ACP medicine, 3rd Edition


Diseases Producing Malabsorption and Maldigestion

Charles M. Mansbach II MD1

Professor of Medicine and Physiology and Chief

1Division of Gastroenterology, Department of Medicine, University of Tennessee, Memphis, College of Medicine

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

November 2006


Malabsorption classically means the impaired absorption of fat (steatorrhea), because fat absorption is the best indicator of the normality of the overall process of nutrient absorption. Under certain conditions, however, fat absorption may be normal but other specific substances may be poorly absorbed, such as iron, calcium, bile salts, or, in certain hereditary conditions, specific amino acids, disaccharides, or monosaccharides.

Overview of Diseases Producing Malabsorption


There are three principal causes of fat malabsorption: small bowel disease, liver or biliary tract disease, and pancreatic exocrine insufficiency [see Table 1].

Table 1 Causes of Malabsorptive Syndromes

Diseases of the small intestine

Gluten-sensitive enteropathy
Tropical sprue
Collagenous sprue
Eosinophilic enteritis
Radiation enteritis
Whipple disease
Intestinal lymphangiectasia
Immunoproliferative small intestinal disease
Ischemic bowel disease
Giardia lamblia infection
Short bowel syndrome
Ileal resection
Ileitis (e.g., Crohn disease)

Diseases of the liver and biliary tract

Cirrhosis/parenchymal liver disease
Intrahepatic cholestasis syndrome
Cholestasis due to extrahepatic obstruction

Diseases of the pancreas

Chronic pancreatitis
Cystic fibrosis

Combined or multiple defects in digestion and absorption

Diabetes mellitus
Carcinoid syndrome
Zollinger-Ellison syndrome
Postgastrectomy (Billroth II type)

Small Bowel Disease

Small bowel disease can result in moderate amounts of fat in the stool (7 to 30 g/day on a diet containing 100 g of fat). Patients with small bowel disease may leak protein (protein-losing enteropathy) through a diseased intestinal mucosa, which results in a reduced serum albumin concentration. Deficiencies of fat-soluble vitamins (i.e., vitamins A, D, E, and K) may occur in small bowel disease. Severe disease or surgical resection (usually over 60 cm) of the terminal ileum may result in malabsorption of vitamin B12. Folic acid may also be malabsorbed, and hypocalcemia and hypomagnesemia may also be present.

Liver or Biliary Tract Disease

Patients with liver or biliary tract disease usually have only small increases in fat in the stool (7 to 15 g/day) and may also malabsorb fat-soluble vitamins. The association of cholestatic liver disease, especially primary biliary cirrhosis, with osteoporosis is well known. Osteoporosis may be the presenting symptom of the liver disease. Vitamin K deficiency, as manifested by a prolonged prothrombin time, may also occur. Administration of vitamin K corrects the clotting defect, provided that the liver disease is not severe enough to impede clotting factor synthesis.

Pancreatic Exocrine Insufficiency

Patients with pancreatic exocrine insufficiency may have up to 80 g of fat/day in the stool. Any fat absorption that does take place occurs through the action of gastric lipases. Gastric lipase is present in the chief cells of the human stomach1 and is thought to account for any lipid absorbed in the setting of chronic pancreatitis, as exemplified by cystic fibrosis. Indeed, in cystic fibrosis, an increase in gastric lipase has been reported.2


The symptoms of malabsorption are protean. In the most obvious case, the patient complains of weight loss despite a good appetite. In these cases, there is a clear change in the quality of the stool and usually an increase in stool number. Because of excess fat and gas,3 the stool becomes softer in consistency, more malodorous, buoyant, and difficult to flush down the toilet. Oil drops or a lipid sheen may appear on the water. Depending on other dietary constituents that are malabsorbed, patients may experience a distended abdomen, borborygmi, abdominal cramps (lactose intolerance), easy bruising (vitamin K deficiency), osteopenia or tetany (vitamin D deficiency and calcium malabsorption), iron deficiency, or night blindness (vitamin A deficiency). The most challenging cases are those in which the possibility of malabsorption is not raised because the quality of the stools does not change.

The diarrhea of malabsorption is classified as osmotic and usually stops during fasting. In fat malabsorption, the diarrhea is caused not only by the excessive osmotically active particles but also by fatty acids, which stimulate cyclic adenosine monophosphate (cAMP)-dependent Cl-secretion.

Specific physical findings of various diseases may accompany the malabsorptive state and assist in making the diagnosis. For example, the skin changes of scleroderma or dermatitis herpetiformis may be present. Signs of diabetic neuropathy may be disclosed. Although thyrotoxicosis may be associated with excessive fat in the stool, patients with thyrotoxicosis usually eat gluttonously but absorb a normal percentage of dietary fat eaten (95%) and therefore do not malabsorb in the true sense.


The tests for malabsorption involve determining whether there is excessive fecal fat excretion [see Table 2]. Protein is produced in large quantities by the digestive tract, especially the pancreas, making creatorrhea difficult to interpret. Malabsorbed carbohydrate delivered to the colon may be metabolized by colonic bacteria to short-chain fatty acids, which are in part absorbed by the colon. Thus, the quantitative measurement of carbohydrate absorption is inaccurate, although a fall in stool pH occurs, which is indicative of excessive amounts of the short-chain fatty acids that are excreted under these conditions.

Table 2 Tests of Digestive-Absorptive Function



Clinical Use

Fecal fat analysis


Simple microscopic study for increase in fat globules

Chemical analysis for fat excretion during a 72 hr period by titration with NaOH; most sensitive test for malassimilation of fat; normal is < 6 g/day; does not distinguish between small intestine, pancreatic, or luminal abnormalities

A good screening test for moderate increase in stool fat, but quantitative fecal fat analysis is preferable
The most important test to identify maldigestion or malabsorption; indicated in all patients suspected of having malassimilation

Xylose absorption

As a pentose not requiring luminal or intestinal surface digestion, xylose allows assessment of small intestine function; normally, > 4 g/5 hr is excreted in urine after ingestion of 25 g; plasma xylose should be 10–20 mg/dl/1.73 m2 of body surface area at 60–75 min

Indicated whenever quantitative fecal fat is abnormal; not as sensitive as fat analysis but localizes the abnormality to the small intestine

Small intestine x-ray

Allows analysis of continuity of small intestine and identification of diverticula or alteration of mucosa; diseased pancreas may impinge on duodenum

Indicated when quantitative fecal fat excretion is increased

Small intestine peroral biopsy

Permits direct histologic examination of mucosa; characteristic alterations occur in several diseases producing malabsorption

Indicated when fecal fat excretion is increased, particularly if the xylose test or small intestine x-ray is abnormal; a portion of biopsy may be assayed for disaccharidases

Bile acid breath test

In small intestine bacterial overgrowth or ileal disease that produces malabsorption, 14C-glycocholic acid (5 µCi) will be deconjugated, metabolized, and excreted via the lungs as 14CO2

Indicated in patients with documented steatorrhea caused by suspected bacterial overgrowth or ileal dysfunction

Bentiromide test

The peptide bond in this nonabsorbable arylamine is cleaved specifically by intraluminal chymotrypsin to yield PABA, which is then readily absorbed and excreted by the intestine

Indicated when fecal fat excretion is increased; less sensitive than quantitative fat analysis but, when positive, establishes insufficiency of intraduodenal pancreatic digestive enzyme levels
Not available in U. S.

PABA—P-aminobenzoic acid

Measurement of Fecal Fat

Fecal fat can be measured qualitatively and quantitatively. The qualitative measurement of fecal fat using Sudan III staining and microscopy has been shown to be surprisingly accurate,4 especially if clinically significant amounts of fat are being excreted. The skill of the microscopist is crucial to success. The quantitative measurement of fecal fat is the benchmark by which all other tests are ranked. It is important to remember that the stool must be collected for 3 days. Carmine dye-containing capsules are ingested at the start of the study and 3 days later. Stool collection is begun after the passage of the first red stool and stops when the second wave of red stool is passed. The test cannot be performed unless the patient is able to eat at least 80 g, preferably 100 g, of fat a day. An alternative is the acid steatocrit, in which homogenized stool is mixed with perchloric or hydrochloric acid and the percentage of stool occupied by the fatty layer after centrifugation is calculated. A newer method for measuring fecal fat, not widely available, is near infrared reflectance analysis (NIF).5

D-Xylose Absorption Test

The absorptive surface area of the intestine is measured by the ability of the patient to absorb the sugar xylose. Unlike glucose, xylose is not actively absorbed by the intestine but is absorbed by the slower process of passive diffusion. In the D-xylose absorption test, 25 g of D-xylose is given by mouth and the urine is collected for 5 hours. The normal urinary excretion of xylose is greater than 4 g over 5 hours. For an adequate urinary flow to be ensured, the patient should drink 500 ml of water after drinking the xylose. This intake should result in a urine volume of at least 300 ml during the collection period. Xylose excretion can be falsely low in patients with reduced renal function or in patients with ascites in which the xylose is diluted in the ascitic fluid. To avoid falsely low results, it is advisable to measure the concentration of xylose in blood [see Table 2]. Malabsorbed xylose reaches the colon and can be metabolized by the resident bacteria to hydrogen. Hydrogen may be quantitated in the breath; this test is reportedly as accurate as the measurement of xylose in the serum or urine.

Imaging Studies

A plain film or ultrasonogram of the abdomen is usually not helpful in most cases of malabsorption. However, 30% of patients with chronic pancreatitis have visible calcifications on an abdominal plain film. Detection of pancreatic calcification can be increased if computed tomography or ultrasonography is used. CT or ultrasonography also can identify dilated pancreatic ducts, another characteristic sign of chronic pancreatitis. Endoscopic retrograde pancreatography (ERP) can also be helpful when ductular changes indicative of chronic pancreatitis are seen [see 4:V Diseases of the Pancreas] as can magnetic resonance cholangiopancreatography (MRCP).

Radiographic studies of the small intestine after oral ingestion of barium can aid in the diagnosis of several abnormalities. The presence of diverticula of the small intestine or of impaired peristalsis, as seen in scleroderma or idiopathic intestinal dysmotility, can be an indicator of bacterial overgrowth. A careful examination of the terminal ileum can identify Crohn disease. Strictures may be identified in some patients with radiation injury or injury caused by nonsteroidal anti-inflammatory drugs. Hypoalbuminemia affecting the small intestine may lead to thickening of small bowel folds and the so-called stack-of-coins sign.

Small Bowel Biopsy

A biopsy sample of the small bowel, read by an experienced pathologist, may be helpful in determining the cause of malabsorption. Biopsy results can support the diagnoses of gluten-sensitive enteropathy (with or without dermatitis herpetiformis), hypogammaglobulinemic sprue, tropical sprue, Whipple disease, Mycobacterium avium complex disease, stasis (bacterial overgrowth) syndrome, amyloidosis, and intestinal lymphangiectasia.

Assessment of Pancreatic Exocrine Function

More than 90% of pancreatic exocrine function needs to be destroyed before symptomatic malabsorption results [see 4:V Diseases of the Pancreas].6 The most sensitive test of pancreatic exocrine function requires the passage of a double-lumen tube.7 Cholecystokinin (CCK) or secretin is administered intravenously, and gastric and duodenal secretions are collected separately. However, secretin has been unavailable in the United States since 1999, when the manufacturer discontinued production. If CCK is given, lipase or trypsin activity is determined using appropriate substrates. When secretin is administered, duodenal fluid volume and bicarbonate concentration are measured.

The noninvasive bentiromide test is based on the action of trypsin on bentiromide to yield p-aminobenzoic acid (PABA) and benzoyl-tyrosine. PABA is readily absorbed by the intestine and excreted into the urine. In healthy persons, when 500 mg of bentiromide is ingested, 57% or more of the PABA appears in the urine within 6 hours. In patients with chronic pancreatitis, the absence of trypsin results in failure to cleave bentiromide, and consequently the amount of PABA excreted is significantly less, averaging 42%. Using the 57% excretion as a cutoff, the sensitivity is 67% to 80% and the specificity is 95%.8 PABA may also be measured in the plasma 120 minutes after ingestion of bentiromide, which may enhance the sensitivity of the test.9 Plasma measurements are helpful in patients with impaired renal excretion (e.g., some elderly patients). Because PABA is identified colorimetrically, the presence of other arylamines (e.g., acetaminophen, lidocaine, procainamide, sulfonamides, and thiazide diuretics) can interfere with its determination.10 Impaired intestinal absorption, such as with sprue, may reduce the absorption of released PABA, leading to a falsely low urinary recovery (a false positive result). Unfortunately, the bentiromide test remains normal when less than 90% of the pancreatic gland is destroyed (a false negative result). Nevertheless, the test may be useful in the workup of a patient with steatorrhea, because steatorrhea does not develop until an equal amount of glandular destruction has occurred.

Although the vast majority of pancreatic proteases and lipases are stored in zymogen granules and are released from the apical portion of the pancreatic exocrine cell into the pancreatic duct, a small percentage leaks into the interstitium of the gland, is carried into the circulation, and can be measured (i.e., by the serum trypsinogen assay). Because the activation peptide of trypsin is not yet released and any active trypsin is quickly bound by α1-antitrypsin, the free-circulating form of trypsin is trypsinogen. In patients who have chronic pancreatitis with exocrine insufficiency, the serum concentration of trypsinogen is lower than in healthy persons (2 to 18 ng/ml, compared with 29 to 79 ng/ml in healthy persons).11 A low serum trypsinogen level appears to have a high degree of specificity for chronic pancreatitis but is only modestly sensitive. Measurement of the fecal concentration of pancreatic elastase 1 has a high degree of sensitivity (> 90 %) for patients with moderate to severe pancreatic exocrine function, as judged by the secretin-CCK test in both adults12 and children.13

Bile Acid Absorption Tests

Bile acids are synthesized from cholesterol in the liver and require conjugation by either glycine or taurine before they are excreted into the intestine via the common bile duct. These bile acid conjugates solubilize the products of triacylglycerol hydrolysis into complex micelles, which facilitate the rapid absorption of dietary lipid. Bile acids are not absorbed in the proximal intestine with dietary lipid but, rather, are absorbed in the distal ileum. The bile acid pool recirculates six times a day. About 95% of bile acids are reabsorbed and recirculate in the enterohepatic circulation each day; approximately 0.5 g of bile acids appears in the stool daily, which equals the hepatic synthesis rate under steady-state conditions. If bile acids are not adequately absorbed, diarrhea results (choleretic enteropathy). In the complete absence of bile salts, fatty acids are less efficiently absorbed, with up to 25% to 50% of ingested lipid appearing in the stool. In patients with idiopathic diarrhea or with diarrhea after ileal resection (≥30 cm), the malabsorption of bile acids is an etiologic possibility. Also, children who have unexplained diarrhea may have a congenital defect of the sodium-dependent bile salt transporter in the terminal ileum.14

To test for the presence of bile acid malabsorption, two methods are available, although they are not widely used. The first is the 14C-glycocholic acid breath test, and the second is the selenium-75-labeled homocholic acid-taurine (75SeHCAT) absorption test. In the former test [see Figure 1], a trace amount of 14C-glycocholic acid is given by mouth. Many bacteria are capable of hydrolyzing the amide bond and releasing the 14C-glycine; either it is absorbed and 14CO2 is produced in the liver, or it is further metabolized in the intestinal lumen to14CO2. In either event, the 14CO2 appears in the breath in measurable amounts. The percentage of the ingested dose excreted in the breath increases if there is intestinal stasis, in which case the intestinal lumen contains more bacteria than normal, or ileal dysfunction, in which case an excess of bile acids is delivered to the colon. A gastric antisecretory drug may also increase the resident population of bacteria in the intestine to a level that results in an abnormal breath test.15 The usefulness of this test as an indicator of bile acid malabsorption is therefore limited. The 75SeHCAT test has more potential clinical usefulness because of its strong correlation with cholate excretion and the ease of measurement of 75Se retention by the whole-body gamma camera. Normal persons retain greater than 19% of an orally administered dose of 75Se after 7 days, whereas patients with significant ileal dysfunction or resection retain less than 12%.16


Figure 1In the bile acid breath test, a small dose of 14C-glycocholic acid is ingested and its fate determined by measurement of 14CO2 excretion in breath. In a normal person, little of the 14C-glycocholic acid is metabolized for excretion in breath because it passes intact to the ileum for absorption and return to the enterohepatic circulation. If there is either intestinal bacterial overgrowth or ileal dysfunction, however, bacterial enzymes will deconjugate the bile acid (broken blue lines), releasing cholic acid and 14C-glycine. The radioactive glycine may be transported across the intestinal mucosa (upper broken gray line) and subsequently degraded to 14CO2 by tissue enzymes; alternatively, the 14C-glycine may be metabolized within the intestinal lumen to 14CO2, which then diffuses (lower broken gray line) into the circulation and is carried to the lungs. Consequently, 14CO2 excretion is 10 times greater in either intestinal bacterial overgrowth or ileal dysfunction than it is in the normal state.

Now that the human sodium-dependent bile acid transporter has been cloned, congenital defects are being discovered that lead to bile acid malabsorption resulting in diarrhea.14 Such defects may be the cause of primary bile acid malabsorption.

Tests for Short Bowel Syndrome

The length of bowel remaining after intestinal resection can be measured at surgery or after a barium small bowel follow-through x-ray examination. Another method that predicts small bowel function (with 95 % positive predictive value) is the measurement of the nonprotein amino acid citrulline with a cutoff value of 20 µmol/L.17

Small Bowel Diseases Producing Malabsorption


Gluten-sensitive enteropathy (GSE) was once called celiac disease in children and idiopathic or nontropical sprue in adults. In 1960, it was recognized that the diseases are the same, caused by the major wheat protein gluten and, more specifically, its alcohol-soluble component, gliadin.18 Current data from serum antibody testing in both adults and children suggest that the prevalence of GSE is much higher than originally thought (1:133 to 1: 250),19,20,21 although in many affected persons, there is no clinical expression.

Genetic and Etiologic Factors

GSE is associated with haplotypes HLA-DQ2 (DQA1*501, DQB1*201) and HLA-DQ8 (DQA1*031, DQB1*302). Another, unknown (nongenetic) factor appears to be important in disease causation, however, given that concordance for GSE in monozygotic twins is only about 70%. A 33-amino acid peptide part of gliadin has been shown to be poorly digested by proteases and to cause T cell activation in GSE patients.22,23This may be partly because of the impaired intracellular digestion of gliadin peptides by patients with active GSE but not those with treated GSE.24

Pathogenesis of Steatorrhea

The causes of steatorrhea in GSE are many. CCK cells are either reduced in number or so defective that the amount of CCK present in the duodenal mucosa is greatly reduced.18 This CCK deficiency leads to a reduced amount of pancreatic lipase and bile acids delivered to the intestinal lumen in response to dietary lipid. The intestinal crypt cells are the major fluid-secreting cells of the intestine, via their cAMP-dependent Cl- secretion with attendant water secretion. In GSE, the cryptal portion of the villous complex is greatly expanded, leading to increased water secretion. Because the villous tip cells, which normally absorb the water, are diseased and reduced in number, water and electrolyte absorption is impaired, and the intestine becomes secretory.18 Thus, the concentration of bile acids in the intestinal lumen is reduced below that expected simply from the impaired CCK release. The ability of bile acids to solubilize the products of lipolysis depends on the presence of bile salts at a concentration greater than their critical micellar concentration (CMC) of 1.4 mM.25 Normally, the intestine has a postprandial bile salt concentration of 10 mM.26 The brush borders at the surface of mature enterocytes are severely affected in GSE. Further, the villous structures are flattened. These two conditions lead to a severely reduced surface area that limits lipid absorption. The amount of reduction in surface area can be estimated by the D-xylose absorption test. The enterocytes that are at the surface of the intestine are not as mature as normal enterocytes, because their turnover rate is greatly increased, which probably results in a reduced capacity to process absorbed lipid.


Clinical manifestations

Although GSE may start in childhood and respond to gluten withdrawal, children with the disease undergo a remission in their teenage years even if they ingest a diet containing gluten. As adults, these patients, 25% or more of whom were symptomatic in childhood, may present with a variety of complaints. Usually, weight loss, fatigue, abdominal cramps, distention, bloating, and diarrhea (steatorrhea) are prominent, although there may be no loss of appetite. In some patients, the disease is insidious in onset and the symptoms are mild. It is only after these patients have been treated that they realize, in retrospect, how ill they were. In population studies in which the presence of disease was determined by intestinal biopsy, patients whose biopsy result was consistent with GSE were often asymptomatic but sometimes of shorter stature than unaffected siblings. Because nothing specifically leads to the diagnosis, especially in the absence of clinically evident steatorrhea, the realization that the patient has GSE may be delayed. This problem is most likely to occur with patients who do not have steatorrhea but do have osteoporosis, easy bruising as a result of vitamin K deficiency, or unexplained iron deficiency anemia. Because the classic presenting symptoms of diarrhea, steatorrhea, and weight loss are much less common today than is the insidious onset of GSE, physicians should include GSE in the differential diagnosis in patients with osteoporosis or iron deficiency anemia without an obvious intestinal bleeding site.

Laboratory tests

In a patient in whom the likelihood of GSE is high—such as a first-degree relative of a known GSE patient; a patient who has a history of a childhood disease that caused diarrhea, was evaluated by a specialist, and was treated with a special diet; or a patient with malabsorption who is not an alcoholic and does not have another obvious reason for malabsorbing fat—a positive tissue transglutaminase antibody test makes the diagnosis almost certain [see Figure 2].27 Alternatively, the diagnosis might rest on small bowel biopsy findings [see Figures 3aand 3b]. Classic features include partial or complete villous atrophy, abnormal-appearing enterocytes at the villous tips, an increase in intraepithelial lymphocytes, a lamina propria infiltrate consisting predominantly of lymphocytes and macrophages, an increase in the size of the crypts both vertically and horizontally, and an increase in the number of mitotic figures.18 These features, although typical, are not pathognomonic. For the diagnosis to be definitive, the patient must respond to dietary therapy. Symptomatic improvement can be expected in 80% of patients within 1 month, but histologic improvement lags behind considerably. Another 10% of patients do not respond until 2 months have passed, and the remainder may take up to 2 years. Even with the strictest dietary control, the biopsy findings might not return to normal. Most often, the patients' diets remain under good control because of the symptomatic improvement while on the diet, but many patients will eventually either test whether they are cured or be in a situation that forces them to commit a dietary indiscretion. This lapse inevitably results in recurrence of symptoms, further securing the diagnosis.


Figure 2Procedure for the diagnosis of gluten-sensitive enteropathy (GSE).


Figure 3Biopsy specimen from the small intestine of a patient with untreated celiac sprue (a) demonstrates a flat surface with plasmocytic infiltration of the subepithelial region (magnified 400 times). In contrast, a biopsy sample taken from a patient with pancreatic exocrine insufficiency (b) is indistinguishable from a normal specimen and shows tall, scalloped villi and minimal subepithelial mononuclear infiltration (magnified 100 times).

Another helpful test is the identification of an antiendomysial antibody. This antibody is present in up to 95% of patients and is rarely present in control subjects.28 Other tests of malabsorption, such as the D-xylose absorption test or stool fat studies, may be abnormal. Low levels of clotting factors, anemia caused by folate or iron deficiency, or osteoporosis may also be present. None of these conditions are specific for GSE, however.


The treatment of GSE is a strict gluten-exclusion diet—no wheat, rye, or barley. Oats are thought to be safe but are usually avoided during the early stage, when the clinical response to the diet is being judged. Keeping the patient on the diet is sometimes difficult because many foods have hidden gluten content. In addition to its necessity for controlling symptoms, maintaining a gluten-exclusion diet is important because intestinal lymphomas are more likely to develop in patients who do not.29 Support groups, such as those organized by the American Celiac Society, can be helpful, especially when the disease is newly diagnosed [see]. Information such as what to look for on package labels and recipes for gluten-free dishes can be instrumental in helping the patient maintain the gluten-exclusion diet. During the trial period, patients should not consume beer, ale, or whiskey, which may contain enough gluten to cause sensitization. After a clear dietary response has occurred, patients may try these drinks, if they wish, to determine whether they are sensitive. Other products that are not usually thought of as containing gluten, but often do, are ice cream, communion wafers, and even some drugs (as a filler). Despite the restrictions, many dietary options are open to the patient, including certain breakfast cereals, milk, cheese, eggs, meat, chicken, fish, chocolate, and products made from corn, rice, or potato flour. Patients may also wish to explore less well-known gluten-free grains, such as amaranth, millet, and quinoa.

If the patient does not respond, the most likely reason is failure to follow the diet fully. In such cases, it is helpful to have a dietitian carefully go over the patient's dietary history.18 Less often, the patient will have an intestinal stasis syndrome or pancreatic insufficiency. When these subsidiary problems are diagnosed and successfully treated, the patient usually shows a response to the diet.


Dermatitis Herpetiformis and GSE

Many patients with dermatitis herpetiformis will have GSE.30 The intensely pruritic, blistering lesions appear on the knees, elbows, shoulders, and buttocks [see 2:I Cutaneous Manifestations of Systemic Diseases]. Skin biopsies of dermatitis herpetiformis lesions have characteristic immunoglobulin A (IgA) deposits. On a gluten-exclusion diet, both the dermatologic and the intestinal lesions improve, indicating a linkage between the two. However, the skin lesions respond to dapsone treatment and the intestinal lesions do not, which indicates that there are differences between the two diseases as well.

Tropical Sprue

Tropical sprue is a malabsorptive illness that appears in certain areas of the world, especially the tropics, among both the indigenous populations and tourists. In two carefully studied populations, 5% to 13% of North Americans living in Puerto Rico for 6 months or longer experienced symptoms of tropical sprue. Expatriates from the United States who return from the tropics or other areas endemic for tropical sprue may experience symptoms of tropical sprue more than 10 years after their return.31 Peace Corps volunteers from the United States who spent time in Pakistan had demonstrable small bowel lesions and functional abnormalities that reverted to normal over several months after returning home.32 Indians and Pakistanis living in the United States may take a longer time (up to 4 years) to excrete normal amounts of D-xylose.33 Exactly what causes these changes in the small bowel is not clear, but the tropical sprue syndrome is thought to be caused by one or more species of coliform bacteria, such as Klebsiella species, 25 of which colonize the upper intestinal tract.


The symptoms of tropical sprue differ from those of GSE. Weight loss caused mostly by anorexia is very prominent, as is diarrhea. A sore tongue (70% of patients), pedal edema (25% of patients), folate and vitamin B12 deficiency (75% to 100% of patients), or an abnormal result on the Schilling test (96% to 100% of patients) is much more common in tropical sprue than in nontropical sprue.34 The symptoms can be quite severe, sometimes leading to death in endemic areas. However, the prognosis, in general, is excellent for treated patients, whether they remain in the tropics or return to the United States.

The diagnosis of tropical sprue is made by performing a small bowel biopsy in patients with a compatible clinical presentation and travel history. Villi are leaflike or blunt, and the lamina propria are packed with inflammatory cells [see Figure 4]. Thin villous structures are seen in North Americans and Europeans [see Figures 3a and 3b]. In considering this disease, it should be noted that intestinal biopsy results in residents of endemic areas or in tourists who do not stay in mainstream hotels in endemic areas would be classified as abnormal in persons living in the United States or Europe.


Figure 4In a biopsy specimen from the small intestine of a patient with tropical sprue, villi are broadened and shortened and the crypts are deepened; these changes yield a villus-to-crypt ratio of 1:1 (magnified 100 times).


Treatment of tropical sprue should begin with folic acid (5 mg/day).34 This therapy is associated with rapid improvement in appetite, and it eliminates most of the clinical symptoms. In patients with a short duration of symptoms (less than 4 months), folate given for 6 months to 1 year may suffice. For patients with a longer duration of symptoms (more than 4 months), antibiotics, such as tetracycline (2 g/day for 1 year), should be added. Most patients returning to the United States gain weight quickly even if the results of absorption tests or intestinal biopsies do not return to normal.

Collagenous Sprue

Collagenous sprue is a rare, devastating disease in which there is a layer of collagen underneath the enterocytes of the small bowel. The relation of collagenous sprue to collagenous colitis is unclear, but the basic histologic feature of subepithelial collagen deposition is the same. The origin of collagenous colitis is unknown, but it develops in approximately half the patients who have refractory celiac disease (i.e., those unresponsive to the gluten-exclusion diet).35 Although it is known that type 6 collagen is deposited in the more commonly diagnosed collagenous colitis, the type of collagen laid down in the small bowel in collagenous sprue is unknown. In collagenous colitis, the symptoms (primarily diarrhea) are usually modest, but in collagenous sprue, symptoms are more severe and include obvious malabsorption. This severity of symptoms is probably caused by the diffusion barrier presented by the collagen, which prevents nutrients from diffusing either into the portal capillaries or into the lymphatics.


The diagnosis of collagenous sprue is made by the classic histologic picture of villous atrophy and subepithelial collagen deposition. If the diagnosis is missed, however, and the patient is thought to have GSE on the basis of the flat villous structure, the patient will usually not respond to the gluten-free diet.


Therapy for collagenous sprue is uncertain. The most common problem is the osmotic diarrhea caused by the gross malabsorptive state induced by the disease process. In this event, the patient is treated as if he or she had the short bowel syndrome. Some patients respond to steroid therapy.36 A few respond to steroids and a gluten-exclusion diet, with the patient's improved condition eventually making it possible to taper the steroid dosage.37

Hypogammaglobulinemic Sprue

The gastrointestinal tract is the largest lymphoid organ in the body. The environment to which this immune system is exposed is filled with foreign antigens that must be sorted, identified, and, if necessary, reacted to. Thus, it is not surprising that intestinal dysfunction may develop in patients who are immune deficient, particularly those with IgA deficiency, because IgA is the most important immunoglobulin of the intestine. Some patients who have one of the hypogammaglobulinemic syndromes experience malabsorption.38 Patients with IgA deficiency also usually have a history of recurrent respiratory infections,38 which further distinguishes them from patients who have GSE. The most common cause of malabsorption seen in this condition is giardiasis.


The diagnosis is suspected if the patient has signs and symptoms of malabsorption and low levels of serum immunoglobulins, especially IgA. Intestinal biopsy specimens lack plasma cells and thus are easily distinguishable from those of patients with GSE, in which plasma cell types are abundant. Plasma cells are readily seen in normal biopsy specimens as well. Giardia lamblia organisms may also be present in hypogammaglobulinemic sprue.


Frequently, the intestinal symptoms of hypogammaglobulinemic sprue improve if metronidazole is given at 750 mg/day for 10 days to treat giardiasis.

Malabsorption Secondary to Massive Small Bowel Resection

Massive small bowel resection is used to treat various diseases, including mesenteric ischemia, volvulus, and Crohn disease. Because the intestine requires a certain surface area over which absorption can occur, reducing the area below a critical value results in malabsorption. Depending on the amount of bowel resected, the results can range from mildly inconvenient to catastrophic. Retention of the ileocecal valve lessens symptoms. The ileum responds to jejunal resection by hyperplasia much more effectively than the jejunum responds to an ileal resection. There are also specialized mechanisms present in the ileum that are not available to the jejunum, such as bile salt and vitamin B transporters. The maintenance of an adequate bile acid pool is important for fat absorption because the reduced absorptive surface area in patients who have undergone bowel resection makes it necessary for fat absorption to be as efficient as possible. Alternatively, the ileum can perform most of the functions of the jejunum except for absorption of folic acid, Ca2+, and Fe2+. However, these can be replenished by appropriate supplementation.


The diagnosis is made by history of bowel resection in combination with barium x-ray evidence of a short bowel and clinical manifestations of the short bowel syndrome such as diarrhea, steatorrhea, weight loss, trace-element deficiencies, hyponatremia, and hypokalemia. A low blood citrulline concentration (< 20 µmol/L) is also helpful.17


Treatment in these patients is dependent on what part of the bowel and how much bowel has been resected. Protein requires the greatest surface area for absorption.39 Thus, achieving adequate assimilation may become problematic, despite the water solubility of proteins and their hydrolytic products. Vitamins and minerals also need to be added to any therapeutic regimen, depending on what part of the bowel is missing. Treatment can include eating multiple small meals each day, eating quickly absorbed foods such as canned liquid nutritional supplements, having food finely chopped or ground, and eating foods containing medium-chain triglycerides, which can be absorbed in the absence of bile salts.39 Foods rich in polyunsaturated fatty acids, such as vegetable oils, are more easily absorbed than meats, which have more saturated fat. Finally, completely hydrolyzed dietary supplements are rapidly absorbed. To slow bowel transit, diphenoxylate-atropine, loperamide, or deodorized tincture of opium can be used effectively. An alternative method is to have the patient drink a small amount of safflower oil just before a meal. The lipid quickly goes to the ileum (if present), the colon, or both40 and elaborates peptide YY,41 which is the putative ileal brake, slowing gastric emptying. Having patients try different diets will often enable them to ingest food orally rather than receive total parenteral nutrition, which is less desirable.


Injury of the intestine is an all too common result of delivery of ionizing radiation as oncologic treatment. Injury to the small bowel is more common if the patient has had previous abdominal surgery, which may restrict the movement of the small bowel. The terminal ileum may become involved during pelvic irradiation.


Whipple disease is a rare wasting disease caused by the bacterium Tropheryma whippelii.42 Accurate diagnosis is imperative because mortality approaches 100% without antibiotic treatment.


Clinical manifestations

Classically, Whipple disease begins in a middle-aged man with a nondeforming arthritis that usually starts years before the onset of the intestinal symptoms. Other complaints include fever, abdominal distention, diarrhea, weight loss, lymphadenopathy, hyperpigmentation of the skin, and steatorrhea.43 Many patients express the HLA-B27 isotype. Occasionally, intestinal symptoms are absent, even in some patients with central nervous system involvement.44 In a well-documented but unusual case, intestinal involvement was not identified, even after extensive biopsies in two laboratories, despite the fact that the patient otherwise had typical symptoms of the disease.45 Interestingly, as many as 35% of clinically normal persons may harbor T. whippelii DNA in their saliva46; for that reason, DNA evidence alone, without a clinical component, does not establish a diagnosis of Whipple disease.

Laboratory tests

The recognition of Whipple disease in patients without intestinal symptoms or involvement by the disease is increasing with the advent of polymerase chain reaction (PCR) techniques that identify the unique 16S ribosomal RNA of T. whippelii.47 The diagnosis rests on identifying the classic periodic acid-Schiff (PAS)-positive macrophages, which contain sickleform particles.43 By far the most common site of biopsy that yields positive results is the intestine. The histologic lesion shows distended villi (so-called clubbed villi) filled with the foamy, PAS-positive macrophages and lymphatic dilatation. In extreme cases, the villous surface is flat. These findings need to be differentiated in the appropriate clinical setting from those of M. avium complex disease, in which PAS-positive macrophages are also found. A stain for acid-fast bacilli should differentiate between them. CNS involvement, occasionally associated with typical macrophages in the cerebrospinal fluid, as substantiated by the more sensitive PCR technique, may be present in the absence of neurologic symptoms.48 Occasionally, a brain biopsy is required, which can be guided by magnetic resonance imaging. Cardiac and pulmonary involvement may also be found.49


Because Whipple disease is so uncommon, a well-defined treatment plan is difficult to establish. The originally proposed treatment was penicillin (250 mg q.i.d.) and streptomycin (1 g I.M.) for 2 weeks, followed by tetracycline (1 g) for 1 year. Currently, the regimen typically used consists of trimethoprim-sulfamethoxazole (one double-strength tablet b.i.d.) given for 1 year; this may be preceded by 2 weeks of cephalosporins.50 All antimicrobial agents are used in customary doses.

Although the intestinal and systemic symptoms respond readily to either treatment, the major concern is treatment of CNS manifestations. Usually, in those patients who do not have CNS involvement initially, CNS symptoms may appear a year or more after treatment of the systemic and intestinal symptoms, especially if the antibiotic used is one that does not cross the blood-brain barrier. The pathognomonic signs of CNS Whipple disease, when present, are oculomasticatory myorhythmia and oculofacial-skeletal myorhythmia; progressive dementia may also occur.51 Antibiotics that cross the blood-brain barrier are therefore required. Interestingly, the short period of penicillin-streptomycin administration is enough to block CNS symptoms, whereas even long-term trimethoprim-sulfamethoxazole therapy occasionally fails to prevent CNS manifestations of Whipple disease.52 Tetracycline alone does not eradicate CNS disease and should not be given by itself, even though it is effective in treating the intestinal and systemic symptoms. An important aspect to keep in mind is that in 50% of patients, the CSF may contain Whipple disease macrophages or PCR-positive material even in the absence of CNS symptoms.48 Once CNS involvement occurs, treatment is usually not curative, although with treatment, some improvement may be noted and the disease may not progress.


Immunoproliferative small intestinal disease (IPSID), previously known as primary intestinal lymphoma, is a condition in which the lamina propria of the small bowel is intensely infiltrated with lymphocytes and the overlying enterocytes are normal morphologically [see Figure 5]. In a series of Chinese patients, six of 45 patients with intestinal lymphoma had this condition.53 These patients presented with severe malabsorption. Among lymphoma patients without IPSID, 65% had abdominal pain, weight loss, abdominal masses, obstruction, and perforation. IPSID is associated with α heavy chains (from IgA), with paraprotein present in the serum, urine, or jejunal fluid. The disease is rare in developed nations and more common in underprivileged populations, primarily in persons in the second and third decades of life, with a male predominance. It is a B cell disorder involving the mucosa-associated lymphoid tissue (MALT) and is one of the infectious pathogen-associated lymphomas. Campylobacter jejuni is the inciting agent.54 Duodenography shows thickened folds and many nodular elevations without ulceration. The diagnosis may be made by small bowel biopsy in 85% of cases.55 Early in the course of the disease, the condition appears to be treatable with antibiotics. If allowed to progress, however, it may develop into more aggressive forms of lymphoma.56


Figure 5Small intestinal biopsy specimen from a patient with primary intestinal lymphoma shows a single broadened villus (magnified 400 times). The epithelium is composed of normal columnar cells, but the lamina propria is packed with plasma cells and other mononuclear cells. Surgical biopsies in this patient revealed evidence of generalized subepithelial histiocytic lymphoma.


Intestinal lymphangiectasia is often a congenital condition in which deformed lymphatics impair the transport of chylomicrons from the enterocytes to the mesenteric lymph duct. A similar pathophysiologic picture is acquired in certain cases of intestinal lymphomas, granulomatous enteritis, tuberculous enteritis, or Whipple disease in which normal lymphatic drainage is blocked.


The blockage of lymphatic drainage may result in chylous ascites, chyluria, or chylometrorrhea.57 Protein-losing enteropathy and lymphopenia are prominent features. Modest steatorrhea is also present, with fat excretion commonly reaching 20 g/day. In the congenital form of the disease, lymphedema of the legs or of one leg and one arm is seen. On endoscopic examination, white villi, white nodules, and submucosal elevations may be noted.58 The white appearance of the mucosa is undoubtedly caused by retained chylomicron triacylglycerol. Double-contrast barium x-ray examination shows smooth nodular protrusions and thick mucosal folds without ulceration.59 On histologic examination, dilated lymphatics with club-shaped villi are seen, sometimes in asymptomatic patients, in whom the outcome is benign.


Treatment is directed toward any identified causative process. In patients with the congenital condition, in whom improvement of the deranged lymphatics is not expected, a low-fat diet supplemented with medium-chain triglycerides is usually helpful. Surgery can be used to remove isolated areas of lymphatic dysfunction, if these areas can be identified, or to anastomose a lymph duct to the venous system. Sometimes a peritoneovenous (LeVeen) shunt is helpful.


Persons with the rare congenital condition of abetalipoproteinemia do not have postprandial chylomicronemia, because they are unable to adequately couple apolipoprotein B to the developing chylomicron. Because lipid and lipid-soluble vitamins are transported from the intestine in chylomicrons, the consequent reduction in lipid and lipid-soluble vitamin absorption results in symptomatic steatorrhea, neurologic abnormalities, a variant of retinitis pigmentosa, and spiculated red cells. In contrast to earlier theories about the etiology of this disease, these patients have normally transcribed apolipoprotein B mRNA from which the protein is adequately translated. Nevertheless, apolipoprotein B is not secreted from the intestinal cell. The defect in this condition is in various mutations in the gene that encodes the M component of microsomal triglyceride transport protein.60 This chaperonelike protein complex, which consists of a 97 kd M component and a 55 kd component (protein disulfide isomerase), helps to translocate the apolipoprotein across the membrane of the endoplasmic reticulum.61Without this step, the apolipoprotein is degraded by cytosolic and microsomal peptidases. The result of this defect is that both the intestine and the liver are unable to produce and secrete their triacylglycerol-rich lipoproteins, chylomicrons, and very low density lipoproteins. Because chylomicrons cannot transport the fat out of the enterocyte, it is presumed, but not proved, that the surprisingly large amount of lipid that is absorbed (80%) is absorbed via the portal vein.62


In addition to having intestinal symptoms, patients with abetalipoproteinemia have severe neurologic problems. These neurologic problems may be caused in part by essential fatty acid deficiency and in part by either the impaired delivery of lipid to nerves or an interference with the local synthesis of lipids. The result is a demyelinating condition resulting in a sensory ataxia caused by the loss of position and vibratory sensations. The symptoms are similar to but less severe than those of Friedreich ataxia.63 Patients may have muscle weakness and athetoid movements. Patients also experience retinitis pigmentosa, usually with mild loss of visual acuity but preservation of central vision. In addition to the neurologic abnormalities, patients have acanthocytes in their blood. Acanthocytes are spiculated red cells that have a near-normal life span but that demonstrate an increased susceptibility to mechanical trauma on in vi-tro testing.

These patients have low plasma triacylglycerol and cholesterol levels. On histologic examination, the enterocytes are seen to be laden with fat. Despite this phenotype, the amount of steatorrhea is modest (about 20 g/day).

Abetalipoproteinemia is usually discovered in childhood because patients with the disease fail to thrive and have steatorrhea. In adults, the disease can be recognized by the combination of neurologic and ophthalmologic findings, the red cell morphology, the very low levels of plasma lipids, and the modest steatorrhea. On small bowel biopsy, the enterocytes are seen to be stuffed with lipid even after an overnight fast, indicating that the absorbed lipid cannot exit the enterocytes.64


Treatment should include vitamin E as well as the other fat-soluble vitamins and medium-chain triglycerides to reduce the steatorrhea, if required.


Eosinophilic gastroenteritis is a rare disease that is characterized by the presence of eosinophilic infiltration of one or more portions of the GI tract, anywhere from the esophagus to the colon, in conjunction with gastrointestinal symptoms. Rarely, the pancreas is involved as well.65 No identifiable cause of the eosinophilic infiltrate, such as parasitic infestation, is present. Many patients have an underlying allergic diathesis (e.g., hay fever, asthma, atopic dermatitis, or drug allergies).

It is not known why eosinophils congregate in the GI tract in this condition, but evidence suggests that eosinophils, once activated, can produce cytokines that self-perpetuate the accumulation of additional eosinophils. These cytokines are interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which have been identified in eosinophils of patients but not in control subjects with irritable bowel syndrome. Local production of these cytokines is suggested by the finding that serum levels of IL-5 are normal in patients with eosinophilic gastroenteritis, in contrast to patients with the hypereosinophilic syndrome, who have increased levels of IL-5 in their blood.66


Although eosinophils are a normal constituent of the GI tract, in eosinophilic gastroenteritis the eosinophils appear more numerous than normal and are more invasive. For example, eosinophilic invasion of the crypts in the small intestine is a hallmark of this condition. A peripheral eosinophilia is often seen but is not always present.

Eosinophilic gastroenteritis can be divided into two basic forms: a tumorous mass of eosinophils producing a granulomatous-type lesion and a more diffusely infiltrative form. In the former case, the lesions are most often in the distal stomach, which may produce obstructive symptoms, or the masses may be found in the more proximal stomach, small bowel, or colon. When lesions are in the small bowel or colon, the condition needs to be differentiated from a lymphoma or Crohn disease.67 In the case of diffuse disease involving the small bowel, the infiltration can be mucosal, with symptoms of protein-losing enteropathy or malabsorption. If the infiltration is primarily in the muscle layers of the intestine, obstructive symptoms are common. Finally, the disease may be found in the subserosal area of the intestine, with resultant eosinophilic ascites.68


Most patients respond to conservative measures and steroids. Surgery should be avoided unless it is needed to relieve persistent pyloric or small bowel obstruction.

Prednisone, 40 mg orally every morning and tapered slowly over 2 weeks, is the most effective therapy for patients with obstructive symptoms and ascites. If high-dose steroids are needed to maintain remission, azathioprine can be added for its steroid-sparing effect.

Diet elimination therapy may be beneficial in patients with mucosal layer involvement.


Crohn disease, a stenosing, fistulizing disease of the intestine, may impair intestinal absorption by at least two mechanisms, ileal dysfunction and the stasis syndrome [see Stasis (Bacterial Overgrowth) Syndrome, below]. In the case of either ileal resection or severe ileal involvement with Crohn disease, the ileum cannot absorb bile salts normally. In that event, postprandial bile salt deficiency occurs in the upper intestine; this condition may become more severe the later in the day a meal is eaten.69 Postprandial bile salt deficiency occurs despite increased bile acid synthesis by the liver, in response to bile acid loss from the enterohepatic circulation. The increase in bile salt synthesis is not adequate because each time the gallbladder contracts in response to a meal, most of the bile salt pool is lost to the colon if significant amounts of the ileum have been resected.70 Thus, the liver does not have time to generate enough replacement bile salts for the complete absorption of the meal just eaten or the next one. The colonic perfusion of bile acids may result in diarrhea. This condition has been termed choleretic enteropathy and may occur when more than 30 cm of the terminal ileum is resected. The excess fluid in the colon is caused by cAMP-driven Cl- secretion, specifically by the dihydroxylated bile acids chenodeoxycholate and deoxycholate, not trihydroxylated cholic acid.71


The loss of bile acids to the colon and thus to the enterohepatic circulation can be associated with no or minimal steatorrhea.72

With more extensive (100 cm or greater) ileal resection, however, the diarrhea is caused not only by bile acids but also by malabsorbed fatty acids (steatorrhea).73 Thus, diarrhea in patients with Crohn disease may be caused not by active disease but rather by the results of ileal resection. This scenario is suggested by diarrhea that occurs when the patient first eats after surgery—a time when disease activity may be low secondary to active disease resection—or by the fact that the patient had no or minimal diarrhea before surgery, with diarrhea becoming more prominent afterward.

Because of the stenosis present in some patients with Crohn disease, the stasis syndrome can develop [see Stasis (Bacterial Overgrowth) Syndrome, below].


When the diarrhea is caused by bile acid loss, the treatment is cholestyramine (4 g a.c. and h.s.).73 This resin preferentially binds the dihydroxylated bile acids, reducing their aqueous concentration and reducing their proportion in the total bile acid pool. Both effects are beneficial. In the case of larger ileal resections in which steatorrhea is prominent, cholestyramine may actually provoke more diarrhea and malabsorption because it reduces the aqueous bile acid concentration in the upper intestine when taken before meals. In this case, medium-chain fatty acids are used as a replacement for the long-chain fatty acids. The results of this strategy are often not as good as desired. Vitamin B12 absorption should also be evaluated in all patients with ileal resection; if absorption is found to be abnormal, vitamin B12 should be given parenterally.

Some patients with severe Crohn disease undergo extensive intestinal resection, resulting effectively in short bowel syndrome. Similarly, patients who have numerous enteroenteric fistulas also have symptoms of short bowel syndrome because the fistulas cause the chyme to bypass large sections of the small intestine. Both types of patients should be treated as if they had short bowel syndrome.


The stasis (bacterial overgrowth) syndrome occurs when intestinal stasis allows bacteria to proliferate locally. This condition has a multiplicity of causes. The most prominent causes are diabetes; scleroderma; intestinal diverticulosis; afferent loop of a gastrojejunostomy; and intestinal obstruction caused by strictures, adhesions, or cancer. These disorders may be present years before the development of symptoms. Symptoms may appear in an otherwise stable patient because of the administration of a proton pump inhibitor, which reduces gastric acid production, allowing gastric and small bowel overgrowth; or the administration of an opiate that further reduces intestinal motility.


Intestinal dysfunction in the stasis syndrome is probably caused by bacterial glycosidases that hydrolyze the carbohydrate moieties that form the extensive glycosylation of the apical brush-border proteins.74 Although bile acid deconjugation occurs in the stasis syndrome, which may theoretically lead to impaired solubilization of the products of triglyceride hydrolysis, studies have shown that in fact the fatty acid concentration in the aqueous phase of postprandial intestinal content is normal.75 Electron micrographs, however, show that there is damage to the enterocytes, in that absorbed lipid collects in the endoplasmic reticulum and does not progress normally to the Golgi apparatus.75


Clinical manifestations

Symptoms of the stasis syndrome are similar to those of other malabsorptive states and include steatorrhea and anemia. The patient may have vitamin B12 deficiency, which has several causes, including binding of the vitamin to bacteria76 and bacterial metabolism of the vitamin to metabolically ineffective metabolites. Folic acid levels are usually high, secondary to bacterial production of folate.77 Serum albumin levels may be low secondary to protein-losing enteropathy and remain low for months after adequate treatment. The diagnosis is usually made in a patient with malabsorption in the appropriate clinical setting. Intestinal (usually jejunal) diverticulosis is usually unsuspected until a small bowel x-ray is performed.

Laboratory tests

Establishing the diagnosis of the stasis syndrome is not simple. The most accurate way is to pass an aspiration tube into the intestine. The fluid must be quantitatively cultured both aerobically and especially anaerobically. In most cases, more than 105 anaerobes will be found. Alternatively, the noninvasive hydrogen breath test may be used. A high resting hydrogen level or a quick increase in the breath hydrogen in response to a fermentable substrate, such as glucose or lactulose, can be used. Another breath test is the 1 g (14C)-D-xylose test, in which the breath 14CO2 is measured.


The first choice of treatment for the stasis syndrome is surgical correction of defects, such as an afferent loop that is harboring bacteria, or a jejunocolic fistula. If the surgical option is not available, then recurrent dosing of an antibiotic is required. Tetracycline, at a dosage of 1 to 2 g/day for a 7- to 10-day course, gives good results, or another antibiotic that is active against anaerobic bacteria may be used (e.g., trimethroprim-sulfamethoxazole, one double-strength tablet b.i.d.). The patient will need to be re-treated if clinical symptoms reappear, or the patient can receive treatment for 1 week every month.


The intestine is often involved in patients with systemic amyloidosis, especially if they have polyneuropathy. In patients older than 85 years, 36% have intestinal involvement with amyloidosis,78 although most are asymptomatic. Endoscopically, mucosal erosion, friability, or polypoid protrusions can be seen.79 The diagnosis is made by either full-thickness or peroral intestinal biopsies. If a peroral biopsy is performed, it must be deep enough to have arteries visible, so that amyloid, if present, can be demonstrated. Congo red-stained arterioles that become apple green under polarized light confirm the diagnosis. Small bowel follow-through x-rays may show swollen intestinal plicae, possibly with separated loops of bowel. If steatorrhea is present, it may be the result either of bacterial overgrowth caused by intestinal dysmotility or of impaired bile acid absorption.80 No specific effective therapy is available. If bacterial overgrowth is present, then appropriate antibiotics should be given.


In this rare condition, the skin (99% of cases), bones (9%), liver (12%), spleen (11%), lymph nodes, and GI tract are involved with proliferating mast cells. Diarrhea or abdominal pain or both (23% of cases), peptic ulceration (4%), and itching and flushing (36%) may be seen. Headache, fatigue, and malaise are seen in 12% of cases. There may also be cognitive dysfunction. Eosinophilia is seen in 12% to 50% of cases.81 Many of these manifestations of the disease are secondary to histamine, which is released from the mast cells. Histamine release may be precipitated by alcohol, aspirin, narcotics, and nonsteroidal anti-inflammatory drugs, causing episodic disturbances of flushing, diarrhea, abdominal pain, and hypotension that may progress to syncope.81

Excess histamine is excreted into the urine in approximately 75% of patients with systemic mastocytosis, making this test useful for diagnostic purposes.81 The urinary excretion of a metabolite of prostaglandin D2 from mast cells may be an even better test.82 X-ray studies of the small intestine may show thickened folds or nodulation. These findings are not diagnostic but may point to a diseased small bowel.

Histamine-mediated overproduction of gastric acid may lead to peptic ulceration. H2 blockers or proton pump inhibitors are effective in controlling symptoms in such patients. In the skin, urticaria pigmentosa may be effectively treated with H1 receptor antagonists such as diphenhydramine (25 mg every 6 to 8 hours). If diarrhea persists, cromolyn sodium may be given at a dosage of 100 mg orally four times a day.

Parasitic Infestations

Hookworm and G. lamblia infections can cause mild malabsorption that is rarely clinically important. Eradication of the parasites cures the absorptive defect. These issues are discussed more fully elsewhere [see 7:XXXV Helminthic Infections and 7:XXXIV Protozoan Infections].

Chronic Pancreatitis with Exocrine Insufficiency

Most cases of chronic pancreatitis are caused by alcoholism. In rare cases, the disease is inherited. Patients experience weight loss resulting from malabsorption of food. Malabsorption caused by pancreatitis is discussed elsewhere [see 4:V Diseases of the Pancreas].

Combined or Multiple Defects in Digestion and Absorption


One of the consequences of gastric surgery is steatorrhea, primarily in patients who have the Billroth II gastric resection with a gastrojejunostomy. In this operation, the antrum and a variable portion of the body of the stomach are resected, the stomach is sutured closed, and a gastrojejunostomy is created. Thus, food bypasses the duodenum and most proximal jejunum, the sites of maximal cholecystokinin and secretin concentrations and the active sites for folate, calcium, and iron absorption. Approximately one half of patients who have undergone the Billroth II procedure have steatorrhea of 10 to 15 g of fat/day. This condition is thought to result from food entering the jejunum without the hormone-sensitive sites in the duodenum receiving the appropriate signals for hormone release. Thus, there is poor gallbladder contraction and reduced release of pancreatic digestive enzymes to the intestine, resulting in poor admixing of the chyme with pancreatic enzymes and bile acids. The afferent loop, which drains the duodenum and proximal jejunum, may become blocked or atonic and harbor bacteria. The stasis syndrome may occur if enough bacteria are present. Because of their small stomachs, these patients cannot eat as much as they previously could. This decrease in food consumption, in combination with steatorrhea, causes many patients who undergo the Billroth II procedure to maintain a lower weight than they did before surgery. Osteopenia and iron deficiency anemia are also found. The constant loss of small amounts of blood from the gastric ostomy site, combined with impaired iron absorption, contribute to the iron-deficient state, which is the most common form of anemia. Folate deficiency secondary to the inability to generate absorbable monoglutamyl folate from nonabsorbable heptaglutamyl folate (the common form of folate found in the diet) is also found.83 Least commonly seen is vitamin B12 deficiency caused by hypochlorhydria and resection of intrinsic factor-containing gastric parietal cells. Treatment of the steatorrhea is usually not necessary, because it is not clinically significant. Iron, calcium, or vitamin B12 and folic acid must be replaced as indicated. If the patient has early satiety, multiple small meals may be efficacious.

Symptoms of GSE may develop in patients after gastric surgery.84 It is likely that these patients had clinically silent GSE before the operation. The operation itself causes modest steatorrhea (10 to 15 g of fat/day) in 50% of cases, even in patients whose intestine is otherwise normal. In the previously compensated GSE patient, however, surgery is enough to cause clinical symptoms. Therefore, an evaluation for GSE is warranted in postgastrectomy patients who exhibit excessive steatorrhea. Inflammatory bowel disease that develops in patients after gastrectomy may likewise be an indication of the presence of previously silent GSE.85


Diarrhea, a common complication of diabetes, has multiple causes86 and may result in malabsorption [see 4:III Diarrheal Diseases]. The most common causes are bacterial overgrowth, secondary to diabetic autonomic dysfunction that results in intestinal stasis, and GSE. In one study, screening with antiendomysial antibody assays identified GSE in three of 47 diabetic patients (6%), a much higher incidence than would be expected by chance.87


Figure 1 Dana Burns-Pizer.


  1. Moreau H, Gargouri Y, Bernadal A, et al: Etude biochemique et physiologique des lipases préduodéales d'origines animale et humaine. Revue Française des Corps Gras 35:169, 1988
  2. Roulet M, Weber A, Roy C: Perspectives in Cystic Fibrosis. Canada Cystic Fibrosis Foundation, Toronto, 1980, p 172
  3. Levitt MD, Duane WC: Floating stools: flatus versus fat. N Engl J Med 286:973, 1972
  4. Drummy GD, Benson JA Jr: Jones CM: Microscopical examination of the stool for steatorrhea. N Engl J Med 264:85, 1961
  5. Neucker AV, Bijleveld CM, Wolthers BG, et al: Comparison of near infrared reflectance analysis of fecal fat, nitrogen and water with conventional methods, and fecal energy content. Clin Biochem 35:29, 2002
  6. DiMagno EP, Go VLW, Summerskill WHJ: Relation between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 288:813, 1973
  7. Dreiling DA, Janowitz HD: The measurement of pancreatic secretory function. The Exocrine Pancreas. De Reuck AVS, Cameron MP, Eds. Ciba Foundation Symposium. Little, Brown & Co, New York, 1961, p 225
  8. Kato H, Nakao A, Kishimoto W, et al: 13C-labeled trioctanoin breath test for exocrine pancreatic function test in patients after pancreatoduodenectomy. Am J Gastroenterol 88:64, 1993
  9. Lang C: Value of serum PABA as a pancreatic function test. Gut 25:508, 1984
  10. Bando N, Ogawa T, Tsuji H: Enzymatic method for selective determination of 4 aminobenzoic acid in urine. Clin Chem 36:1937, 1990
  11. Jacobson DG, Curlington C, Connery K, et al: Trypsin-like immunoreactivity as a test for pancreatic insufficiency. N Engl J Med 310:1307, 1984
  12. Loser C, Mollgaard A, Folsch UR: Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut 39:580, 1996
  13. Walkowiak J, Cichy WK, Herzig KH: Comparison of fecal elastase-1 determination with the secretin-cholecystokinin test in patients with cystic fibrosis. Scand J Gastroenterol 34:202, 1999
  14. Oelkers P, Kirby LC, Heubi JE, et al: Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene. J Clin Invest 99:1880, 1997
  15. Shindo K, Yamazaki R, Koide K, et al: Alteration of bile acid metabolism by cimetidine in healthy humans. J Investig Med 44:462, 1996
  16. Nyhlin H, Merrick MV, Eastwood MA, et al: Evaluation of ileal function using 23-selena-25-homotaurocholate, a γ-labeled conjugated bile acid. Gastroenterology 84:63, 1983
  17. Crenn P, Coudray-Lucas C, Thuillier F, et al: Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology 119:1496, 2000
  18. Make M, Collin P: Coeliac disease. Lancet 349:1755, 1997
  19. Not T, Horvath K, Hill ID, et al: Celiac disease risk in the USA: high prevalence of antiendomysium antibodies in healthy blood donors. Scand J Gastroenterol 33:494, 1998
  20. Catassi C, Fabiani E, Ratsch IM, et al: The coeliac iceberg in Italy: a multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl 412:29, 1996
  21. Fasano A, Berti I, Gerarduzzi T, et al: Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 163:286, 2003
  22. Anderson RP, Degano P, Godkin AJ, et al: In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant α-gliadin T-cell epitope. Nat Med 6:337, 2000
  23. Shan L, Molberg O, Parrot I, et al: Structural basis for gluten intolerance in celiac sprue. Science 297:2218, 2002
  24. Matysiak-Budnik T, Candalh C, Dugave C, et al: Alterations of the intestinal transport and processing of gliadin peptides in celiac disease. Gastroenterology 125:696, 2003
  25. Hofmann AF: The function of bile salts in fat absorption. Biochem J 89:57, 1963
  26. Mansbach CM II, Cohen RS, Leff PB: Isolation and properties of the mixed micelles present in intestinal content during fat digestion in man. J Clin Invest 56:781, 1975
  27. Dieterich W, Laag E, Schöpper H, et al: Autoantibodies to tissue transglutaminase as predictors of coeliac disease. Gastroenterology 115:1317, 1998
  28. Volta V, Molinaro N, deFranceschi L, et al: IgA antiendomysial antibodies on human umbilical cord tissue for celiac disease screening. Dig Dis Sci 40:1902, 1995
  29. Holmes GKT, Prior P, Lane MR, et al: Malignancy in coeliac disease: effect of a gluten-free diet. Gut 30:333, 1989
  30. Gawkrodger DJ, Vestey JP, O'Mahouny S: Dermatitis herpetiformis and established coeliac disease. Br J Dermatol 129:694, 1993
  31. Klipstein FA, Falaiye JM: Tropical sprue in expatriates from the tropics living in the continental United States. Medicine (Baltimore) 48:475, 1969
  32. Lindenbaum J, Gerson CD, Kent TH: Recovery of small intestinal structure and function after residence in the tropics: I. studies in Peace Corps volunteers. Ann Intern Med 74:218, 1971
  33. Gerson CD, Kent TH, Saha JR, et al: Recovery of small intestinal structure and function after residence in the tropics: II. studies in Indians and Parkistanis living in New York City. Ann Intern Med 75:41, 1971
  34. Haghighi P, Wolf PL: Tropical sprue and subclinical enteropathy: a vision for the nineties. Crit Rev Clin Lab Sci 34:313, 1997
  35. Robert ME, Ament ME, Weinstein WM: The histologic spectrum and clinical outcome of refractory and unclassified sprue. Am J Surg Pathol 24:676, 2000
  36. Freeman HJ: Collagenous mucosal inflammatory diseases of the gastrointestinal tract. Gastroenterology 129:338, 2005
  37. McCashland TM, Donovan JP, Strobach RS, et al: Collagenous enterocolitis: a manifestation of gluten-sensitive enteropathy. J Clin Gastroenterol 15:45, 1992
  38. Hermaszewski RA, Webster AD: Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 86:31, 1993
  39. Ladefoged K, Hessov I, Jarnum S: Nutrition in short-bowel syndrome. Scand J Gastroenterol 216(suppl):122, 1996
  40. Lin HC, Zhao XT, Wang L: Fat absorption is not complete by midgut but is dependent on load of fat. Am J Physiol 271(1 pt 1):G62, 1996
  41. Lin HC, Zhao XT, Wong H: Fat-induced ileal brake in the dog depends on peptide YY. Gastroenterology 110:1491, 1996
  42. Redman DA, Schmidt TM, McDermott RP, et al: Identification of the uncultured bacillus of Whipple's disease. N Engl J Med 327:393, 1992
  43. Durand DV, Lecomte C, Cathebras P, et al: Whipple disease: clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Medicine (Baltimore) 76:170, 1997
  44. Dobbins WO III: HLA antigens in Whipple's disease. Arthritis Rheum 30:102, 1987
  45. Mansbach CM II, Shelburne J, Stevens RD, et al: Lymph node bacilliform bodies morphologically resembling those of Whipple's disease in a patient without intestinal involvement. Ann Intern Med 89:64, 1978
  46. Street S, Donoghue HD, Neild GH: Tropheryma whippeliiDNA in saliva of healthy people. Lancet 354:1178, 1999
  47. Swartz MN: Whipple's disease: past, present and future. N Engl J Med 342:648, 2000
  48. von Herbay A, Ditton HJ, Schumacher F, et al: Whipple's disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology 113:434, 1997
  49. Kelly CA, Egan M, Rawlinson J: Whipple's disease presenting with lung involvement. Thorax 51:343, 1996
  50. Monkemuller K, Fry LC, Rickes S, et al: Whipple's disease. Curr Infect Dis Rep 8:96, 2006
  51. Louis ED, Lynch T, Kaufmann P, et al: Diagnostic guidelines in central nervous system Whipple's disease. J Ann Neurol 40:561, 1996
  52. Feurle GE, Marth T: An evaluation of antimicrobial treatment for Whipple's disease: tetracycline versus trimethoprim-sulfamethoxazole. Dig Dis Sci 39:1642, 1994
  53. Shih LY, Liaw SJ, Dunn P, et al: Primary small-intestinal lymphomas in Taiwan: immunoproliferative small-intestinal disease and nonimmunoproliferative small-intestinal disease. J Clin Oncol 12:1375, 1994
  54. Al-Saleem T, Al-Mondhiry H: Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms. Blood 105:2274, 2005
  55. Halphen M, Najjar T, Jaafoura H, et al: Diagnostic value of upper intestinal fiber endoscopy in primary small intestinal lymphoma: a prospective study by the Tunisian-French Intestinal Lymphoma Group. Cancer 58:2140, 1986
  56. Khojasteh A, Haghighi P: Immunoproliferative small intestinal disease: portrait of a potentially preventable cancer from the Third World. Am J Med 89:483, 1990
  57. Fox C, Lucani G: Disorders of the intestinal mesenteric lymphatic system. Lymphology 26:61, 1993
  58. Aoyagi K, Iida M, Yao T, et al: Characteristic endoscopic features of intestinal lymphangiectasia: correlation with histological findings. Hepatogastroenterology 44:133, 1997
  59. Aoyagi K, Iida M, Yao T, et al: Intestinal lymphangiectasia: value of double-contrast radiographic study. Clin Radiol 49:814, 1994
  60. Sharp D, Blinderman L, Combs KA, et al: Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365:65, 1993
  61. Gordon DA, Jamil H, Gregg RE, et al: Inhibition of the microsomal triglyceride transfer protein blocks the step of apolipoprotein B lipoprotein assembly but not the addition of bulk core lipids in the second step. J Biol Chem 271:33047, 1996
  62. Mansbach CM II, Dowell RF, Pritchett D: Portal transport of absorbed lipids in the rat. Am J Physiol 261:G530, 1991
  63. Isselbacher KJ, Scheig R, Plotkin GR, et al: Congenital β-lipoprotein deficiency: an hereditary disorder involving a defect in the absorption and transport of lipids. Medicine (Baltimore) 43:347, 1964
  64. Ways PO, Parmentier CM, Kayden HJ, et al: Studies on the absorptive defect for triglyceride in abetalipoproteinemia. J Clin Invest 46:35, 1967
  65. Lyngbaek S, Adamsen S, Aru A, et al: Recurrent acute pancreatitis due to eosinophilic gastroenteritis: case report and literature review. JOP 7:211, 2006
  66. Desreumaux P, Blogot F, Seguy D, et al: Interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 in eosinophilic gastroenteritis. Gastroenterology 110:768, 1996
  67. Salmon PR, Paulley JW: Eosinophilic granuloma of the gastrointestinal tract. Gut 8:8, 1967
  68. Klein NC, Hargrove RL, Sleisenger MH, et al: Eosinophilic gastroenteritis. Medicine (Baltimore) 49:299, 1970
  69. Van Deest BW, Fordtran JS, Morawski SG, et al: Bile salt and micellar fat concentration in proximal small bowel contents of ileectomy patients. J Clin Invest 47:1314, 1968
  70. Low-Beer TS, Wilkins RM, Lack L, et al: Effect of one meal on enterohepatic circulation of bile salts. Gastroenterology 67:490, 1974
  71. Merhjian HS, Phillips SF, Hofmann AF: Colonic secretion of water and electrolytes induced by bile acids: perfusion studies in man. J Clin Invest 50:1569, 1971
  72. Mansbach CM II, Newton DF, Stevens RD: Fat digestion in patients with bile acid malabsorption but minimal steatorrhea. Dig Dis Sci 25:353, 1980
  73. Hofmann AF, Poley JR: Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection: I. Response to cholestyramine or replacement of dietary long chain triglyceride by medium chain triglyceride. Gastroenterology 62:918, 1972
  74. Riepe S, Goldstein J, Alpers DH: Effect of secreted Bacteroidesproteases on human intestinal brush border hydrolases. J Clin Invest 66:314, 1980
  75. Ament ME, Shimoda SS, Saunders DR, et al: Pathogenesis of steatorrhea in three cases of small intestinal stasis syndrome. Gastroenterology 63:728, 1972
  76. Gianella RA, Broitman SA, Zamcheck N: Vitamin B12uptake by intestinal microorganisms: mechanisms and relevance to syndromes of bacterial overgrowth. J Clin Invest 50:1100, 1971
  77. Hoffbrand AV, Tabaqchali S, Booth CC, et al: Small intestinal bacterial flora and folate status in gastrointestinal disease. Gut 12:27, 1971
  78. Rocken C, Saeger W, Linke RP: Gastrointestinal amyloid deposits in old age: report of 110 consecutive autopsical patients and 98 retrospective bioptic specimens. Pathol Res Pract 190:641, 1994
  79. Tada S, Iida M, Yao KK, et al: Endoscopic features in amyloidosis of the small intestine: clinical and morphologic differences between chemical types of amyloid protein. Gastrointest Endosc 40:45, 1994
  80. Suhr O, Danielsson A, Steen L: Bile acid malabsorption caused by gastrointestinal motility dysfunction? An investigation of gastrointestinal disturbances in familial amyloidosis with polyneuropathy. Scand J Gastroenterol 27:201, 1992
  81. Golkar L, Bernhard JD: Mastocytosis. Lancet 349:1379, 1997
  82. Morrow JD, Guzzo C, Lazarus G, et al: Improved diagnosis of mastocytosis by measurements of the major urinary metabolite of prostaglandin D2. J Invest Dermatol 104:937, 1995
  83. Rosenberg IH: Folate absorption and malabsorption. N Engl J Med 293:1303, 1975
  84. Bai J, Moran C, Martinez C: Celiac sprue after surgery of the upper gastrointestinal tract: report of 10 patients with special attention to diagnosis, clinical behavior, and follow-up. J Clin Gastroenterol 13:521, 1991
  85. Kitis G, Holmes GTK, Cooper BT: Association of coeliac disease and inflammatory bowel disease. Gut 21:636, 1980
  86. Valdovinos MA, Camilleri M, Zimmerman BR: Chronic diarrhea in diabetes mellitus: mechanisms and an approach to diagnosis and treatment. Mayo Clin Proc 68:691, 1993
  87. Rensch MJ, Merenich JA, Lieberman M, et al: Gluten-sensitive enteropathy in patients with insulin-dependent diabetes mellitus. Ann Intern Med 124:564, 1996

Editors: Dale, David C.; Federman, Daniel D.