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Normal Absorption in the Small Intestine
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Fifty to 100 g of fat is ingested daily by an adult, mainly as long-chain triglycerides. Pancreatic lipase hydrolyzes triglycerides to fatty acids and monoglycerides. The fatty acids and monoglycerides, along with fat-soluble vitamins, are complexed with bile acids to form a globular structure called a micelle.
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The micelles dissociate at the surface of the intestinal mucosal cell, and the fatty acids, monoglycerides, and fat-soluble vitamins move into the cell while the bile acids remain in the lumen. The bile acids are finally reabsorbed in the terminal ileum and pass to the liver for reexcretion (the enterohepatic circulation of bile acids).
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Fat absorption occurs mainly in the upper jejunum, and about 100 cm are required for normal fat absorption. In the intestinal cells, monoglycerides are further hydrolyzed by mucosal cell lipase. The fatty acids are then reconverted to triglycerides in the endoplasmic reticulum and complexed with protein, phospholipid, and some cholesterol to form chylomicrons. Chylomicrons exit the cell at the antiluminal border of the mucosal cell, enter intestinal lymphatics, and pass to the jugular vein via the thoracic duct.
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Medium-chain triglycerides (containing 6 to 10 fatty acids), which normally form a small component of fat in the diet, are handled differently. They are better absorbed because they are more completely hydrolyzed and form micelles more readily than long-chain triglycerides. Limited absorption (30% of an oral dose) is also possible without formation of micelles, the medium chain triglycerides passing directly into the mucosal cell, where they are hydrolyzed by cellular lipase into fatty acids. Medium-chain fatty acids can pass directly into the portal circulation without reesterification and formation of chylomicrons. For these reasons, medium-chain triglycerides are useful in the treatment of some patients with malabsorption syndrome.
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Absorption of Protein & Carbohydrate
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Proteins and carbohydrates are hydrolyzed by enzymes in saliva (amylase), gastric juice (pepsin), pancreatic juice (amylase, trypsin, and chymotrypsin), and intestinal juice (disaccharidases, carboxypeptidases) into amino acids and monosaccharides. Because they are hydrophilic molecules, these substances are absorbed into the mucosal cells and pass into the portal venous radicals.
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Definition of Malabsorption Syndrome
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Malabsorption syndrome is a clinical syndrome characterized by increased fecal excretion of fat (steatorrhea) and the systemic effects of deficiency of vitamins, minerals, protein, and carbohydrates (Table 39-3). The complete clinical syndrome of malabsorption may not be present in all patients. Some patients have malabsorption of specific types of dietary constituents.
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Steatorrhea is passage of soft, yellowish, greasy stools containing an increased amount of fat. The presence of steatorrhea is established when fat excretion exceeding 6 g/d is demonstrated in a 72-hour stool sample. The high fat content of the stool makes it float in water, and flushing it down the toilet may be difficult—a feature in a patient's history that is highly suggestive of steatorrhea.
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Pathophysiology of Malabsorption
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Deficiency of Pancreatic Enzymes
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Pancreatic juice contains numerous enzymes. Pancreatic lipase is essential for complete fat digestion, and its absence leads to steatorrhea. Pancreatic amylase and trypsin are important for carbohydrate and protein digestion, but their function can be taken over by other enzymes in intestinal juice.
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Absence of pancreatic lipase is usually the result of primary pancreatic disease, commonly chronic pancreatitis. Rarely, lipase secretion is normal but its activity is decreased, either because of increased gastric acidity (eg, Zollinger-Ellison syndrome) or because rapid gastric emptying dilutes pancreatic enzymes.
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Deficiency of Bile Acids
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Bile acid deficiency occurs when bile does not enter the intestine, as in biliary obstruction, or as a result of bile salt deconjugation in the intestinal lumen resulting from overgrowth of bacteria. The small intestine is free of bacteria in about 50% of individuals; in the remainder, small numbers of bacteria (up to 1000 organisms per gram of luminal contents) are present. The small intestine becomes colonized with bacteria when there is stasis of luminal contents from any cause.
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A third mechanism of bile acid deficiency is failure of reabsorption of bile acids in the terminal ileum, due either to absence or disease of that segment of intestine.
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Deficiency of bile acids results in failure of micelle formation, interfering with absorption of fat and fat-soluble vitamins. Medium-chain triglycerides, proteins, and carbohydrates are absorbed normally.
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Abnormalities in the Absorptive Mucosa
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Quantitative and qualitative abnormalities in the absorptive mucosa are a common cause of malabsorption. Quantitative abnormalities occur (1) when there is a reduction in the length of small intestine due to extensive surgical resection; or (2) when the surface area of villi decreases, as occurs in villous atrophy (Figure 39-3) (celiac disease, tropical sprue, giardiasis, radiation, etc) or when the villous surface is abnormal, as in severe giardiasis.
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Qualitative abnormalities of the villi such as amyloidosis and Whipple's disease also result in malabsorption.
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Decreased Intestinal Transit Time
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Digestion and absorption require a certain minimum amount of time. In conditions where there is increased intestinal motility such as carcinoid syndrome (serotonin stimulates smooth muscle) and after gastrectomy, there may be malabsorption.
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Failure of Removal of Intestinal Triglyceride
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Triglycerides formed in the mucosal cell must be complexed with a carrier protein to form chylomicrons before they can enter the intestinal lymphatics. This fails in abetalipoproteinemia, a rare autosomal recessive inherited disease characterized by decreased serum betalipoprotein levels and abnormal erythrocytes. The triglyceride accumulates in the intestinal mucosal cell (fatty change), which can be seen on intestinal biopsy.
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Synthesized chylomicrons pass from the intestine into the lymphatics. Obstruction of lymphatics, as in intestinal lymphangiectasia and extensive intestinal lymphomas, may cause malabsorption. In macroglobulinemia, IgM is precipitated in lymphatics and may obstruct them.
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Diseases Causing Malabsorption
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Celiac Disease (Nontropical Sprue; Gluten-Induced Enteropathy)
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Celiac disease is caused by the action of acidic peptides contained in the gliadin fraction of the wheat protein gluten on the intestinal mucosa. The exact mechanism of damage is not certain, but immunologic hypersensitivity seems most likely. Serum contains IgA antibodies to gliadin in most patients, and antibody titers fall when these patients are maintained on a gluten-free diet. The possibility that the disease is a direct toxic effect of gliadin on the mucosal cells has not been ruled out.
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Susceptibility to gluten-induced intestinal damage is rare and has a familial tendency; 80–90% of patients have the histocompatibility antigen human leukocyte antigen (HLA)-B8 or HLA-DR3.
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Celiac disease occurs commonly in children; onset in adults is not rare. Celiac disease is associated with dermatitis herpetiformis (see Chapter 61: Diseases of the Skin).
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The changes of celiac disease are restricted to the small intestinal mucosa. The basic abnormality is thought to be an increased rate of loss of epithelial cells. The crypt cell shows increased activity but cannot keep pace with the loss of cells, resulting in progressive decrease in height of villi (villous atrophy). The crypts are hyperplastic and become elongated. The epithelial cells show decreased cytoplasm and mucus, appearing cuboidal. There is associated lymphocytic infiltration of the epithelium, suggesting that cell-mediated immunologic mechanisms may have a part in the genesis of the lesion. Immunologic studies show the presence of anti-gliadin IgA antibodies in the mucosa.
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Intestinal biopsy shows a decrease in the villus:crypt ratio. Normally (Figure 39-1), the villi are 3–4 times the height of the crypts (ratio of 3–4:1); in celiac disease, the ratio decreases progressively (partial, subtotal, and total villous atrophy). The shortened villi are also wider than normal (spade-like rather than finger-like) and infiltrated by chronic inflammatory cells. In severe celiac disease, the villi are completely atrophic (ratio of 0:1, or total villous atrophy; Figure 39-3).
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Villous atrophy is a nonspecific abnormality resulting from increased loss of epithelial cells due to any cause. Total villous atrophy rarely occurs except in celiac disease.
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Clinical Features & Diagnosis
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Celiac disease presents with severe malabsorption syndrome. The diagnosis may be suggested by an abnormal mucosal pattern on small bowel follow-through radiologic studies and confirmed by the findings of total villous atrophy and epithelial abnormalities on jejunal biopsy.
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Withdrawal of gluten from the diet produces dramatic improvement in both clinical symptoms and histologic changes in the small intestine. The ultimate diagnostic test is the demonstration of reversal of histologic changes after the patient has been on a gluten-free diet for 6 months.
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Celiac disease is associated with an increased incidence of intestinal malignant lymphoma, most commonly of T cell origin. It is not known whether removal of gluten from the diet eliminates the risk of lymphoma.
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Tropical sprue is an acquired disease that is commonly seen in the Caribbean, Far East, and India. It is thought to result from chronic bacterial infection of the small intestine because treatment with broad-spectrum antibiotics is often successful.
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Tropical sprue occurs in adults and is characterized by a severe malabsorption syndrome in which folic acid deficiency is often a dominant feature.
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Jejunal biopsy shows villous atrophy that is usually partial. Total villous atrophy is rare. The correlation between the degree of villous atrophy and malabsorption is poor.
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Whipple's Disease (Intestinal Lipodystrophy)
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Whipple's disease is a rare disease characterized pathologically by distention of the lamina propria of the small intestine by macrophages with abundant pale foamy cytoplasm (Figure 39-4). The macrophages contain large numbers of bacilli (seen on electron microscopy) that produce a fine granular staining with periodic acid-Schiff (PAS) reagent. Infiltration of the mucosa by these cells results in a gross increase in size of the villi, which gives the mucosal surface a coarse appearance resembling the pile of a shaggy rug.
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Treatment with antibiotics causes improvement of symptoms as well as disappearance of the bacillary bodies, suggesting that this is also a form of bacterial infection. The specific organism or organisms responsible have not been identified.
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The disease occurs mainly in males over 30 years of age. Presentation is with severe malabsorption syndrome. The diagnosis may be made by demonstration of the typical macrophages on jejunal biopsy.
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Forty percent of patients have the abnormal macrophages in tissues other than the small intestine—usually lymph nodes, commonly mesenteric; rarely, the spleen, liver, kidney, lungs, heart, and brain may be affected. Fever is present in 30% of patients, and polyarthritis and polyserositis (pleural effusion and ascites) are common. Extraintestinal Whipple's disease may sometimes occur in the absence of intestinal symptoms.