Celiac disease is a common cause of malabsorption of one or more nutrients. Although celiac disease was originally considered 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 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).
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).
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., 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.
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 antibodies—IgA antigliadin, antiendomysial, and anti-tTG antibodies—are present, but it is not known whether such antibodies are primary or secondary to the tissue damage. The presence of antiendomysial antibody is 90–95% sensitive and 90–95% specific; the antigen recognized by antiendomysial antibody is tTG, which deaminates gliadin, which is presented to HLA-DQ2 or HLA-DQ8 (see below). Antibody studies are frequently used to identify patients with celiac disease; patients with these antibodies should undergo duodenal biopsy. This autoantibody has not been linked to a pathogenetic mechanism (or mechanisms) responsible for celiac disease. Nonetheless, this antibody is useful in establishing the true prevalence of celiac disease in the general population. A 4-week course of treatment with prednisolone induces a remission in a patient with celiac disease who continues to eat gluten and converts the “flat” abnormal duodenal biopsy to a more normal-appearing one. In addition, gliadin peptides interact with gliadin-specific T cells that mediate tissue injury and induce the release of one or more cytokines (e.g., interferon γ) that cause tissue injury.
Genetic factor(s) are also involved in celiac disease. The incidence of symptomatic celiac disease varies widely in different population groups (high among whites, low among blacks and 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.
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.
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 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 necessary.
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.
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 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.
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.
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.
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.
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; patients with collagenous sprue generally do not respond to a gluten-free diet and often have a poor prognosis.
Tropical sprue is a poorly understood syndrome that affects both expatriates and natives in certain but not all tropical areas 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.
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.
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 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 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.
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.
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.
TREATMENT Tropical Sprue
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.
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). 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, (4) 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.
Three different situations in adults mandate intestinal resection: (1) 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).
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.
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 intolerance as a result of the removal of lactase-containing mucosa as well as gastric hypersecretion may also contribute to the diarrhea.
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 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 capacity. Inhibition of gastric acid secretion with proton pump inhibitors can help reduce diarrhea and steatorrhea, but only for the first 6 months.
TREATMENT Short-Bowel Syndrome
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.
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.
BACTERIAL OVERGROWTH SYNDROMES
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.
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. 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.
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. 349-3C); (2) fistulas and strictures related to Crohn’s disease (Fig. 349-3D); (3) a proximal duodenal afferent loop following subtotal gastrectomy and gastrojejunostomy; (4) a bypass of the intestine (e.g., a jejunoileal bypass for 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 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.
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.
TREATMENT Bacterial Overgrowth Syndromes
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 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.
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.
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.
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.
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.
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.
TREATMENT Whipple’s Disease
The treatment for Whipple’s disease is prolonged use of antibiotics. The current regimen of choice is ceftriaxone or meropenem for 2 weeks followed by oral TMP-SMX (160/800 mg) twice a day 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.
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, 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.
The diagnosis of protein-losing enteropathy is suggested 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 24- or 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.
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.
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.
TREATMENT Protein-Losing Enteropathy
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.
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.