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three of these criteria is poor, the specificity for organic disorders is 90 percent or higher. No single screening test has enough sensitivity to determine an organic basis for chronic diarrhea. In the absence of the above criteria suggesting an organic disorder, a diagnosis of functional diarrhea is sometimes made. However, so many organic disorders would be missed by this approach that patients in this category should also be evaluated thoroughly. OUTPATIENT EVALUATION OF SPECIFIC DISEASES The initial examination and a limited laboratory evaluation often point to the causes of the diarrhea, which are listed in Table 1 in order of frequency. If the cause of chronic diarrhea is not obvious after the evaluation and laboratory studies, one strategy is to proceed with an immediate, extensive, and exhaustive workup. However, we propose instead a stepwise approach, beginning with the tests outlined in Table 2 (stage 1). If the patient is referred after an initial evaluation, the quality of the studies and not just the results must be reviewed. If the cause is still unclear, a second series of more costly and more invasive tests, listed in Table 2 (stage 2), is performed. Some chronic diarrheal diseases have specific characteristics. In giardiasis, the diarrhea is often associated with upper abdominal cramps and “frothy” stool. Giardia organisms are found predominantly in the duodenum and proximal jejunum. The examination of up to three fixed, concentrated stool specimens for ova and parasites has a sensitivity of 60 to 85 percent. An enzyme-linked immunosorbent assay for giardia antigen in stool (sensitivity, 92 percent; specificity, 98 percent) has largely supplanted intestinal biopsies, wet preparations, and the duodenal string test, particularly since the assay becomes negative after therapy.16,17 Only after these studies do we consider an empirical trial of metronidazole or quinacrine hydrochloride (Atabrine). Amebic diarrhea can be either watery or bloody and can last many years, with a variable presence of fecal leukocytes. Although examination of three fixed specimens of stools is the best initial screening test for amebiasis (sensitivity, 60 to 90 percent), two factors should be kept in mind concerning the collection of stool. Stool must be collected directly into fixative or into a dry container (urine and water destroy the parasite), and barium in the gastrointestinal tract hampers the detection of amebae for some time. Chronic diarrhea in hosts positive for the human immunodeficiency virus (HIV), with or without the acquired immunodeficiency syndrome, is due to an identifiable infectious agent in 75 to 85 percent of cases and has been reviewed elsewhere.9,10 Early in its course, Crohn’s disease of the small bowel is often difficult to diagnose radiologically, and a normal small-bowel series does not eliminate it as a possibility. If Crohn’s is suspected clinically, enteroclysis

CURRENT CONCEPTS

EVALUATION OF PATIENTS WITH CHRONIC DIARRHEA MARK DONOWITZ, M.D., FREDDY T. KOKKE, M.D., AND R OXAN S AIDI , M.D. ATIENTS who report having diarrhea for more than four weeks should be evaluated for chronic diarrheal diseases, since most infectious enteritides and other causes of acute diarrhea generally resolve spontaneously within this period.1-3 We suggest a twostage outpatient evaluation, which relies initially on the history and physical examination to direct studies and then on a systematic outpatient evaluation, followed, if necessary, by a third-stage inpatient evaluation. This approach should lead to a diagnosis in approximately 90 percent of patients. Patients with diarrhea experience a change in the consistency or frequency of their bowel movements. Diarrheal diseases are almost always associated with an increase in stool water. The daily loss of stool water on an American or British diet averages 130 ml per 24 hours, and stool is normally 65 to 85 percent water. Thus, diarrheal diseases can be objectively defined by daily stool weights of more than 200 g. Before the evaluation, the patient should follow a lactose-free diet for several days, since diarrhea that continues after an acute episode is often due to secondary lactase deficiency. Chronic diarrhea often causes dehydration, which should be corrected with oral rehydration solutions4 (premade electrolyte mixtures diluted according to World Health Organization recommendations or available commercially) while further evaluation continues. Popular remedies such as Gatorade, chicken broth, and soft drinks have concentrations of electrolytes too low to be used in severe forms of diarrhea. Are there any clues from the initial evaluation that predict the presence of an organic as opposed to a functional cause of diarrhea? Certain criteria suggest an organic disorder: a shorter duration of diarrhea (usually less than three months), predominantly nocturnal diarrhea, continual rather than intermittent diarrhea, a sudden onset, weight loss of more than 5 kg, a high erythrocyte sedimentation rate, a low hemoglobin level, a low albumin level, and an average daily fecal weight of more than 400 g.5-8 Although the sensitivity of at least
From the Departments of Medicine and Physiology, Gastroenterology Division, the Johns Hopkins University School of Medicine, Baltimore. Address reprint requests to Dr. Donowitz at 918 Ross Research Bldg., Gastroenterology Division, Department of Medicine, the Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD 21205–2195.

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and air under fluoroscopy to cause optimal distention. small bowel. but rather gas production by bacteria. diffuse gut lymphoma† Epidemic chronic diarrhea (perhaps infectious agent in raw milk. and is normally converted by bacteria into short-chain fatty acids that are efficiently absorbed. potassium. However. measurement of erythrocyte sedimentation rate.95] 2). hyper. if there is skin flushing. mastocytosis13 Infiltrative disorders: scleroderma. patients with steatorrhea may consume much less fat to reduce their diarrhea. and microscopic and collagenous colitis). poorly absorbed substances (wheat starch. creatinine. ethanol. measurement of vasoactive intestinal polypeptide. 9. A history of floating stools indicates not 19 steatorrhea. Half of patients with steatorrhea have watery diarrhea. carcinoid tumor. cholecystectomy. sorbitol. measurement of pH. substance P. measurement of fecal sodium. Sorbitol (used as a nonabsorbable sweetener in diet foods) and fructose in corn syrup are osmotically active and can cause diarrhea. calcitonin. fiber. fructose). cellulose. The diarrhea of carbohydrate malabsorption can be intermittent and is usually accompanied by symptoms of bloating. Thus. osmolality (see Table 3) Urine studies Thin-layer chromatography for bisacodyl.or hypothyroidism. intestinal resection Endocrine causes: adrenal insufficiency. . which damages the small intestinal mucosa. Crohn’s disease. Clostridium difficile Inflammatory bowel diseases: ulcerative colitis. A stool pH of less than 5. sucrose). The absorption coefficient for fat is approximately 0. In addition. he or she has significant steatorrhea. high-quality barium studies of the upper gastrointestinal tract. blood urea nitrogen. histamine (usually available only through a commercial laboratory) Radiologic studies Plain abdominal radiography (for pancreatic calcification).† collagenous colitis.22 As many as 4 percent of cases of chronic diarrhea are due to medications and food additives. since less carbohydrate is needed to produce excessive gas than to cause diarrhea. and at zero uptake approximately 2 g of fat is excreted in the stool. electrolytes. Experimentally induced watery diarrhea produces up to 13 g of fat per 24 hours. phosphate. Stage 1 Stool studies Tests for fecal leukocytes. lactulose. antihypertensive drugs. In a study of volunteers. and oil in the toilet bowl that requires a brush to remove. Table 2. alkalinization assay (for phenolphthalein). or to antibiotic therapy. if the patient produces 14 g of fat per 24 hours.20 Therefore. antiarrhythmic agents. This type of diarrhea can be primary or secondary to viral enteritis. ova. thyroid-stimulating hormone. caffeine Previous surgery: gastrectomy. A qualitative assay for stool fat with Sudan stain has a sensitivity of 90 percent when fecal fat measures more than 10 g per 24 hours. and a diagnosis is only made by means of colonic biopsies.18 This procedure involves nasoduodenal intubation and the administration of barium. including alcohol and caffeine. flatus. ganglioneuroma. fat in 72-hr sample while patient consuming 75– 100 g of fat per 24 hr Blood studies Complete blood count and differential count. antacids (magnesium-containing). greasy or bulky stools that are difficult to flush. and colon Endoscopic studies Sigmoidoscopy and biopsy (before a barium study and without hyperosmotic preparation) Other Nutritionist-supervised trial of lactose-free diet. thyroxine.21 the antibiotic-induced change in bacteria can lead to a colonic osmotic diarrhea. There is a linear relation between the amount of long-chain fatty acids consumed and the amount excreted in the stool. The presence of steatorrhea is determined by a 72-hour collection of stool fat. vagotomy. 1995 should be performed to show more mucosal detail. microscopic (lymphocytic) colitis Steatorrhea Carbohydrate malabsorption: disaccharidase deficiency (lactose. More suggestive of steatorrhea is a history of weight loss. may not increase the amount of fat they consume for the test.10 †Often missed on evaluation. giardiasis. upper endoscopy including small-bowel biopsy Other Test of bile acid or other breath test for bacterial overgrowth in the stool collection. gastrin. The table does not include causes of chronic diarrhea in HIV-positive patients. self-limited Fecal incontinence†14 Food allergy15 *Causes are listed in order of frequency. and parasites three times (before barium studies) and C. if diarrhea 1 liter per day and especially if there is hypokalemia. difficile toxin. abdominal computed tomography Endoscopic studies Colonoscopy and ileoscopy with biopsy (for right-sided colitis. pheochromocytoma. and despite instructions to the contrary. a bad odor. medullary thyroid carcinoma. Since approximately 30 g of ingested carbohydrate enters the colon daily. amebiasis. 48 percent had diarrhea. urine 5-hydroxyindoleacetic acid assay Stage 2 (if stage 1 unrevealing) Stool studies Enzyme-linked immunosorbent assay for giardia antigen. and of air–contrast medium to outline small-bowel mucosa. which alters colonic bacteria. and cramping. sulfate. anthraquinones Radiologic studies Enteroclysis. If the daily amount of stool fat is between 7 and 13 g. leading to a falsely low loss of fat Table 1. VIPoma. Collagenous colitis and microscopic (also called lymphocytic) colitis often appear normal on colonoscopy. weight in grams per 24 hr (must be requested specifically). Crohn’s disease. diarrhea itself can cause reduced fat absorption. the steatorrhea may be secondary to other causes of diarrhea. Causes of Chronic Diarrhea. diabetes11 Laxative abuse† Ischemic bowel disease Radiation enteritis or colitis12 Paradoxical diarrhea: colon cancer Idiopathic (functional) diarrhea Less frequent causes Hormone-producing tumors: gastrinoma. the amount of fecal fat associated with a normal American diet of 75 to 100 g of fat per day is 7 g per 24 hours (100 [100 0.95.726 THE NEW ENGLAND JOURNAL OF MEDICINE March 16.* Common causes Chronic or relapsing gastrointestinal infection†: amebiasis. for which the differential diagnosis is reviewed elsewhere. amyloidosis. sweeteners (sorbitol.3 is diagnostic of carbohydrate intolerance. fructose) Medications and food additives: commonly antibiotics. untreated water) Chronic idiopathic diarrhea. phenolphthalein. Outpatient Evaluation of Chronic Diarrhea. antineoplastic agents. because secretion of colonic water and electrolytes can be induced by fatty acids and the hydroxyfatty acids. villous adenoma.

7 to 31 months). Laboratory Evaluation for Laxative Abuse.8.25 Most of the specific diarrheal diseases mentioned above can be diagnosed with the studies listed in Table 2. mineral oil. colonic inflammation. the Brainerd and Henderson County epidemics) have been associated with the ingestion of raw milk33 or untreated water. their condition is diagnosed as a form of irritable bowel syndrome. bisacodyl turns purple-blue Spectrophotometry* or thin-layer chromatography*27 of urine or stool water: detects anthraquinones. The diarrhea did not improve with antibiotics but eventually resolved over a mean period of 15 months (range. since 100 percent of patients have low potassium levels and 93 percent have levels below 2. steatorrhea. since malabsorbed bile acids cause colonic secretion of water and electrolytes. and protein-losing enteropathy. can be detected by thin-layer chromatography but is not measured in the currently available laxative screens. and bloating with ingestion of 10 g of sorbitol (equivalent to the ingestion of four to five sugar-free mints). and there was no response to antibiotics. Hormone-producing tumors such as those of pancreatic cholera produce a dramatic diarrhea almost from the outset and are often rapidly diagnosed. If abdominal pain is also present. occurs surprisingly often.29. Laxative abuse with resulting factitious diarrhea is found in approximately 4 percent of new patients visiting gastroenterology clinics for evaluation of chronic diarrhea and in as many as 15 to 20 percent of those evaluated by tertiary referral centers. Thus. lous adenomas can present with diarrhea and electrolyte losses caused by as-yet-unidentified secretagogues or by prostaglandin E2 production. p atients with Munchausen’s syndrome. In three series with exhaustive evaluations of patients with chronic diarrhea.37. In addition. Shorter intestinal resections ( 100 cm) can lead to bile acid diarrhea. but we classify it as “idiopathic” to avoid a pejorative term and to acknowledge our lack of understanding of the pathobiology. There are five categories of patients with laxative-related factitious diarrhea1: patients with eating disorders including anorexia nervosa and bulimia. uric acid kidney stones. the active ingredient in Colace.26 That is also the most common cause of diarrhea of undetermined origin (see below). and began one to four weeks after travel in the United States. can detect anthraquinones 32 hr after one dose28 Measurement of stool osmolality: only useful if 250 mOsm per kilogram (implying dilution of stool with water or urine) Measurement of stool sodium and potassium. osteomalacia.32 These tumors are usually over 3 to 4 cm in diameter and are located in the distal colon or rectum.5 mmol per liter. was associated with weight loss.30 Laxatives can be used intermittently.g. Screening tests for laxatives in urine or stool water are summarized in Table 3. The diarrhea persisted during fasting.35 No organism was identified in those epidemics. If these are normal. and a stool pH of more than 6. All the patients studied have had over 0.Vol. measure stool magnesium (normally 45 mmol per liter or 30 meq per day) Measurement of stool sulfate and phosphate *These tests are usually done in a commercial or referral laboratory. Several studies document the frequent failure of physicians to screen for laxative abuse. phenolphthalein.7 liter of stool per 24 hours. 727 abdominal pain. bisacodyl. clubbing. less than 15 to 20 g of stool fat per 24 hours. however. hysterical patients..31 Vil- Barium enema to test for cathartic colon (ahaustral right colon) Sigmoidoscopy for gross presence of melanosis coli (microscopic form is often a normal variant) Alkalinization assay of stool: phenolphthalein. Patients nearly always deny laxative ingestion. inflammatory or primarily malabsorptive diarrhea is unlikely. Several epidemics of chronic diarrhea (e.23 Long resections of the ileum and right colon can cause diarrhea due to a lack of absorptive surface. These include hypokalemia (with or without nephropathy). These patients often have major metabolic derangements and clinical manifestations that can be confused with those of other chronic diarrheal diseases.39). patients driven by emotional problems. and responds to fasting and cholestyramine. spectrophotometric. except the presence of psychiatric disease and macroscopic melanosis coli on sigmoidoscopy. phenolphthalein. calculation of fecal osmotic gap: 290 2 (stool sodium concentration stool potassium concentration) Stool osmotic gap: if 50 mOsm per kilogram.34. we consider the patients to have diarrhea of undetermined origin. 30 to 60 percent of patients were in this category. even by inpatients.5-7 DIARRHEA OF UNDETERMINED ORIGIN If no cause of patients’ chronic diarrhea is found after the initial evaluation (not including patients with “irritable bowel” who have associated abdominal pain38. They are asked whether they . 70 percent have over 3 liters per 24 hours. This diarrhea occurs after meals. urine should be screened for laxatives several times by alkalinization and thin-layer chromatography. bisacodyl. and other causes of watery diarrhea must be sought by more invasive and costly measures (Table 2. and volumes of 10 to 21 liters per 24 hours have been reported. and a smaller bile acid pool (leading to steatorrhea that is unresponsive to cholestyramine). The stool specimen should be liquid and frozen. and children who are abused by being given laxatives (the so-called Polle syndrome). and other methods of detecting anthraquinones. Docusate sodium. some anthraquinones.24 decreased transit time. although secretion of water and electrolytes in other parts of the gut can occur as well. In most of these patients the onset was sudden. with no clear cause or associated systemic illness ever found. although continued use. and rhubarb turn red. malabsorption of bile acids. hyperpigmentation of the skin. stage 1. and phosphate. 11 percent of patients evaluated for chronic diarrhea in a tertiary referral center had negative evaluations. Hypokalemia is also a sensitive but nonspecific indication of the presence of pancreatic cholera.36 There is a large group of patients with chronic watery diarrhea in whom an organic abnormality is not uncovered by the outpatient evaluation described in Table 2 and for whom the course is protracted. usually involves about 300 g of stool per 24 hours. stage 2). 332 No. Water can be seen pouring from the surface. 11 CURRENT CONCEPTS Table 3. A “laxative survey” request will usually result in chromatographic. the episodes were self-limited.38 Sometimes this group is described as having “functional” illness. and no single clinical feature can provide a clue. magnesium. castor oil. called cholerheic enteropathy.

. bile acids. Secretory diarrheal diseases are those in which diarrhea persists or stops only partially after 48 hours of fasting. phosphate. and half of the remainder can be diagnosed on the basis of the systematic outpatient evaluation we have described. there is no need to continue fast. Our experience in the evaluation of diarrhea of undetermined origin almost entirely mimics that of Read et al. INPATIENT EVALUATION Inpatient evaluation (Table 4) is necessary because many cases of diarrhea elude diagnosis as a result of poor tests or inadequate stool collections in the outpatient setting. repeating them. but continues with 200 g of stool per 24 hr. diarrhea that stops on fasting indicates that dietary substances are causing the diarrhea. Incontinence accompanies chronic diarrhea in as many as 50 percent of cases. Stepwise Evaluation of Hospitalized Patients with Diarrhea of Undetermined Origin. 9 (33 percent) were taking laxatives or diuretics surreptitiously. and initial studies. patients are placed on their usual at-home diet. Inpatient evaluation leads to a definite diagnosis in at least two thirds of patients admitted for diarrhea of undetermined origin. inflammatory bowel diseases (including microscopic [lymphocytic] and c ollagenous colitis). Day 1 Confirmation and review of results of outpatient evaluation Measurement of stool weight or volume on normal diet Urine laxative screening by thin-layer chromatography Stool alkalinization assay Measurement of stool sodium.42 The diseases associated with this type of unresponsive diarrhea are listed in Table 5. No detailed study has measured the success of the initial outpatient evaluation of chronic diarrhea. These cases are usually due to either laxative abuse or unabsorbed carbohydrates. if necessary. 1995 want further evaluation.5 kg per 24 hours. After comprehensive outpatient and subsequent inpatient evalua- . Mycobacterium tuberculosis. Rather. Secretory diarrhea often decreases greatly with fasting. especially if hydration is difficult to maintain. directly or indirectly. As Fordtran40 and Binder41 have discussed.5 They found that of 27 patients referred after extensive evaluation for chronic severe diarrhea.22. the patient is disabled by incontinence. sulfate. If the stool output is less than 0. Recording stool Table 4.2 kg per 24 hours. If the stool output is more than 0.728 THE NEW ENGLAND JOURNAL OF MEDICINE March 16. and 4 had microscopic colitis). After reviewing these and. fecal incontinence. especially during the second and third day of fasting. but perhaps one third of cases can be diagnosed on the basis of clues from the history. 7. potassium. the next goal is to determine whether the patient has true diarrhea and whe ther it responds to fasting. stool electrolytes account for most of the stool osmolality. Types (or causes) responsive to fasting Incontinence Bile acid diarrhea After cholecystectomy After ileal resection Steatorrhea Osmotic diarrhea Carbohydrate malabsorption Excessive carbohydrate ingestion Laxatives (containing poorly absorbable anions: sodium sulfate. sodium phosphate. the patient does not have diarrhea. stool osmolality. or sodium citrate). 2 had other organic disorders (bacterial overgrowth. On admission. calculation of stool osmotic gap Days 2–4 Imposition of 72-hr fast with intravenous hydration (If diarrhea stops completely in 24 hr. and 8 Table 5. Most patients want a definitive cause of the diarrhea to be found. amebae) Hyperthyroidism Congenital diarrhea Chloride–bicarbonate exchange deficiency Sodium–hydrogen exchange deficiency Microvillus inclusion disease Bacterial overgrowth weights daily. 2 (7 percent) had anal-sphincter dysfunction. 6 (22 percent) had inflammatory bowel diseases (2 had ulcerative colitis.g. or fatty acids (Table 5). The most common causes found at this stage are laxative abuse.14 A 72-hour fast with intravenous hydration is the next part of the diagnostic evaluation. beef allergy). There is often a fecal osmotic gap of more than 50 mOsm per kilogram of water (see Table 3 for the formula for calculating the osmotic gap). irritable bowel disease is unlikely. and a 24-hour stool weight is determined. allows clinical differentiation of osmotic from secretory diarrheas. and only 2 remained undiagnosed. Patients with incontinence who do not have a diarrheal illness often progress to this stage of evaluation for diarrhea of undetermined origin before volunteering incontinence as their chief symptom. has irritable bowel syndrome. or has rectal disease. and other causes listed in Table 1 that were missed on the initial evaluation. In these diarrheas.) Monitoring of daily stool weights Days 5–8 Imposition of diet containing 75–100 g of fat per 24 hr Monitoring of 24-hr mean stool weight and fat content on days 6. magnesium Food allergy Types (or causes) not responsive or only partly responsive to fasting Laxative or diuretic abuse Inflammatory bowel diseases Celiac sprue Intestinal lymphoma Neuroendocrine tumors Zollinger–Ellison syndrome Pancreatic cholera Carcinoid tumor Medullary carcinoma of the thyroid Systemic mastocytosis Villous adenoma of the rectosigmoid Chronic infection (e. and the fecal osmotic gap is less than 50 mOsm per kilogram of water. giardia. physical examination. Most would have been diagnosed during the initial outpatient evaluation. Functional Classification of Types of Chronic Diarrhea on the Basis of Responsiveness to Fasting. 6 had irritable bowel syndrome.

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Fordtran JS. 2. In: Yamada T. Am J Med 1993. J Infect Dis 1984. Fordtran JS. Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders. Q J Med 1962. Avery ME.78:264-71. Aetiology. The irritable colon syndrome: a study of the clinical features. Bytzer P. Sears CL. Afzalpurkar RG. 30.100:458-64. Arrambide KA. Talley NJ.149:90-7. Russell RI. Russell RI. The gastroenterologist’s osmotic gap: fact or fiction? Gastroenterology 1992. Philadelphia: W. Fordtran JS. 35. Gastrointestinal food hypersensitivity: basic mechanisms of pathophysiology.5. Trock SC. 7. 17. Scand J Gastroenterol Suppl 1988. Multifocal colitis associated with an epidemic of chronic diarrhea. The fecal osmotic gap: technical aspects regarding its calculation.80:678-81. 28. Gastroenterology 1992.Vol. Chronic diarrhea in diabetes mellitus: mechanisms and an approach to diagnosis and treatment. Geraedts AAM. Morawski SG. Horowitz M.