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InternalMed_Harrison. and stool together or so-called factitious diarrhea, a form of Münchausen’s syndrome. When the calculated difference in the formula above is >50, an osmotic gap exists; its presence suggests that the diarrhea is due to a nonabsorbed dietary nutrient—e.g., a fatty acid and/or a carbohydrate. When this difference is <25, it is presumed that a dietary nutrient is not responsible for the diarrhea. Since elements of both osmotic diarrhea (i.e., due to malabsorption of a dietary nutrient) and secretory diarrhea may be present, this distinction at times is less clear-cut at the bedside than when used as a teaching example. Ideally, the presence of an osmotic gap will be associated with a marked decrease in stool output during a prolonged 1933 fast, while an osmotic gap will likely be absent in an individual whose stool output is not reduced substantially during a period of fasting.


InternalMed_Harrison

InternalMed_Harrison. The lengths of the small intestine and the colon are ~300 cm and ~80 cm, respectively. However, the effective functional surface area is ~600-fold greater than that of a hollow tube as a result of folds, villi (in the small intestine), and microvilli. The functional surface area of the small intestine is somewhat greater than that of a doubles tennis court. In addition to nutrient digestion and absorption, the intestinal epithelia have several other functions: 1. Barrier and immune defense. The intestine is exposed to a large number of potential antigens and enteric and invasive microorganisms, and it is extremely effective at preventing the entry of almost all of these agents. The intestinal mucosa also synthesizes and secretes secretory IgA. 2.


InternalMed_Harrison

InternalMed_Harrison. 2. Fluid and electrolyte absorption and secretion. The intestine absorbs ~7–8 L of fluid daily, a volume comprising dietary fluid intake (1–2 L/d) and salivary, gastric, pancreatic, biliary, and intestinal fluid (6–7 L/d). Several stimuli, especially bacteria and bacterial enterotoxins, induce fluid and electrolyte secretion that may lead to diarrhea (Chap. 160). 3. Synthesis and secretion of several proteins. The intestinal mucosa is a major site for the production of proteins, including apolipoproteins. 4. Production of several bioactive amines and peptides. The intestine is one of the largest endocrine organs in the body and produces several amines (e.g., 5-hydroxytryptophan) and peptides that serve as paracrine and hormonal mediators of intestinal function.


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InternalMed_Harrison. The small and large intestines are distinct anatomically (villi are present in the small intestine but are absent in the colon) and functionally (nutrient digestion and absorption take place in the small intestine but not in the colon). No precise anatomic characteristics separate duodenum, jejunum, and ileum, although certain nutrients are absorbed exclusively in specific areas of the small intestine. However, villous cells in the small intestine (surface epithelial cells in the colon) and crypt cells have distinct anatomic and functional characteristics. Intestinal epithelial cells are continuously renewed; new proliferating epithelial cells at the base of the crypt migrate over 48–72 h to the tip of the villus (or surface of the colon), where they exist as well-developed epithelial cells with digestive and absorptive function. This high rate of cell turnover explains the relatively rapid resolution of diarrhea and other digestive-tract side effects during chemotherapy as new cells


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InternalMed_Harrison. with digestive and absorptive function. This high rate of cell turnover explains the relatively rapid resolution of diarrhea and other digestive-tract side effects during chemotherapy as new cells not exposed to these toxic agents are produced. Equally important is the paradigm of separation of villous/surface cell and crypt cell functions. Digestive hydrolytic enzymes are present primarily in the brush border of villous epithelial cells. Absorptive and secretory functions are also separate: villous/surface cells are primarily, but not exclusively, the site for absorptive function, while secretory function is located in crypts of both the small and large intestines.


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InternalMed_Harrison. Nutrients, minerals, and vitamins are absorbed by one or more active-transport mechanisms. These mechanisms are energy dependent and are mediated by membrane transport proteins. These processes will result in the net movement of a substance against or in the absence of an electrochemical concentration gradient. Intestinal absorption of amino acids and monosaccharides (e.g., glucose) is also a specialized form of active transport—secondary active transport. The movement of actively transported nutrients against a concentration gradient is Na+ dependent and is due to a Na+ gradient across the apical membrane. The Na+ gradient is maintained by Na+,K+-adenosine triphosphatase (ATPase), the so-called Na+ pump located on the basolateral membrane, which extrudes Na+ and maintains low intracellular [Na] as well as the Na+ gradient across the apical membrane. As a result, active glucose absorption and glucose-stimulated Na+ absorption require both the apical membrane transport protein SGLT1


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InternalMed_Harrison. [Na] as well as the Na+ gradient across the apical membrane. As a result, active glucose absorption and glucose-stimulated Na+ absorption require both the apical membrane transport protein SGLT1 and the basolateral Na+,K+-ATPase. In addition to exhibiting Na+ for its absorption, glucose stimulates Na+ and fluid absorption; this effect is


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InternalMed_Harrison. Disorders of Absorption 1934 the physiologic basis of oral rehydration therapy for the treatment of diarrhea (Chap. 55). The mechanisms of intestinal fluid and electrolyte absorption and secretion are discussed in Chap. 55. Although the intestinal epithelial cells are crucial mediators of absorption and of ion and water flow, the several cell types in the lamina propria (e.g., mast cells, macrophages, myofibroblasts) and the enteric nervous system interact with the epithelium to regulate mucosal cell function. Intestinal function results from the integrated responses and interactions of intestinal epithelial cells and intestinal muscle.


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InternalMed_Harrison. Bile acids are not present in the diet but are synthesized in the liver by a series of enzymatic steps that also represent cholesterol catabolism. Indeed, interruption of the enterohepatic circulation of bile acids can reduce serum cholesterol levels by 10% before a new steady state is established. Bile acids are either primary or secondary. Primary bile acids are synthesized in the liver from cholesterol, and secondary bile acids are synthesized from primary bile acids in the intestine by colonic bacterial enzymes. The two primary bile acids in humans are cholic acid and chenodeoxycholic acid; the two most abundant secondary bile acids are deoxycholic acid and lithocholic acid. The liver synthesizes ~500 mg of bile acids daily; the bile acids are conjugated to either taurine or glycine (to form tauroconjugated and glycoconjugated bile acids, respectively) and are secreted into the duodenum in bile. The primary functions of bile acids are (1) to promote bile flow, (2) to solubilize


InternalMed_Harrison

InternalMed_Harrison. (to form tauroconjugated and glycoconjugated bile acids, respectively) and are secreted into the duodenum in bile. The primary functions of bile acids are (1) to promote bile flow, (2) to solubilize cholesterol and phospholipid in the gallbladder by mixed micelle formation, and (3) to enhance dietary lipid digestion and absorption by forming mixed micelles in the proximal small intestine.


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InternalMed_Harrison. Bile acids are primarily absorbed by an active, Na+-dependent process that takes place exclusively in the ileum; to a lesser extent, they are absorbed by non-carrier-mediated transport processes in the jejunum, ileum, and colon. Conjugated bile acids that enter the colon are deconjugated by colonic bacterial enzymes. The unconjugated bile acids are rapidly absorbed by nonionic diffusion. Colonic bacterial enzymes also dehydroxylate bile acids to secondary bile acids.


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InternalMed_Harrison. Bile acids absorbed from the intestine return to the liver via the portal vein and are then re-secreted (Fig. 349-1). Bile acid synthesis is largely autoregulated by 7α-hydroxylase, the initial enzyme in cholesterol degradation. A decrease in the volume of bile acids returning to the liver from the intestine is associated with an increase in bile acid synthesis/cholesterol catabolism, which helps keep the bile-acid pool size relatively constant. However, the capacity to increase bile acid synthesis is limited to ~2to 2.5-fold (see below). The bile-acid pool size is ~4 g. The pool is circulated via the enterohepatic circulation about twice during each meal, or six to eight times during a 24-h period. A relatively small quantity of bile acids is not absorbed and is excreted in stool daily; this fecal loss is matched by hepatic bile-acid synthesis.


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InternalMed_Harrison. Defects in any of the steps in enterohepatic circulation of bile acids can result in a decrease in the duodenal concentration of conjugated bile acids and consequently in the development of steatorrhea. Thus, steatorrhea can be caused by abnormalities in bile acid synthesis and excretion, their physical state in the intestinal lumen, and reabsorption (Table 349-1). Synthesis Decreased bile acid synthesis and steatorrhea have been demonstrated in chronic liver disease, but steatorrhea often is not a major component of illness in these patients.


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InternalMed_Harrison. Synthesis Decreased bile acid synthesis and steatorrhea have been demonstrated in chronic liver disease, but steatorrhea often is not a major component of illness in these patients. Secretion Although bile acid secretion may be reduced or absent in biliary obstruction, steatorrhea is rarely a significant medical problem in these patients. In contrast, primary biliary cirrhosis represents a defect in canalicular excretion of organic anions, including bile acids, and not infrequently is associated with steatorrhea and its consequences (e.g., chronic bone disease). Thus, the osteopenia/osteomalacia and other chronic bone abnormalities often present in patients with primary biliary cirrhosis and other cholestatic syndromes are secondary to steatorrhea that then leads to calcium and vitamin D malabsorption as well as to the effects of cholestasis (e.g., bile acids and inflammatory cytokines). 0.5 g synthesized Bile acid pool size 4.0 g IleumNa0.5 gBile acidsexcreted per day COLON


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InternalMed_Harrison. 0.5 g synthesized Bile acid pool size 4.0 g IleumNa0.5 gBile acidsexcreted per day COLON FIGURE 349-1 Schematic representation of the enterohepatic circulation of bile acids. Bile acid synthesis is cholesterol catabolism and occurs in the liver. Bile acids are secreted in bile and are stored in the gallbladder between meals and at night. Food in the duodenum induces the release of cholecystokinin, a potent stimulus for gallbladder contraction resulting in bile acid entry into the duodenum. Bile acids are primarily absorbed via an Na-dependent transport process that is located only in the ileum. A relatively small quantity of bile acids (~500 mg) is not absorbed in a 24-h period and is lost in stool. Fecal bile acid losses are matched by bile acid synthesis. The bile acid pool (the total amount of bile acids in the body) is ~4 g and is circulated twice during each meal or six to eight times in a 24-h period.


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InternalMed_Harrison. Maintenance of Conjugated Bile Acids In bacterial overgrowth syndromes associated with diarrhea, steatorrhea, and macrocytic anemia, a colonic type of bacterial flora is increased in the small intestine. Steatorrhea is primarily a result of the decrease in conjugated bile acids secondary to their deconjugation by colonic-type bacteria. Two complementary explanations account for the resulting impairment of micelle formation: (1) Unconjugated bile acids are rapidly absorbed in the jejunum by nonionic diffusion, and the result is a reduced concentration of duodenal bile acids. (2) The critical micellar concentration (CMC) of unconjugated bile acids is higher than that of conjugated bile acids; therefore, unconjugated bile acids are less effective than conjugated bile acids in micelle formation.


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InternalMed_Harrison. Reabsorption Ileal dysfunction caused by either Crohn’s disease or surgical resection results in a decrease in bile acid reabsorption in the ileum and an increase in the delivery of bile acids to the large intestine. The resulting clinical consequences—diarrhea with or without steatorrhea—are determined by the degree of ileal dysfunction and the response of the enterohepatic circulation to bile acid losses (Table 349-2). Patients with limited ileal disease or resection often have diarrhea but not steatorrhea. The diarrhea, a result of stimulation of active Cl secretion by bile acids in the colon, has been called bile acid diarrhea or choleretic enteropathy and responds promptly to cholestyramine, an anion-binding resin. Steatorrhea does not develop because hepatic synthesis of bile acids increases to compensate for the rate of fecal bile-acid losses, resulting in maintenance of both the bile-acid pool size and the intraduodenal concentrations of bile acids. In contrast, patients with


InternalMed_Harrison

InternalMed_Harrison. increases to compensate for the rate of fecal bile-acid losses, resulting in maintenance of both the bile-acid pool size and the intraduodenal concentrations of bile acids. In contrast, patients with greater degrees of ileal disease and/or resection often have diarrhea and steatorrhea that do not respond to cholestyramine. In this situation, ileal disease is also associated with increased volumes of bile acids entering the colon; however, hepatic synthesis can no longer increase sufficiently to maintain the bile-acid pool size. As a consequence, the intraduodenal concentration of bile acids is reduced to less than the CMC, and the result is impaired micelle formation and steatorrhea. This second situation is often called fatty acid diarrhea. Cholestyramine may not be effective (and may even exacerbate the diarrhea by further depleting the intraduodenal bile-acid concentration); however, a low-fat diet to reduce fatty acid entry into the colon can be effective. Two clinical


InternalMed_Harrison

InternalMed_Harrison. (and may even exacerbate the diarrhea by further depleting the intraduodenal bile-acid concentration); however, a low-fat diet to reduce fatty acid entry into the colon can be effective. Two clinical features—the length of the ileal section removed and the degree of steatorrhea—can predict whether an individual patient will respond to cholestyramine. Unfortunately, these predictors are imperfect, and a therapeutic trial of cholestyramine is often necessary to establish whether an individual patient will benefit from cholestyramine. Table 349-2 contrasts the characteristics of bile acid diarrhea (small ileal dysfunction) and fatty acid diarrhea (large ileal dysfunction).


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InternalMed_Harrison. Bile acid diarrhea can also occur in the absence of ileal inflammation and/or resection and is characterized by an abnormal 75SeHCAT retention study and reduced ileal release of fibroblast growth factor 19, a negative regulator of bile acid synthesis, with a consequent increase in bile acid synthesis and secretion that exceeds ileal bile-acid absorption. The diarrhea in these patients also responds to cholestyramine.


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InternalMed_Harrison. Steatorrhea is caused by one or more defects in the digestion and absorption of dietary fat. The average intake of dietary fat in the United States is ~120–150 g/d, and fat absorption is linear to dietary fat intake. The total load of fat presented to the small intestine is considerably greater, as substantial amounts of lipid are secreted in bile each day (see “Enterohepatic Circulation of Bile Acids,” above). Three types of fatty acids compose fats: long-chain fatty acids (LCFAs), medium-chain fatty acids (MCFAs), and short-chain fatty acids (SCFAs) (Table 349-3). Dietary fat is exclusively composed of long-chain triglycerides (LCTs)—i.e., glycerol that is bound via ester linkages to three LCFAs. While the majority of dietary LCFAs have carbon chain lengths of 16 or 18, all fatty acids of carbon chain length >12 are metabolized in the same manner; saturated and unsaturated fatty acids are handled identically.


InternalMed_Harrison

InternalMed_Harrison. Assimilation of dietary lipid requires three integrated processes: (1) an intraluminal, or digestive, phase; (2) a mucosal, or absorptive, phase; and (3) a delivery, or postabsorptive, phase. An abnormality at any site involved in these processes can cause steatorrhea (Table 349-4). Therefore, it is essential that any patient with steatorrhea be evaluated to identify the specific physiologic defect in overall lipid digestion/ absorption, as therapy will be determined by the specific etiology.


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InternalMed_Harrison. The digestive phase has two components, lipolysis and micelle formation. Although dietary lipid is in the form of LCTs, the intestinal mucosa does not absorb triglycerides; they must first be hydrolyzed (Fig. 349-2). The initial step in lipid digestion is the formation of emulsions of finely dispersed lipid, which is accomplished by mastication and gastric contractions. Lipolysis, the hydrolysis of triglycerides to free fatty acids, monoglycerides, and glycerol by lipase, is initiated in the stomach by lingual and gastric lipases that have a pH optimum of 4.5–6.0. About 20–30% of total lipolysis occurs in the stomach. Lipolysis is completed in the duodenum and jejunum by pancreatic lipase, which is inactivated by a pH <7.0. Pancreatic lipolysis is greatly enhanced by the presence of a second pancreatic enzyme, colipase, which facilitates the movement of lipase to the triglyceride.


InternalMed_Harrison

InternalMed_Harrison. Impaired lipolysis can lead to steatorrhea and can occur in the presence of pancreatic insufficiency due to chronic pancreatitis in adults or cystic fibrosis in children and adolescents. Normal lipolysis can be maintained by ~5% of maximal pancreatic lipase secretion; thus, steatorrhea is a late manifestation of these disorders. A reduction in intra-duodenal pH can also result in altered lipolysis, as pancreatic lipase is inactivated at pH <7. Thus, ~15% of patients who have gastrinoma (Chap. 348), with substantial increases in gastric acid secretion from ectopic production of gastrin (usually from an islet cell adenoma), have diarrhea, and some have steatorrhea believed to be secondary to acid inactivation of pancreatic lipase. Similarly, patients who have chronic pancreatitis (with reduced lipase secretion) often have a decrease in pancreatic bicarbonate secretion, which will also result in a lowering of intraduodenal pH and inactivation of endogenous pancreatic lipase or of


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InternalMed_Harrison. reduced lipase secretion) often have a decrease in pancreatic bicarbonate secretion, which will also result in a lowering of intraduodenal pH and inactivation of endogenous pancreatic lipase or of therapeutically administered lipase.


InternalMed_Harrison

InternalMed_Harrison. Overlying the microvillus membrane of the small intestine is the so-called unstirred water layer, a relatively stagnant aqueous phase that must be traversed by the products of lipolysis that are primarily water insoluble. Water-soluble mixed micelles provide a mechanism Disorders of Absorption 1936 Pancreas Liver Jejunal Mucosa Lymphatics lymphangiectasia) may also be associated with steatorrhea as well as protein loss (see below). Steatorrhea can result from defects at any of the with Bile Acid several steps in lipid digestion/absorption. The mechanism of lipid digestion/absorption outlined above is limited to dietary lipid, which is almost exclusively in the form of LCTs (Table for utilization 349-3). Medium-chain triglycerides (MCTs), composed of fatty acids with carbon chain lengths Phospholipid of 8–12, are present in large amounts in coconut oil and are used as a nutritional supplement.


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InternalMed_Harrison. Phospholipid of 8–12, are present in large amounts in coconut oil and are used as a nutritional supplement. formation different from that involved in LCT digestion and absorption; at one time, MCTs held promise as an important treatment for steatorrhea of almost


InternalMed_Harrison

InternalMed_Harrison. formation different from that involved in LCT digestion and absorption; at one time, MCTs held promise as an important treatment for steatorrhea of almost FIGURE 349-2 Schematic representation of lipid digestion and absorption. Dietary all etiologies. Unfortunately, they have been less lipid is in the form of long-chain triglycerides. The overall process can be divided into (1) therapeutically effective than expected because, a digestive phase that includes both lipolysis and micelle formation requiring pancreatic for reasons that are not completely understood, their use often is not associated with an increase lipase and conjugated bile acids, respectively, in the duodenum; (2) an absorptive phase for mucosal uptake and re-esterification; and (3) a postabsorptive phase that includes chy-in body weight. lomicron formation and exit from the intestinal epithelial cell via lymphatics. (Courtesy of In contrast to LCTs, MCTs do not require


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InternalMed_Harrison. John M. Dietschy, MD; with permission.) by which the water-insoluble products of lipolysis can reach the luminal plasma membrane of villous epithelial cells—the site for lipid absorption. Mixed micelles are molecular aggregates composed of fatty acids, monoglycerides, phospholipids, cholesterol, and conjugated bile acids. These mixed micelles are formed when the concentration of conjugated bile acids is greater than its CMC, which differs among the several bile acids present in the small-intestinal lumen. Conjugated bile acids, synthesized in the liver and excreted into the duodenum in bile, are regulated by the enterohepatic circulation (see above). Steatorrhea can result from impaired movement of fatty acids across the unstirred aqueous fluid layer in two situations: (1) an increase in the relative thickness of the unstirred water layer that occurs in bacterial overgrowth syndromes (see below) secondary to functional stasis (e.g., scleroderma); and (2) a decrease in the duodenal


InternalMed_Harrison

InternalMed_Harrison. in the relative thickness of the unstirred water layer that occurs in bacterial overgrowth syndromes (see below) secondary to functional stasis (e.g., scleroderma); and (2) a decrease in the duodenal concentration of conjugated bile acids below the CMC, resulting in impaired micelle formation. Thus, steatorrhea can be caused by one or more defects in the enterohepatic circulation of bile acids.


InternalMed_Harrison

InternalMed_Harrison. Uptake and re-esterification constitute the absorptive phase of lipid digestion/absorption. Although passive diffusion has been thought to be responsible, a carrier-mediated process may mediate fatty acid and monoglyceride uptake. Regardless of the uptake process, fatty acids and monoglycerides are re-esterified by a series of enzymatic steps in the endoplasmic reticulum to form triglycerides, in which lipid exits from the intestinal epithelial cell. Impaired lipid absorption as a result of mucosal inflammation (e.g., celiac disease) and/or intestinal resection can also lead to steatorrhea.


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InternalMed_Harrison. The re-esterified triglycerides require the formation of chylomicrons to permit their exit from the small-intestinal epithelial cell and their delivery to the liver via the lymphatics. Chylomicrons are composed of β-lipoprotein and contain triglycerides, cholesterol, cholesterol esters, and phospholipids and enter the lymphatics, not the portal vein. Defects in the postabsorptive phase of lipid digestion/absorption can also result in steatorrhea, but these disorders are uncommon. Abetalipoproteinemia, or acanthocytosis, is a rare disorder of impaired synthesis of β-lipoprotein associated with abnormal erythrocytes (acanthocytes), neurologic problems, and steatorrhea (Chap. 421). Lipolysis, micelle formation, and lipid uptake are all normal in patients with abetalipoproteinemia, but the re-esterified triglyceride cannot exit the epithelial cell because of the failure to produce chylomicrons. Small-intestinal biopsy samples obtained from these rare patients in the postprandial state


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InternalMed_Harrison. re-esterified triglyceride cannot exit the epithelial cell because of the failure to produce chylomicrons. Small-intestinal biopsy samples obtained from these rare patients in the postprandial state reveal lipid-laden small-intestinal epithelial cells that become perfectly normal in appearance after a 72to 96-h fast. Similarly, abnormalities of intestinal lymphatics (e.g., intestinal pancreatic lipolysis as they can be absorbed intact by the intestinal epithelial cell. Further, micelle formation is not necessary for the absorp tion of MCTs (or MCFAs, if hydrolyzed by pancreatic lipase). MCTs are absorbed more efficiently than LCTs for the following reasons: (1) The rate of absorption is greater for MCTs than for LCFAs. (2) After absorption, MCFAs are not reesterified. (3) After absorption, MCTs are hydrolyzed to MCFAs.


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InternalMed_Harrison. (4) MCTs do not require chylomicron formation to exit intestinal epithelial cells. (5) The route of MCT exit is via the portal vein and not via lymphatics. Thus, the absorption of MCTs is greater than that of LCTs in pancreatic insufficiency, conditions with reduced intraduodenal bile acid concentrations, small-intestinal mucosal disease, abetalipoproteinemia, and intestinal lymphangiectasia.


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InternalMed_Harrison. SCFAs are not dietary lipids but are synthesized by colonic bacterial enzymes from nonabsorbed carbohydrate and are the anions present at the highest concentration in stool (80–130 mM). The SCFAs in stool are primarily acetate, propionate, and butyrate, whose carbon chain lengths are 2, 3, and 4, respectively. Butyrate is the primary nutrient for colonic epithelial cells, and its deficiency can be associated with one or more colitides. SCFAs conserve calories and carbohydrate: carbohydrates that are not completely absorbed in the small intestine will not be absorbed in the large intestine because of the absence of both disaccharidases and SGLT1, the transport protein that mediates monosaccharide absorption. In contrast, SCFAs are rapidly absorbed and stimulate colonic NaCl and fluid absorption. Most antibiotic-associated diarrhea not caused by Clostridium difficile is due to antibiotic suppression of the colonic microbiota, with a resulting decrease in SCFA production. As C. difficile


InternalMed_Harrison

InternalMed_Harrison. Most antibiotic-associated diarrhea not caused by Clostridium difficile is due to antibiotic suppression of the colonic microbiota, with a resulting decrease in SCFA production. As C. difficile accounts for only ~15–20% of all antibiotic-associated diarrhea, a relative decrease in colonic production of SCFA is likely the cause of most antibiotic-associated diarrhea.


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InternalMed_Harrison. The clinical manifestations of steatorrhea are a consequence both of the underlying disorder responsible for its development and of steatorrhea per se. Depending on the degree of steatorrhea and the level of dietary intake, significant fat malabsorption may lead to weight loss. Steatorrhea per se can be responsible for diarrhea; if the primary cause of the steatorrhea has not been identified, a low-fat diet can often ameliorate the diarrhea by decreasing fecal fat excretion. Steatorrhea is commonly associated with fat-soluble vitamin deficiency, which requires replacement with water-soluble preparations of these vitamins.


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InternalMed_Harrison. Disorders of absorption may also be associated with malabsorption of other dietary nutrients— most often carbohydrates—with or without a decrease in dietary lipid digestion and absorption. Therefore, knowledge of the mechanisms of digestion and absorption of carbohydrates, proteins, and other minerals and vitamins is useful in the evaluation of patients with altered intestinal nutrient absorption. Ethnic Group Prevalence of Lactase Deficiency, % Source: From FJ Simoons: Am J Dig Dis 23:963, 1978. Carbohydrates in the diet are present in the form of starch, disaccharides (sucrose and lactose), and glucose. Carbohydrates are absorbed only in the small intestine and only in the form of monosaccharides. Therefore, before their absorption, starch and disaccharides must first be digested by pancreatic amylase and intestinal brush border disaccharidases to monosaccharides. Monosaccharide absorption occurs by a Na-dependent process mediated by the brush border transport protein SGLT1.


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InternalMed_Harrison. Lactose malabsorption is the only clinically important disorder of carbohydrate absorption. Lactose, the disaccharide present in milk, requires digestion by brush border lactase to its two constituent monosaccharides, glucose and galactose. Lactase is present in almost all species in the postnatal period but then disappears throughout the animal kingdom, except in humans. Lactase activity persists in many individuals throughout life. Two different types of lactase deficiency exist—primary and secondary. In primary lactase deficiency, a genetically determined decrease or absence of lactase is noted, while all other aspects of both intestinal absorption and brush border enzymes are normal. In a number of nonwhite groups, primary lactase deficiency is common in adulthood. In fact, Northern European and North American whites are the only groups to maintain small-intestinal lactase activity throughout adult life. Table 349-5 presents the incidence of primary lactase deficiency in several


InternalMed_Harrison

InternalMed_Harrison. European and North American whites are the only groups to maintain small-intestinal lactase activity throughout adult life. Table 349-5 presents the incidence of primary lactase deficiency in several ethnic groups. Lactase persistence in adults is an abnormality due to a defect in the regulation of its maturation. In contrast, secondary lactase deficiency occurs in association with small-intestinal mucosal disease, with abnormalities in both structure and function of other brush border enzymes and transport processes. Secondary lactase deficiency is often seen in celiac disease.


InternalMed_Harrison

InternalMed_Harrison. As lactose digestion is rate-limiting compared to glucose/galactose absorption, lactase deficiency is associated with significant lactose malabsorption. Some individuals with lactose malabsorption develop symptoms such as diarrhea, abdominal pain, cramps, and/or flatus. Most individuals with primary lactase deficiency do not have symptoms. Since lactose intolerance may be associated with symptoms suggestive of irritable bowel syndrome, persistence of such symptoms in an individual who exhibits lactose intolerance while on a strict lactose-free diet suggests that the person’s symptoms were related to irritable bowel syndrome. The development of symptoms of lactose intolerance is related to several factors: 1. Amount of lactose in the diet. 2.


InternalMed_Harrison

InternalMed_Harrison. The development of symptoms of lactose intolerance is related to several factors: 1. Amount of lactose in the diet. 2. Rate of gastric emptying. Symptoms are more likely when gastric emptying is rapid than when it is slower. Therefore, skim milk is more likely to be associated with symptoms of lactose intolerance than whole milk, as the rate of gastric emptying after skim milk intake is more rapid. Similarly, diarrhea following subtotal gastrectomy is often a result of lactose intolerance, as gastric emptying is accelerated in patients with a gastrojejunostomy. 3. Small-intestinal transit time. Although the small and large intestines both contribute to the development of symptoms, many symptoms of lactase deficiency are related to the interaction of colonic bacteria and nonabsorbed lactose. More rapid small-intes-1937 tinal transit makes symptoms more likely.


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InternalMed_Harrison. 4. Colonic compensation by production of SCFAs from nonabsorbed lactose. Reduced levels of colonic microflora, which can follow antibiotic use, are associated with increased symptoms after lactose ingestion, especially in a lactase-deficient individual.


InternalMed_Harrison

InternalMed_Harrison. Glucose-galactose or monosaccharide malabsorption may also be associated with diarrhea and is due to a congenital absence of SGLT1. Diarrhea develops when individuals with this disorder ingest carbo hydrates that contain actively transported monosaccharides (e.g., glucose, galactose) but not when they ingest monosaccharides that are not actively transported (e.g., fructose). Fructose is absorbed by the brush border transport protein GLUT 5, a facilitated diffusion process that is not Na-dependent and is distinct from SGLT1. In contrast, some individuals develop diarrhea as a result of the consumption of large quantities of sorbitol, a sugar used in diabetic candy; sorbitol is only minimally absorbed because of the absence of an intestinal absorptive transport mechanism for this sugar.


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InternalMed_Harrison. Protein is present in food almost exclusively as polypeptides and requires extensive hydrolysis to diand tripeptides and amino acids before absorption. Proteolysis occurs in both the stomach and the small intestine; it is mediated by pepsin, which is secreted as pepsinogen by gastric chief cells, and by trypsinogen and other peptidases from pancreatic acinar cells. The proenzymes pepsinogen and trypsinogen must be activated to pepsin (by pepsin at a pH <5) and to trypsin (by the intestinal brush border enzyme enterokinase and subsequently by trypsin), respectively. Proteins are absorbed by separate transport systems for diand tripeptides and for different types of amino acids—e.g., neutral and dibasic. Alterations in either protein or amino acid digestion and absorption are rarely observed clinically, even in the presence of extensive small-intestinal mucosal inflammation. However, three rare genetic disorders involve protein digestion/absorption: (1) Enterokinase deficiency is due to


InternalMed_Harrison

InternalMed_Harrison. clinically, even in the presence of extensive small-intestinal mucosal inflammation. However, three rare genetic disorders involve protein digestion/absorption: (1) Enterokinase deficiency is due to an absence of the brush border enzyme that converts the proenzyme trypsinogen to trypsin and is associated with diarrhea, growth retardation, and hypoproteinemia. (2) Hartnup’s syndrome, a defect in neutral amino acid transport, is characterized by a pellagra-like rash and neuropsychiatric symptoms. (3) Cystinuria, a defect in dibasic amino acid transport, is associated with renal calculi and chronic pancreatitis.


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InternalMed_Harrison. APPROACH TO THE PATIENT: The clues provided by the history, symptoms, and initial preliminary observations will serve to limit extensive, ill-focused, and expensive laboratory and imaging studies. For example, a clinician evaluating a patient who has symptoms suggestive of malabsorption and who has recently undergone extensive small-intestinal resection for mesenteric ischemia should direct the initial assessment almost exclusively to defining whether a short-bowel syndrome might explain the entire clinical picture. Similarly, the development of a pattern of bowel movements suggestive of steatorrhea in a patient with long-standing alcohol abuse and chronic pancreatitis should prompt an assessment of pancreatic exocrine function.


InternalMed_Harrison

InternalMed_Harrison. The classic picture of malabsorption is rarely seen today in most parts of the United States. As a consequence, diseases with malabsorption must be suspected in individuals who have less severe symptoms and signs and subtle evidence of the altered absorption of only a single nutrient rather than obvious evidence of the malabsorption of multiple nutrients. Although diarrhea can be caused by changes in fluid and electrolyte movement in either the small or the large intestine, dietary nutrients are absorbed almost exclusively in the small intestine. Disorders of Absorption


InternalMed_Harrison

InternalMed_Harrison. Disorders of Absorption Therefore, the demonstration of diminished absorption of a dietary nutrient provides unequivocal evidence for small-intestinal disease, although colonic dysfunction may also be present (e.g., Crohn’s disease may involve both the small and large intestines). Dietary nutrient absorption may be segmental or diffuse along the small intestine and is site specific. Thus, for example, calcium, iron, and folic acid are exclusively absorbed by active-transport processes in the proximal small intestine, especially the duodenum; in contrast, the active-transport mechanisms for both cobalamin and bile acids are operative only in the ileum. Therefore, in an individual who years previously has had an intestinal resection, the details of which are not presently available, a presentation with evidence of calcium, folic acid, and/or iron malabsorption but without cobalamin deficiency makes it likely that the duodenum and proximal jejunum, but not the ileum, were resected.


InternalMed_Harrison

InternalMed_Harrison. Some nutrients—e.g., glucose, amino acids, and lipids—are absorbed throughout the small intestine, although their rate of absorption is greater in the proximal than in the distal segments. However, after segmental resection of the small intestine, the remaining segments undergo both morphologic and functional “adaptation” to enhance absorption. Such adaptation is secondary to the presence of luminal nutrients and hormonal stimuli and may not be complete in humans for several months after resection. Adaptation is critical for the survival of individuals who have undergone massive resection of the small intestine and/or colon.


InternalMed_Harrison

InternalMed_Harrison. Establishing the diagnosis of steatorrhea and identifying its specific cause are often quite difficult. The “gold standard” remains a timed, quantitative stool-fat determination. From a practical standpoint, stool collections are invariably difficult and often incomplete, as nobody wants to handle stool. A qualitative test—Sudan III staining—has long been available to document an increase in stool fat. This test is rapid and inexpensive but, as a qualitative test, does not establish the degree of fat malabsorption and is best used as a preliminary screening study. Many of the blood, breath, and isotopic tests that have been developed (1) do not directly measure fat absorption; (2) exhibit excellent sensitivity when steatorrhea is obvious and severe but poor sensitivity when steatorrhea is mild (e.g., assays for stool chymotrypsin and elastase, which can potentially distinguish pancreatic from nonpancreatic etiologies of steatorrhea); or (3) have not survived the transition from the


InternalMed_Harrison

InternalMed_Harrison. is mild (e.g., assays for stool chymotrypsin and elastase, which can potentially distinguish pancreatic from nonpancreatic etiologies of steatorrhea); or (3) have not survived the transition from the research laboratory to commercial application.


InternalMed_Harrison

InternalMed_Harrison. Nevertheless, routine laboratory studies (i.e., complete blood count, prothrombin time, serum protein determination, alkaline phosphatase) may suggest dietary nutrient depletion, especially deficiencies of iron, folate, cobalamin, and vitamins D and K. Additional studies include measurement of serum carotene, cholesterol, albumin, iron, folate, and cobalamin levels. The serum carotene level can also be reduced if the patient’s dietary intake of leafy vegetables is poor.


InternalMed_Harrison

InternalMed_Harrison. If steatorrhea and/or altered absorption of other nutrients is suspected, then history, clinical observations, and laboratory testing can help detect deficiency of a nutrient, especially of a fat-soluble vitamin (A, D, E, or K). Thus, evidence of metabolic bone disease with elevated alkaline phosphatase concentrations and/or reduced serum calcium levels suggests vitamin D malabsorption. A deficiency of vitamin K is suggested by an elevated prothrombin time in an individual without liver disease who is not taking anticoagulants. Macrocytic anemia leads to an evaluation for possible cobalamin or folic acid malabsorption. Iron-deficiency anemia in the absence of occult bleeding from the gastrointestinal tract in either a male patient or a nonmenstruating female patient requires an evaluation for iron malabsorption and the exclusion of celiac disease, as iron is absorbed exclusively in the proximal small intestine.


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InternalMed_Harrison. At times, however, a timed (72-h) quantitative stool collection, preferably while the patient is on a defined diet, must be undertaken in order to determine stool fat content and establish the diagnosis of steatorrhea. The presence of steatorrhea then requires further assessment to identify the pathophysiologic process(es) responsible for the defect in dietary lipid digestion/absorption (Table 349-4). Other studies include the Schilling test (Chap. 350e), the D-xylose test, duodenal mucosal biopsy, small-intestinal radiologic examination, and tests of pancreatic exocrine function. This test (Chap. 350e) is performed to determine the cause of cobalamin malabsorption. An understanding of the physiology and pathophysiology of cobalamin absorption is very valuable, enhancing comprehension of aspects of gastric, pancreatic, and ileal function. Unfortunately, the Schilling test has not been available commercially in the United States for the past few years.


InternalMed_Harrison

InternalMed_Harrison. The urinary d-xylose test for carbohydrate absorption provides an assessment of proximal small-intestinal mucosal function. d-Xylose, a pentose, is absorbed almost exclusively in the proximal small intestine. The d-xylose test is usually performed by administering 25 g of d-xylose and collecting urine for 5 h. An abnormal test (excretion of <4.5 g) primarily reflects duodenal/jejunal mucosal disease. The d-xylose test can also be abnormal in patients with blind loop syndrome (as a consequence primarily of an abnormal intestinal mucosa) and, as a false-positive study, in patients with large collections of fluid in a third space (i.e., ascites, pleural fluid). The ease of obtaining a mucosal biopsy of the small intestine by endoscopy and the false-negative rate of the d-xylose test have led to its diminished use. When small-intestinal mucosal disease is suspected, a small-intestinal mucosal biopsy should be performed.


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InternalMed_Harrison. Radiologic examination of the small intestine using barium contrast (small-bowel series or study) can provide important information in the evaluation of the patient with presumed or suspected malabsorption. This study is most often performed in conjunction with an examination of the esophagus, stomach, and duodenal bulb. Because insufficient barium is given to the patient to permit an adequate examination of the small-intestinal mucosa, especially in the ileum, many gastrointestinal radiologists alter the procedure by performing either a small-bowel series in which a large amount of barium is given by mouth, without concurrent examination of the esophagus and stomach, or an enteroclysis study in which a large amount of barium is introduced into the duodenum via a fluoroscopically placed tube. In addition, many of the diagnostic features initially described by radiologists to denote the presence of small-intestinal disease (e.g., flocculation, segmentation) are rarely seen with current


InternalMed_Harrison

InternalMed_Harrison. In addition, many of the diagnostic features initially described by radiologists to denote the presence of small-intestinal disease (e.g., flocculation, segmentation) are rarely seen with current barium suspensions. Nonetheless, in skilled hands, barium contrast examination of the small intestine can yield important information. For example, with extensive mucosal disease, intestinal dilation can be seen as a dilution of barium from increased intestinal fluid secretion (Fig. 349-3). A normal barium contrast study does not exclude the possibility of small-intestinal disease. However, a small-bowel series remains useful in the search for anatomic abnormalities, such as strictures and fistulas (as in Crohn’s disease) or blind loop syndrome (e.g., multiple jejunal diverticula) and to define the extent of a previous surgical resection. Other imaging studies that assess the integrity of small-intestinal morphology are CT enterography and magnetic resonance enterography. Capsule endoscopy


InternalMed_Harrison

InternalMed_Harrison. the extent of a previous surgical resection. Other imaging studies that assess the integrity of small-intestinal morphology are CT enterography and magnetic resonance enterography. Capsule endoscopy and double-balloon enteroscopy are other useful aids in the diagnostic assessment of small-intestinal pathology.


InternalMed_Harrison

InternalMed_Harrison. A small-intestinal mucosal biopsy is essential in the evaluation of a patient with documented steatorrhea or chronic diarrhea (i.e., that lasting >3 weeks) (Chap. 55). The ready availability of endoscopic equipment to examine the stomach and duodenum has led to its almost uniform use as the preferred method of obtaining Disorders of Absorption FIGURE 349-3 Barium contrast small-intestinal radiologic examinations. A. Normal individual. B. Celiac sprue. C. Jejunal diverticulosis. D. Crohn’s disease. (Courtesy of Morton Burrell, MD, Yale University; with permission.) histologic material from the proximal small-intestinal mucosa. The primary indications for a small-intestinal biopsy are evaluation of a patient (1) either with documented or suspected steatorrhea or with chronic diarrhea, and (2) with diffuse or focal abnormalities of the small intestine defined on a small-intestinal series. Lesions seen on small-bowel biopsy can be classified into three categories (Table 349-6): 1.


InternalMed_Harrison

InternalMed_Harrison. Diffuse, specific lesions. Relatively few diseases associated with altered nutrient absorption have specific histopathologic abnormalities on small-intestinal mucosal biopsy, and these diseases are uncommon. Whipple’s disease is characterized by the presence of periodic acid–Schiff (PAS)–positive macrophages in the lamina propria; the bacilli that are also present may require electron microscopic examination for identification (Fig. 349-4). Abetalipoproteinemia is characterized by a normal mucosal appearance except for the presence of mucosal absorptive cells that contain lipid postprandially and disappear after a prolonged period of either fat-free intake or fasting. Immune globulin deficiency is associated with a variety of histopathologic findings on small-intestinal mucosal biopsy. The characteristic feature is the absence of or substantial reduction in the number of plasma cells in the lamina propria; the mucosal architecture may be either perfectly normal or flat (i.e., villous


InternalMed_Harrison

InternalMed_Harrison. characteristic feature is the absence of or substantial reduction in the number of plasma cells in the lamina propria; the mucosal architecture may be either perfectly normal or flat (i.e., villous atrophy). As patients with immune globulin deficiency are often infected with Giardia lamblia, Giardia trophozoites may also be seen in the biopsy.


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InternalMed_Harrison. 2.


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InternalMed_Harrison. Patchy, specific lesions. Several diseases feature an abnormal small-intestinal mucosa with a patchy distribution. As a result, biopsy samples obtained randomly or in the absence of endoscopically visualized abnormalities may not reveal diagnostic features. Intestinal lymphoma can at times be diagnosed on mucosal biopsy by the identification of malignant lymphoma cells in the lamina propria and submucosa (Chap. 134). Dilated lymphatics in the submucosa and sometimes in the lamina propria indicate lymphangiectasia associated with hypoproteinemia secondary to protein loss into the intestine. Eosinophilic gastroenteritis comprises a heterogeneous group of disorders with a spectrum of presentations and symptoms, with an eosinophilic infiltrate of the lamina propria, and with or without peripheral eosinophilia. The patchy nature of the infiltrate and its presence in the sub-mucosa often lead to an absence of histopathologic findings on mucosal biopsy. As the involvement of the duodenum in


InternalMed_Harrison

InternalMed_Harrison. eosinophilia. The patchy nature of the infiltrate and its presence in the sub-mucosa often lead to an absence of histopathologic findings on mucosal biopsy. As the involvement of the duodenum in Crohn’s disease is also submucosal and not necessarily continuous, mucosal biopsies are not the most direct approach to the diagnosis of duodenal Crohn’s disease (Chap. 351). Amyloid deposition can be identified by Congo Red staining in some patients with amyloidosis involving the duodenum (Chap. 136).


InternalMed_Harrison

InternalMed_Harrison. 3. Diffuse, nonspecific lesions. Celiac disease presents with a characteristic mucosal appearance on duodenal/proximal jejunal mucosal biopsy that is not diagnostic of the disease. The diagnosis of celiac disease is established by clinical, histologic, and immunologic responses to a gluten-free diet. Tropical sprue (see below) is associated with histologic findings similar to those of celiac disease after a tropical or subtropical exposure but does not respond to gluten restriction; most often symptoms improve with antibiotics and folate administration.


InternalMed_Harrison

InternalMed_Harrison. Several microorganisms can be identified in small-intestinal biopsy samples, establishing a correct diagnosis. At times, the biopsy is performed specifically to diagnose infection (e.g., Whipple’s disease or giardiasis). In most other instances, the infection is detected incidentally during the workup for diarrhea or other abdominal symptoms. Many of these infections occur in immunocompromised patients with diarrhea; the etiologic agents include Cryptosporidium, Isospora belli, microsporidia, Cyclospora, Toxoplasma, cytomegalovirus, adenovirus, Mycobacterium aviumintracellulare, and G. lamblia. In immunocompromised patients, when Candida, Aspergillus, Cryptococcus, or Histoplasma organisms are seen on duodenal biopsy, their presence generally reflects systemic infection. Apart from Whipple’s disease and infections in the immunocompromised host, small-bowel biopsy is seldom used as the primary mode of diagnosis of infection. Even giardiasis is more easily diagnosed by stool antigen


InternalMed_Harrison

InternalMed_Harrison. disease and infections in the immunocompromised host, small-bowel biopsy is seldom used as the primary mode of diagnosis of infection. Even giardiasis is more easily diagnosed by stool antigen studies and/or duodenal aspiration than by duodenal biopsy.


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InternalMed_Harrison. Patients with steatorrhea require assessment of pancreatic exocrine function, which is often abnormal in chronic pancreatitis. The secretin test that collects pancreatic secretions by duodenal intubation following intravenous administration of secretin is the only test that directly measures pancreatic exocrine function but is available only at a few specialized centers. Endoscopic approaches (endoscopic retrograde cholangiopancreatography, endoscopic ultrasound) provide an excellent assessment of pancreatic duct anatomy but do not assess exocrine function (Chap. 370). Table 349-7 summarizes the results of the d-xylose test, the Schilling test, and small-intestinal mucosal biopsy in patients with steatorrhea of various etiologies.


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InternalMed_Harrison. Celiac disease is a common cause of malabsorption of one or more nutrients. Although celiac disease was originally consid ered largely a disease of white individuals, especially persons of European descent, recent observations have established that it is a common disease with protean manifestations, a worldwide distribution, and an estimated incidence in the United States that is as high as 1 in 113 people. Its incidence has increased over the past 50 years. Celiac disease has had several other names, including nontropical sprue, celiac sprue, adult celiac disease, and gluten-sensitive enteropathy. The etiology of celiac disease is not known, but environmental, immunologic, and genetic factors are important. Celiac disease is considered an “iceberg” disease. A small number of individuals have classical symptoms and manifestations related to nutrient malabsorption along with a varied natural history; the onset of symptoms can occur at all points from the first year of life through the


InternalMed_Harrison

InternalMed_Harrison. have classical symptoms and manifestations related to nutrient malabsorption along with a varied natural history; the onset of symptoms can occur at all points from the first year of life through the eighth decade. A much larger number of individuals have “atypical celiac disease”, with manifestations that are not obviously related to intestinal malabsorption (e.g., anemia, osteopenia, infertility, and neurologic symptoms). Finally, an even larger number of persons have “silent celiac disease”; they are essentially asymptomatic despite abnormal small-intestinal histopathology and serologies (see below).


InternalMed_Harrison

InternalMed_Harrison. The hallmark of celiac disease is an abnormal small-intestinal biopsy (Fig. 349-4) and the response of the condition (including symptoms and histologic changes on small-intestinal biopsy) to the elimination of gluten from the diet. The histologic changes have a proximal-to-distal intestinal distribution of severity, which probably reflects the exposure of the intestinal mucosa to varied amounts of dietary gluten. The symptoms do not necessarily correlate with histologic changes, especially as many newly diagnosed patients with celiac disease may be asymptomatic or only minimally symptomatic (often with no gastrointestinal symptoms).


InternalMed_Harrison

InternalMed_Harrison. The symptoms of celiac disease may appear with the introduction of cereals into an infant’s diet, although spontaneous remissions often occur during the second decade of life that may be either permanent or followed by the reappearance of symptoms over several years. Alternatively, the symptoms of celiac disease may first become evident at almost any age throughout adulthood. In many patients, frequent spontaneous remissions and exacerbations occur. The symptoms range from significant malabsorption of multiple nutrients, with diarrhea, steatorrhea, weight loss, and the consequences of nutrient depletion (i.e., anemia and metabolic bone disease), to the absence of gastrointestinal symptoms despite evidence of the depletion of a single nutrient (e.g., iron or folate deficiency, osteomalacia, edema from protein loss). Asymptomatic relatives of patients with celiac disease have been identified as having this disease either by small-intestinal biopsy or by serologic studies (e.g.,


InternalMed_Harrison

InternalMed_Harrison. edema from protein loss). Asymptomatic relatives of patients with celiac disease have been identified as having this disease either by small-intestinal biopsy or by serologic studies (e.g., antiendomysial antibodies, tissue transglutaminase [tTG], deamidated gliadin peptide). The availability of these “celiac serologies” has led to a substantial increase in the frequency of diagnosis of celiac disease, and the diagnosis is now being made primarily in patients without “classic” symptoms but with atypical and subclinical presentations.


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InternalMed_Harrison. Etiology The etiology of celiac disease is not known, but environmental, immunologic, and genetic factors all appear to contribute to the disease. One environmental factor is the clear association of the disease with gliadin, a component of gluten that is present in wheat, barley, and rye. In addition to the role of gluten restriction in treatment, the instillation of gluten into both the normal-appearing rectum and the distal ileum of patients with celiac disease results in morphologic changes within hours. An immunologic component in the pathogenesis of celiac disease is critical and involves both adaptive and innate immune responses. Serum Disorders of Absorption


InternalMed_Harrison

InternalMed_Harrison. FIGURE 349-4 Small-intestinal mucosal biopsies. A. Normal individual. B. Untreated celiac sprue. C. Treated celiac sprue. D. Intestinal lymphangiectasia. E. Whipple’s disease. F. Lymphoma. G. Giardiasis. (Courtesy of Marie Robert, MD, Yale University; with permission.) antibodies—IgA antigliadin, antiendomysial, and anti-tTG antibodies— true prevalence of celiac disease in the general population. A 4-week are present, but it is not known whether such antibodies are primary or course of treatment with prednisolone induces a remission in a patient secondary to the tissue damage. The presence of antiendomysial anti-with celiac disease who continues to eat gluten and converts the “flat” body is 90–95% sensitive and 90–95% specific; the antigen recognized by abnormal duodenal biopsy to a more normal-appearing one. In addiantiendomysial antibody is tTG, which deaminates gliadin, which is pre-tion, gliadin peptides interact with gliadin-specific T cells that mediate sented to HLA-DQ2 or


InternalMed_Harrison

InternalMed_Harrison. normal-appearing one. In addiantiendomysial antibody is tTG, which deaminates gliadin, which is pre-tion, gliadin peptides interact with gliadin-specific T cells that mediate sented to HLA-DQ2 or HLA-DQ8 (see below). Antibody studies are fre-tissue injury and induce the release of one or more cytokines (e.g., interquently used to identify patients with celiac disease; patients with these feron γ) that cause tissue injury. antibodies should undergo duodenal biopsy. This autoantibody has not


InternalMed_Harrison

InternalMed_Harrison. Genetic factor(s) are also involved in celiac disease. The incibeen linked to a pathogenetic mechanism (or mechanisms) responsible dence of symptomatic celiac disease varies widely in different for celiac disease. Nonetheless, this antibody is useful in establishing the population groups (high among whites, low among blacks and 1942 Asians) and is 10% among first-degree relatives of celiac disease patients. However, serologic studies provide clear evidence that celiac disease is present worldwide. Furthermore, all patients with celiac disease express the HLA-DQ2 or HLA-DQ8 allele, although only a minority of people expressing DQ2/DQ8 have celiac disease. Absence of DQ2/DQ8 excludes the diagnosis of celiac disease.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis A small-intestinal biopsy is required to establish a diagnosis of celiac disease (Fig. 349-4). A biopsy should be performed when patients have symptoms and laboratory findings suggestive of nutrient malabsorption and/or deficiency as well as a positive tTG antibody test. Since the presentation of celiac disease is often subtle, without overt evidence of malabsorption or nutrient deficiency, a relatively low threshold for biopsy performance is important. It is more prudent to perform a biopsy than another test of intestinal absorption that can never completely exclude or establish this diagnosis.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of celiac disease requires the detection of characteristic histologic changes on small-intestinal biopsy together with a prompt clinical and histologic response after the institution of a gluten-free diet. If IgA antiendomysial or tTG antibodies have been detected in serologic studies, they too should disappear after a gluten-free diet is started. With the increase in the number of patients diagnosed with celiac disease (mostly by serologic studies), the spectrum of histologic changes seen on duodenal biopsy has increased and includes findings that are not as severe as the classic changes shown in Fig. 349-4. The classic changes seen on duodenal/jejunal biopsy are restricted to the mucosa and include (1) an increase in the number of intraepithelial lymphocytes; (2) absence or a reduced height of villi, which causes a flat appearance with increased crypt cell proliferation resulting in crypt hyperplasia and loss of villous structure, with consequent villous, but not


InternalMed_Harrison

InternalMed_Harrison. or a reduced height of villi, which causes a flat appearance with increased crypt cell proliferation resulting in crypt hyperplasia and loss of villous structure, with consequent villous, but not mucosal, atrophy; (3) a cuboidal appearance and nuclei that are no longer oriented basally in surface epithelial cells; and (4) increased numbers of lymphocytes and plasma cells in the lamina propria (Fig. 349-4B). Although these features are characteristic of celiac disease, they are not diagnostic because a similar appearance can develop in tropical sprue, eosinophilic enteritis, and milk-protein intolerance in children and occasionally in lymphoma, bacterial overgrowth, Crohn’s disease, and gastrinoma with acid hypersecretion. However, a characteristic histologic appearance that reverts toward normal after the initiation of a gluten-free diet establishes the diagnosis of celiac disease (Fig. 349-4C). Readministration of gluten, with or without an additional small-intestinal biopsy, is not


InternalMed_Harrison

InternalMed_Harrison. normal after the initiation of a gluten-free diet establishes the diagnosis of celiac disease (Fig. 349-4C). Readministration of gluten, with or without an additional small-intestinal biopsy, is not necessary.


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InternalMed_Harrison. A number of patients exhibit gluten sensitivity; i.e., they have gastrointestinal symptoms that respond to gluten restriction but do not have celiac disease. The basis for such gluten sensitivity is not known.


InternalMed_Harrison

InternalMed_Harrison. Failure to Respond to Gluten Restriction The most common cause of persistent symptoms in a patient who fulfills all the criteria for the diagnosis of celiac disease is continued intake of gluten. Gluten is ubiquitous, and a significant effort must be made to exclude all gluten from the diet. Use of rice flour in place of wheat flour is very helpful, and several support groups provide important aid to patients with celiac disease and to their families. More than 90% of patients who have the characteristic findings of celiac disease respond to complete dietary gluten restriction. The remainder constitute a heterogeneous group (whose condition is often called refractory celiac disease or refractory sprue) that includes some patients who (1) respond to restriction of other dietary protein (e.g., soy); (2) respond to glucocorticoid treatment; (3) are “temporary” (i.e., whose clinical and morphologic findings disappear after several months or years); or (4) fail to respond to all measures


InternalMed_Harrison

InternalMed_Harrison. soy); (2) respond to glucocorticoid treatment; (3) are “temporary” (i.e., whose clinical and morphologic findings disappear after several months or years); or (4) fail to respond to all measures and have a fatal outcome, with or without documented complications of celiac disease, such as the development of intestinal T cell lymphoma or autoimmune enteropathy.


InternalMed_Harrison

InternalMed_Harrison. Therapeutic approaches that do not include a gluten-free diet are being developed and include the use of peptidases to inactivate toxic gliadin peptides and of small molecules to block toxic peptide uptake across intestinal tight junctions. Mechanism of Diarrhea The diarrhea in celiac disease has several pathogenetic mechanisms. Diarrhea may be secondary to (1) steatorrhea, which is primarily a result of changes in jejunal mucosal function; (2) secondary lactase deficiency, a consequence of changes in jejunal brush border enzymatic function; (3) bile acid malabsorption resulting in bile acid–induced fluid secretion in the colon (in cases with more extensive disease involving the ileum); and (4) endogenous fluid secretion resulting from crypt hyperplasia. Celiac disease patients with more severe involvement may improve temporarily with dietary lactose and fat restriction while awaiting the full effects of total gluten restriction, which constitutes primary therapy.


InternalMed_Harrison

InternalMed_Harrison. Associated Diseases Celiac disease is associated with dermatitis herpetiformis (DH), but this association has not been explained. Patients with DH have characteristic papulovesicular lesions that respond to dapsone. Almost all patients with DH have histologic changes in the small intestine consistent with celiac disease, although usually much milder and less diffuse in distribution. Most patients with DH have mild or no gastrointestinal symptoms. In contrast, relatively few patients with celiac disease have DH. Celiac disease is also associated with diabetes mellitus type 1, IgA deficiency, Down syndrome, and Turner’s syndrome. The clinical importance of the association with diabetes is that, although severe watery diarrhea without evidence of malabsorption is most often diagnosed as “diabetic diarrhea” (Chap. 417), assay of antiendomysial antibodies and/or a small-intestinal biopsy must be considered to exclude celiac disease.


InternalMed_Harrison

InternalMed_Harrison. Complications The most important complication of celiac disease is the development of cancer. The incidences of both gastrointestinal and nongastrointestinal neoplasms as well as intestinal lymphoma are elevated among patients with celiac disease. For unexplained reasons, the frequency of lymphoma in patients with celiac disease is higher in Ireland and the United Kingdom than in the United States. The possibility of lymphoma must be considered whenever a patient with celiac disease who has previously done well on a gluten-free diet is no longer responsive to gluten restriction or a patient who presents with clinical and histologic features consistent with celiac disease does not respond to a gluten-free diet. Other complications of celiac disease include the development of intestinal ulceration independent of lymphoma and so-called refractory sprue (see above) and collagenous sprue. In collagenous sprue, a layer of collagen-like material is present beneath the basement membrane;


InternalMed_Harrison

InternalMed_Harrison. ulceration independent of lymphoma and so-called refractory sprue (see above) and collagenous sprue. In collagenous sprue, a layer of collagen-like material is present beneath the basement membrane; patients with collagenous sprue generally do not respond to a gluten-free diet and often have a poor prognosis.


InternalMed_Harrison

InternalMed_Harrison. Tropical sprue is a poorly understood syndrome that affects and is manifested by chronic diarrhea, steatorrhea, weight loss, and nutritional deficiencies, including those of both folate and cobalamin. This disease affects 5–10% of the population in some tropical areas. Chronic diarrhea in a tropical environment is most often caused by infectious agents, including G. lamblia, Yersinia enterocolitica, C. difficile, Cryptosporidium parvum, and Cyclospora cayetanensis. Tropical sprue should not be entertained as a possible diagnosis until the presence of cysts and trophozoites has been excluded in three stool samples. Chronic infections of the gastrointestinal tract and diarrhea in patients with or without AIDS are discussed in Chaps. 160, 161, and 226.


InternalMed_Harrison

InternalMed_Harrison. The small-intestinal mucosa of individuals living in tropical areas is not identical to that of individuals who reside in temperate climates. In residents of tropical areas, biopsies reveal a mild alteration of villous architecture with a modest increase in mononuclear cells in the lamina propria, which on occasion can be as severe as that seen in celiac disease. These changes are observed both in native residents and in expatriates living in tropical regions and are usually associated with mild decreases in absorptive function, but they revert to “normal” when an individual moves or returns to a temperate area. Some have suggested that the changes seen in tropical enteropathy and in tropical sprue represent different ends of the spectrum of a single entity, but convincing evidence to support this concept is lacking.


InternalMed_Harrison

InternalMed_Harrison. Etiology Because tropical sprue responds to antibiotics, the consensus is that it may be caused by one or more infectious agents. Nonetheless, the etiology and pathogenesis of tropical sprue are uncertain. First, its occurrence is not evenly distributed in all tropical areas; rather, it is found in specific locations, including southern India, the Philippines, and several Caribbean islands (e.g., Puerto Rico, Haiti), but is rarely observed in Africa, Jamaica, or Southeast Asia. Second, an occasional individual does not develop symptoms of tropical sprue until long after having left an endemic area. For this reason, celiac disease (often referred to as celiac sprue) was originally called nontropical sprue to distinguish it from tropical sprue. Third, multiple microorganisms have been identified in jejunal aspirates, with relatively little consistency among studies. Klebsiella pneumoniae, Enterobacter cloacae, and E. coli have been implicated in some studies of tropical sprue, while


InternalMed_Harrison

InternalMed_Harrison. in jejunal aspirates, with relatively little consistency among studies. Klebsiella pneumoniae, Enterobacter cloacae, and E. coli have been implicated in some studies of tropical sprue, while other studies have favored a role for a toxin produced by one or more of these bacteria. Fourth, the incidence of tropical sprue appears to have decreased substantially during the past two or three decades, perhaps in relation to improved sanitation in many tropical countries during this time. Some have speculated that the reduced occurrence is attributable to the wider use of antibiotics in acute diarrhea, especially in travelers to tropical areas from temperate countries. Fifth, the role of folic acid deficiency in the pathogenesis of tropical sprue requires clarification. Folic acid is absorbed exclusively in the duodenum and proximal jejunum, and most patients with tropical sprue have evidence of folate malabsorption and depletion. Although folate deficiency can cause changes in


InternalMed_Harrison

InternalMed_Harrison. absorbed exclusively in the duodenum and proximal jejunum, and most patients with tropical sprue have evidence of folate malabsorption and depletion. Although folate deficiency can cause changes in small-intestinal mucosa that are corrected by folate replacement, several earlier studies reporting that tropical sprue could be cured by folic acid did not provide an explanation for the “insult” that was initially responsible for folate malabsorption.


InternalMed_Harrison

InternalMed_Harrison. The clinical pattern of tropical sprue varies in different areas of the world (e.g., India vs. Puerto Rico). Not infrequently, individuals in southern India initially report the occurrence of acute enteritis before the development of steatorrhea and malabsorption. In contrast, in Puerto Rico, a more insidious onset of symptoms and a more dramatic response to antibiotics are seen than in some other locations. Tropical sprue in different areas of the world may not be the same disease, and similar clinical entities may have different etiologies.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis The diagnosis of tropical sprue is best based on an abnormal small-intestinal mucosal biopsy in an individual with chronic diarrhea and evidence of malabsorption who is either residing or has recently lived in a tropical country. The small-intestinal biopsy in tropical sprue does not reveal pathognomonic features but resembles, and can often be indistinguishable from, that seen in celiac disease (Fig. 349-4). The biopsy sample in tropical sprue has less villous architectural alteration and more mononuclear cell infiltrate in the lamina propria. In contrast to those of celiac disease, the histologic features of tropical sprue manifest with a similar degree of severity throughout the small intestine, and a gluten-free diet does not result in either clinical or histologic improvement in tropical sprue.


InternalMed_Harrison

InternalMed_Harrison. Broad-spectrum antibiotics and folic acid are most often curative, especially if the patient leaves the tropical area and does not return. Tetracycline should be used for up to 6 months and may be associated with improvement within 1–2 weeks. Folic acid alone induces hematologic remission as well as improvement in appetite, weight gain, and some morphologic changes in small-intestinal biopsy. Because of marked folate deficiency, folic acid is most often given together with antibiotics.


InternalMed_Harrison

InternalMed_Harrison. Short-bowel syndrome is a descriptive term for the myriad clinical problems that follow resection of various lengths of small intestine or, on rare occasions, are congenital (e.g., microvillous inclusion disease). 1943 The factors that determine both the type and degree of symptoms include (1) the specific segment (jejunum vs. ileum) resected, (2) the length of the resected segment, (3) the integrity of the ileocecal valve, whether any large intestine has also been removed, (5) residual disease in the remaining small and/or large intestine (e.g., Crohn’s disease, mesenteric artery disease), and (6) the degree of adaptation in the remaining intestine. Short-bowel syndrome can occur in persons of any age, from neonates to the elderly.


InternalMed_Harrison

InternalMed_Harrison. Three different situations in adults mandate intestinal resection: mesenteric vascular disease, including atherosclerosis, thrombotic phenomena, and vasculitides; (2) primary mucosal and submucosal disease (e.g., Crohn’s disease); and (3) operations without preexisting small-intestinal disease (e.g., after trauma).


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InternalMed_Harrison. After resection of the small intestine, the residual intestine undergoes adaptation of both structure and function that may last for up to 6–12 months. Continued intake of dietary nutrients and calories is required to stimulate adaptation via direct contact with the intestinal mucosa, the release of one or more intestinal hormones, and pancreatic and biliary secretions. Thus, enteral nutrition with calorie administration must be maintained, especially in the early postoperative period, even if an extensive intestinal resection requiring parenteral nutrition (PN) has been performed. The subsequent ability of such patients to absorb nutrients will not be known for several months, until adaptation is complete.


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InternalMed_Harrison. Multiple factors besides the absence of intestinal mucosa (required for lipid, fluid, and electrolyte absorption) contribute to diarrhea and steatorrhea in these patients. Removal of the ileum, and especially the ileocecal valve, is often associated with more severe diarrhea than jejunal resection. Without part or all of the ileum, diarrhea can be caused by an increase in bile acids entering the colon; these acids stimulate colonic fluid and electrolyte secretion. Absence of the ileocecal valve is also associated with a decrease in intestinal transit time and bacterial overgrowth from the colon. The presence of the colon (or a major portion) is associated with substantially less diarrhea and a lower likelihood of intestinal failure (an inability to maintain nutrition without parenteral support) as a result of fermentation of nonabsorbed carbohydrates to SCFAs. The latter are absorbed in the colon and stimulate Na and water absorption, improving overall fluid balance. Lactose


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InternalMed_Harrison. support) as a result of fermentation of nonabsorbed carbohydrates to SCFAs. The latter are absorbed in the colon and stimulate Na and water absorption, improving overall fluid balance. Lactose intolerance as a result of the removal of lactase-containing mucosa as well as gastric hypersecretion may also contribute to the diarrhea.


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InternalMed_Harrison. In addition to diarrhea and/or steatorrhea, a range of nonintestinal symptoms is observed in some patients. The frequency of renal calcium oxalate calculi increases significantly in patients with a small-intestinal resection and an intact colon; this greater frequency is due to an increase in oxalate absorption by the large intestine, with subsequent enteric hyperoxaluria. Two possible mechanisms for the increase in oxalate absorption in the colon have been suggested: (1) increased bile acids and fatty acids that augment colonic mucosal permeability, resulting in enhanced oxalate absorption; and (2) increased fatty acids that bind calcium, resulting in an enhanced amount of soluble oxalate that is then absorbed. Since oxalate is high in relatively few foods (e.g., spinach, rhubarb, tea), dietary restrictions alone do not constitute adequate treatment. Cholestyramine (an anion-binding resin) and calcium have proved useful in reducing hyperoxaluria. Similarly, an increase in cholesterol


InternalMed_Harrison

InternalMed_Harrison. restrictions alone do not constitute adequate treatment. Cholestyramine (an anion-binding resin) and calcium have proved useful in reducing hyperoxaluria. Similarly, an increase in cholesterol gallstones is related to a decrease in the bile-acid pool size, which results in the generation of cholesterol supersaturation in gallbladder bile. Gastric hypersecretion of acid occurs in many patients after large resections of the small intestine. The etiology is unclear but may be related to either reduced hormonal inhibition of acid secretion or increased gastrin levels due to reduced small-intestinal catabolism of circulating gastrin. The resulting gastric acid secretion may be an important factor contributing to diarrhea and steatorrhea. A reduced pH in the duodenum can inactivate pancreatic lipase and/or precipitate duodenal bile acids, thereby increasing steatorrhea, and an increase in gastric secretion can create a volume overload relative to the reduced small-intestinal absorptive


InternalMed_Harrison

InternalMed_Harrison. lipase and/or precipitate duodenal bile acids, thereby increasing steatorrhea, and an increase in gastric secretion can create a volume overload relative to the reduced small-intestinal absorptive capacity. Inhibition of gastric acid secretion with proton pump inhibitors can help reduce diarrhea and steatorrhea, but only for the first 6 months.


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InternalMed_Harrison. Disorders of Absorption duodenal afferent loop following subtotal gastrectomy and gastrojejunostomy; (4) a bypass of the intestine (e.g., a jejunoileal bypass for


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InternalMed_Harrison. Treatment of short-bowel syndrome depends on the severity of symptoms and on whether the individual is able to maintain caloric and electrolyte balance with oral intake alone. Initial treatment includes judicious use of opiates (including codeine) to reduce stool output and to establish an effective diet. If the colon is in situ, the initial diet should be low in fat and high in carbohydrate in order to minimize diarrhea from fatty acid stimulation of colonic fluid secretion. MCTs (see Table 349-3), a low-lactose diet, and various soluble fiber–containing diets should also be tried. In the absence of an ileocecal valve, possible bacterial overgrowth must be considered and treated. If gastric acid hypersecretion is contributing to diarrhea and steatorrhea, a proton pump inhibitor may be helpful. Usually none of these therapeutic approaches provides an instant solution, but each can contribute to the reduction of disabling diarrhea.


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InternalMed_Harrison. The patient’s vitamin and mineral status must also be monitored; replacement therapy should be initiated if indicated. Fat-soluble vitamins, folate, cobalamin, calcium, iron, magnesium, and zinc are the most critical factors to monitor on a regular basis. If these approaches are not successful, home PN is an established therapy that can be maintained for many years. Small-intestinal transplantation is becoming established as a possible approach for individuals with extensive intestinal resection who cannot be maintained without PN—i.e., those with intestinal failure. A recombinant analogue of glucagon-like peptide 2 (GLP-2; teduglutide) is approved for use in patients with PN-dependent short-bowel syndrome on the basis of its ability to increase intestinal growth and improve absorption.


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InternalMed_Harrison. Bacterial overgrowth syndromes comprise a group of disorders with diarrhea, steatorrhea, and macrocytic anemia whose common feature is the proliferation of colonic-type bacteria within the small intestine. This bacterial proliferation is due to stasis caused by impaired peristalsis (functional stasis), changes in intestinal anatomy (anatomic stasis), or direct communication between the small and large intestine. These conditions have also been referred to as stagnant bowel syndrome or blind loop syndrome.


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InternalMed_Harrison. Pathogenesis The manifestations of bacterial overgrowth syndromes are a direct consequence of the presence of increased amounts of a colonic-type bacterial flora, such as E. coli or Bacteroides, in the small intestine. Macrocytic anemia is due to cobalamin—not folate—deficiency. Most bacteria require cobalamin for growth, and increasing concentrations of bacteria use up the relatively small amounts of dietary cobalamin. Steatorrhea is due to impaired micelle formation as a consequence of a reduced intraduodenal concentration of conjugated bile acids and the presence of unconjugated bile acids. Certain bacteria, including Bacteroides, deconjugate conjugated bile acids to unconjugated bile acids. Unconjugated bile acids are absorbed more rapidly than conjugated bile acids; as a result, the intraduodenal concentration of bile acids is reduced. In addition, the CMC of unconjugated bile acids is higher than that of conjugated bile acids, and the result is a decrease in micelle formation.


InternalMed_Harrison

InternalMed_Harrison. intraduodenal concentration of bile acids is reduced. In addition, the CMC of unconjugated bile acids is higher than that of conjugated bile acids, and the result is a decrease in micelle formation. Diarrhea is due, at least in part, to steatorrhea, when it is present. However, some patients manifest diarrhea without steatorrhea, and it is assumed that the colonic-type bacteria in these patients are producing one or more bacterial enterotoxins that are responsible for fluid secretion and diarrhea.


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InternalMed_Harrison. Etiology The etiology of these different disorders is bacterial proliferation in the small-intestinal lumen secondary to anatomic or functional stasis or to a communication between the relatively sterile small intestine and the colon, with its high levels of aerobic and anaerobic bacteria. Several examples of anatomic stasis have been identified: (1) one or more diverticula (both duodenal and jejunal) (Fig. 294-3C); (2) fistulas and strictures related to Crohn’s disease (Fig. 349-3D); (3) a proximal obesity); and (5) dilation at the site of a previous intestinal anastomosis. These anatomic derangements are often associated with the presence of a segment (or segments) of intestine out of continuity of propagated peristalsis, with consequent stasis and bacterial proliferation. Bacterial overgrowth syndromes can also occur in the absence of an anatomic blind loop when functional stasis is present. Impaired peristalsis and bacterial overgrowth in the absence of a blind loop occur in


InternalMed_Harrison

InternalMed_Harrison. overgrowth syndromes can also occur in the absence of an anatomic blind loop when functional stasis is present. Impaired peristalsis and bacterial overgrowth in the absence of a blind loop occur in scleroderma, where motility abnormalities exist in both the esophagus and the small intestine (Chap. 382). Functional stasis and bacterial overgrowth can also develop in association with diabetes mellitus and in the small intestine when a direct connection exists between the small and large intestines, including an ileocolonic resection, or occasionally after an enterocolic anastomosis that permits entry of bacteria into the small intestine as a result of bypassing the ileocecal valve.


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InternalMed_Harrison. Diagnosis The diagnosis may be suspected from the combination of a low serum cobalamin level and an elevated serum folate level, as enteric bacteria frequently produce folate compounds that are absorbed in the duodenum. Ideally, the bacterial overgrowth syndromes are diagnosed by the demonstration of increased levels of aerobic and/or anaerobic colonic-type bacteria in a jejunal aspirate obtained by intubation. However, this specialized test is rarely available. Breath hydrogen testing with administration of lactulose (a nondigestible disaccharide) has also been used to detect bacterial overgrowth. The Schilling test can diagnose bacterial overgrowth (see Chap. 350e) but is not available routinely. Often the diagnosis is suspected clinically and confirmed by the response to treatment.


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InternalMed_Harrison. Primary treatment should be directed, if at all possible, to the surgical correction of an anatomic blind loop. In the absence of functional stasis, it is important to define the anatomic relationships responsible for stasis and bacterial overgrowth. For example, bacterial overgrowth secondary to strictures, one or more diverticula, or a proximal afferent loop can potentially be cured by surgical correction of the anatomic state. In contrast, the functional stasis of scleroderma or certain anatomic stasis states (e.g., multiple jejunal diverticula) cannot be corrected surgically, and these conditions should be treated with broad-spectrum antibiotics. Tetracycline used to be the initial drug of choice; because of increasing resistance, however, other antibiotics, such as metronidazole, amoxicillin/clavulanic acid, rifaximin and cephalosporins, have been employed. The antibiotic should be given for ~3 weeks or until symptoms remit. Although the natural history of these conditions is


InternalMed_Harrison

InternalMed_Harrison. amoxicillin/clavulanic acid, rifaximin and cephalosporins, have been employed. The antibiotic should be given for ~3 weeks or until symptoms remit. Although the natural history of these conditions is chronic, antibiotics should not be given continuously. Symptoms usually remit within 2–3 weeks of initial antibiotic therapy. Treatment need not be repeated until symptoms recur. For frequent recurrences, several treatment strategies exist, but the use of antibiotics for 1 week per month, whether or not symptoms are present, is often most effective.


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InternalMed_Harrison. Unfortunately, therapy for bacterial overgrowth syndromes is largely empirical, with an absence of clinical trials on which to base rational decisions regarding antibiotic choice, treatment duration, and/or the best approach to therapy for recurrences. Bacterial overgrowth may also occur as a component of another chronic disease, such as Crohn’s disease, radiation enteritis, or short-bowel syndrome. Treatment of the bacterial overgrowth in these settings will not cure the underlying problem but may be very important in ameliorating a subset of clinical problems that are related to bacterial overgrowth.


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InternalMed_Harrison. Whipple’s disease is a chronic multisystemic disease associated with diarrhea, steatorrhea, weight loss, arthralgia, and central nervous system (CNS) and cardiac problems; it is caused by the bacterium Tropheryma whipplei. Until the identification of T. whipplei by polymerase chain reaction, the hallmark of Whipple’s disease had been the presence of PAS-positive macrophages in the small intestine (Fig. 349-4E) and other organs with evidence of disease. Etiology T. whipplei, a small (50–500 nm) gram-positive bacillus in the group Actinobacteria, has low virulence but high infectivity. Symptoms of Whipple’s disease are relatively minimal compared to the bacterial burden in multiple tissues.


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InternalMed_Harrison. Clinical presentation The onset of Whipple’s disease is insidious and is characterized by diarrhea, steatorrhea, abdominal pain, weight loss, migratory large-joint arthropathy, and fever as well as ophthalmologic and CNS symptoms. Dementia is a relatively late symptom and an extremely poor prognostic sign, especially in patients who experience relapse after the induction of a remission with antibiotics. For unexplained reasons, the disease occurs primarily in middle-aged white men. The steatorrhea in these patients is generally believed to be secondary to both small-intestinal mucosal injury and lymphatic obstruction due to the increased number of PAS-positive macrophages in the lamina propria of the small intestine.


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InternalMed_Harrison. Diagnosis The diagnosis of Whipple’s disease is suggested by a multisystemic disease in a patient with diarrhea and steatorrhea. Tissue biopsy of the small intestine and/or other organs that may be involved (e.g., liver, lymph nodes, heart, eyes, CNS, or synovial membranes), given the patient’s symptoms, is the primary approach. The presence of PAS-positive macrophages containing the characteristic small bacilli is suggestive of this diagnosis. However, T. whipplei–containing macrophages can be confused with PAS-positive macrophages containing M. avium complex, which may be a cause of diarrhea in AIDS. The presence of the T. whipplei bacillus outside of macrophages is a more important indicator of active disease than is their presence within the macrophages. T. whipplei has now been successfully grown in culture.


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InternalMed_Harrison. The treatment for Whipple’s disease is prolonged use of antibiotics. The current regimen of choice is double-strength trimethoprimsulfamethoxazole for ~1 year. PAS-positive macrophages can persist after successful treatment, and the presence of bacilli outside of macrophages is indicative of persistent infection or an early sign of recurrence. Recurrence of disease activity, especially with dementia, is an extremely poor prognostic sign and requires an antibiotic that crosses the blood-brain barrier. If trimethoprim-sulfamethoxazole is not tolerated, chloramphenicol is an appropriate second choice.


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InternalMed_Harrison. Protein-losing enteropathy is not a specific disease but rather a group of gastrointestinal and nongastrointestinal disorders with hypoproteinemia and edema in the absence of either proteinuria or defects in protein synthesis (e.g., chronic liver disease). These diseases are characterized by excess protein loss into the gastrointestinal tract. Normally, ~10% of total protein catabolism occurs via the gastrointestinal tract. Evidence of increased protein loss into the gastrointestinal tract is found in more than 65 different diseases, which can be classified into three groups: (1) mucosal ulceration, such that the protein loss primarily represents exudation across damaged mucosa (e.g., ulcerative colitis, gastrointestinal carcinomas, and peptic ulcer); (2) nonulcerated mucosa, but with evidence of mucosal damage so that the protein loss represents loss across epithelia with altered permeability (e.g., celiac disease and Ménétrier’s disease in the small intestine and stomach,


InternalMed_Harrison

InternalMed_Harrison. with evidence of mucosal damage so that the protein loss represents loss across epithelia with altered permeability (e.g., celiac disease and Ménétrier’s disease in the small intestine and stomach, respectively); and (3) lymphatic dysfunction, representing either primary lymphatic disease or lymphatic disease secondary to partial lymphatic obstruction that may occur as a result of enlarged lymph nodes or cardiac disease.


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InternalMed_Harrison. Diagnosis The diagnosis of protein-losing enteropathy is suggested 1945 by peripheral edema and low serum albumin and globulin levels in the absence of renal and hepatic disease. An individual with protein-losing enteropathy only rarely has selective loss of only albumin or only globulins. Therefore, marked reduction of serum albumin with normal serum globulins should not initiate an evaluation for protein-losing enteropathy but should suggest renal and/or hepatic disease. Likewise, reduced serum globulins with normal serum albumin levels are more likely a result of reduced globulin synthesis rather than enhanced globulin loss into the intestine. An increase in protein loss into the gastrointestinal tract has been documented by the administration of one of several radiolabeled proteins and its quantitation in stool during a 24or 48-h period. Unfortunately, none of these radiolabeled proteins is available for routine clinical use. α1-Antitrypsin, a protein that accounts for ~4% of


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InternalMed_Harrison. and its quantitation in stool during a 24or 48-h period. Unfortunately, none of these radiolabeled proteins is available for routine clinical use. α1-Antitrypsin, a protein that accounts for ~4% of total serum proteins and is resistant to proteolysis, can be used to detect enhanced rates of serum protein loss into the intestinal tract but cannot be used to assess gastric protein loss because of its degradation in an acid milieu. α1-Antitrypsin clearance is measured by determining stool volume as well as both stool and plasma α1-antitrypsin concentrations. In addition to the loss of protein via abnormal and distended lymphatics, peripheral lymphocytes may be lost via lymphatics, with consequent relative lymphopenia. Thus, lymphopenia in a patient with hypoproteinemia indicates increased loss of protein into the gastrointestinal tract.


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InternalMed_Harrison. Patients with increased protein loss into the gastrointestinal tract from lymphatic obstruction often have steatorrhea and diarrhea. The steatorrhea is a result of altered lymphatic flow as lipid-containing chylomicrons exit from intestinal epithelial cells via intestinal lymphatics (Table 349-4; Fig. 349-4). In the absence of mechanical or anatomic lymphatic obstruction, intrinsic intestinal lymphatic dysfunction— with or without lymphatic dysfunction in the peripheral extremities—has been designated intestinal lymphangiectasia. Similarly, ~50% of individuals with intrinsic peripheral lymphatic disease (Milroy’s disease) also have intestinal lymphangiectasia and hypoproteinemia. Other than steatorrhea and enhanced protein loss into the gastrointestinal tract, all other aspects of intestinal absorptive function are normal in intestinal lymphangiectasia.


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InternalMed_Harrison. Other Causes Patients who appear to have idiopathic protein-losing enteropathy without evidence of gastrointestinal disease should be examined for cardiac disease—especially right-sided valvular disease and chronic pericarditis (Chaps. 284 and 288). On occasion, hypoproteinemia can be the only presenting manifestation in these two types of heart disease. Ménétrier’s disease (also called hypertrophic gastropathy) is an uncommon entity that involves the body and fundus of the stomach and is characterized by large gastric folds, reduced gastric acid secretion, and, at times, enhanced protein loss into the stomach.


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InternalMed_Harrison. As excess protein loss into the gastrointestinal tract is most often secondary to a specific disease, treatment should be directed primarily to the underlying disease process and not to the hypoproteinemia. For example, if significant hypoproteinemia with resulting peripheral edema is secondary to celiac disease or ulcerative colitis, a gluten-free diet and mesalamine, respectively, would be the initial therapy. When enhanced protein loss is secondary to lymphatic obstruction, it is critical to establish the nature of this obstruction. Identification of mesenteric nodes or lymphoma may be possible by imaging studies. Similarly, it is important to exclude cardiac disease as a cause of protein-losing enteropathy, either by echosonography or, on occasion, by a right-heart catheterization.


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InternalMed_Harrison. The increased protein loss that occurs in intestinal lymphangiectasia is a result of distended lymphatics associated with lipid malabsorption. The hypoproteinemia is treated with a low-fat diet and the administration of MCTs (Table 349-3), which do not exit from the intestinal epithelial cells via lymphatics but are delivered to the body via the portal vein. Disorders of Absorption taBle 349-8 ClassifiCation of malaBsorPtion syndromes Deficiency or inactivation of pancreatic lipase Exocrine pancreatic insufficiency Pancreatic insufficiency—congenital or acquired Gastrinoma—acid inactivation of lipasea Cholestatic liver disease Bacterial overgrowth in small intestine: Interrupted enterohepatic circulation of bile salts