Original Article
The Self-Limited Nature of Chronic Idiopathic Diarrhea
N Engl J Med 1992; 327:1849-1852December 24, 1992
- Abstract
- Abstract
Background.
Little is known about the clinical presentation and natural history of previously healthy patients in whom chronic idiopathic diarrhea develops.
Methods.
We reviewed the case records of 152 patients with chronic diarrhea who had no history of gastrointestinal surgery and who were evaluated in detail as part of a chronic-diarrhea protocol from 1985 to 1990. Patients were considered to have chronic idiopathic diarrhea if they had persistently loose stools for more than four weeks, no systemic illness, and no identifiable cause of diarrhea.
Results.
Seventeen patients (10 men and 7 women) ranging in age from 33 to 72 years met the criteria for chronic idiopathic diarrhea. Each patient had a history of a relatively abrupt onset of symptoms, often soon after returning home from a trip, starting two to seven months before evaluation. Their diarrhea did not occur during a local outbreak of diarrhea, and other family members did not become ill. Stool frequency ranged from 5 to 25 movements per day, stool weights ranged from 417 to 1480 g per day, and fecal electrolyte and osmolality values were consistent with a diagnosis of secretory diarrhea. The results of biopsies of the small intestine and colon were normal, as were small-bowel roentgenograms. Extensive studies for infectious causes of diarrhea were negative, and no patient responded to antibiotic therapy. In every patient the diarrhea stopped without specific therapy after 7 to 31 months (mean, 15) and did not recur during a follow-up period averaging 38 months.
Conclusions.
Sporadic idiopathic chronic diarrhea is a recognizable syndrome that can last many months, but is self-limited. (N Engl J Med 1992;327:1849–52.)
Media in This Article
Table 1
Components of an Evaluation for Chronic Diarrhea.Table 2
Clinical and Epidemiologic Features of the Patients with Chronic Idiopathic Diarrhea.Article Activity
- Article
THERE are many well-described causes of chronic diarrhea, but in some patients no cause can be found, even after exhaustive diagnostic studies.1 2 3 4 5 These patients often become alarmed at the prospect of endless diarrhea, usually fear they have cancer, and continue to seek an answer to their problem. Doctors also become concerned when dealing with these patients for fear of missing a diagnosis, despite many negative tests, and may undertake increasingly risky interventions.
The purpose of this study was to define the clinical manifestations and natural history of chronic idiopathic diarrhea. To do this, we reviewed the records of patients with chronic diarrhea who were studied systematically, and identified 17 patients in whom we were unable to explain the cause of diarrhea. The results of our studies in this group were tabulated, and their subsequent courses for periods of up to six years were determined by telephone interview. The histories, clinical findings, and subsequent courses of these patients proved to be remarkably similar.
Methods
Patients were considered for this study if they had chronic (>4 weeks) and persistent passage of loose stools (without periods of having formed stools or of constipation) and had not had abdominal surgery (other than appendectomy). The records of 152 such patients seen for chronic diarrhea and studied systematically at Baylor University Medical Center from 1985 to 1990 were reviewed. Most of these patients had been extensively evaluated by their referring physicians and had had one or more therapeutic trials, but still had troublesome diarrhea. To be included in this study, the patients had to meet two additional criteria for chronic idiopathic diarrhea. First, the cause of their diarrhea could not be established after a thorough diagnostic evaluation (Table 1Table 1
Components of an Evaluation for Chronic Diarrhea.).1 Second, they could not have any systemic disease that could cause chronic diarrhea, such as diabetes mellitus or hyperthyroidism.From among these 152 patients, we identified 17 (11 percent of the total group) who fulfilled these criteria for chronic idiopathic diarrhea. Their clinical histories and the results of their diagnostic evaluations were tabulated, and each patient was contacted by telephone and interviewed to verify the historical data and to obtain information about his or her subsequent course.
Results
Clinical History and Epidemiology
The clinical features of the 17 patients are listed in Table 2Table 2
Clinical and Epidemiologic Features of the Patients with Chronic Idiopathic Diarrhea.. Before the onset of diarrhea all the patients had been healthy and had had normal stool frequencies, except for Patient 6, who had been constipated. The diarrhea had begun two to seven months before evaluation. The onset was sudden in 16 patients, starting on a specific day that could be remembered; in the other patient (Patient 4), the diarrhea began over a period of two to three days. In two patients (Patients 3 and 9) the onset of diarrhea was associated with myalgia and feverishness. In one patient (Patient 3) the onset was also associated with nausea and vomiting. None of the patients had fever, nausea, or vomiting after the first few days of the illness. During the chronic phase of the diarrheal illness, the stool frequency was quite abnormal (Table 2); 10 patients had nocturnal or early-morning bowel movements, or both. Five patients had urgency to defecate, six patients had fecal incontinence, and five patients had abdominal cramps with their diarrhea. None of the patients had severe abdominal pain, flatulence, abdominal distention, or excessive mucus in their stools. The diarrhea was exacerbated by eating in eight patients. Twelve patients had moderate weight loss (Table 2).Fourteen of the patients lived in cities, two in towns, and one in a rural area. Nine were from Texas, three were from Oklahoma, and one each was from Georgia, Mississippi, Louisiana, Arkansas, and Missouri. Four patients consumed potentially contaminated water. None of the patients had consumed untreated water from a lake, and none had ingested raw milk.
Ten of the 17 patients had a history of recent travel before the onset of diarrhea to the places listed in Table 2. The diarrhea began one to four weeks after the trip was completed. A brother of one patient (Patient 5) began to have chronic diarrhea at approximately the same time as the patient; the patient and his brother had not lived or traveled together within the preceding four weeks. A brief diarrheal illness occurred in one patient's husband (Patient 6), who had accompanied her on a trip; otherwise, no other household members had diarrhea.
General Evaluation
The physical examination was normal in all patients. Complete blood counts were normal in all but Patient 3, who had a history of chronic myelogenous leukemia and who had a few myelocytes in his peripheral-blood smear; he also had elevated serum γ-glutamyltransferase and alkaline phosphatase concentrations. No other patient had any abnormal liver-function tests. Six patients had hypokalemia (potassium level, <3.5 mmol per liter) on at least one occasion; the lowest serum potassium concentration was 2.4 mmol per liter (in Patient 8). Otherwise, serum electrolyte concentrations were normal. Serum protein and thyroid hormone concentrations were normal in all patients.
Stool Evaluation
Examinations of stool samples for pathogenic bacteria (including salmonella, shigella, campylobacter, yersinia, aeromonas, and plesiomonas), ova, parasites, occult blood, white cells, and Clostridium difficile toxin were negative in all patients.
Stool was collected quantitatively under refrigeration for 48 to 72 hours from all patients while they ate a regular diet (Table 3Table 3
Analysis of Stool Samples from the Patients with Chronic Idiopathic Diarrhea.). The weights of the specimens were each more than twice the upper limit of normal. The mean osmotic gap was small, and fecal pH was 5.6 or higher in each patient, making carbohydrate malabsorption unlikely.7 Steatorrhea was uncommon and never severe. The fecal chymotrypsin concentration was normal in each patient. None of the patients had phenolphthalein or anthraquinone in their stool or urine, and all had normal fecal magnesium excretion.8 Stools were also collected from 10 of the 17 patients during fasts lasting 24 to 48 hours; the stool weight during these periods of fasting averaged 383 g per day (range, 185 to 1092).Other Diagnostic Tests
Schilling tests with intrinsic factor were undertaken in 12 patients, and the results were normal in each. An attempt was made to obtain jejunal fluid from each patient for quantitative aerobic and anaerobic culture, and such fluid was obtained from 14 of them. Four patients (Patients 7, 8, 11, and 13) had excessive colonization of jejunal fluid (>105 organisms per milliliter), but their diarrhea was unaffected by treatment with any of several antibiotic regimens (trimethoprim–sulfamethoxazole, metronidazole, tetracycline, and doxycycline).
Upper gastrointestinal and small-bowel roentgenograms were obtained in all patients. Five patients had rapid transit; the studies were normal in the other patients. Upper gastrointestinal endoscopy was performed in all but one patient. All but Patient 6 had normal results; she had a hyperplastic inflammatory polyp in the gastric antrum, which was removed endoscopically with no effect on the diarrhea. Biopsy specimens of the small bowel, obtained from 16 patients, were normal histologically and negative for giardia and other parasites. Colonoscopy, performed in all the patients, revealed normal mucosa, except in Patient 1, who had submucosal petechiae and erythema in the right side of the colon. Three patients (Patients 7, 8, and 17) had adenomatous polyps in their colons; neither endoscopic removal of the polyps nor, in Patient 8, surgical resection had any effect on the diarrhea. Multiple colonoscopic biopsies were performed in all the patients and revealed no evidence of inflammation. One patient (Patient 6) had melanosis coli; she had habitually taken laxatives for chronic constipation in the past, but not recently, and had no evidence of laxatives in stool water or urine.
Abdominal ultrasonography, performed in five patients, and computed tomography of the abdomen, performed in eight patients, were normal.
All 17 patients had normal vasoactive intestinal polypeptide and calcitonin concentrations and urinary excretion of 5-hydroxyindoleacetic acid. Serum gastrin levels were elevated in 2 of 12 patients (Patients 6 and 11), both of whom had achlorhydria.
Therapeutic Trials
Fifteen patients had been treated for a week or more with metronidazole before their referral; none had improvement in diarrhea. Nine patients had been treated unsuccessfully with other antimicrobial drugs before their evaluation, including trimethoprim–sulfamethoxazole, doxycycline, tetracycline, and ciprofloxacin. As noted previously, we treated the four patients with high jejunal bacterial counts with antibiotics for at least one week without improvement. All patients tried opiate antidiarrheal drugs; 3 of 6 treated with tincture of opium improved, 4 of 10 treated with loperamide improved, and 1 did not respond to codeine. Three patients (Patients 10, 12, and 17) were treated with octreotide (a somatostatin analogue), with no benefit. Some other medications that these patients received that were not beneficial included cholestyramine, dicyclomine, kaolin and pectin with belladonna alkaloids (Donnagel), sulfasalazine, and prednisone.
Subsequent Course
All the patients had spontaneous complete remission of their diarrhea; in most this occurred gradually over a period of two to three months. The mean duration of diarrhea was 15 months. As shown in Table 2, the total duration of diarrhea ranged from 7 to 31 months, continuing for an average of 11 months after our evaluation. No patient had a recurrence of diarrhea during an average of 38 months (range, 4 to 83) after its cessation. Nine of the 12 patients who had lost weight during their diarrheal illness regained it. One of the three patients who did not regain weight (Patient 14) had been following a weight-reducing diet. At the most recent follow-up, all the patients were healthy.
Discussion
The diarrhea in these patients began suddenly, but not during a local outbreak. It rapidly became a severe problem, with stool frequencies ranging from 5 to 25 movements per day (average, 10). Most patients lost some weight. The diarrhea lasted for an average of 15 months (range, 7 to 31) and then resolved spontaneously. These clinical features were remarkably similar from patient to patient, so much so that the syndrome could often be recognized even before the diarrhea resolved.
We were unable to identify the cause of the diarrhea in these patients. Stool weights were substantially increased, fecal electrolyte concentrations revealed no substantial osmotic gap, and diarrhea persisted during periods of fasting, suggesting that the diarrhea was secretory in nature.3 However, we could find no infectious agent, and there was no evidence of inflammation or tumor, which might cause a secretory diarrhea. Four patients had abnormal growth of bacteria in aspirated jejunal fluid. None of them had diverticula or other anatomical abnormalities favoring bacterial overgrowth, and the results of quantitative cultures were consistent with mild-to-moderate contamination. Only one of these patients (Patient 8) had steatorrhea, one of the hallmarks of the bacterial overgrowth syndrome.9 Antibiotic therapy had no effect on the diarrhea in any of the patients. We therefore do not believe that bacterial overgrowth was the cause of their diarrhea. Two other patients (Patients 5 and 6) had slight increases in fecal excretion of fat, which was probably due to the diarrhea rather than its cause.6
Ten of the 17 patients had taken a trip before the onset of their diarrhea, and it is possible that travel was somehow related to the cause of their illness. Yet this syndrome is unlike typical traveler's diarrhea.10 The travel was mostly to areas within the United States, none of which are recognized as places where bacterial or parasitic infection is commonly transmitted or where the residents have unusual intestinal flora. In addition, traveler's diarrhea typically subsides in a few days,10 rather than after months.
The acute onset of symptoms and their eventual resolution are compatible with an illness caused by a viral, bacterial, or protozoal pathogen that we were unable to identify with standard clinical methods. Agents such as unusually persistent viruses, toxigenic Escherichia coli, or other bacteria not identified by routine culture methods could be involved. However, the lack of response to antibiotic therapy and the absence of person-to-person transmission to family members do not support this hypothesis.
This chronic diarrheal illness has some features in common with two epidemics of chronic diarrhea that have been traced to point sources. One was an outbreak in Brainerd, Minnesota, caused by the ingestion of raw milk,11 and the other was associated with drinking untreated water at a restaurant in Henderson County, Illinois.12 , 13 As was true in our study, the diarrhea affected men and women equally, there was no response to antibiotics in these point-source outbreaks, and the diarrhea was secretory in nature and long-lasting. The main clinical feature that distinguishes the illnesses in these patients from those in our patients, in addition to the absence of a point source, is that the results of colon biopsies in our patients were normal, whereas in most of the Minnesota and Illinois cases the colon biopsies revealed inflammation. Likewise, fecal leukocytes were not seen in our patients, whereas they were noted in 17 percent and 7 percent of the Minnesota and Illinois patients, respectively.11 , 12 Finally, whereas all of our patients had spontaneous remissions of their diarrhea, spontaneous resolution occurred in only 75 percent and 13 percent, respectively, of the patients in the two outbreaks.11 , 12
Physicians should know about this syndrome so that they can avoid using unnecessary interventional diagnostic procedures and hazardous therapies. A tentative diagnosis of this syndrome rests on the typical clinical history of the abrupt onset of chronic, persistent diarrhea in a previously healthy person with no history of gastrointestinal disease or surgery. If the subsequent evaluation shows evidence of a secretory diarrhea and no evidence of intestinal inflammation, tumor, laxative abuse, or other known causes of chronic secretory diarrhea (by means of the studies listed in Table 1), the diagnosis of self-limited, chronic diarrhea is likely. Once this syndrome is recognized, patients can be reassured that their chronic diarrhea will probably subside; this information will comfort them while they endure a seemingly endless illness.
Supported by a Public Health Service grant (R01-DK37172–07) from the National Institute of Diabetes and Digestive and Kidney Diseases.
We are indebted to Mary Gomez for assistance in the preparation of the manuscript.
Source Information
From the Department of Internal Medicine, Baylor University Medical Center, 3500 Gaston Ave., Dallas, TX 75246, where reprint requests should be addressed to Dr. Fordtran.
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Duc J. Vugia, Sharon Abbott, Eric D. Mintz, Jennifer Richmond, Sheldon Meshulam, Kusum Stokes, Ann Lindsay, Thomas H. Tsang. (2006) A Restaurant‐Associated Outbreak of Brainerd Diarrhea in California. Clinical Infectious Diseases 43:1, 62-64
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David A. Bryant, Eric D. Mintz, Nancy D. Puhr, Patricia M. Griffin, Robert E. Petras. (1996) Colonic Epithelial Lymphocytosis Associated with an Epidemic of Chronic Diarrhea. The American Journal of Surgical Pathology 20:9, 1102-1109
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