-1761. 1996. 2003. 1997. 89:1863-1866. Online. 102:576-580. 1998.. Ann Intern Med 1985.Provides guidelines to establish an optimal investigative scheme for patients presenting with chronic diarrhea in order to .. Tenner and Steinberg. 1998. Sanduleanu et al. Simon. Tenner S: Laboratory diagnostic tests in acute pancreatitis. Ann Intern Med 1997. Shanahan. Alpen B. 34:459-464. Romano TJ. Goldstein SS. 93:1306-1312. Remaley AT: Rapid intraoperative immunoassay of parathyroid hormone and other hormones: A new paradigm for point-of-care testing. Steinberg W: The admission serum lipase/amylase ratio.. et al: Urinary trypsinogen activation peptide (TAP) predicts severity in patients with acute pancreatitis.. J Clin Gastroenterol 2002. Shanahan F: Neutrophil autoantibodies in inflammatory bowel disease: are they important. 18(3):467-483. Davis ND. Dobbins JW: Evaluation of the patient with suspected malabsorption. Morgner A. Samloff IM: Pepsinogens I and II: Purification from gastric mucosa and radioimmunoassay in serum. 113:S61-S64. 1994. 21:105-110. et al: Diagnostic assays in acute pancreatitis: a study of sensitivity and Ramzan et al. Charrier G. 2002. Gastroenterology 1997. Forbes A. Sternby B.. Dig Dis Sci 1983.Poutanen and Simor. Eur J Clin Invest 2003.. Gut 2003. 33(2):147-154. Tenner S. Singer.. Srur G. Gastroenterologist 1998. Fernandez-del Castillo C. Zinsmeister AR. CMAJ 2004. J Clin Gastroenterol 1994. 1994. 2004. Available: http://www. Clin Chem 2004. 1992. et al: Anti-Saccharomyces cerevisiae mannan antibodies in familial Crohn's disease. Sugal E. Steinberg W: Predicting gallstone pancreatitis with laboratory parameters: a meta-analysis. 171(1):51-58. Loftus Jr E. Tenner SM. Radebold K: VIPomas. 19:206-209. 55:699704. Samloff. Wians FH. 6(1):66-78. Thomas et al. Thiede C... 2003. Am J Gastroenterol 1994. Ramzan NN. Sendid B. Am J Gastroenterol 1998. Gastroenterol Clin North Am 1989. Poutanen SM. Simon JB: Fecal occult blood testing: clinical value and limitations. 1985. Radebold. Thomas PD. Burgart LJ. Thiede et al. Spechler et al. et al: Prevalence of normal serum amylase levels in patients with acute alcoholic pancreatitis. Am J Gastroenterol 1992. Steinberg W. Green J.. Vazquez H. Sternby et al. Quinton JF. 28:865-875. 2nd ed. Simor AE: Clostridium difficile-associated diarrhea in adults. et al: What role does Helicobacter pylori eradication play in gastric MALT and gastric MALT lymphoma?. Warshaw A. O'Brien JF. Dubner H. 71:1138-1144. Sokoll LJ. 2003. Tenner et al. 52(Suppl V):v1-v15. Spechler SJ. Bruine A. 107:586-590. Steinberg et al. 2004. Sendid et al. Tenner S. eMedicine. et al: Diagnosis and monitoring of Whipple disease by polymerase chain reaction.

J Clin Microbiol 1996. 1980. 1994. Email to Colleague Print Version Copyright © 2007 Elsevier . Also features summary/recommendation tables with sections devoted to noninvasive testing. Ditton HJ. Keane CT. 49:289-299. Zaman et al. Wang and Dockray.www. J Med Microbiol 1994. Trier. Gastroenterology 1980. Jansz AR. van de Wouw et al. Warshaw and Lee.. duodenal ulcer. Xia HX. Gastroenterology 1964. 2004.. Physiological studies with gastrin in transgenic mice. Wang TC. Whitcomb DC: Genetic predispositions to acute and chronic pancreatitis. CMAJ 1994. Schuhmacher F. Tietz and Shuey. 1996. Molinaro N. Van Orshoven A. 1993. et al: IgA anti-endomyseal antibodies on human umbilical cord tissue for celiac disease screening. Volta et al. Dockray GJ: Lessons from genetically engineered animal models. In Vinik A (ed): Diffuse Hormonal Systems and Endocrine Tumor Syndromes. de Franceschi L. Veldhuyzen van Zanten and Sherman. 1994. Veldhuyzen van Zanten SJ. van de Wouw BAM. Annu Rev Med 1998. All rights reserved. 40:1902-1908. Zieve. gastric cancer and nonulcer dyspepsia: A systematic overview. Available: http://www. 39:746-756. Ch 6. de Boer WA. 2004. 277:G6-G11. Xia et al. Tietz NW. et al: Simultaneous macroamylasemia and macrolipasemia. Online. 113:434-441. 2000. Clin Chem. Med Clin North Am 2000. Dig Dis Sci 1995. Gastroenterology 1997. 1995. Maiwald M: Whipple's disease: Staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. 1964.. Trier JS: Diagnosis of celiac sprue. 40:939. 46:62-71. 1998. 34:94-97. 79:1246-1251. O'Morain CA: Pre-formed urease activity of Helicobacter pylori as determined by a variable cell count technique – clinical implications. 1993. Volta U. Lee KH: Aging changes of pancreatic isoamylases and the appearance of „old amylase' in the serum of patients with pancreatic pseudocysts. Sherman PM: Helicobacter pylori infection as a cause of gastritis. Shuey DF: Lipase in serum: the elusive enzyme: an overview. et al: Comparison of three commercially available enzyme-linked immunosorbent assays and biopsy-dependent diagnosis for detecting Helicobacter pylori infection.. 1999. I. 1997. 84:531-547. von Herbay A. Vinik A: Vasoactive intestinal peptide tumor (VIPoma). 115:211-216. Zaman Z. Gastroenterology 1998. Whitcomb. Clin Chem 1994. 1998.. Save both money and monkeys. Wotherspoon AC: Gastric lymphoma of mucosa-associated lymphoid tissue and Helicobacter pylori.mdconsult. Zieve L: Clinical value of determinations of various pancreatic enzymes in serum. Am J Physiol 1999. Warshaw AL. 150:177-185.. von Herbay et al. Endotext. 1994. Vinik. .endotext. Marien G.maximize positive diagnosis while minimizing the number and invasiveness of investigations.