Protein-Losing Enteropathy with Collagenous Colitis

Collagenous colitis is a distinct cause of chronic watery diarrhea characterized by abnormal deposition of collagen in the subepithelial region of the colonic mucosa. Typically, laboratory tests of blood, urine, and stool are normal. A few patients have laboratory evidence of small bowel dysfunction and malabsorption, but excessive enteric protein loss is not a commonly recognized manifestation of collagenous colitis. We report a 62-yr-old woman who had collagenous colitis associated with a marked protein-losing enteropathy in the absence of obvious small intestinal disease or colonic ulceration. Biopsies of endoscopically normal-appearing colonic mucosa should be performed in patients with protein-losing enteropathy in whom no cause is apparent after initial evaluation.     

Bile acid-mediated postcholecystectomy diarrhea

Diarrhea that develops after cholecystectomy may be due to increased amounts of bile acids presented to the large bowel, a "cholerheic enteropathy." We have studied eight patients to determine the cause for chronic diarrhea after cholecystectomy and found no abnormality other than elevated bile acids in the stool of six of them. All patients with bile acid malabsorption had daily stool weights greater than 200 g and total fecal bile acids three to ten times greater than normal. Patients responded dramatically to treatment with cholestyramine resin.     

Bile acid malabsorption

Opinion statement Patients with bile acid malabsorption typically present with chronic, watery diarrhea. Bile acids recirculate between the liver and small intestine in the enterohepatic circulation. They are reabsorbed in the distal small intestine, and normally only a small fraction of the bile acid pool is lost to the colon during each cycle. In patients with bile acid malabsorption, a larger amount of bile acids is spilled into the colon, where the acids stimulate electrolyte and water secretion, which results in loose to watery stools. The common causes of bile acid malabsorption are ileal resection and diseases of the terminal ileum (Crohn’s disease and radiation enteritis), which result in a loss of bile acid transporters and, consequently, diminished reabsorption. Bile acid malabsorption also has been documented in a small group of patients with chronic, watery diarrhea who have no demonstrable ileal disease (idiopathic bile acid malabsorption). The amount of bile acid loss to the colon determines the clinical presentation. Patients with mild to moderate bile acid malabsorption present with watery diarrhea and generally respond very well to treatment (with abolishment of diarrhea) with bile acid binders such as cholestyramine. Patients with more severe bile acid malabsorption have both diarrhea and steatorrhea. Treatment with cholestyramine is of no benefit in this group of patients and may, in fact, worsen steatorrhea. These patients are best treated with a low-fat diet supplemented with medium-chain triglycerides.     

Gastro 2013 APDW/WCOG Shanghai Working Party Report: Chronic diarrhea: Definition,classification, diagnosis

Diarrhea is best defined as passage of loose stools often with more frequent bowel movements. For clinical purposes, the Bristol Stool Form Scale works well to distinguish stool form and to identify loose stools. Laboratory testing of stool consistency has lagged behind. Acute diarrhea is likely to be due to infection and to be self‐limited. As diarrhea becomes chronic, it is less likely to be due to infection; duration of 1 month seems to work well as a cut‐off for chronic diarrhea, but detailed scientific knowledge is missing about the utility of this definition. In addition to duration of diarrhea, classifications by presenting scenario, by pathophysiology, and by stool characteristics (e.g. watery, fatty, or inflammatory) may help the canny clinician refine the differential diagnosis of chronic diarrhea. In this regard, a careful history remains the essential part of the evaluation of a patient with diarrhea. Imaging the intestine with endoscopy and radiographic techniques is useful, and biopsy of the small intestine and colon for histological assessment provides key diagnostic information. Endomicroscopy and molecular pathology are only now being explored for the diagnosis of chronic diarrhea. Interest in the microbiome of the gut is increasing; aside from a handful of well‐described infections because of pathogens, little is known about alterations in the microbiome in chronic diarrhea. Serological tests have well‐defined roles in the diagnosis of celiac disease but have less clearly defined application in autoimmune enteropathies and inflammatory bowel disease. Measurement of peptide hormones is of value in the diagnosis and management of endocrine tumors causing diarrhea, but these are so rare that these tests are of little value in screening because there will be many more false‐positives than true‐positive results. Chemical analysis of stools is of use in classifying chronic diarrhea and may limit the differential diagnosis that must be considered, but interpretation of the results is still evolving. Breath tests for assessment of carbohydrate malabsorption, small bowel bacterial overgrowth, and intestinal transit are fraught with technical limitations that decrease sensitivity and specificity. Likewise, tests of bile acid malabsorption have had limited utility beyond empirical trials of bile acid sequestrants.     

Chronic urticaria: a cutaneous manifestation of celiac disease.

Celiac disease, or gluten-sensitive enteropathy, is an immune-mediated disease of the small bowel that results in malabsorption. It classically presents with gastrointestinal symptoms including chronic diarrhea, weight loss, abdominal bloating and anorexia. It is becoming more frequently identified in asymptomatic patients with a diagnosis of deficiencies related to malabsorption of iron, folic acid, vitamin B12 and vitamin D. It is increasingly identified as a cause for early or refractory osteoporosis. Occasionally, celiac disease presents with cutaneous manifestations alone. Dermatitis herpetiformis is a well-recognized cutaneous manifestation of celiac disease. Other cutaneous manifestations include alopecia, angular stomatitis and aphthous ulcerations. Described here is a case of a 24-year-old woman who presented with intermittent urticaria and gastrointestinal complaints. She was found to have celiac disease on small-bowel biopsy. Both her gastrointestinal symptoms and urticaria resolved when she was put on a gluten-free diet, suggesting that her urticaria was a cutaneous manifestation of celiac disease.     

Clinical approach to diarrhea

Diarrhea is defined as reduced stool consistency, increased water content and number of evacuations per day. A wide array of causes and pathophysiological mechanisms underlie acute and chronic forms of diarrhea. This review focuses on the major clinical aspects which should aid clinicians to diagnose chronic diarrhea. Clinical history, physical examination and stool evaluation and the predominant stool characteristic, i.e., bloody, watery, and fatty diarrhea, may narrow the differential diagnosis. Although mainly involved in acute diarrhea, many different infectious agents, including bacteria, viruses and protozoa, can be identified in chronic bloody/inflammatory diarrhea by appropriate microbiological tests and colonoscopic biopsy analysis. Osmotic diarrhea can be the result of malabsorption or maldigestion, with a subsequent passage of fat in the stool leading to steatorrhea. Secretory diarrhea is due to an increase of fluid secretion in the small bowel lumen, a mechanism often identified in gastroenteropancreatic neuroendocrine tumors. The evaluation of the fecal osmotic gap may help to characterize whether a chronic diarrhea is osmotic or secretory. Fatty diarrhea (steatorrhea) occurs if fecal fat output exceeds the absorptive/digestive capacity of the intestine. Steatorrhea results from malabsorption or maldigestion states and tests should differentiate between these two conditions. Individualized diagnostic work ups tailored on pathophysiological and clinical features are expected to reduce costs for patients with chronic diarrhea.     

Studies of the prevalence and significance of radiolabeled bile acid malabsorption in a group of patients with idiopathic chronic diarrhea

We studied radiolabeled fecal bile acid excretion in 11 normal subjects and 17 patients with idiopathic chronic diarrhea for three major purposes: to establish normal values for this test in the presence of increased stool volumes (induced in normal subjects by ingestion of poorly absorbable solutions); to test for bile acid malabsorption in the patients and to correlate this with an independent test of ileal function, the Schilling test; and to compare the results of the bile acid excretion test with the subsequent effect of a bile acid binding agent (cholestyramine) on stool weight. In normal subjects fecal excretion of the radiolabel was increased with increasing stool volumes. As a group, patients with idiopathic chronic diarrhea excreted radiolabeled bile acid more rapidly than normal subjects with induced diarrhea (t1/2 56 +/- 8 vs. 236 +/- 60 h, respectively, p less than 0.005). There was a statistically significant positive correlation between t1/2 of radiolabeled bile acid and Schilling test results in these patients. Although 14 of 17 patients absorbed labeled taurocholic acid less well than any of the normal subjects with comparable volumes of induced diarrhea, cholestyramine had no statistically significant effect on stool weight in the patient group, and in none of the patients was stool weight reduced to within the normal range. In summary, most patients with idiopathic chronic diarrhea have bile acid malabsorption (as measured by fecal excretion of labeled bile acid), but they do not respond to cholestyramine therapy with a significant reduction in stool weight. Although the significance of these findings was not clearly established, the most likely interpretation is that bile acid malabsorption is a manifestation of an underlying intestinal motility or absorptive defect rather than the primary cause of diarrhea.     

Review: Management of postprandial diarrhea syndrome

Unexpected, urgent, sometimes painful bowel movements after eating are common complaints among adults. Without a clear etiology, if pain is present and resolves with the movements, this is usually labeled "irritable bowel syndrome-diarrhea" based solely on symptoms. If this symptom-based approach is applied exclusively, it may lead physicians not to consider treatable conditions: celiac disease, or maldigestion due to bile acid malabsorption, pancreatic exocrine insufficiency, or an a-glucosidase (sucrase, glucoamylase, maltase, or isomaltase) deficiency. These conditions can be misdiagnosed as irritable bowel syndrome-diarrhea (or functional diarrhea, if pain is not present). Limited testing is currently available to confirm these conditions (antibody screens for celiac disease; fecal fat as a surrogate marker for pancreatic function). Therefore, empirical treatment with alpha amylase, pancreatic enzymes, or a bile acid-binding agent may simultaneously treat these patients and serve as a surrogate diagnostic test. This review will summarize the current evidence for bile acid malabsorption, and deficiencies of pancreatic enzymes or a-glucosidases as potential causes for postprandial diarrhea, and provide an algorithm for treatment options.     

Chronic diarrhea with normal stool and colonic examinations: organic or functional?

To investigate whether the clinical history and basic laboratory test results can differentiate between an organic or functional cause of chronic diarrhea and thus avoid unnecessary hospital admissions and invasive procedures, we reviewed the charts of 58 adult patients admitted during 6 years because of chronic diarrhea who had normal stool and colonic examinations. The final diagnoses were irritable bowel syndrome in 34 patients, organic diarrhea in 21, and unknown cause in three. The following clinical data did not help in the differential diagnosis: age, sex, duration of diarrhea, presence of continuous diarrhea, abdominal pain, stool frequency or volume, and presence of stool mucus. Significant weight loss, nocturnal diarrhea, and the absence of tenesmus were associated with an organic cause. One or more laboratory alterations (increased erythrocyte sedimentation rate, anemia, hypokalemia, and low serum albumin level) were found in 62% of patients with organic diarrhea but in only 3% of those with functional disease; p less than 0.001. In 20 of 21 patients with organic diarrhea, an syndromic diagnosis (fat malabsorption, n = 13; inflammatory bowel disease, n = 4; and secretory diarrhea, n = 3) could be obtained with three simple tests (stool fat, rectal biopsy, and fecal water osmolality and electrolyte determination, respectively). Our study confirms that a detailed history and a few simple laboratory data can help to distinguish between functional and organic diarrhea and so avoid extensive investigation. The syndromic diagnosis of organic diarrhea can also be approximated with relatively easy tests.     

Bile Acid Malabsorption in AIDS-Associated Chronic Diarrhea: A Prospective 1-Year Study

Objectives: In patients with chronic diarrhea associated with acquired immunodeficiency syndrome, bile acid malabsorption, very rarely investigated, may have an important pathogenetic role. Methods: In this 1-yr prospective study, 15 patients with AlDS-associated chronic diarrhea and 10 AIDS-controls were studied for bile acid malabsorption by means of the SeHCAT abdominal retention test. The patients with diarrhea underwent the glucose hydrogen breath test to identify any bacterial proliferation in the small bowel. Results: the chronic diarrhea group, only one case of small bowel bacterial overgrowth, and seven cases (47%) with generally severe bile acid malabsorption, were observed. Among the controls, only one had an abnormal low SeHCAT retention. In hoth cases with Cryptosporidium infection, the SeHCAT test was pathological. Conclusions: These data are of clinical importance for the pathogenetic study of AIDS-associated chronic diarrhea and for specific treatment with cholestyramine.     

Rapid intestinal transit as a primary cause of severe chronic diarrhea in patients with amyloidosis

OBJECTIVE: The cause of severe diarrhea in patients with systemic amyloidosis is obscure. We therefore performed pathophysiological studies in three such patients in an effort to determine the mechanism of amyloid diarrhea. METHODS: Epithelial cell absorption rate of electrolytes was measured during steady state GI perfusion of a saline-mannitol solution. GI transit time of PEG and absorption of radiolabeled bile acid were measured simultaneously while subjects ingested three meals per day. To obtain a diarrhea control group for transit time and bile acid absorption, normal subjects were studied when they had diarrhea caused by ingestion of Milk of Magnesia (MOM). RESULTS: Diarrhea could not be explained by malabsorption of ingested nutrients, bacterial overgrowth, bile acid malabsorption, or epithelial cell malabsorption of electrolytes. However, 25% of polyethylene glycol (PEG) ingested with a standard meal was recovered in stool in 45 min, which is 10 times faster than in normal subjects with equally severe diarrhea caused by ingestion of MOM. All of the patients had autonomic neuropathy that remained unrecognized for 15-36 months after onset of chronic diarrhea; it seems likely that this was the cause of rapid transit. CONCLUSIONS: Severe chronic diarrhea in three patients with systemic amyloidosis was mediated by extremely rapid transit of chyme and digestive secretions through the intestine.     

Diagnosis of small bowel malabsorption syndromes in adults

Patients with malabsorption represent a small proportion of presentations with chronic diarrhea. In spite of some progress, the last twenty years were not very innovating in malabsorption investigations. Supporting history may direct investigations toward either the small bowel or pancreas. Serological testing for celiac disease will determine most cases without invasive investigation, but individuals suspected to have small bowel malabsorption, despite negative celiac serology, should have endoscopic distal duodenal biopsies taken to exclude other rare forms of small bowel enteropathy. This strategy has largely supplanted many older tests of small bowel function.     

Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea

Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients.     

REVIEW: Nongranulomatous Chronic Idiopathic Enterocolitis

Nongranulomatous chronic idiopathic enterocolitis is characterized by sudden onset of severe watery diarrhea, malabsorption, exudative enteropathy, frequent appearance of shallow ulcerations, and variable degrees of villus atrophy. In the absence of infectious and pharmacologic causes, the presence of a predominantly acute inflammatory infiltrate limited to the lamina propria establishes the diagnosis. No underlying disease appears during prolonged follow-up. The etiology remains unknown. The disease is generally corticosteroid-responsive; low-dose maintenance therapy is frequently required. The long-term prognosis is guarded. Three of 11 patients died of opportunistic infections or resistance to therapy.     

Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with multiple cases of idiopathic bile acid malabsorption

INTRODUCTION Bile acids are synthesized from cholesterol in the liver and secreted into the small intestine, where they facilitate absorption of fat, fat-soluble vitamins and cholesterol[1]. The bile acids are then reabsorbed from the intestine and return…     

A practical approach to treating patients with chronic diarrhea

Although diarrhea is a common complaint, its evaluation and treatment can be challenging. Appropriately defining and classifying diarrhea provide the framework for approaching diagnostic and therapeutic options. Diarrhea can be defined based on frequency, consistency, and/or weight, and classified as acute or chronic with specific clinical characteristics and stool appearance. Colonoscopy is the most common diagnostic tool used in the evaluation of patients with chronic diarrhea. Other evaluation strategies include timed stool collections, evaluation of inflammatory markers, and hydrogen breath tests. A focused workup of chronic diarrhea may yield a specific diagnosis, including diarrhea-predominant IBS (dIBS), functional diarrhea, diabetic diarrhea, bile acid-induced diarrhea, and microscopic colitis. Ideally, therapeutic decisions are specifically tailored to target the underlying pathophysiology, including, for example, gluten restriction for celiac disease, rotating antibiotics for small bowel bacterial overgrowth, budesonide therapy for collagenous colitis, and loperamide for treatment of functional diarrhea. It is also important to assess the role of diet and medications in chronic diarrhea. However, if no specific causes are identified following workup, empiric therapy with simple opiate antidiarrheals such as loperamide may be effective. If this proves unsuccessful, the use of more potent agents, including codeine and opium, may be considered.     

Collagenous colitis: physiologic and histopathologic studies in seven patients

Collagenous colitis is a clinicopathologic syndrome with chronic watery diarrhea, diffuse colitis with surface epithelial injury, and a distinctive collagen band beneath the surface epithelium especially in the proximal colon. The cases of seven patients (including six middle-aged women) with chronic, watery, noninfectious diarrhea were studied. Roentgenographic and endoscopic findings were not diagnostic. Two patients had rectal mucosal inflammation but sparing of the distal colon from subepithelial collagen. Other findings included thyroid disease (four patients), urethral fibrosis (three), elevated erythrocyte sedimentation rate (six), and eosinophilia (three). The colon was thought to be the main source of diarrheal fluid, but bile salt malabsorption, steatorrhea, and net small-bowel secretion were additive factors in some patients. With antiinflammatory treatment the diarrhea abated, the surface epithelial injury decreased, and the subepithelial collagen resolved (two patients), but lamina propria inflammation persisted. Collagenous colitis seems to be a chronic systemic, and perhaps autoimmune, disorder.     

Mechanisms of Diarrhea

Diarrhea is a symptom common to a wide variety of gastrointestinal illnesses, and is an important public health challenge in underdeveloped regions of the world. Normal intestinal absorption is a complex process. Recent research offers new insights into normal physiology and pathophysiology. The role of the enteric nervous system and neurotransmitters in the pathogenesis of diarrhea in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) is being actively investigated. In patients with IBD, ileal and sigmoid biopsies showed altered transepithelial sodium and fluid transport, specifically from decreased expression of the NHE3, NHERF-1, and NHE1 epithelial Na channel. This results in changes in normal intestinal electroneutral NaCl absorption and may be an additional factor contributing to the diarrhea in patients with IBD. Physiologic studies in humans suggest that primary bile acid malabsorption may be caused by an abnormal feedback system resulting in the increased bile salts, which may explain the watery diarrhea. Finally, the role of zinc in treatment of infectious diarrhea led to studies of its effect on intracellular human enterocyte ion secretion. Understanding such basic mechanisms may lead to better and novel therapies for treatment of diarrhea.     

Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption

BACKGROUND: A congenital form of idiopathic intestinal bile acid malabsorption (IBAM) has been associated with dysfunctional mutations in the ileal apical sodium-dependent bile acid transporter (ASBT). The aim of this study was to determine whether mutations in the ASBT gene (SLC10A2) predispose to the development of adult-onset idiopathic bile acid malabsorption and chronic watery diarrhea. METHODS: Genomic DNA was obtained from 13 adult IBAM patients previously diagnosed on the basis of clinical data, response to cholestyramine, and abnormal 75Se-homocholic acid taurine (SeHCAT) test values. The ASBT gene was screened for the presence of mutations or polymorphisms by single-stranded conformation polymorphism analysis (SSCP) and DNA sequencing. RESULTS: ASBT gene polymorphisms were detected in 5 of the 13 adult IBAM patients. Four patients were heterozygous for a common polymorphism in exon 3, leading to an alanine to serine substitution at codon 171 (A171S). An additional subject was heterozygous for a polymorphism in exon 1 that causes a valine to isoleucine substitution at codon 98 (V981). These functional polymorphisms were also found in unaffected subjects and do not appear to affect ASBT function. CONCLUSIONS: Adult-onset IBAM is not directly related to dysfunctional mutations in the coding region or intron/exon junctions of the SLC10A2 gene. In the absence of apparent ileal disease or intestinal motility defects, inappropriate down-regulation of the ileal bile acid transporter or defects in ileocyte transfer of bile acids into the portal circulation could explain this form of adult IBAM.     

Fructose-sorbitol malabsorption

Important dietary carbohydrates such as fructose and sorbitol are incompletely absorbed in the normal small intestine. This malabsorption is sometimes associated with abdominal complaints and diarrhea development, symptoms indistinguishable from those of functional bowel disease. Recently, polymerized forms of fructose (fructans) also were implicated in symptom production in patients with irritable bowel syndrome (IBS). Evidence from uncontrolled and controlled challenge studies suggests that malabsorbed sugars (fructose, sorbitol, lactose) and fructans may act as dietary triggers for clinical symptoms suggestive of IBS. Further placebo-controlled studies are needed to obtain definite conclusions about the role of dietary sugar malabsorption in functional bowel disease.