You are on page 1of 5

Vol.

332

No. 11

CURRENT CONCEPTS

725

REVIEW ARTICLE
three of these criteria is poor, the specicity 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 specic 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 xed, 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; specicity, 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 xed 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 xative 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 immunodeciency virus (HIV), with or without the acquired immunodeciency syndrome, is due to an identiable infectious agent in 75 to 85 percent of cases and has been reviewed elsewhere.9,10 Early in its course, Crohns disease of the small bowel is often difcult to diagnose radiologically, and a normal small-bowel series does not eliminate it as a possibility. If Crohns 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 dened 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 deciency. 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 212052195.

Downloaded from www.nejm.org on May 31, 2005 . This article is being provided free of charge for use in India. Copyright 1995 Massachusetts Medical Society. All rights reserved.

726

THE NEW ENGLAND JOURNAL OF MEDICINE

March 16, 1995

should be performed to show more mucosal detail.18 This procedure involves nasoduodenal intubation and the administration of barium, cellulose, and air under uoroscopy to cause optimal distention, and of aircontrast medium to outline small-bowel mucosa. Collagenous colitis and microscopic (also called lymphocytic) colitis often appear normal on colonoscopy, and a diagnosis is only made by means of colonic biopsies. Half of patients with steatorrhea have watery diarrhea, because secretion of colonic water and electrolytes can be induced by fatty acids and the hydroxyfatty acids. A history of oating stools indicates not steatorrhea, but rather gas production by bacteria.19 More suggestive of steatorrhea is a history of weight loss, greasy or bulky stools that are difcult to ush, a bad odor, and oil in the toilet bowl that requires a brush to remove. The presence of steatorrhea is determined by a 72-hour collection of stool fat. There is a linear relation between the amount of long-chain fatty acids consumed and the amount excreted in the stool. The absorption coefcient for fat is approximately 0.95, and at zero uptake approximately 2 g of fat is excreted in the stool. Thus, 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] 2). However, patients with steatorrhea may consume much less fat to reduce their diarrhea, and despite instructions to the contrary, may not increase the amount of fat they consume for the test, leading to a falsely low loss of fat
Table 1. Causes of Chronic Diarrhea.*
Common causes Chronic or relapsing gastrointestinal infection: amebiasis, giardiasis, Clostridium difcile Inammatory bowel diseases: ulcerative colitis, Crohns disease, collagenous colitis, microscopic (lymphocytic) colitis Steatorrhea Carbohydrate malabsorption: disaccharidase deciency (lactose, sucrose), poorly absorbed substances (wheat starch, ber, lactulose, sorbitol, fructose) Medications and food additives: commonly antibiotics, antihypertensive drugs, antiarrhythmic agents, antineoplastic agents, antacids (magnesium-containing), sweeteners (sorbitol, fructose), ethanol, caffeine Previous surgery: gastrectomy, vagotomy, cholecystectomy, intestinal resection Endocrine causes: adrenal insufciency, hyper- or hypothyroidism, diabetes11 Laxative abuse Ischemic bowel disease Radiation enteritis or colitis12 Paradoxical diarrhea: colon cancer Idiopathic (functional) diarrhea Less frequent causes Hormone-producing tumors: gastrinoma, VIPoma, villous adenoma, medullary thyroid carcinoma, ganglioneuroma, pheochromocytoma, carcinoid tumor, mastocytosis13 Inltrative disorders: scleroderma, amyloidosis, diffuse gut lymphoma Epidemic chronic diarrhea (perhaps infectious agent in raw milk, untreated water) Chronic idiopathic diarrhea, self-limited Fecal incontinence14 Food allergy15
*Causes are listed in order of frequency. The table does not include causes of chronic diarrhea in HIV-positive patients, for which the differential diagnosis is reviewed elsewhere.9,10 Often missed on evaluation.

Table 2. Outpatient Evaluation of Chronic Diarrhea.


Stage 1 Stool studies Tests for fecal leukocytes, ova, and parasites three times (before barium studies) and C. difficile toxin; measurement of pH, weight in grams per 24 hr (must be requested specically), fat in 72-hr sample while patient consuming 75 100 g of fat per 24 hr Blood studies Complete blood count and differential count, measurement of erythrocyte sedimentation rate, electrolytes, blood urea nitrogen, creatinine, thyroid-stimulating hormone, thyroxine, gastrin; if diarrhea 1 liter per day and especially if there is hypokalemia, measurement of vasoactive intestinal polypeptide, substance P, calcitonin, histamine (usually available only through a commercial laboratory) Radiologic studies Plain abdominal radiography (for pancreatic calcication); high-quality barium studies of the upper gastrointestinal tract, small bowel, and colon Endoscopic studies Sigmoidoscopy and biopsy (before a barium study and without hyperosmotic preparation) Other Nutritionist-supervised trial of lactose-free diet; if there is skin ushing, urine 5-hydroxyindoleacetic acid assay Stage 2 (if stage 1 unrevealing) Stool studies Enzyme-linked immunosorbent assay for giardia antigen; alkalinization assay (for phenolphthalein); measurement of fecal sodium, potassium, sulfate, phosphate, osmolality (see Table 3) Urine studies Thin-layer chromatography for bisacodyl, phenolphthalein, anthraquinones Radiologic studies Enteroclysis, abdominal computed tomography Endoscopic studies Colonoscopy and ileoscopy with biopsy (for right-sided colitis, amebiasis, Crohns disease, and microscopic and collagenous colitis), upper endoscopy including small-bowel biopsy Other Test of bile acid or other breath test for bacterial overgrowth

in the stool collection. In addition, diarrhea itself can cause reduced fat absorption. Experimentally induced watery diarrhea produces up to 13 g of fat per 24 hours.20 Therefore, if the patient produces 14 g of fat per 24 hours, he or she has signicant steatorrhea. If the daily amount of stool fat is between 7 and 13 g, the steatorrhea may be secondary to other causes of diarrhea. 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. The diarrhea of carbohydrate malabsorption can be intermittent and is usually accompanied by symptoms of bloating, atus, and cramping, since less carbohydrate is needed to produce excessive gas than to cause diarrhea. This type of diarrhea can be primary or secondary to viral enteritis, which damages the small intestinal mucosa, or to antibiotic therapy, which alters colonic bacteria. Since approximately 30 g of ingested carbohydrate enters the colon daily, and is normally converted by bacteria into short-chain fatty acids that are efciently absorbed,21 the antibiotic-induced change in bacteria can lead to a colonic osmotic diarrhea. A stool pH of less than 5.3 is diagnostic of carbohydrate intolerance.22 As many as 4 percent of cases of chronic diarrhea are due to medications and food additives, including alcohol and caffeine. Sorbitol (used as a nonabsorbable sweetener in diet foods) and fructose in corn syrup are osmotically active and can cause diarrhea. In a study of volunteers, 48 percent had diarrhea,

Downloaded from www.nejm.org on May 31, 2005 . This article is being provided free of charge for use in India. Copyright 1995 Massachusetts Medical Society. All rights reserved.

Vol. 332

No. 11

CURRENT CONCEPTS
Table 3. Laboratory Evaluation for Laxative Abuse.

727

abdominal pain, and bloating with ingestion of 10 g of sorbitol (equivalent to the ingestion of four to ve sugar-free mints).23 Long resections of the ileum and right colon can cause diarrhea due to a lack of absorptive surface,24 decreased transit time, malabsorption of bile acids, and a smaller bile acid pool (leading to steatorrhea that is unresponsive to cholestyramine). Shorter intestinal resections (100 cm) can lead to bile acid diarrhea, called cholerheic enteropathy, since malabsorbed bile acids cause colonic secretion of water and electrolytes. This diarrhea occurs after meals; usually involves about 300 g of stool per 24 hours, less than 15 to 20 g of stool fat per 24 hours, and a stool pH of more than 6.8; and responds to fasting and cholestyramine.25 Most of the specic diarrheal diseases mentioned above can be diagnosed with the studies listed in Table 2, stage 1. If these are normal, inammatory or primarily malabsorptive diarrhea is unlikely, and other causes of watery diarrhea must be sought by more invasive and costly measures (Table 2, stage 2). 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.26 That is also the most common cause of diarrhea of undetermined origin (see below). There are ve categories of patients with laxative-related factitious diarrhea1: patients with eating disorders including anorexia nervosa and bulimia; hysterical patients; patients driven by emotional problems; patients with Munchausens syndrome; and children who are abused by being given laxatives (the so-called Polle syndrome). Patients nearly always deny laxative ingestion, and no single clinical feature can provide a clue, except the presence of psychiatric disease and macroscopic melanosis coli on sigmoidoscopy. These patients often have major metabolic derangements and clinical manifestations that can be confused with those of other chronic diarrheal diseases. These include hypokalemia (with or without nephropathy), clubbing, hyperpigmentation of the skin, steatorrhea, colonic inammation, uric acid kidney stones, osteomalacia, and protein-losing enteropathy. Screening tests for laxatives in urine or stool water are summarized in Table 3. Several studies document the frequent failure of physicians to screen for laxative abuse.29,30 Laxatives can be used intermittently, although continued use, even by inpatients, occurs surprisingly often. Thus, urine should be screened for laxatives several times by alkalinization and thin-layer chromatography. Hormone-producing tumors such as those of pancreatic cholera produce a dramatic diarrhea almost from the outset and are often rapidly diagnosed. All the patients studied have had over 0.7 liter of stool per 24 hours, 70 percent have over 3 liters per 24 hours, and volumes of 10 to 21 liters per 24 hours have been reported. Hypokalemia is also a sensitive but nonspecic indication of the presence of pancreatic cholera, since 100 percent of patients have low potassium levels and 93 percent have levels below 2.5 mmol per liter.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, some anthraquinones, and rhubarb turn red; bisacodyl turns purple-blue Spectrophotometry* or thin-layer chromatography*27 of urine or stool water: detects anthraquinones, bisacodyl, phenolphthalein; 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; calculation of fecal osmotic gap: 290 2 (stool sodium concentration stool potassium concentration) Stool osmotic gap: if 50 mOsm per kilogram, 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. The stool specimen should be liquid and frozen. A laxative survey request will usually result in chromatographic, spectrophotometric, and other methods of detecting anthraquinones, bisacodyl, phenolphthalein, castor oil, mineral oil, magnesium, and phosphate. Docusate sodium, the active ingredient in Colace, can be detected by thin-layer chromatography but is not measured in the currently available laxative screens.

lous adenomas can present with diarrhea and electrolyte losses caused by as-yet-unidentied secretagogues or by prostaglandin E2 production.32 These tumors are usually over 3 to 4 cm in diameter and are located in the distal colon or rectum. Water can be seen pouring from the surface, although secretion of water and electrolytes in other parts of the gut can occur as well. Several epidemics of chronic diarrhea (e.g., the Brainerd and Henderson County epidemics) have been associated with the ingestion of raw milk33 or untreated water.34,35 No organism was identied in those epidemics, and there was no response to antibiotics; however, the episodes were self-limited. In addition, 11 percent of patients evaluated for chronic diarrhea in a tertiary referral center had negative evaluations, with no clear cause or associated systemic illness ever found. In most of these patients the onset was sudden. The diarrhea persisted during fasting, was associated with weight loss, and began one to four weeks after travel in the United States. The diarrhea did not improve with antibiotics but eventually resolved over a mean period of 15 months (range, 7 to 31 months).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. If abdominal pain is also present, their condition is diagnosed as a form of irritable bowel syndrome.37,38 Sometimes this group is described as having functional illness, but we classify it as idiopathic to avoid a pejorative term and to acknowledge our lack of understanding of the pathobiology. In three series with exhaustive evaluations of patients with chronic diarrhea, 30 to 60 percent of patients were in this category.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 pain38,39), we consider the patients to have diarrhea of undetermined origin. They are asked whether they

Downloaded from www.nejm.org on May 31, 2005 . This article is being provided free of charge for use in India. Copyright 1995 Massachusetts Medical Society. All rights reserved.

728

THE NEW ENGLAND JOURNAL OF MEDICINE

March 16, 1995

want further evaluation, especially if hydration is difcult to maintain. Most patients want a denitive cause of the diarrhea to be found. Our experience in the evaluation of diarrhea of undetermined origin almost entirely mimics that of Read et al.5 They found that of 27 patients referred after extensive evaluation for chronic severe diarrhea, 9 (33 percent) were taking laxatives or diuretics surreptitiously, 6 (22 percent) had inammatory bowel diseases (2 had ulcerative colitis, and 4 had microscopic colitis), 6 had irritable bowel syndrome, 2 (7 percent) had anal-sphincter dysfunction, 2 had other organic disorders (bacterial overgrowth, beef allergy), and only 2 remained undiagnosed. The most common causes found at this stage are laxative abuse, inammatory bowel diseases (including microscopic [lymphocytic] and collagenous colitis), fecal incontinence, and other causes listed in Table 1 that were missed on the initial evaluation. 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. After reviewing these and, if necessary, repeating them, the next goal is to determine whether the patient has true diarrhea and whether it responds to fasting. On admission, patients are placed on their usual at-home diet, and a 24-hour stool weight is determined. If the stool output is more than 0.5 kg per 24 hours, irritable bowel disease is unlikely. If the stool output is less than 0.2 kg per 24 hours, the patient does not have diarrhea. Rather, the patient is disabled by incontinence, has irritable bowel syndrome, or has rectal disease. Incontinence accompanies chronic diarrhea in as many as 50 percent of cases. 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.14 A 72-hour fast with intravenous hydration is the next part of the diagnostic evaluation. Recording stool
Table 4. Stepwise Evaluation of Hospitalized Patients with Diarrhea of Undetermined Origin.
Day 1 Conrmation 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, potassium, sulfate, phosphate, stool osmolality; calculation of stool osmotic gap Days 24 Imposition of 72-hr fast with intravenous hydration (If diarrhea stops completely in 24 hr, there is no need to continue fast. Secretory diarrhea often decreases greatly with fasting, but continues with 200 g of stool per 24 hr.) Monitoring of daily stool weights Days 58 Imposition of diet containing 75100 g of fat per 24 hr Monitoring of 24-hr mean stool weight and fat content on days 6, 7, and 8

Table 5. Functional Classication of Types of Chronic Diarrhea on the Basis of Responsiveness to Fasting.
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, or sodium citrate), magnesium Food allergy Types (or causes) not responsive or only partly responsive to fasting Laxative or diuretic abuse Inammatory bowel diseases Celiac sprue Intestinal lymphoma Neuroendocrine tumors ZollingerEllison syndrome Pancreatic cholera Carcinoid tumor Medullary carcinoma of the thyroid Systemic mastocytosis Villous adenoma of the rectosigmoid Chronic infection (e.g., Mycobacterium tuberculosis, giardia, amebae) Hyperthyroidism Congenital diarrhea Chloridebicarbonate exchange deciency Sodiumhydrogen exchange deciency Microvillus inclusion disease Bacterial overgrowth

weights daily, especially during the second and third day of fasting, allows clinical differentiation of osmotic from secretory diarrheas. As Fordtran40 and Binder41 have discussed, diarrhea that stops on fasting indicates that dietary substances are causing the diarrhea, directly or indirectly. These cases are usually due to either laxative abuse or unabsorbed carbohydrates, bile acids, or fatty acids (Table 5). 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). Secretory diarrheal diseases are those in which diarrhea persists or stops only partially after 48 hours of fasting. In these diarrheas, stool electrolytes account for most of the stool osmolality, and the fecal osmotic gap is less than 50 mOsm per kilogram of water.22,42 The diseases associated with this type of unresponsive diarrhea are listed in Table 5. Most would have been diagnosed during the initial outpatient evaluation. No detailed study has measured the success of the initial outpatient evaluation of chronic diarrhea, but perhaps one third of cases can be diagnosed on the basis of clues from the history, physical examination, and initial studies, and half of the remainder can be diagnosed on the basis of the systematic outpatient evaluation we have described. Inpatient evaluation leads to a denite diagnosis in at least two thirds of patients admitted for diarrhea of undetermined origin. After comprehensive outpatient and subsequent inpatient evalua-

Downloaded from www.nejm.org on May 31, 2005 . This article is being provided free of charge for use in India. Copyright 1995 Massachusetts Medical Society. All rights reserved.

Vol. 332

No. 11

CURRENT CONCEPTS

729

tions, a diagnosis can thus be made in about 90 percent of patients: about a third will have an organic disorder, about 20 percent will be found to be taking laxatives or diuretics surreptitiously, and the rest will be given a diagnosis of functional or idiopathic diarrhea. In the latter group are many with watery diarrhea of recent acute onset that is self-limited.5,8 As our understanding of and ability to detect intestinal pathophysiologic conditions improve, more patients with undiagnosed chronic diarrhea will be found to have an organic rather than a functional disorder. REFERENCES
1. Schiller LR. Chronic diarrhea of obscure origin. In: Field M, ed. Diarrheal diseases. New York: Elsevier, 1991:219-38. 2. Fine KD, Krejs GJ, Fordtran JS. Diarrhea. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease: pathophysiology, diagnosis, management. 5th ed. Vol. 2. Philadelphia: W.B. Saunders, 1993:1043-72. 3. Powell DW. Approach to the patient with diarrhea. In: Yamada T, ed. Textbook of gastroenterology. Philadelphia: J.B. Lippincott, 1991:732-78. 4. Avery ME, Snyder JD. Oral therapy for acute diarrhea the underused simple solution. N Engl J Med 1990;323:891-4. 5. Read NW, Krejs GJ, Read MG, Santa Ana CA, Morawski SG, Fordtran JS. Chronic diarrhea of unknown origin. Gastroenterology 1980;78:264-71. 6. Geraedts AAM, Esseveld MR, Tytgat GNJ. The value of non-invasive examinations of patients with chronic diarrhoea. Scand J Gastroenterol Suppl 1988;154:46-56. 7. Bytzer P, Stokholm M, Andersen I, Lund-Hansen B, Schaffalitzky de Muckadell OB. Aetiology, medical history, and faecal weight in adult patients referred for diarrhoea: a prospective survey. Scand J Gastroenterol 1990;25: 572-8. 8. Bertomeu A, Ros E, Barragan V, Sachje L, Navarro S. Chronic diarrhea with normal stool and colonic examinations: organic or functional? J Clin Gastroenterol 1991;13:531-6. 9. Greenson JK, Belitsos PC, Yardley JH, Bartlett JG. AIDS enteropathy: occult enteric infections and duodenal mucosal alterations in chronic diarrhea. Ann Intern Med 1991;114:366-72. 10. Bartlett JG, Belitsos PC, Sears CL. AIDS enteropathy. Clin Infect Dis 1992; 15:726-35. 11. Valdovinos MA, Camilleri M, Zimmerman BR. Chronic diarrhea in diabetes mellitus: mechanisms and an approach to diagnosis and treatment. Mayo Clin Proc 1993;68:691-702. 12. Yeoh E, Horowitz M, Russo A, et al. Effect of pelvic irradiation on gastrointestinal function: a prospective longitudinal study. Am J Med 1993;95: 397-406. 13. Cherner JA, Jensen RT, Dubois A, ODorisio TM, Gardner JD, Metcalfe DD. Gastrointestinal dysfunction in systemic mastocytosis: a prospective study. Gastroenterology 1988;95:657-67. 14. Madoff RD, Williams JG, Caushaj PF. Fecal incontinence. N Engl J Med 1992;326:1002-7. 15. Crowe SE, Perdue MH. Gastrointestinal food hypersensitivity: basic mechanisms of pathophysiology. Gastroenterology 1992;103:1075-95. 16. Isaac-Renton JL. Laboratory diagnosis of giardiasis. Clin Lab Med 1991;11: 811-27. 17. Ungar BL, Yolken RH, Nash TE, Quinn TC. Enzyme-linked immunosorbent assay for the detection of Giardia lamblia in fecal specimens. J Infect Dis 1984;149:90-7.

18. Maglinte DD, Chernish SM, Kelvin FM, OConnor KW, Hage JP. Crohn disease of the small intestine: accuracy and relevance of enteroclysis. Radiology 1992;184:541-5. 19. Levitt MD, Duane WC. Floating stools atus versus fat. N Engl J Med 1972;286:973-5. 20. Fine KD, Fordtran JS. The effect of diarrhea on fecal fat excretion. Gastroenterology 1992;102:1936-9. 21. Bond JH Jr, Levitt MD. Fate of soluble carbohydrate in the colon of rats and man. J Clin Invest 1976;57:1158-64. 22. Eherer AJ, Fordtran JS. Fecal osmotic gap and pH in experimental diarrhea of various causes. Gastroenterology 1992;103:545-51. 23. Jain NK, Rosenberg DB, Ulahannan MJ, Glasser MJ, Pitchumoni CS. Sorbitol intolerance in adults. Am J Gastroenterol 1985;80:678-81. 24. Arrambide KA, Santa Ana CA, Schiller LR, Little KH, Santangelo WC, Fordtran JS. Loss of absorptive capacity for sodium chloride as a cause of diarrhea following partial ileal and right colon resection. Dig Dis Sci 1989; 34:193-201. 25. Fromm H, Malavolti M. Bile acid-induced diarrhoea. Clin Gastroenterol 1986;15:567-82. 26. Duncan A, Cameron A, Stewart MJ, Russell RI. Diagnosis of the abuse of magnesium and stimulant laxatives. Ann Clin Biochem 1991;28:56873. 27. Perkins SL, Livesey JF. A rapid high-performance thin-layer chromatographic urine screen for laxative abuse. Clin Biochem 1993;26:179-81. 28. de Wolff FA, Edelbroek PM, de Haas EJ, Vermeij P. Experience with a screening method for laxative abuse. Hum Toxicol 1983;2:385-9. 29. Bytzer P, Stokholm M, Andersen I, Klitgaard NA, Schaffalitzky de Muckadell OB. Prevalence of surreptitious laxative abuse in patients with diarrhoea of uncertain origin: a cost benet analysis of a screening procedure. Gut 1989;30:1379-84. 30. Duncan A, Morris AJ, Cameron A, Stewart MJ, Brydon WG, Russell RI. Laxative induced diarrhoea a neglected diagnosis. J R Soc Med 1992;85: 203-5. 31. Rood RP, Donowitz M. Endocrine tumor-associated diarrheal syndromes. In: Field M, ed. Diarrheal diseases. New York: Elsevier, 1991:397-411. 32. Smelt AH, Meinders AE, Hoekman K, Noort WA, Keirse MJ. Secretory diarrhea in villous adenoma of rectum: effect of treatment with somatostatin and indomethacin. Prostaglandins 1992;43:567-72. 33. Osterholm MT, MacDonald KL, White KE, et al. An outbreak of a newly recognized chronic diarrhea syndrome associated with raw milk consumption. JAMA 1986;256:484-90. 34. Janda RC, Conklin JL, Mitros FA, Parsonnet J. Multifocal colitis associated with an epidemic of chronic diarrhea. Gastroenterology 1991;100:458-64. 35. Parsonnet J, Trock SC, Bopp CA, et al. Chronic diarrhea associated with drinking untreated water. Ann Intern Med 1989;110:985-91 36. Afzalpurkar RG, Schiller LR, Little KH, Santangelo WC, Fordtran JS. The self-limited nature of chronic idiopathic diarrhea. N Engl J Med 1992;327: 1849-52. 37. Talley NJ, Weaver AL, Zinsmeister AR, Melton LJ III. Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders. Am J Epidemiol 1992;136:165-77. 38. Chaudhary NA, Truelove SC. The irritable colon syndrome: a study of the clinical features, predisposing causes, and prognosis in 130 cases. Q J Med 1962;31:307-22. 39. Lynn RB, Friedman LS. Irritable bowel syndrome. N Engl J Med 1993;329: 1940-5. 40. Fordtran JS. Speculations on the pathogenesis of diarrhea. Fed Proc 1967; 26:1405-14. 41. Binder HJ. The gastroenterologists osmotic gap: fact or ction? Gastroenterology 1992;103:702-4. 42. Duncan A, Robertson C, Russell RI. The fecal osmotic gap: technical aspects regarding its calculation. J Lab Clin Med 1992;119:359-63.

Downloaded from www.nejm.org on May 31, 2005 . This article is being provided free of charge for use in India. Copyright 1995 Massachusetts Medical Society. All rights reserved.

You might also like