1. 1
    Current Diagnosis

    • Recognize the presence of generalized malabsorption by the combination of typical symptoms: diarrhea, greasy stools, flatulence, weight loss, fatigue, edema.

    • Recognize the presence of specific malabsorption by associated symptoms and those symptoms particular to deficiency states of the malabsorbed substance: flatus, diarrhea, anemia, dermatitis, glossitis, neuropathy, paresthesias, tetany, ecchymosis.

    • Documentation of generalized malabsorption is best done by stool analysis demonstrating steatorrhea and acid stools (reflecting carbohydrate malabsorption). Diagnosis depends on visualization of the small bowel by endoscopy or radiography and small bowel biopsy. Additional tests may be needed.

    • Documentation of specific malabsorption is best done by demonstrating low blood levels of the malabsorbed substance or by tests designed to measure absorption of that substance. Diagnosis depends on studies designed to identify the likely diagnosis for a given situation.

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  2. 2
    Current Therapy
    • Once a diagnosis is reached, therapy can be directed toward that specific problem:
      • Gluten-free diet for celiac disease
      • Antibiotics for bacterial overgrowth
      • Lactose-free diet for lactase deficiency

    Every day the average human being consumes 2000–3000 kcal of food, much of it in the form of polymers or other complex molecules that must be digested and absorbed by the gut. The processes of digestion and absorption are complex and are readily disturbed by pathologic processes. More than 200 conditions have been described that can adversely affect nutrient absorption.

    Strictly speaking, maldigestion refers to impaired hydrolysis of nutrients, usually due to lack of luminal factors, such as bile acids and pancreatic enzymes, and malabsorption refers to impaired mucosal transport. For clinical purposes, “malabsorption” is used to describe both processes.

    Malabsorption can be generalized (panmalabsorption) or limited to a specific category of nutrients. Generalized malabsorption is usually due to maldigestion or to extensive mucosal dysfunction. Specific malabsorption occurs when a single transporter is disabled.

    The causes of malabsorption can be divided into three categories: impaired luminal hydrolysis, impaired mucosal function (mucosal hydrolysis, uptake, packaging, and excretion), and impaired removal of nutrients from the mucosa (Box 1).

    Box 1  
    Causes of Malabsorption or  Maldigestion
    •  Impaired luminal hydrolysis or solublization
      •  Bile acid deficiency
      •  Impaired mucosal hydrolysis, uptake, or packaging
      •   Pancreatic exocrine insufficiency
      •  Postgastrectomy syndrome
      • Rapid intestinal transit
      • Small bowel bacterial overgrowth
      • Zollinger-Ellison syndrome
    • Brush border or metabolic disorders
      •  Abetalipoproteinemia
      • Glucose-galactose malabsorption
      • Lactase deficiency
      • Sucrase-isomaltase deficiency
    • Mucosal diseases
      • Amyloidosis
      • Crohn’s disease
      •  Celiac sprue
      • Collagenous sprue
      • Eosinophilic gastroenteritis
      • Immunoproliferative small intestinal disease (IPSID)
      • Lymphoma
      • Nongranulomatous ulcerative jejunoileitis
      • Olmesartan enteropathy
      • Radiation enteritis
      • Systemic mastocytosis
    • Infectious diseases
      • AIDS enteropathy
      • Mycobacterium avium-intracellulare
      • Parasitic diseases
      • Small bowel bacterial overgrowth
      • Tropical sprue
      • Whipple’s disease
      • After intestinal resection
      • Chronic mesenteric ischemia
    • Impaired removal of nutrients
      • Lymphangiectasia
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  3. 3

    Symptoms and Signs

    Most patients with panmalabsorption have changes in their stools (Box 2). Steatorrhea (excess fat in stools) is characterized by pale color, bulkiness, greasiness, and a tendency to float (probably because of incorporated gas). Occasionally patients with malabsorption present with watery stools due to the osmotic effects of unabsorbed carbohydrates and short-chain fatty acids.

    Box 2
    Symptoms and Signs of Malabsorption or Maldigestion
    • Changes in stool characteristics
      • Floating stools
      • Pale, bulky, greasy stools
      • Watery diarrhea
    • Increased colonic gas production
      •    Abdominal distention
      •    Borborygmi
    •    Vitamin and mineral deficiencies
      •    Anemia
      •    Cheilosis
      •    Glossitis
      •    Dermatitis
      •    Neuropathy
      •    Night blindness
      •    Osteomalacia
      •    Paresthesia
      •    Tetany
      •    Ecchymosis
      •    Fatigue, weakness
      •    Edema
      •    Weight loss, muscle wasting

    Abdominal distention and excess flatus also commonly occur due to fermentation of unabsorbed carbohydrate by colonic bacteria. This can occur not only with panmalabsorption but also with specific malabsorption of carbohydrate (e.g., lactase deficiency).

    Weight loss is typical with severe panmalabsorption, but it might not be very prominent with lesser degrees of malabsorption due to compensatory hyperphagia. Weight loss is most prominent early in the course of the illness, but body weight usually stabilizes as calorie absorption and body weight come into balance again. This is in contrast to illnesses like cancer or tuberculosis that produce continuing weight loss. If a patient with malabsorption has continuing weight loss, inflammatory bowel disease or lymphoma should be considered.

    Abdominal pain is usually not present with malabsorption, although some cramping may be associated with diarrhea. Severe pain should bring chronic pancreatitis, Zollinger-Ellison syndrome, lymphoma, Crohn’s disease, or mesenteric ischemia to mind.

    Constitutional symptoms of fatigue and weakness commonly occur, even early in the course. In contrast, appetite is impaired only late in the course of most malabsorption states. Edema is uncommon until late in the course unless protein-losing enteropathy is present.

    Vitamin and mineral deficiencies can lead to several symptoms or signs. Glossitis and cheilosis are common in patients with water- soluble vitamin deficiencies. Florid beriberi, pellagra, and scurvy are not commonly seen unless malabsorption has been particularly severe or long-lasting. Fat-soluble vitamin deficiencies also are unlikely to develop except when malabsorption has been long-standing because of substantial body stores.

    Miscellaneous findings occasionally seen in patients with malabsorption can provide clues to the diagnosis. Aphthous ulcers in the mouth may be seen with celiac disease, Behçet’s syndrome, or Crohn’s disease. Hyperpigmentation is seen in Whipple’s disease, and dermatitis herpetiformis (pruritic, blistering skin lesions) is seen in celiac disease. Scleroderma can manifest with tight skin, digital ulceration, nail changes, and Raynaud’s phenomenon. Chronic sinusitis, bronchitis, and recurrent pneumonia suggest cystic fibrosis or IgA deficiency. Several systemic diseases can be associated with malabsorption syndrome (Box 3).

    Box 3
    Systemic Diseases Associated with Malabsorption or Maldigestion

    Endocrine Diseases

    •   Addison’s disease

    •   Diabetes mellitus

    •   Hypoparathyroidism

    •   Hyperthyroidism, hypothyroidism

    Collagen-Vascular and Miscellaneous Diseases

    •   AIDS

    •   Amyloidosis

    •   Scleroderma

    •   Vasculitis (systemic lupus erythematosus, polyarteritis nodosa)


    Routine Laboratory Tests

    Routine laboratory tests (Box 4) commonly are abnormal in patients with established malabsorption syndrome. Anemia is common but not universal. Iron deficiency anemia may be the only finding in some patients with celiac disease. Microcytic anemia may be presentin Whipple’s disease (due to occult blood loss) and in lymphomas manifesting with malabsorption. Macrocytic anemia due to folate or vitamin B12 deficiency can occur in short bowel syndrome, small bowel bacterial overgrowth, or ileal disease. Lymphopenia may be present in patients with AIDS or lymphangiectasia.

    Box 4
    Laboratory Tests for Evaluation of Malabsorption or Maldigestion

    Routine Blood Tests

    •    Complete blood count
    •    Hemoglobin/hematocrit
    •    Platelet count
    •    WBC differential count

    Biochemistry Tests

    •   Blood urea nitrogen
    •    Potassium
    •    Prothrombin time
    •    Serum albumin
    •    Serum calcium
    •    Serum creatinine

    Blood Levels of Potentially Malabsorbed  Substances

    •   Serum iron, vitamin B12, folate, 25-OH vitamin D, carotene

    Fat absorption

    •    Qualitative fecal fat
    •    Quantitative fecal fat

    Protein Absorption and Protein-Losing Enteropathy

    • α1-Antitrypsin clearance
    • Fecal nitrogen excretion

    Carbohydrate Absorption

    • Osmotic gap in stool water
    • Quantitative excretion (anthrone)
    • Stool pH <5.5
    • Stool reducing substances
    • D-Xylose absorption test
    • Oral glucose, sucrose, and lactose tolerance tests
    • Breath hydrogen tests

    Vitamin B12  Absorption

    • Serum B12 level

    Bile Acid Malabsorption

    • 14C-glycocholic acid breath test
    • Fecal bile acid excretion
    • Serum 7α-hydroxy-4-cholesten-3-one (C4)
    • 75SeHCAT retention

    Small Bowel Bacterial Overgrowth

    • 14C-glycocholic acid breath test
    • 14C-xylose breath test
    • Glucose breath hydrogen test
    • Quantitative culture of jejunal aspirate

    Exocrine Pancreatic Insufficiency

    • Secretin/CCK test
    • Stool elastase or chymotrypsin concentration

    Serologic Testing for Celiac Disease

    • Anti-tissue transglutaminase antibody (lgA)
    • Anti-endomysial antibody (lgA)

    Abbreviations: CCK = cholecystokinin; SLE = systemic lupus erythematosus; 75SeHCAT = selenium-75-labeled taurohomocholic acid; WBC = white blood cell.

    Electrolyte abnormalities may be due to a combination of poor intake and excess loss in stool. Renal function usually is well maintained in malabsorption syndrome, but blood urea nitrogen may be low due to poor protein absorption, and serum creatinine concentration may be low due to depletion of muscle mass. Serum calcium levels may be low due to malabsorption, vitamin D deficiency, or intraluminal complexing of calcium by fatty acids.

    Hypomagnesemia can produce hypocalcemia or hypokalemia that is resistant to intravenous repletion. Serum phosphorus, cholesterol, and triglyceride levels may be reduced due to poor intake or malabsorption. Liver tests may be abnormal due to fatty liver. Serum protein and albumin levels are well preserved in patients with malabsorption unless protein-losing enteropathy or an acute illness is present.

    Prothrombin time is normal unless vitamin K malabsorption (typically associated with steatorrhea), anticoagulant therapy, antibiotic therapy, or colectomy is present.

    Assays are available for several potentially malabsorbed substances, including iron, vitamin B12, folate, 25-hydroxyvitamin D, and β- carotene. Malabsorption tends to lower blood levels, but substantial body stores of many of these can mitigate the reduction in concentration that otherwise might occur. Thus, the sensitivity and specificity of these assays for malabsorption are poor.

    Tests for Malabsorption Fat Malabsorption

    The simplest test for fat malabsorption is a qualitative microscopic examination of stool using a fat-soluble stain, such as Sudan III. The finding of more than 5 stained droplets per high power field is abnormal and correlates well with quantitative measurement of fecal fat excretion. The test is subject to false-positive results with some drugs and food additives, such as mineral oil, orlistat, and olestra.

    A more precise estimate of fat absorption is obtained by a quantitative analysis of a timed stool collection (48 or 72 hours). During the collection, a diary of dietary intake should be maintained so that fat excretion can be assessed as a percentage of intake. Normal fat excretion is <7% of intake when stool weight is normal, but it can be twice as high due to voluminous diarrhea without indicating defective mucosal transport of fat. Thus, fat excretion must be judged against stool weight. Stool fat concentration (grams of fat per 100 grams of stool) also is of value. Pancreatic exocrine insufficiency is associated with high fecal fat concentration (>10 g/100 g stool) because unlike hydrolyzed fat, unhydrolyzed fat does not stimulate colonic water and electrolyte secretion that would dilute fecal fat concentration.

    Protein Malabsorption

    Fecal nitrogen excretion can be employed as a marker of protein malabsorption, but is not often used in clinical medicine because it adds little to the evaluation. If protein-losing enteropathy is suspected, an α1-antitrypsin clearance study can be done. In this study, fecal excretion of α1-antitrypsin, a serum protein that is relatively resistant to hydrolysis by luminal enzymes, is divided by serum concentration of α1-antitrypsin, and the volume of serum leaked into the lumen can be calculated. Values of more than 180 mL/day are associated with hypoalbuminemia.

    Carbohydrate Malabsorption

    Carbohydrate malabsorption is difficult to measure directly because fermentation of malabsorbed carbohydrate by colonic bacteria reduces the amount of intact carbohydrate that can be recovered in stool.

    Indirect estimates of carbohydrate malabsorption can be made by examining fecal pH (<5.5 with carbohydrate malabsorption) or fecal osmotic gap (> 100 mOsm/kg with osmotic diarrhea). Oral carbohydrate tolerance tests may be used to evaluate absorption of sugars, such as lactose or fructose. Following an oral load of a given sugar, blood glucose levels are monitored; failure of blood glucose to increase suggests malabsorption.

    Another test for carbohydrate malabsorption is the D-xylose absorption test. In this test, a 25-gram dose of D-xylose is given orally; blood xylose levels are measured 1 and 3 hours later, and urinary excretion of xylose is measured for 5 hours. Failure of blood xylose to rise above 20 mg/dL at 1 hour or above 22.5 mg/dL at 3 hours or failure of urinary excretion to exceed 5 g in 5 hours suggests malabsorption. In addition, because xylose does not require pancreatic enzymes or bile acids for absorption, an abnormal D-xylose test suggests a mucosal problem as the cause for malabsorption. The results of this test can be misleading if the patient is dehydrated or has ascites, if renal function is compromised, or if bacterial overgrowth is present in the upper small bowel.

    Breath hydrogen testing is another method to assess carbohydrate absorption. If substrates such as lactose or sucrose are not absorbed in the small intestine, they pass into the colon, where bacterial fermentation produces hydrogen gas. The hydrogen is absorbed into the bloodstream and then is exhaled. The concentration of hydrogen in exhaled breath can be measured easily; a rise of more than 10 to 20 ppm after ingestion of a specific substrate is consistent with malabsorption. False-positive results can be seen in patients with small bowel bacterial overgrowth, and false-negative results can be seen in patients who lack hydrogen-producing flora or who have been on antibiotics recently.

    Vitamin B12  Malabsorption

    Although the Schilling test has been used to measure Vitamin B12 absorption, commercial testing kits are no longer available in the United States. Instead, serum B12 levels are measured: low levels are consistent with B12 malabsorption, but normal levels do not exclude it because B12 is stored in the liver and can maintain serum levels for several years.

    Bile Acid Malabsorption

    Tests for bile acid malabsorption are not widely available in the United States. Direct measurement of bile acid excretion has been used mainly in research studies. Retention of a radioactive taurocholic acid analogue (SeHCAT, selenium-75-labeled taurohomocholic acid)

    is used in Europe to assess bile acid malabsorption. A breath test using 14C-glycocholic acid has been used for evaluating small bowel bacterial overgrowth, but it may have application for assessing bile acid malabsorption as well. Serum 7α-hydroxy-4-cholesten-3-one (C4) reflects bile acid synthesis; higher levels reflect increased synthesis in patients with bile acid malabsorption.

    Small Bowel Bacterial Overgrowth

    The gold standard method used to test for small bowel bacterial overgrowth in the upper intestine is quantitative culture of jejunal fluid. The sample can be obtained during endoscopy and sent to the laboratory with instructions to quantitate the aerobic and anaerobic flora. Finding more than 105bacteria per mL confirms bacterial overgrowth. Breath tests using glucose, 14C-xylose, and lactulose also have been described for this purpose.

    Pancreatic Exocrine Insufficiency

    Tests for pancreatic exocrine insufficiency are not commonly used. The gold standard test is a secretin test. This study requires duodenal intubation, injection of secretin, and measurement of bicarbonate output. A tubeless test, the bentiromide test, had average clinical utility; it is no longer available in the United States. Measurement of fecal chymotrypsin or elastase activity is only moderately useful in predicting the presence of exocrine pancreatic insufficiency. For most situations, a therapeutic trial using a high dose of pancreatic enzymes with monitoring of the effect on steatorrhea is the best that can be done.

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  4. 4
    Evaluation of Suspected Malabsorption

    When malabsorption is suspected because of the history, physical findings, and setting, the physician must decide if the malabsorption involves a specific nutrient or represents a generalized process (Figure 1). If the malabsorption seems to be specific, a diet and symptom diary, breath tests using the presumptively malabsorbed substrate, and stool pH to identify acid stools seen with carbohydrate malabsorption are reasonable diagnostic maneuvers.

    FIGURE 1    Flow chart for evaluation of malabsorption or  maldigestion. Abbreviations: CT = computed tomography; R/O = rule out; SB = small bowel.

    Suspected generalized malabsorption requires a more intense evaluation. Steatorrhea should be confirmed with either a qualitative fecal fat test (e.g., Sudan stain) or a quantitative stool collection for measurement of fat excretion. If steatorrhea is confirmed, the small bowel should be visualized with either capsule endoscopy or radiography (small bowel follow-through examination or computed tomography) and biopsied from above by enteroscopy and from below by colonoscopy. During enteroscopy, an aspirate of small bowel contents can be obtained for quantitative culture to look for small bowel bacterial overgrowth. An alternative method to detect small bowel bacterial overgrowth is breath testing (see earlier). Stool samples also should be examined with microscopy or immunoassay for the presence of parasites that may be associated with malabsorption.

    This sequence of evaluation often leads to a specific diagnosis.

    When it does not, empiric trials of pancreatic enzyme replacement or bile acid supplementation can lead to a presumptive diagnosis of pancreatic exocrine insufficiency or bile acid deficiency. Hard endpoints (e.g., quantitative fat excretion) should be used to assess the effectiveness of these empiric trials.

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  5. 5
    Specific Disorders Associated with Malabsorption

    Malabsorption of Specific Nutrients

    Disaccharidase Deficiency

    Ingested disaccharides such as lactose and sucrose and starch- digestion products such as maltotriose and α-limit dextrins must be hydrolyzed by brush border enzymes into monosaccharides for abosorption by the mucosa. If these brush border enzymes are not active or if the brush border is damaged, malabsorption of the specific carbohydrate substrate results. This can result in gaseousness or osmotic diarrhea when those substrates are ingested. This rarely occurs on a congenital basis, but it commonly occurs as an acquired disorder.

    Lactase deficiency is the most common acquired disaccharidase deficiency. Infant mammals all rely on lactose as the carbohydrate source in milk, but lactase activity is shut off after weaning in most species. Most human populations lose lactase activity during adolescence as a normal part of maturation. Members of the northern European gene pool might maintain lactase activity into adult life, but lactase activity declines gradually in many. At some point the amount of lactose ingested might exceed the ability of the remaining enzyme to hydrolyze it, resulting in lactose malabsorption and symptoms.

    This also can occur with acute conditions such as gastroenteritis that can disturb the mucosa and temporarily reduce lactase activity.

    Patients might not recognize lactose ingestion as a cause of their problem because they have not had difficulty tolerating lactose in the past. Restriction of lactose in the diet (or use of products that have predigested lactose) mitigates symptoms. Use of exogenous lactase as a tablet may only be partially effective because of incomplete hydrolysis of ingested lactose.

    Transport Defects at the Brush Border

    Glucose-galactose malabsorption is a rare congenital disorder resulting from an inactive hexose transporter in the brush border. Hydrolysis of lactose is intact, but transport across the apical membrane of the enterocyte fails to occur. Fructose absorption, which is mediated by a different carrier, is unaffected.

    In all human beings, the ability to absorb fructose is limited by the availability of carriers in the brush border and may be overwhelmed when excess fructose is ingested. This can occur relatively easily nowadays, because high-fructose corn syrup is used frequently as a sweetener in commercial products such as soda pop. Limiting the amount of fructose ingested will reduce symptoms.

    Abetalipoproteinemia is a rare condition that prevents absorption of long-chain fatty acids due to failure to form chylomicrons. Use of medium-chain triglycerides that do not require transport in chylomicrons can bypass this defect.

    Pernicious anemia develops when failure to secrete intrinsic factor in the stomach prevents vitamin B12 absorption by the ileal mucosa. Parenteral replacement with cyanocobalamin by injection (Cyanoject) or nasal spray (Nascobal) is necessary.

    Generalized Malabsorption

    Celiac Disease

    Celiac disease (also known as celiac sprue) is a disorder in which the mucosa of the small bowel is damaged due to activation of the mucosal immune system by ingestion of gluten, a protein component found in wheat, barley, and rye. People who have HLA-DQ2 or DQ8 are susceptible to this condition because these specific antigen- presenting proteins produce particularly strong reactions by interacting with a unique peptide digestion product of gluten. Tissue transglutaminase, an enzyme produced in the mucosa, is an important cofactor in pathogenesis by amplifying the immunogenicity of gluten peptide fragments and is the target of autoantibodies that are characteristic of this disease. The condition produces generalized malabsorption by destroying the villi of the small intestine, reducing the surface area available for absorption.

    In addition to malabsorption syndrome with diarrhea and weight loss, celiac disease can produce a host of nonspecific symptoms, including abdominal pain, fatigue, muscle and joint pains, and headaches and seemingly unrelated problems such as iron deficiency anemia, abnormal liver tests, and osteoporosis. These protean manifestations mean that celiac disease must be considered in the differential diagnosis of many conditions. The clinical course is quite variable, with symptoms coming and going. Symptoms can develop during childhood and produce growth retardation or first become manifest in adulthood.

    Testing for celiac disease has been simplified by the development of an assay for anti–tissue transglutaminase antibodies. This test largely supplants measurement of antigluten antibodies, although these remain of some use in evaluating adherence to a gluten-free diet. IgA antibodies are the most useful for diagnosis, but IgA deficiency is common enough that an IgA level should be measured concomitantly.

    Although serologic tests have high sensitivity and specificity, the implications of adhering to a gluten-free diet are so extreme that the diagnosis of celiac disease should be confirmed whenever possible by small bowel mucosal biopsy, now obtained routinely by endoscopy.

    An empiric trial of a gluten-free diet may be difficult to interpret because many persons with gastrointestinal symptoms improve with dietary carbohydrate restriction. Wheat starch is particularly hard to digest (due to gluten coating wheat starch granules), and ordinarily 20% of wheat starch is not absorbed by the small bowel and enters the colon.

    Treatment of celiac disease at present involves strict lifetime exclusion of gluten from the diet. This is a difficult regimen that excludes most processed foods. Assistance of a dietitian is most helpful. The prognosis with effective treatment is very good.

    Symptoms should respond to the diet within weeks; failure to do so should prompt an examination of compliance with the diet or reconsideration of the diagnosis. Failure to respond may be seen when lymphoma or adenocarcinoma complicate the course of celiac disease or in cases of “refractory sprue” or “collagenous sprue,” which can have a different autoimmune basis from classic celiac disease and which might respond to immunosuppressive drugs such as corticosteroids or azathioprine (Imuran).1 Persistent diarrhea may be observed in patients with celiac disease who have concomitant microscopic colitis, another condition that is linked to HLA-DQ2 and HLA-DQ8.

    Inflammatory Diseases

    Diseases that produce extensive mucosal damage by inflammation cause generalized malabsorption by reduction of mucosal surface area, by promotion of small bowel bacterial overgrowth, by ileal dysfunction, or by development of enteroenteral or enterocolic fistulas. Examples include jejunoileitis due to Crohn’s disease, nongranulomatous ulcerative jejunoileitis, radiation enteritis, and chronic mesenteric ischemia. With Crohn’s disease, previous resection can add to the problem (see later). Therapy aimed at the underlying process can improve absorption; in some cases (e.g., radiation enteritis) no effective therapy is available for the underlying problem, and symptomatic management is all that is possible. This includes use of antidiarrheal drugs to prolong contact time between luminal contents and the small bowel mucosa, ingestion of a reduced fat diet to reduce steatorrhea, and use of vitamin and mineral supplements to prevent deficiency states.

    Infiltrative Disorders

    Several conditions involve infiltration of the intestinal mucosa with cells or extracellular matrix that impede absorption or modify mucosal function by secretion of cytokines and other regulatory substances. These include eosinophilic gastroenteritis, systemic mastocytosis, immunoproliferative small intestinal disease (IPSID), lymphoma, and amyloidosis. These conditions are diagnosed by mucosal biopsy, but special stains might have to be employed to identify the infiltrating cells or matrix accurately.

    Treatment of the underlying processes can improve absorption, but it is not uniformly effective. For eosinophilic gastroenteritis, a hypoallergenic (elimination) diet and corticosteroids may be useful.

    Mild systemic mastocytosis is treated with the mast cell-stabilizer sodium chromoglycate, H1- and H2-receptor antagonists, and low-? dose aspirin. More advanced disease might respond to interferon or cytotoxic chemotherapy. IPSID initially is treated with antibiotics because small bowel bacterial overgrowth may be a causative factor. Once malignant change has occurred, it is treated like lymphoma with cytotoxic chemotherapy. Amyloidosis affecting the gut is not amenable to therapy and is usually fatal.

    Infectious Diseases

     Small Bowel Bacterial Overgrowth

    Small bowel bacterial overgrowth in the jejunum can produce generalized malabsorption. It can occur whenever the mechanisms that reduce overgrowth are compromised. These situations include achlorhydria or hypochlorhydria, motility disorders of the small intestine (e.g., diabetes mellitus or scleroderma), and anatomic alterations (e.g., diverticulosis, gastrocolic fistula, or blind loops postoperatively). Fat malabsorption is attributed to bacterial deconjugation of bile acid. Bacterial toxins or free fatty acids can produce patchy mucosal damage, leading to less efficient carbohydrate and protein absorption. Bacteria also can compete with the mucosa for uptake of certain nutrients such as vitamin B12.

    Diagnosis of small bowel bacterial overgrowth can be difficult (see earlier). Treatment consists of antibiotic therapy unless a surgically correctable anatomic defect is discovered. Tetracycline is no longer uniformly effective; amoxicillin–clavulinic acid (Augmentin), cephalosporins, ciprofloxacin (Cipro), metronidazole (Flagyl), and rifaximin (Xifaxan) may be employed. Therapy should be given for 1 to 2 weeks initially and then discontinued. It should be restarted when symptoms recur. If this occurs quickly, longer treatment periods should be considered. Continuous antibiotic therapy is needed rarely.

    Tropical Sprue

    Tropical sprue is a progressive, chronic malabsorptive condition occurring in both the indigenous population and in visitors residing in certain tropical countries for extended periods. The prevalence of tropical sprue seems to be decreasing for uncertain reasons. The disease starts as an acute diarrheal disease that becomes a persistent diarrhea associated with substantial weight loss and typically megaloblastic anemia. Villi become shortened and thickened (partial villous atrophy), but the flat mucosa of celiac disease is not usually present. Enterocytes have disrupted brush borders and can have megaloblastic changes; the submucosa has a chronic inflammatory infiltrate. Intestinal biopsy is required for diagnosis.

    Currently, tropical sprue is believed to represent a form of bacterial overgrowth with organisms that secrete enterotoxins. Most patients have evidence of excessive gram-negative bacterial colonization of the jejunum. The declining prevalence of tropical sprue may be due to improved nutrition, better sanitation, or prompt treatment of acute diarrhea with antibiotics. Treatment consists of pharmacologic doses of folic acid1 (folate) (5 mg daily3), injection of cyanocobalamin (if deficient), and antibiotic therapy for 1 to 6 months. Tetracycline1 250 mg four times a day or sulfonamide is the treatment of choice. Newer antibiotics have not been tested extensively in this condition. Improvement should be noted after a few weeks. The prognosis with treatment is excellent; without treatment, tropical sprue can be fatal. Recurrence can occur.

    Whipple’s Disease

    Whipple’s disease is a rare chronic bacterial infection with multisystem involvement. The small bowel typically is heavily infiltrated with foamy macrophages containing periodic acid–Schiff (PAS)-positive material, distorting the villi. Small bowel biopsy with special stains or electron microscopy or a specific polymerase chain reaction (PCR) is diagnostic. Foamy macrophages and bacteria can be found outside the intestine in lymph nodes, spleen, liver, central nervous system, heart, and synovium. Accordingly, symptoms are protean. The bacterium has been identified as Tropheryma whippelii, a relative of Acinetobacter. It does not appear to be very contagious, and no direct person-to-person transmission has been demonstrated.

    Presumably, differences in host resistance allow proliferation within macrophages without clearance of the bacteria.

    Whipple’s disease occurs mainly in older white men, but women and all ethnic groups are susceptible. Patients can present with malabsorption syndrome or with symptoms related to the extraintestinal disease (arthritis, fever, dementia, headache, or muscle weakness). Gross or occult gastrointestinal bleeding can occur.

    Protein-losing enteropathy may be present.

    Treatment with any of several antibiotics (penicillin, erythromycin, ampicillin, tetracycline, chloramphenicol, or trimethoprim- sulfamethoxazole [TMP-SMX]) produces excellent symptomatic responses within days to weeks, but it should be continued for months to years. Even with protracted courses, relapses are common.

    Other Infections

    Mycobacterium avium–intracellulare is another chronic bacterial infection that can cause malabsorption, particularly in patients with AIDS. Mucosal biopsy with special stains to distinguish it from Whipple’s disease is essential. Antibiotic therapy can reduce the intensity of infection; clearance depends on immunologic reconstitution with antiretroviral therapy. Clarithromycin (Biaxin) and ethambutol (Myambutol) are recommended as initial therapy.

    Parasitic diseases can produce malabsorption by competing for nutrients and causing mechanical occlusion of the absorptive surface and epithelial damage. Protozoa that may be associated with malabsorption include Giardia lamblia, Isospora belli, Cryptosporidium, and Enterocytozoon bieneusi. Tapeworms associated with malabsorption include Taenia saginata (beef tapeworm), Hymenolepis nana (dwarf tapeworm), and Diphyllobothrium latum (fish tapeworm).

    Giardia lamblia is a cosmopolitan parasite acquired from contaminated water or from another person by fecal-oral transmission. Cysts are relatively hardy, and ingestion of as few as 10 cysts is sufficient to establish infection. Patients with dysgammaglobulinemia (especially IgA deficiency) are likely to become infected. Diagnosis depends on finding the organism (cysts or trophozoites) in stool by microscopy (sensitivity ~50% for a single specimen), or detection of giardia antigens by immunologic testing of stool (sensitivity >90%), or discovery of the organism on small bowel biopsy.

    Therapy consists of a single dose of tinidazole (Tindamax) (2 g), metronidazole (Flagyl)1 (250 mg three times a day for a week), nitazoxanide (Alinia) (500 mg twice a day for three days), or quinacrine2  (100 mg three times a day for a week).

    Isospora belli and Cryptosporidium spp. are coccidia, protozoa that disrupt the epithelium by intracellular invasion (Isospora) or by attaching to the brush border, destroying microvilli (Cryptosporidium). Stool examination or small bowel biopsy can identify the organism.

    Cryptosporidium antigen can be discovered by immunoassay on stool with excellent sensitivity. Isospora can be treated with TMP-SMX1 or furazolidone.2Cryptosporidium can be treated by nitazoxanide.

    Microsporidia are intracellular organisms now believed to be most closely related to fungi and are implicated in diarrhea and malabsorption in patients with AIDS and other immunodeficiency states. Small bowel biopsy can show partial villous atrophy, and electron microscopy displays characteristic changes. Stool examination occasionally is helpful. No treatment is of proven value.

    Tapeworms compete with their hosts for nutrients in the lumen.

    Diphyllobothrium latum can produce vitamin B12 deficiency. The others can result in more extensive nutritional deficiencies. Diagnosis is based on stool examination, and treatment depends on the particular organism identified.

    Luminal Problems Causing Malabsorption Pancreatic Exocrine Insufficiency

    Pancreatic exocrine insufficiency is the most common luminal problem that results in maldigestion. Patients develop symptoms of malabsorption when pancreatic enzyme secretion is reduced by >90%. There are several clinical features that distinguish pancreatic exocrine insufficiency from mucosal disorders, such as celiac disease. When fat is not digested, it is transported through the gastrointestinal tract as intact triglyceride, which can appear as oil in the stool. In contrast, if fat is digested but not absorbed, it is in the form of fatty acids that can produce secretory diarrhea in the colon, resulting in more voluminous, even watery stools. This has two important ramifications: Fecal fat concentration is lower with mucosal disease (typically <9% by weight), and hypocalcemia due to formation of soaps (calcium plus 2 fatty acids) is seen with mucosal disease but not with pancreatic exocrine insufficiency. In addition, patients with mucosal disease tend to have more problems with water-soluble vitamin deficiencies than those with pancreatic exocrine insufficiency. In some patients with pancreatic exocrine insufficiency, carbohydrate malabsorption can produce substantial bloating, flatulence, and watery diarrhea.

    Tests to document pancreatic exocrine insufficiency are not widely available or are nonspecific (see earlier), and so diagnosis usually hinges on a consistent history, demonstration of anatomic problems in the pancreas (calcification or abnormal ducts), and documentation of a response of steatorrhea to empiric treatment with a large dose of exogenous enzymes.

    Bile Acid Deficiency

    Bile acid deficiency is a less common cause of maldigestion, and malabsorption in this setting is limited to fat and fat-soluble vitamins. The usual setting is a patient with an extensive ileal resection (see later), but this also occurs in certain cholestatic conditions in which bile acid secretion by the liver is markedly compromised, such as advanced primary biliary cirrhosis, or complete extrahepatic biliary obstruction. As with pancreatic exocrine insufficiency, stools tend to have high fat concentrations (>9% by weight) when bile acid secretion is limited by hepatic or biliary disorders.

    Zollinger-Ellison Syndrome

    Zollinger-Ellison syndrome produces several abnormalities that can affect absorption. High rates of gastric acid secretion produce persistently low pH in the duodenum, which precipitates bile acid and inactivates pancreatic enzymes. In addition, excess acid can damage the absorptive cells directly.

    Postoperative Malabsorption

    Substantial malabsorption can result from gastric surgeries. Weight loss can result from inadequate intake due to early satiety or symptoms of dumping syndrome. Malabsorption can result from impaired mechanical disruption of food, mismatching of chyme delivery and enzyme secretion, rapid transit, or small bowel bacterial overgrowth due to loss of the gastric acid barrier. In addition, gastric surgery sometimes brings out latent celiac disease.

    Short intestinal resections are well tolerated, but more extensive resections produce diarrhea and malabsorption of variable severity. When these symptoms are associated with weight loss or dehydrating diarrhea, short bowel syndrome is said to exist. In general, nutrient absorptive needs can be met if at least 100 cm of jejunum are preserved, but fluid absorption will be insufficient and diarrhea may be profuse. The process of intestinal adaptation permits improved absorption with time; it depends on exposure of the absorptive surface to nutrients. Absorption of specific substances, such as bile acids or vitamin B12, is reduced permanently by resection of the terminal ileum.

    Malabsorption in short bowel syndrome is not due solely to loss of absorptive surface area. Gastric acid hypersecretion, bile acid deficiency, rapid transit (due to loss of the ileal brake), and bacterial overgrowth may be present. These conditions are amenable to treatment and therapy with antisecretory drugs, exogenous bile acids, opiate antidiarrheals, or antibiotics can produce substantial improvement. Injection of teduglutide, a glucagon-like peptide-2 intestinal growth factor, or growth hormone in combination with glutamine and a special diet have been approved as treatments for short bowel syndrome; they can reduce the volume of parenteral fluid or nutrients required. Results with small bowel transplantation are improving with the use of better immunosuppressive regimens, and it remains the only cure for select patients with postresection malabsorption.

    Attention to nutrition is vital in any patient with malabsorption. If adequate nutrition cannot be maintained by oral intake, nutritional therapy is needed. Because of impaired bowel function, success with enteral nutrition may be impossible; parenteral nutrition may be needed. It is important to distinguish between the need for supplemental fluid and electrolytes and the need for nutrients; total parenteral nutrition is not a good choice for patients who only require fluids and electrolytes.

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    1  Not FDA approved for this  indication.

    3  Exceeds dosage recommended by the  manufacturer.

    1  Not FDA approved for this  indication.

    2  Not available in the United  States.

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