Articles on Medical Diseases and Conditions

Category: Gastrointestinal Function

Gastrointestinal Function

  • Diarrhea

    Differential tests

    There are many conditions that produce a chronic diarrhea, which must be differentiated from the relatively common types that last only a few days and usually respond to ordinary treatment. Diarrhea in infants will not be specifically discussed, since this is a special problem peculiar to that age group.

    In patients of all ages with long-term or chronic diarrhea, a stool should be obtained for culture to rule out the presence of Salmonella or Shigella bacteria. In some areas, Campylobacter or Yersinia infection might be the etiology. A stool should also be obtained for ova and parasites, with special emphasis on the possibility of amebae or Giardia being present. In children, malabsorption is caused either by cystic fibrosis of the pancreas or celiac disease. In adults, the various forms of sprue and, more rarely, some of the secondary malabsorption causes might be considered. In children and young and middle-aged adults, ulcerative colitis is a possibility, especially if there is blood in the stools. This calls for a sigmoidoscopic or colonoscopic examination. In adults over age 40 years, carcinoma of the colon is the cause of diarrhea in a significant number of cases. A barium enema and colonoscopic examination are necessary. In the aged, in addition to carcinoma, fecal impaction is a frequent cause of diarrhea, and this usually can be determined easily by ordinary rectal examination.

    One study reports that diarrhea is more frequent in patients with serum albumin levels less than 2.5 g/100 ml (25 g/L). Chronic diarrhea in diabetics occurs in 8%-22% of patients; in one study, about 50% had a known cause determined. It is more frequent in patients with poorly controlled diabetes treated with insulin who also have peripheral neuropathy and autonomic nervous system dysfunction. The diarrhea may be intermittent. Steatorrhea may or may not be associated. In many cases no organic etiology for persistent diarrhea can be found. This situation is often called “functional diarrhea” and is attributed to psychiatric causes. The organic diseases listed here must be ruled out before deciding that a patient has a psychosomatic disorder.

    Differential Diagnosis of Diarrhea (More Frequent Etiologies)

    Infection—bacterial
    Salmonella, Shigella, Campylobacter, Yersinia enterocolitica, enteropathic Escherichia coli, Clostridium difficile enterocolitis.
    Infection—virus
    Rotovirus, fastidious enteric adenovirus, Norwalk virus
    Infection—parasites
    Giardia lamblia, Entamoeba histolytica
    Ulcerative colitis—regional enteritis
    Partial obstruction of colon
    Colon carcinoma
    Fecal impaction
    Malabsorption—steatorrhea
    Celiac disease: nontropical sprue, tropical sprue, disaccharide enzyme deficiency
    Other
    Diabetic neuropathy
    Zollinger-Ellison syndrome
    Hypoalbuminemia-associated

    Persons infected by the human immunodeficiency virus 1 (HIV-1) often develop diarrhea, especially if they progress to the stages of disease known as acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Common infecting organisms in these patients are Mycobacterium avium, Mycobacterium intracellulare, Salmonella, Cryptosporidium, Microsporidium, cytomegalovirus, Giardia, Strongyloides stercoralis, and Isospora belli. However, numerous other organisms have been reported.

  • Tests for Gastric Blood

    Until the middle of the 1980s, there was no commonly accepted method to test for blood in gastric contents. Methods I have personally seen used in different laboratories include urine dipsticks, orthotolidine tablets, and guaiac-impregnated filter paper. Studies have indicated that small numbers of red blood cells (RBCs) are present in most gastric aspirates without clinical evidence of bleeding. These RBCs are often sufficient to produce a reaction with orthotolidine or the urine dipsticks. The guaiac-impregnated filter paper tests used for stool occult blood are less sensitive and also appear to detect clinically significant amounts of blood but were shown to lose sensitivity at pH levels below 3.0 (literature range, 2.5-4.0). In addition, cimetadine, a medication frequently used to decrease gastric acid production, can produce false negative guaiac tests. A new guaiac test introduced in 1985 called Gastroccult is buffered so as to maintain sensitivity down to pH 1.0. In addition, the reagent contains a substance that inhibits plant peroxidase and thereby decreases chances of a false positive result from that source. Also, Gastroccult is not affected by cimetadine. Gastroccult has a sensitivity of approximately 5 mg of hemoglobin/100 ml of gastric contents (equivalent to about 50 µl of whole blood/100 ml of gastric contents), with a detection range in the literature of 30-200 µl of blood/100 ml of diluent. Although there is no consensus regarding the exact amount of gastric blood considered significant, 50 µl/100 ml seems to be acceptable. Ascorbic acid (vitamin C) inhibits both the standard guaiac test and Gastroccult. Large amounts of antacids may also inhibit the test reaction; the manufacturer states that this possibility must be taken into consideration if testing is done within 1 hour after administering the antacid.

  • Gastric Analysis

    Gastric analysis has two main uses: to determine gastric acidity and to obtain material for exfoliative cytology. I shall discuss only the first here.

    When gastric aspiration is performed to determine gastric acidity, the usual purpose is either (1) to determine the degree of acid production in persons with ulcer or ulcer symptoms of (2) to determine if the stomach is capable of producing acid as part of a workup for pernicious anemia. Since passing the necessary large-caliber tube is not met with enthusiasm by the patient, it is important that the physician understand what information can be obtained and be certain that this information is really necessary.

    Outdated gastric acidity method. One problem in evaluating gastric acid secretion data from the literature is the term “achlorhydria,” which is often used as a synonym for “anacidity.” The classic method of gastric analysis involved titration with 0.1N sodium hydroxide to the end point of Topfer’s reagent (pH, 2.9-4.0); this represented “free HCl.” Next the specimen was titrated to the end point of phenolphthalein (pH, 8.3-10.0); this represented “total acid.” The difference was said to represent “combined acid,” thought to consist of protein-bound and weak organic acids but probably including small amounts of HCl. Achlorhydria technically is defined as absence of free acid (pH will not drop below 3.5 on stimulation) but not necessarily complete lack of all acid. True anacidity is absence of all acid, now defined as a pH that does not fall below 6.0 or decrease more than 1 pH unit after maximum stimulation. Therefore, achlorhydria is not the same as anacidity. Nevertheless, the two terms are often used interchangeably. Gastric acidity by the old method was reported in degrees or units; this was the same as milliequivalents per liter. Reference values for total 12-hour gastric secretion were 20-100 ml and for 12-hour total acid content were 10-50 mEq/L (literature range, 2-100 mEq/L).

    Currently recommended gastric acidity procedure. All authorities today recommend that the old gastric acidity procedure be replaced by a timed collection protocol with results reported in milliequivalents per hour, that is, secretion rate instead of concentration. A 1-hour basal specimen is collected (basal acid output [BAO]). Reference values are not uniform but seem most often to be quoted as 1-6 mEq/hour. An acid production stimulant is then injected. Either pentagastrin, betazole (Histolog), or histamine can be used; pentagastrin has the fewest side effects and histamine the most. After injection of the acid stimulant, four 15-minute consecutive specimens are collected (using continuous suction if possible). Maximum acid output (MAO) is the sum of all four 15-minute poststimulation acid collections. Acidity can be measured by titration with the chemical indicator methyl red, but many laboratories now use a pH electrode.

    Proper placement of the gastric tube is critical; many recommend assistance by fluoroscopy. Reference values for MAO are less than 40 mEq/hour. The BAO/MAO ratio should be less than 0.3.

    Conditions in which gastric analysis is useful

    Diagnosis of pernicious anemia. Presence of acid secretion rules out pernicious anemia. Complete lack of acid secretion after maximum stimulation is consistent with pernicious anemia but may occur in up to 30% of persons over age 70 and occasionally in presumably normal younger persons. If basal secretion fails to demonstrate acid, stimulation is necessary. Alcohol or caffeine stimulation has been used; but since these agents do not produce maximal stimulation of acid production, it would be necessary to repeat the test using pentagastrin, betazole, or histamine if no acid production were found. Therefore, a stronger stimulant, such as pentagastrin, is preferred as the original stimulation agent. Anacidity rather than achlorhydria is the classic gastric analysis finding in pernicious anemia; but, as noted previously, the older term achlorhydria is still being used with the same meaning as anacidity.

    Many hematologists perform the Schilling test without preliminary gastric analysis if they suspect pernicious anemia. If the Schilling test produces clear-cut evidence either for or against pernicious anemia, gastric aspiration usually is not necessary. This is especially true if test results are definitely normal, since the greatest technical problem of the Schilling test is incomplete urine collection leading to a falsely low result. If the Schilling test result is equivocal, or if there is some doubt regarding an excretion value suggesting pernicious anemia, gastric aspiration can still be carried out since it is not affected by the Schilling test.

    Diagnosis of gastric cancer. Given a known gastric lesion, anacidity after maximum stimulation is strong evidence against peptic ulcer. However, only about 20% of gastric carcinomas are associated with complete anacidity, so gastric analysis in most cases has been replaced by fiberoptic gastroscopy with direct visualization and biopsy of the lesion.

    Diagnosis of Zollinger-Ellison syndrome.

    These patients have a gastrin-producing tumor, usually in the pancreas, and typically demonstrate a high basal acid secretion with minimal change after stimulation. Specifically, gastric analysis is strongly suggestive when the BAO is 15 mEq/hour or the BAO/MAO ratio is 0.6 or greater (i.e., BAO is 60% or more of the MAO after maximum stimulation). Some consider a BAO of 10 mEq/hour and a BAO/MAO ratio greater than 0.4 as evidence suggesting a need for further workup so as not to miss a gastrin-producing tumor. About 70% of Zollinger-Ellison patients have a BAO more than 15 mEq/hour (literature range, 50%-82%) as opposed to about 8% of duodenal ulcer patients (literature range, 2%-10%). About 55% of patients with Zollinger-Ellison syndrome (literature range, 35%-75%) have a BAO/MAO ratio higher than 0.6 as opposed to about 2% (literature range, 1%- 5%) of duodenal ulcer patients. The definitive diagnostic procedure for gastrinoma is serum gastrin assay. If Zollinger-Ellison syndrome is a possibility, many physicians proceed directly to serum gastrin assay without gastric acid studies.

    Diagnosis of marginal ulcer. After partial gastric resection with gastrojejunostomy (Billroth II procedure or one of its variants), abdominal pain or GI bleeding may raise the question of ulcer in the jejunum near the anastomosis. An MAO value above 25 mEq/hour is strongly suggestive of marginal ulcer; MAO less than 15 mEq/hour is evidence against this diagnosis.

    Differentiation of gastric from duodenal ulcer. Duodenal ulcer patients as a group tend to have gastric acid hypersecretion, whereas gastric ulcer patients most often have normal or even low rates. Patients with gastric ulcer usually have MAO values less than 40 mEq/hour. About 25%-50% of duodenal ulcer patients have MAOs greater than 40 mEq/hour. Conversely, very low acid secretion rates are evidence against duodenal ulcer. Basal secretion greater than 10 mEq/hour is evidence against gastric ulcer.

    Determining type and extent of gastric resection. Knowing the amount of acid is sometimes helpful in the surgical treatment of duodenal ulcer. Some surgeons prefer to do a hemigastrectomy (removal of one half of the stomach) rather than a subtotal gastrectomy (two-thirds resection) because postoperative complications are fewer with a hemigastrectomy. If the patient is a hypersecretor, the surgeon may add vagotomy to a hemigastrectomy or may perform a subtotal resection to reduce HCl-producing cells or lessen stimulation of those that remain.

    Evaluation of vagotomy status. Patients undergoing a surgical procedure that includes bilateral vagotomy may later experience symptoms that might be due to recurrent ulcer or manifest a proved recurrent ulcer. The question then arises whether vagotomy is complete. The Hollander test employs insulin hypoglycemia (20 units of regular insulin, or 0.1 unit/kg) to stimulate gastric acid secretion through intact vagal nerve fibers. Although disagreement exists on what values are considered normal, most physicians use (1) a BAO less than 2mEq/hour; and (2) for postinsulin values, either total acid output less than 2 mEq/hour in any 1-hour period or an increase in acid concentration of less than 20 mEq/hour in 2 hours. Most agree that a “positive” response means incomplete vagal section. Interpretation of the “negative” response (failure to secrete sufficient acid under stimulus of hypoglycemia) is more controversial. Antrectomy or partial gastrectomy removes HCl-secreting cells, and a negative response thus could be due either to vagal section or to intact vagus but insufficient total gastric HCl secretory activity.

  • Gluten-Induced Enteropathy

    Gluten-induced enteropathy includes sprue and celiac disease (childhood nontropical sprue), both diseases that affect the small intestine (predominantly the duodenum and jejunum). Both conditions are caused by immune reaction mediated by T-lymphocytes against gluten, a mixture of proteins found in wheat, rye, barley, and possibly oats. Celiac disease is found predominantly in Europeans, uncommonly in African Americans, and rarely in Asians. It is about 10 to 15 times more common in IgA-deficient persons and to a lesser extent (1%-3%) in patients with type I (insulin-dependent) diabetes mellitus. There is also an association with GI tract T-cell lymphoma and juvenile rheumatoid arthritis. There is increased incidence of the class II histocompatibility complex antigens (HLAs) HLA-DRw3 (about 80%-90% of Northern European-descent patients) and HLA-B8 to a lesser extent. HLA-DR7 is often seen in Southern Europeans. Some feel that HLA-DRw2 is even more important in all affected Europeans. Adults tend to have overt diarrhea more often than children with celiac disease; children are more likely to have anemia, nonspecific chronic illness, or short stature. A substantial number of patients have subclinical or mild disease. In those who are symptomatic there is often some degree of carbohydrate and fat malabsorption that may be accompanied by vitamin B12 and folic acid malabsorption if the ileum is affected.

    Small intestinal mucosa typically first shows blunting (mild widening and shortening) of the mucosal villi and then flattening and loss of the villi with infiltration by lymphocytes. Mucosal biopsy (particularly the proximal jejunum) is still considered the gold standard for diagnosis. About 30%-50% of adult patients (not children) with nontropical sprue are reported to have some evidence of splenic atrophy, which may be seen as RBC Howell-Jolly bodies and thrombocytosis. Gliadin is the toxic protein component of gluten. Antigliadin antibodies (AGA) are found in 95% or more of patients with nontropical sprue or celiac disease. AGA-IgG are present in about 96%-97% (range, 91%-100%) of untreated patients, but only about 80% (range, 58%-95%) have celiac disease. In contrast, AGA-IgA is found in about 75% of patients (range, 42%-100%) but is about 95% specific for celiac disease (range, 80%-100%). One or both AGA are elevated in about 45%-85% of patients with dermatitis herpetiformis, which is a bullous skin disease also triggered by gluten sensitivity. False positive results in either AGA-IgA or IgA are most commonly due to ulcerative colitis or Crohn’s disease.

    Antireticulum antibodies are reported to be elevated in about 50%-60% (range, 28%-97%) of patients, but specificity is said to be about 98% (range, 97%-100%). Endomysial antibodies (EMyA, reacting against the endomysial component of smooth muscle) for unknown reasons is elevated in 90%-95% of celiac disease patients (range, 85%-100%), with specificity of nearly 100%. However, both antireticulum and antiendomysial antibodies have been introduced relatively recently and have been evaluated less frequently than antigliaden antibodies. All of these antibody evaluations have been performed using homemade antibodies, which always differ somewhat and therefore make interpretation of reference laboratory results more difficult. In general, investigators seem to be currently screening patients using AGA-IgG, with ARA or EMyA either concurrently or as confirmation.

    D-xylose absorption testing is said to be positive in about 80% (range, 43%-92%) of cases, but specificity for celiac disease is only about 50%. Another nonspecific absorption test recently advocated for screening purposes is the “differential sugar test,” based on poor absorption of smaller nonmetabolized carbohydrate molecules relative to larger molecules in patients with malabsorption due to small intestine mucosal dysfunction. Although several nonmetabolized sugars have been used, the most current ones are mannitol (small molecule) and lactulose (large molecule). A lactulose/mannitol urine excretion ratio greater than 0.10 was considered abnormal. Sensitivity in celiac disease was said to be 89% with specificity for celiac disease of 54%-100% (depending on the control group).

    Workup for possible malabsorption

    This section has considered certain tests for intestinal malabsorption. In the opinion of many gastroenterologists, the most useful tests in initial screening for malabsorption syndromes are the D-xylose, plasma carotene, and qualitative fecal fat. If the results of all these tests are normal, the chances of demonstrating significant degrees of steatorrhea by other means are low. If one or more results are abnormal and confirmation is desirable, it may be necessary to perform a 72-hour fecal fat study.

    Once steatorrhea is strongly suspected or established, many investigators proceed to a D-xylose test. If the test is abnormal, many will attempt a small intestine mucosal biopsy, both to confirm a diagnosis of sprue and to rule out certain other conditions such as Whipple’s disease. Some prefer a trial period of oral antibiotics to eliminate the possibility of bacterial overgrowth syndrome and then repeat the D-xylose test before proceeding to biopsy. In some centers a biopsy is done without a D-xylose test. If gluten-induced enteropathy is suspected, antigliadin (or possibly antiendomysial) antibody assay could be useful as a screening procedure. If results of the small intestine biopsy are normal, possibilities other than sprue are investigated, such as pancreatic enzyme deficiency and bile salt abnormalities. A trial of pancreatic extract or an endoscopic retrograde cholangiopancreatography examination to investigate pancreatic or common bile duct status might be considered in these patients. Small intestine x-ray series may demonstrate some of the secondary causes of steatorrhea, such as lymphoma, diverticula, blind loops, and regional enteritis. However, barium may interfere with certain tests, such as stool collection for Giardia lamblia.

    If small intestine biopsy is not available, a therapeutic trial of a gluten-free diet could be attempted. However, this requires considerable time and patient cooperation, and adults with nontropical sprue may respond slowly.

    If pernicious anemia is suspected, a Schilling test is the best diagnostic procedure. Bone marrow aspiration could be performed prior to the Schilling test to demonstrate megaloblastic changes, which, in turn, would be useful mainly to suggest folate deficiency if the Schilling test result is normal. It may also reveal coexistent iron deficiency. More widely used than bone marrow aspiration are serum B12 and folic acid (folate) assay.

  • Malabsorption

    The function of the gastrointestinal (GI) tract is to perform certain mechanical and enzymatic procedures on food to prepare food for absorption, to absorb necessary dietary constituents into the bloodstream, and to excrete whatever is not absorbed. When the usual dietary constituents are not absorbed normally, symptoms may develop that form part of the syndrome known as malabsorption. There are three basic types of malabsorption. The first type involves the interruption of one of the stages in fat absorption; this concerns primarily fat absorption and also those substances dependent on the presence of lipid. The second type is related to intrinsic defect of the small bowel mucosa (category IV, A–D). In this kind of malabsorption there is interference not only with fat and fat-soluble substances but also with absorption of carbohydrates and many other materials. The third type of malabsorption is associated with altered bacterial flora (category IV, E) and also with the deficiency disease called “pernicious anemia.” In malabsorption of this kind, lack of a single specific substance normally produced by the GI tract leads to malabsorption of other substances dependent on that substance for absorption. Some of these conditions and their laboratory diagnosis are discussed in detail elsewhere.

    Clinical findings. Steatorrhea, or the appearance of excess quantities of fat in the stool, is a frequent manifestation of most malabsorption syndromes. Many patients with steatorrhea also have diarrhea, but the two are not synonymous; a patient can have steatorrhea without diarrhea. On the other hand, some reports indicate that moderate or severe diarrhea can induce some degree of steatorrhea in about 20%-50% of patients. In children, the principal diseases associated with steatorrhea and malabsorption are celiac disease and cystic fibrosis of the pancreas. In adults, the most common causes are tropical sprue, nontropical sprue (the adult form of celiac disease), and pancreatic insufficiency. The clinical picture of all these diseases is roughly similar but varies according to etiology, severity, and duration. The most common chief complaints in severe malabsorption are diarrhea and weakness, weight loss, and mild functional GI complaints (anorexia, nausea, mild abdominal pain). Physical findings and laboratory test results tend to differ with the various etiologies. In severe cases of sprue, tetany, bone pain, tongue surface atrophy, and even bleeding may be found. Physical examination may show abdominal distention and also peripheral edema in nearly half the patients. In pancreatic insufficiency, physical examination may be normal or show malnutrition. Neurologic symptoms are found with moderate frequency in pernicious anemia but may be present in malabsorption of other causes as well.

    Laboratory findings. Laboratory test findings vary according to severity and etiology of the malabsorption, but in sprue they most often include one or more of the following: anemia, steatorrhea, hypoproteinemia, hypocalcemia, and hypoprothrombinemia. In pancreatic insufficiency, the main laboratory test abnormalities are steatorrhea and decreased carbohydrate tolerance (sometimes overt diabetes). In pernicious anemia the patient has only anemia without diarrhea, steatorrhea, or the other test abnormalities previously listed. Most stomach operations do not cause diarrhea or abnormalities of fat absorption.

    Steatorrhea is caused by excess excretion of fat in the stools due to inability to absorb lipids. Anemia associated with steatorrhea is most often macrocytic but sometimes is caused by iron deficiency or is a mixed type due to various degrees of deficiency of folic acid, vitamin B12, and iron. Calcium may be decreased both from GI loss due to diarrhea and from artifact due to hypoalbuminemia. Prothrombin formation by the liver is often impaired to some degree because of lack of vitamin K. Vitamin K is a fat-soluble vitamin that is obtained from food and also is produced by bacteria in the small bowel. Long-term oral antibiotic use may reduce the bacterial flora by killing these bacteria and thus may interfere with vitamin K formation. Inability to absorb fat secondarily prevents vitamin K and vitamin A, which are dependent on fat solubility for intestinal absorption, from entering the bloodstream. Malnutrition resulting from lack of fat and carbohydrate absorption leads to hypoalbuminemia because of decreased production of albumin by the liver. This also contributes to the peripheral edema that many patients develop.

    Classification of Malabsorptive Disorders (With Comments on Occurrence and Associated Abnormalities)

    I. Inadequate mixing of food with bile salts and lipase. Mild chemical steatorrhea common, but clinical steatorrhea uncommon. Actual diarrhea uncommon. Anemia in approximately 15%-35%; most often iron deficiency, rarely megaloblastic.
    A. Pyloroplasty
    B. Subtotal and total gastrectomy (occasional megaloblastic anemias reported)
    C. Gastrojejunostomy
    II. Inadequate lipolysis — lack of lipase or normal stimulation of pancreatic secretion. Steatorrhea only in far-advanced pancreatic destruction, and diarrhea even less often.
    A. Cystic fibrosis of the pancreas
    B. Chronic pancreatitis
    C. Cancer of the pancreas or ampulla of Vater
    D. Pancreatic fistula
    E. Severe protein deficiency
    F. Vagus nerve section
    III. Inadequate emulsification of fat — lack of bile salts. Clinical steatorrhea uncommon, sometimes occurs in very severe cases. Usually no diarrhea.
    A. Obstructive jaundice
    B. Severe liver disease
    IV. Primary absorptive defect—small bowel.
    A. Inadequate length of normal absorptive surface; unusual complication of surgery
    1. Surgical resection
    2. Internal fistula
    3. Gastroileostomy
    B. Obstruction of mesenteric lymphatics (rare)
    1. Lymphoma
    2. Hodgkin’s disease
    3. Carcinoma
    4. Whipple’s disease
    5. Intestinal tuberculosis
    C. Inadequate absorptive surface due to extensive mucosal disease; except for Giardia infection and regional enteritis, most of these diseases are uncommon; steatorrhea only if there is extensive bowel involvement
    1. Inflammatory
    a. Tuberculosis
    b. Regional enteritis or enterocolitis (diarrhea very common)
    c. Giardia lamblia infection (diarrhea common; malabsorption rare)
    2. Neoplastic
    3. Amyloid disease
    4. Scleroderma
    5. Pseudomembranous enterocolitis (diarrhea frequent)
    6. Radiation injury
    7. Pneumatosis cystoides intestinalis.
    D. Biochemical dysfunction of mucosal cells
    1. “Gluten-induced” (steatorrhea and diarrhea very common)
    a. Celiac disease (childhood)
    b. Nontropical sprue (adult)
    2. Enzymatic defect
    a. Disaccharide malabsorption (diarrhea frequent symptom)
    b. Pernicious anemia (deficiency of gastric “intrinsic factor”)
    3. Cause unknown; uncommon except for tropical sprue (which is common only in the tropics)
    a. Tropical sprue (diarrhea and steatorrhea common)
    b. Severe starvation
    c. Diabetic visceral neuropathy
    d. Endocrine and metabolic disorder (e.g., hypothyroidism)
    e. Zollinger-Ellison syndrome (diarrhea common; steatorrhea may be present)
    f. Miscellaneous
    V. Malabsorption associated with altered bacterial flora (diarrhea fairly common)
    1. Small intestinal blind loops, diverticula, anastomoses (rare)
    2. Drug (oral antibiotic) administration (infrequent but not rare)

    The majority of patients with malabsorption usually present in one of two ways. In the first group the major finding on admission is anemia, and once malabsorption is suspected, either by the finding of megaloblastic bone marrow changes or by other symptoms or signs suggestive of malabsorption, the problem becomes one of differentiating pernicious anemia from other types of malabsorption. In the second group, the patients present with one or more clinical symptoms of malabsorption, either mild or marked in severity. The diagnosis must be firmly established and the etiology investigated. There are several basic tests for malabsorption which, if used appropriately, usually can lead to the diagnosis and in some cases reveal the cause.

    Useful individual laboratory tests

    Qualitative fecal fat. Fat in the feces can be stained with Sudan III dye. Neutral fat can be seen as bright orange droplets, but the fatty acids normally do not stain. Both these fatty acids and the original neutral fat can be converted to stainable fatty acids by heat and acid hydrolysis. The preparation is then stained and examined a second time to determine if the number of droplets has increased from the first examination. The reliability of this procedure is debated in the literature, but it is reported to be reasonably accurate if the technician is experienced. However, it is sometimes difficult to be certain whether Sudan-positive droplets are fat or some other substance. Naturally, there will be difficulty in distinguishing normal results from low-grade steatorrhea. It is possible to get some idea of etiology by estimating the amount of neutral fat versus fatty acid: lack of fatty acid suggests pancreatic disease.

    Quantitative fecal fat. The basic diagnostic test for steatorrhea is quantitative fecal fat. Stool collections are taken over a minimum of 3 full days. The patient should be on a diet containing approximately 50-150 gm/day of fat (average 100 gm/day) beginning 2 days before the test collection. It is necessary to make sure that the patient is actually eating enough of this diet to take in at least 50 gm of fat/day; it is also obviously important to make sure that all the stools are collected and the patient is not incontinent of feces. Patient noncompliance with complete stool collection is probably the most common cause of false negative results. If the patient is constipated (and some are), it may be necessary to use a bedtime laxative. Normal diet results in an average excretion of less than 7 gm of fat/24 hours. Excretion of 5-7 gm/24 hours is equivocal, since many patients with minimal steatorrhea and a small but significant percentage of normal persons have excretion in this range. There are some reports that 24-hour fecal fat excretion less than 9.5 gm/100 gm of stool favors nontropical sprue and celiac disease, whereas excretion greater than 9.5 gm/100 gm of stool favors pancreatic insufficiency, bacterial overgrowth, or biliary tract disease. Finally, some patients with partial or complete malabsorption syndromes may have normal fecal fat excretion. This is most common in tropical sprue.

    Plasma carotene. Carotene is the fat-soluble precursor of vitamin A and is adequately present in most normal diets that contain green or yellow vegetables. Normal values are considered 70-300 µg/100 ml (1.3-5.6 µmol/L). Values of 30-70 µg/100 ml are usually considered moderately decreased, and levels less than 30 µg/100 ml (0.56 µmol/L) indicate severe depletion. Other causes of low plasma carotene, besides malabsorption, are poor diet, severe liver disease, and high fever. There is considerable overlap between the carotene values of malabsorption and the carotene values in normal control patients, but such overlap usually is over the 30-µg level. However, this test is valuable mostly as a screening procedure. The patient must be eating a sufficient quantity of carotene-rich food to draw valid conclusions from a low test result.

    X-ray examination. A small bowel series is done by letting barium pass into the small intestine. There are several changes in the normal radiologic appearance of the small bowel that are suggestive of malabsorption. These changes appear in 70%-90% of patients, depending on the etiology and severity of the disease and the interpretative skill of the investigator. The radiologic literature agrees that many chronic diseases, especially when associated with fever and cachexia, may interfere with digestion so severely as to produce a pattern that may be confused with sprue. Secondary malabsorption cannot be distinguished from primary malabsorption except in certain rare cases such as tumor. The so-called diagnostic patterns of sprue are thus characteristic of, but not specific for, primary small intestine absorption and are not present in about 20% of patients.

    Schilling test. This is the classic test for vitamin B12 malabsorption, since it can differentiate pernicious anemia from other malabsorption etiologies affecting the terminal ileum where B12 is absorbed. This is discussed in Chapter 3.

    D-xylose test. Besides quantitative (fecal) fat studies, the most important test for malabsorption is the D-xylose test. Rather than a screening test for malabsorption per se, it is a test that identifies the sprue-type diseases and differentiates them from other malabsorption etiologies. Originally, an oral glucose tolerance test (OGTT) was used in malabsorption, since it was found that most patients with sprue showed a flat curve. A “flat” OGTT is usually defined as an OGTT peak with a value no greater than 25 mg/100 ml (1.4 mmol/L) above the baseline fasting level, although there is some disagreement about this criterion. However, some patients with obvious malabsorption have a normal curve, and it was also found in several large series that up to 20% of apparently normal persons had a flat curve, so this test was abandoned.

    Test protocol. D-xylose is a pentose isomer that is absorbed in much the same manner as glucose from the jejunum. The standard test dose is 25 gm of D-xylose in 250 ml of water, followed by another 250 ml of water. The patient is fasted overnight, since xylose absorption is delayed by other food. After the test dose, the patient is kept in bed for 5 hours without food. The normal person’s peak D-xylose blood levels are reached in approximately 2 hours and fall to fasting levels in approximately 5 hours. D-xylose is excreted mostly in the urine with approximately 80%-95% of the excretion in the first 5 hours and the remainder in 24 hours. Side effects of oral D -xylose administration are mild diarrhea and abdominal discomfort in a small number of patients.

    Interpretation. Normal values for (2-hour) blood D-xylose levels are more than 25 mg/100 ml (1.66 mmol/L); values of 20-25 mg/100 ml are equivocal, and values less than 20 mg/100 ml (1.33 mmol/L) are strongly suggestive of malabsorption. The 5-hour urinary D-xylose normal values are more than 5 gm/5 hours. It is obviously very important to make sure that urine collection is complete and that there is no fecal contamination of the urine. A catheter may have to be used if the patient is incontinent of urine or if there is a question of fecal contamination, but catheterization should be avoided if at all possible. Two main physiologic circumstances may affect the 5-hour urinary excretion: renal insufficiency and advanced age. There may be abnormally low 5-hour urinary excretion of D-xylose in persons over age 65. However, one study claims that the 24-hour urine collection is normal (also >5 gm) unless actual malabsorption is present. If the serum creatinine level is borderline or elevated, the 5-hour urinary D -xylose excretion is also likely to be abnormally low, and again the 24-hour excretion may be useful. In these cases, however, the 2-hour blood levels may help, because they should be normal and are not affected by age or renal insufficiency. Otherwise, the 5-hour urinary excretion is more reliable than the blood levels, which tend to fluctuate.

    Clinical correlation. The D-xylose test may be helpful in determining if the patient has malabsorption and also provides some clues as to etiology. Most patients with cystic fibrosis and pancreatic insufficiency are said to have normal urinary D-xylose values. This is also true of most patients with liver disease. Patients with classic pernicious anemia have normal D-xylose test results, although it must be remembered that many of these patients are aged and for that reason may have low 5-hour urine results. Some patients with megaloblastic anemia of pregnancy have abnormal D-xylose test results, although probably the majority have normal values. A small percentage of patients with partial gastrectomy reportedly have abnormal urine values. Patients with functional diarrhea and duodenal ulcer have normal results.

    In malabsorption diseases, there is excellent correlation of D-xylose excretion with proved sprue and celiac disease. The urine results are more often clear-cut than the blood levels. There is no correlation with the degree of steatorrhea. Patients with regional enteritis involving extensive areas of the jejunum may have abnormal results, whereas normal results are associated with this disease when it is localized to the ileum. Patients with Whipple’s disease, “blind loop” syndrome (isolated small intestine area of bacterial overgrowth), postgastrectomy, small intestine lymphoma, multiple jejunal diverticula, and some infants with cow’s milk allergy may also have abnormal results. Certain patients with diseases other than classic malabsorption may have an abnormal D-xylose test result. These diseases include myxedema, diabetic neuropathic diarrhea, rheumatoid arthritis, acute or chronic alcoholism, and occasionally severe congestive heart failure. Ascites is reported to produce abnormal urine excretion with normal plasma levels. Although D-xylose excretion is frequently depressed in myxedema, abnormal test results occur in only a small number of patients with the other conditions listed. Some of these conditions can produce decreased absorption of substances other than D-xylose, although such problems are usually mild or moderate in degree and may be due to multiple factors.

    D-xylose tests thus may be abnormal in diseases other than sprue. In nontropical sprue, about 10% of untreated patients have normal D-xylose 5-hour urine test results (literature range, 0%-40%). There is also sufficient overlap in the urine excretion range of 4-5 gm/5 hours from persons without primary small intestine malabsorption to warrant routine collection of a 19-hour urine specimen immediately following the 5-hour specimen (to have a total of 24 hours, if necessary). Several studies found better results in children less than 12 years old using a 5-g oral dose of D-xylose and obtaining a serum specimen (no urine specimen) 1 hour after D-xylose administration. The lower limit of serum reference range was 20 mg/100 ml.

    Hydrogen breath test. An oral test dose of a specific carbohydrate is administered. If the carbohydrate is not absorbed normally in the small intestine, it reaches the colon, where bacteria metabolize the carbohydrate and release various metabolic products, among which is hydrogen gas. About 15%-20% of the hydrogen is absorbed and then released from the lungs in expired air. Expired air is collected in a single-breath collection bag or other apparatus and analyzed for hydrogen content by some variant of gas chromatography. This technique has been used to test for various types of malabsorption. It has proved most useful in diagnosis of deficiency involving the enzyme lactase, small intestine “blind loop” syndrome, and some cases of rapid intestine transit (“intestinal hurry syndrome”). In the case of the blind loop syndrome or rapid transit, the test dose consists of a carbohydrate that normally is not absorbed. The hydrogen breath test has not proved reliable in diagnosis of sprue or glutin-associated malabsorption.

    There are various conditions that interfere with the test. Recent use of antibiotics can affect the bacterial flora, sometimes when discontinued as long as 2 weeks before the test. Use of colon enemas can partially wash out some of the flora. Delayed or unusually swift gastric emptying can change the quantity of the carbohydrate or the time that it reaches the colon. Breath collected during sleep contains 2-3 times the amount of hydrogen obtained when the patient is awake. Cigarette smoking produces large amounts of hydrogen. Finally, the collection apparatus and the analysis equipment are relatively expensive, and the test is usually available only in larger institutions or medical centers.

    Small intestine biopsy. In classic sprue, both tropical and nontropical, the mucosa of the small intestine shows characteristic histologic abnormalities. Instead of the normal monotonous fingerlike villous pattern, the villi are thickened and blunted, with flattening of the cuboidal epithelium, and the villi may eventually fuse or disappear altogether. Depending on the degree of change in the villi, biopsy results may show moderate or severe changes. These same changes may be found to a much lesser degree in many of the other conditions causing malabsorption, including even subtotal gastrectomy. However, these usually are not of the severity seen in sprue and generally can be differentiated by the clinical history or other findings. Other causes of malabsorption, such as the rare Whipple’s disease (which characteristically shows many periodic acid-Schiff-positive macrophages in the mucosa) may be detected on biopsy. In infants less than 1 year of age, transient small intestinal mucosal abnormalities similar to those of sprue have been reported in some patients with acute gastroenteritis and in some with cow’s milk allergy. Eosinophilic gastroenteritis is another cause in older children.