0411-Diseases Producing Malabsorption and Maldigestion

Section 4

XI Diseases Producing Malabsorption and Maldigestion

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Charles K. Mansbach, II, MD

Professor of Medicine and Physiology, Division of Gastroenterology, Department of Medicine, University of Tennessee Health Science Center, College of Medicine, Memphis, TN

10.2310/7900.S04C11

Definition

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Malabsorption refers to the impaired intestinal absorption of nutrients. It can result from congenital defects in the transport of nutrients, from impaired digestive processes within the intestinal lumen, or from acquired defects in the intestinal absorptive cells that line the surface of the intestine. Maldigestion, another factor in nutrient absorption, refers to the impaired digestion of nutrients within the intestinal lumen. Although these two processes are pathophysiologically distinct, they are interdependent, and in clinical practice, malabsorption has come to signify derangements in both processes.

Overview of Diseases Producing Malabsorption

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Malabsorption is clinically defined as impaired absorption of fat (steatorrhea) because measuring 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 substances may be poorly absorbed, such as iron, vitamin B₁₂, calcium, bile salts, or, in certain hereditary conditions, specific amino acids, disaccharides, or monosaccharides.

etiology

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

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 be present. Patients may malabsorb vitamin B₁₂ because of a very diseased or previously resected (usually over 60 cm) terminal ileum. 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 shown by a prolonged prothrombin time, may also occur. Administration of vitamin K corrects the clotting defect in cases in which the extent of the liver disease is not severe enough to impede clotting factor synthesis. It is important to note that these vitamin deficiencies may occur in the absence of clinically evident steatorrhea.

Pancreatic Exocrine Insufficiency

Patients with pancreatic exocrine insufficiency may have up to 80 g of fat/day in the stool. That they absorb fat at all is the result of the action of gastric lipase. 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

clinical manifestations

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. The consistency of the stool softens, and in the presence of excess fat, the stool becomes more malodorous, floats on the toilet water, and is difficult to flush down the toilet. Oil drops or a lipid sheen may appear on the water. The excess gas in the stool causes the stool to float, not the fat.³

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 question of malabsorption is not raised because of a lack of change in the quality of the stools.

The diarrhea of malabsorption is classified as an osmotic diarrhea 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 and the conversion of oleic acid into its 10-hydroxy product, 10-hydroxystearate, which mimics the active incredient in castor oil, ricinoleic acid.

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.

tests for suspected malabsorption

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.

Measurement of Fecal Fat

Fecal fat can be measured qualitatively and quantitatively. The qualitative measurement of fecal fat using Sudan III staining has been shown to be surprisingly accurate,⁴ especially if clinically significant amounts of fat are being excreted. One group reported that counting and measuring the size of fat globules present in the stool significantly improved the sensitivity and specificity of the Sudan assay.⁴ As with many qualitative tests, however, accuracy varies with test performance and interpretation, making the skill of the observer 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 test cannot be performed unless the patient is able to eat at least 80 g, preferably 100 g, of fat a day. However, the test requires storage of the stool in a refrigerator for 3 days, making the chemical fat balance impractical in many hospital or home settings.

Xylose Absorption Test

The absorptive surface area of the intestine is measured by the ability of the patient to absorb xylose, a 5-carbon sugar. Unlike glucose, xylose is not actively absorbed by the intestine but is absorbed by the slower process of facilitative diffusion. In the xylose absorption test, 25 g of 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 reported to be 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 cases of chronic pancreatitis have visible calcifications on an abdominal plain film. Detection of pancreatic calcification can be increased if computed tomography (CT) or ultrasonography is used. CT or ultrasonography also can identify dilatated pancreatic ducts, another characteristic sign of chronic pancreatitis. Endoscopic retrograde pancreatography can also be helpful when ductular changes indicative of chronic pancreatitis are seen [see 4:V Diseases of the Pancreas].

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. Stricturing may be identified in some patients with radiation injury or injury caused by nonsteroidal antiinflammatory drugs. Hypoalbuminemia affecting the small intestine may lead to the so-called stack-of-coins sign seen on small bowel x-ray contrast examination.

Small Bowel Biopsy

An experienced pathologist can be helpful in supporting the diagnoses of gluten-sensitive enteropathy (GSE) (with or without dermatitis herpetiformis), hypogammaglobulinemic sprue, tropical sprue, Whipple disease, Mycobacterium avium complex disease, stasis 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].⁵ The most sensitive test of pancreatic exocrine function requires the passage of a double-lumen tube into the duodenum.⁶ Cholecystokinin (CCK) or secretin is administered intravenously, and gastric and duodenal secretions are collected separately. Secretin became unavailable in the United States when the manufacturer discontinued production in 1999, but a new formulation was approved by the Food and Drug Administration in 2004. 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.

Figure 1. Chemical Structure of Bentiromide

The noninvasive bentiromide test is based on the action of trypsin on bentiromide to yield para-aminobenzoic acid (PABA) and benzoyl-tyrosine [see Figure 1]. 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 amount of PABA excreted is significantly less, averaging 42%. Using the 57% excretion as a cutoff, the sensitivity of the bentiromide test is 67 to 80% and the specificity is 95%.⁷ PABA may also be measured in the plasma 120 minutes after ingestion of bentiromide, which may enhance the sensitivity of the test.⁸ Plasma measurements are helpful in cases of impaired renal excretion, which may be seen in the elderly. PABA is identified colorimetrically; thus, other arylamines can interfere with its determination (e.g., acetaminophen, lidocaine, procainamide, sulfonamides, and thiazide diuretics).⁹ In cases in which intestinal absorption is impaired, such as with celiac sprue, the absorption of released PABA may be reduced, leading to a falsely low urinary recovery. Unfortunately, the bentiromide test becomes positive only when the pancreatic gland is more than 90% destroyed. Nevertheless, in considering the workup of a patient with steatorrhea, the test may be useful because it takes an equal amount of glandular destruction to generate steatorrhea.

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 by the serum trypsinogen assay. Because the activation peptide of trypsin is not yet released and any active trypsin is quickly bound by a₁-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 that in healthy persons (2 to 18 ng/mL compared with 29 to 79 ng/mL in healthy persons).¹⁰ A low serum trypsinogen level appears to have a high degree of specificity for chronic pancreatitis but is only modestly sensitive.

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. The 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 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 synthetic 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 (g30 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.¹¹

Figure 2. Bile Acid Breath Test

To test for the presence of bile acid malabsorption, two methods are available, although 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 2], 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 to ¹⁴CO₂. In either event, the ¹⁴CO₂ appears in the breath in measurable amounts. The percentage of the ingested dose excreted in the breath increases if the intestinal lumen contains more bacteria than normal or if an excess of bile acids is delivered to the colon (ileal dysfunction). 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.¹² 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%.¹³

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.¹¹ Such defects may be the cause of primary bile acid malabsorption.

Diseases Producing Malabsorption

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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 were the same, caused by the major wheat protein gluten and, more specifically, its alcohol-soluble component, gliadin.¹⁴

GSE is generally considered less common in the United States than in Western Europe. However, a recent large multicenter study indicated that the prevalence of GSE in the United States in symptomatic patients (1 in 56) and in not-at-risk persons (1 in 133) is similar to that reported in Europe.¹⁵ Many patients today are identified as celiacs who do not manifest the classic symptoms of steatorrhea and weight loss.

Genetic and Etiologic Factors

GSE is associated with haplotypes HLA-DQ2 (DQA1*501, DQB1* 201) and HLA-DQ8 (DQA1*031, DQB1*302). In sets of monozygotic twins, 30% of the opposite twins from the incidence case do not have GSE. This condition leads to the belief that there is another, unknown (nongenetic) factor that is important in disease causation. 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.¹⁶

Pathogenesis

GSE is associated with impaired CCK release. CCK cells are either reduced in number or so defective that the amount of CCK present in the duodenal mucosa is greatly reduced.¹⁴ 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 not as effective as normal, and the intestine becomes secretory.¹⁴ 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 of 1.4 mM.¹⁷ Normally, the intestine has a postprandial bile salt concentration of 10 mM.¹⁸ A third cause of steatorrhea in GSE patients is a reduced surface area for absorption in the intestine. 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. A fourth cause of steatorrhea derives from the immature nature of the enterocytes of the intestinal absorptive cells, which face the intestinal lumen. These cells are poorly equipped to assemble chylomicrons and their triacylgylcerol cargo, both of which are complex processes and require mature cellular functions.

Diagnosis

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. Only after these patients have been treated do they realize, in retrospect, how ill they were. In population studies in which the presence of disease was determined by intestinal biopsy, people with a biopsy 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. Iron deficiency anemia is common in adult patients with GSE,¹⁹ and one study suggested that fractures may be the only sign of malabsorption in patients with undetected GSE.²⁰

Laboratory tests

Figure 3. Diagnosis of Gluten-Sensitive Enteropathy

Figure 4. Intestinal Biopsy: Untreated Celiac Sprue and Pancreatic Exocrine Insufficiency

In a patient in whom the suspicion of GSE is high (e.g., 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 3].²¹ Alternatively, the diagnosis might rest on small bowel biopsy findings [see Figure 4]. 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.¹⁴ 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 after 2 months, and the remainder may take up to 2 years. Even under the strictest dietary control, the biopsy findings might not return to normal. Most often, the patient remains 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.

Another helpful test is the identification of an antiendomysial antibody. This antibody is present in up to 95% of cases and is rarely present in control subjects.²² Other tests of malabsorption, such as the d-xylose absorption test or stool fat studies, may be abnormal. Low clotting factors, the presence of anemia caused by folate or iron deficiency, or osteoporosis may also be present. None of these conditions are specific for GSE, however.

Treatment

The treatment of GSE is a strict gluten-free diet. Because a gluten-free diet is a lifelong commitment, is more expensive than a normal diet, and may carry social limitations, it should not be recommended until the diagnosis of GSE is firmly established either histologically or by secure antibody testing. A gluten-free diet prohibits the intake of wheat, rye, and 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. Maintaining a gluten-free diet is important because intestinal lymphomas are more likely to develop in patients who do not follow such a diet.²³

Support groups, such as those organized by the Celiac Society of America, can be helpful, especially when the disease is newly diagnosed. Information such as what to look for on package labels and interesting recipes can be very instrumental in helping the patient maintain the gluten-free diet. During the trial period, beer, ale, and whiskey, which may contain enough gluten to sensitize the patient, should not be consumed. After the dietary response is clear, these drinks may be tried, if desired, to determine whether the patient is 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.

If the patient does not respond, the most likely reason is that the patient is not accurately following the diet. In such cases, it is helpful to have a dietitian carefully go over the patient's dietary history.¹⁴ 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. However, a minority of patients who do not respond to a gluten-free diet have what is called refractory sprue.²⁴ Patients with refractory sprue may require treatment with corticosteroids and other immunosuppressants, including azathioprine.²⁵

GSE-Associated Disorders

Dermatitis herpetiformis Many patients with dermatitis herpetiformis have GSE.²¹ 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.

Type 1 diabetes mellitus Patients with type 1 diabetes mellitus are at increased risk of developing GSE. With the use of antiendomysial antibodies as a screen, GSE has been found in three of 47 diabetic patients (6%), a much higher incidence than would be expected by chance.²⁶ Even when patients with type 1 diabetes mellitus show no apparent signs of malabsorption, they are at risk for developing celiac disease; screening for celiac disease in these patients therefore may be advisable.²⁷ One study reported a 5.7% prevalence of celiac sprue in patients with type 1 diabetes and noted a finding of increased autoimmune diseases in these patients.²⁸ The prevalence of autoimmune disorders in patients with celiac disease seems related to duration of gluten exposure, which provides further rationale for the early diagnosis and treatment of GSE.²⁹

other spruelike disorders

Tropical Sprue

Tropical sprue is a malabsorptive illness that appears in certain areas of the world, especially the tropics, in 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.³⁰ 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.³¹ Indians and Pakistanis living in the United States may take a longer time (up to 4 years) to excrete normal amounts of d-xylose.³² 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,³³ which colonize the upper intestinal tract.

Diagnosis 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%), folate and vitamin B₁₂ deficiency (75 to 100%), or an abnormal result on the Schilling test (96 to 100%) is much more common in tropical sprue than in nontropical sprue.³³ The symptoms can be quite severe, sometimes leading to death in endemic areas. However, the prognosis with appropriate treatment, in general, is excellent for patients either remaining in the tropics or returning to the United States.

Figure 5. Intestinal Biopsy: Tropical Sprue

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 5]. In normal North Americans and Europeans, thin villous structures are seen [see Figure 4]. 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.

Treatment Treatment of tropical sprue should begin with folic acid (5 mg/day).³³ 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 (< 4 months), folate given for 6 months to 1 year may suffice. For patients with a longer duration of symptoms (> 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 are not normalized.

Collagenous Sprue

Collagenous sprue is a rare, devastating disease in which a layer of collagen is 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 (those unresponsive to the gluten-exclusion diet).³⁴ 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.

Diagnosis 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 be responsive to the gluten-free diet.

Treatment 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. 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.³⁵

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 may experience malabsorption.³⁶ Patients with IgA deficiency also usually have a history of recurrent respiratory infections,³⁶ which further distinguishes them from patients who have GSE. The most common cause of malabsorption seen in this condition is giardiasis.

Diagnosis The diagnosis of hypogammaglobulinemic sprue 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.

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

small bowel disease secondary to surgery and radiation

Short Bowel Syndrome

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. Also, specialized mechanisms are present in the ileum that are not available to the jejunum, such as bile salt and vitamin B₁₂ 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 folic acid, Ca²⁺, and Fe²⁺ absorption. However, these can be replenished by appropriate medication.

Diagnosis The diagnosis of short bowel syndrome is made by a history of bowel resection in combination with clinical manifestations of the syndrome, such as diarrhea, steatorrhea, weight loss, trace-element deficiencies, hyponatremia, and hypokalemia.

Treatment Treatment of patients with short bowel syndrome depends on the location and the amount of the bowel that has been resected. Protein requires the greatest surface area for absorption.³⁷ 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 caloric supplements, having food finely chopped or ground, and eating foods containing medium-chain triglycerides, which can be absorbed in the absence of bile salts.³⁷ 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 both³⁸ and elaborates peptide YY (PYY),³⁹ which is the putative ileal break, 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 desired.

Radiation Enteritis

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. To prevent radiation injury, it may be advisable to irradiate patients on a turntable so that more than one part of the intestine receives the maximal amount of radiation.

Whipple Disease

Whipple disease is a rare multisystem disease caused by the bacterium Tropheryma whippelii.⁴⁰ The bacillus may be widespread throughout the body, but the sites of invasion show little sign of inflammation, suggesting that an autoimmune deficiency may create a predisposition to the disease.⁴¹ Accurate diagnosis is imperative because mortality approaches 100% without antibiotic treatment.

Diagnosis

Clinical manifestations Classically, Whipple disease begins in a middle-aged male with a nondeforming arthritis that usually starts years before the onset of the intestinal symptoms. Arthralgias, diarrhea, abdominal pain, and weight loss are the cardinal manifestations of Whipple disease. Other complaints include fever, abdominal distention, lymphadenopathy, hyperpigmentation of the skin, and steatorrhea.⁴² Many patients express the HLA-B27 isotype. Occasionally, intestinal symptoms are absent, even in some patients with central nervous system involvement.⁴³ 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.⁴⁴ Cardiac and pulmonary involvement may also be found.⁴⁵

Laboratory tests The recognition of Whipple disease in patients without intestinal symptoms or involvement by the disease has been increasing since the advent of polymerase chain reaction (PCR) techniques that identify the unique 16S ribosomal RNA of T. whippelii.⁴⁶

The diagnosis rests on identifying the classic periodic acid–Schiff (PAS)–positive macrophages, which contain sickleform particles.⁴² By far the most common site of biopsy that yields positive results is the intestine. The histologic lesion shows distended villi (clubbed villi) filled with the foamy, PAS-positive macrophages and lymphatic dilatation. A flat villous surface can be seen in extreme cases. 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. Central nervous system (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,⁴⁷ and a negative result on PCR may predict a low likelihood of clinical relapse.⁴⁸ Occasionally, a brain biopsy is required, which can be guided by magnetic resonance imaging.

Treatment 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 IM) for 2 weeks, followed by tetracycline (1 g) for 1 year. Typically today, trimethoprim- sulfamethoxazole (one double-strength tablet b.i.d.) is given for 1 year. 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 appear a year or more after treatment of the systemic and intestinal symptoms, especially if an antibiotic is administered that does not cross the blood-brain barrier. A progressive dementia may be seen, but the pathognomonic signs of CNS disease, when present, are oculomasticatory myorhythmia and oculofacial-skeletal myorhythmia.⁴⁹ Antibiotics that cross the blood-brain barrier are therefore required in the treatment of Whipple disease. Interestingly, the short period of penicillin-streptomycin administration is enough to block CNS symptoms, whereas even long-term trimethoprim- sulfamethoxazole therapy occasionally may not prevent CNS manifestations of Whipple disease.⁵⁰ 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.⁴⁶ Once CNS involvement occurs, treatment is usually not helpful, although with treatment, some improvement may be noted and the disease may not progress.

immunoproliferative small intestinal disease

Figure 6. Intestinal Biopsy: Primary Intestinal Lymphoma

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 6]. It is a B cell disorder involving the mucosa-associated lymphoid tissue (MALT). 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. In a series of Chinese patients, six of 45 patients with intestinal lymphoma had IPSID.⁵¹ These patients presented with severe malabsorption. Among the lymphoma patients without IPSID, 65% had abdominal pain, weight loss, abdominal masses, obstruction, and perforation. IPSID is associated with heavy chains (from IgA), with paraprotein present in the serum, urine, or jejunal fluid. Duodenography shows thickened folds and many nodular elevations without ulceration. The diagnosis may be made by small bowel biopsy in 85% of cases.⁵² Early in its course, the disease appears to be treatable with antibiotics. If allowed to progress, however, it may develop into more aggressive forms of lymphoma.⁵³

intestinal lymphangiectasia

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 occurs in certain cases of IPSID, granulomatous enteritis, tuberculous enteritis, or Whipple disease in which normal lymphatic drainage is blocked.

Diagnosis

The blockage of lymphatic drainage may result in chylous ascites, chyluria, or chylometrorrhea.⁵⁴ 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. With endoscopic examination, white villi, white nodules, and submucosal elevations may be noted.⁵⁵ 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.⁵⁶ On histologic examination, dilated lymphatics with club-shaped villi are seen, sometimes in asymptomatic patients, in whom the outcome is benign.

Treatment

Treatment is directed toward any identified causative process. In patients with the congenital condition, in whom improvement of the 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.

abetalipoproteinemia

In the rare congenital condition of abetalipoproteinemia, postprandial chylomicronemia does not develop in patients, 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 abetalipoproteinemia, patients with this disease have normally transcribed apolipoprotein B messenger RNA 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 the microsomal triglyceride transport protein.⁵⁷ This chaperonelike protein complex consisting of a 97 kDa M component and a 55 kDa P component (protein disulfide isomerase) helps translocate the apolipoprotein across the membrane of the endoplasmic reticulum.⁵⁸ Without 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, respectively. Because chylomicrons cannot transport the fat out of the enterocyte, it is presumed, but not proved, that the 80% of the lipid that is absorbed is absorbed via the portal vein.⁵⁹

Diagnosis

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 that causes a sensory ataxia because of the loss of position and vibratory sensations. The symptoms are similar to but less severe than those of Friedreich ataxia.⁶⁰ 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 having neurologic abnormalities, patients have acanthocytes in their blood. Acanthocytes are spiculated red cells that have a near-normal life span but demonstrate an increased susceptibility to mechanical trauma on in vitro 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.⁶¹

Treatment

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

Eosinophilic gastroenteritis is a rare disease that is characterized by the presence of eosinophilic infiltration of one or more portions of the gastrointestinal (GI) tract, anywhere from the esophagus to the colon, in conjunction with gastrointestinal symptoms. 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 eosinophilic gastroenteritis, but evidence suggests that eosinophils, once activated, can produce cytokines that self-perpetuate the accumulation of additional eosinophils. These cytokines are interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor, 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.⁶²

Diagnosis

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 eosinophilic gastroenteritis. 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.⁶³ 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.⁶⁴

Treatment

Most patients respond to conservative measures and steroids. Surgery should be avoided unless it is needed to relieve persistent 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

The prevalence of Crohn disease in North America ranges from 26.0 to 198.5 cases per 100,000 persons, with a maximal incidence in people of Jewish decent.^65,66

Pathogenesis

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 since the bile acid pool becomes progressively depleted with each meal.⁶⁷ Postprandial bile salt deficiency occurs despite the liver's response to bile acid loss from the enterohepatic circulation, which is to increase bile acid synthesis. 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 colon⁶⁸ if significant amounts of the ileum have been resected. 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.⁶⁹

Diagnosis

Crohn disease with malabsorption is suggested by the history (e.g., a prior ileal resection); by physical examination in which thickened, tender bowel may be felt; or by imaging studies (e.g., a small bowel barium study showing the absence of the terminal ileum and the presence of strictures, stellate ulcers, or cobblestoning of the mucosa). Ileal dysfunction secondary to ileal resection is suggested by the presence of diarrhea without steatorrhea, but it may difficult to differentiate this presentation from the stasis syndrome. Lipid malabsorption would be suggested by an increase in fat in the stool.

The loss of bile acids to the colon and thus to the enterohepatic circulation can be associated with no or minimal steatorrhea.⁷⁰

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).⁷¹ Thus, the diarrhea associated with Crohn disease may be caused not by active disease but by the results of ileal resection. This scenario is suggested by the finding that the diarrhea occurs when the patient first eats after surgery, a time when disease activity may be low secondary to the resection of areas of disease activity, 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].

Treatment

When the diarrhea is caused by bile acid loss, the treatment is cholestyramine (4 g a.c. and h.s.).⁷¹ 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, and 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 the short bowel syndrome. Similarly, patients who have numerous enteroenteric fistulae also have symptoms of short bowel syndrome because the fistulae may cause the chyme to bypass large sections of the small intestine. Both types of patients should be treated as if they had the short bowel syndrome [see Short Bowel Syndrome, above].

stasis (bacterial overgrowth) syndrome

The stasis (bacterial overgrowth) syndrome occurs when intestinal stasis leads to the opportunity for bacteria to proliferate locally. This condition has a multiplicity of causes. The most prominent causes are diabetes, scleroderma, intestinal diverticulosis, afferent loop following a Billroth II 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 that 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 found in the apical brush-border proteins.⁷² 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.⁷³ 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.⁷³

Diagnosis

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 bacteria,^74,75 bacterial metabolism of the vitamin to metabolically ineffective metabolites, and some internalization of the B₁₂ by the bacteria for its own metabolic uses. Folic acid levels are usually high secondary to bacterial production of folate.⁷⁶ 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 most often 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 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.

Treatment

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, as, for example, in small bowel diverticulosis, 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., trimethoprim-sulfamethoxazole, one double-strength tablet b.i.d.). The patient will need to be retreated if clinical symptoms reappear, or the patient can receive treatment for 1 week every month.

amyloidosis

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,⁷⁷ although most are asymptomatic. Endoscopically, mucosal erosion, friability, or polypoid protrusions can be seen.⁷⁸ 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 arterioles 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.⁷⁹ No specific effective therapy is available. If bacterial overgrowth is present, then appropriate antibiotics should be given.

systemic mastocytosis

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.⁶⁹ 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 antiinflammatory drugs, causing episodic disturbances of flushing, diarrhea, abdominal pain, and hypotension that may progress to syncope.⁸⁰

Excess histamine is excreted into the urine in excess in approximately 75% of patients, making the urinary excretion test useful for diagnostic purposes.⁸⁰ The urinary excretion of a metabolite of prostaglandin D₂ from mast cells may be an even better test.⁸¹ 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. In that event, proton pump inhibitors are effective in controlling symptoms. 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.

chronic pancreatitis with exocrine insufficiency

Most chronic pancreatitis is 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 4:5 Diseases of the Pancreas].

postgastrectomy steatorrhea

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, which are the sites of maximal concentrations of CCK and secretin-secreting cells and the active sites for folate, calcium, and iron absorption. Approximately 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, the affected 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 stabilize at a lower weight than they were before surgery. Osteopenia and iron deficiency anemia are also found. Constant small amounts of blood loss 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 the nonabsorbable heptaglutamyl folate (the common form of folate found in the diet) is also found.⁸² 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.⁸³ It is likely that these patients had clinically silent GSE before the operation. The operation itself causes modest steatorrhea (10 to 15 g 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 symptomatology. Therefore, if postgastrectomy patients exhibit excessive steatorrhea, an evaluation for GSE is warranted. Inflammatory bowel disease that develops in patients after gastrectomy may likewise be an indication of the presence of previously silent GSE.⁸⁴

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

CHARLES M. MANSBACH II, MD, Professor of Medicine and Physiology, Division of Gastroenterology, Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN

Figure 1 Janet Betries.

Figure 2 Dana Burns-Pizer.

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