Chronic diarrhea is a frequent and challenging problem in clinical medicine. In a considerable subgroup of these, no underlying cause is identified and this is referred to as functional diarrhea. A consensus definition for functional diarrhea is based on loose stool consistency and chronicity and absence of coexisting irritable bowel syndrome. Underlying pathophysiology includes rapid intestinal transit, which may be worsened by stress or be triggered by a preceding infectious gastroenteritis. Diagnostic work-up aims at exclusion of underlying organic disease. Treatment starts with dietary adjustments, aiming at decreasing nutrients that enhance transit and stool and at identifying precipitating food items.
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Chronic diarrhea, specifically functional diarrhea, is a clinical problem of considerable magnitude.
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The epidemiology of this condition needs further studies, because the overlap with diarrhea-predominant irritable bowel syndrome (D-IBS) is usually not taken into account in currently available literature.
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The role of stress and of specific nutrient intolerances is incompletely elucidated.
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In clinical practice, a stepwise diagnostic approach can be used to eliminate underlying organic disease in a cost-effective fashion. A similar approach can be used to identify and eliminate potential precipitating or worsening food constituents.
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Although there are many available pharmacologic treatment options that can be used in these patients, comparative studies establishing a hierarchy of cost benefit and a sequence of use of such agents are lacking.
Introduction and definition
Chronic diarrhea is a frequent presenting symptom, seen by both general practitioners and gastroenterologists. The differential diagnosis is broad, and diagnostic evaluation may be complex.
In spite of the large number of causes of chronic diarrhea, and in spite of extensive investigations, no cause for the symptoms is found in a large group of patients, who are referred to as having functional diarrhea.
According to the Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders (Rome III criteria), functional diarrhea is defined as the presence of loose (mushy) or watery stools in at least 75% of stools, in the absence of pain. The presence of pain distinguishes functional diarrhea from D-IBS. In addition, the symptoms have to be chronic, with an onset of at least 6 months before diagnosis and active symptoms during the prior 3 months.
The Rome III criteria used stool consistency rather than frequency or the presence of urgency for the definition of functional diarrhea. This definition is based on the association of stool consistency with transit times and on the possibility for urgency to occur even in the presence of solid stools. Alternatively, frequency and the presence of urgency are important components of self-reported diarrhea in patients and in the general population.
Epidemiology
The prevalence of functional diarrhea in the population is poorly studied. Most available surveys on the epidemiology of chronic diarrhea have not systematically distinguished D-IBS from other types of chronic diarrhea, and in a condition with such a broad differential diagnosis, symptom-based criteria are insufficient to exclude several organic causes. Nevertheless, a telephone survey in the United States found that 26.9% of 1017 respondents reported symptoms of diarrhea or loose stools in the prior month, with similar prevalences in both genders. The definition used in this survey, however, was less stringent than the Rome III consensus definitions.
A recent survey in Olmsted County, Minnesota, studied the prevalence of chronic diarrhea and excluded irritable bowel syndrome (IBS) based on Rome III criteria. In a questionnaire mailed to 892 eligible subjects, 73% responded, with 28% reporting chronic diarrhea. In 60% of these, the diarrhea was painless, and this was associated with self-reported food intolerance and with stress and was less prevalent in women and in those with a higher education. Chronic diarrhea was not associated with age, marital status, body mass index, smoking history, acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs, coffee use, alcohol use, pets, or water supply. The definition used (≥3 bowel movements a day, loose or watery stools, or fecal urgency on at least 25% of the occasions), however, was still less stringent than the Rome III definition for functional diarrhea. In addition, the study could not correct for identifiable causes, such as lactose intolerance and celiac disease, although their impact is likely low.
Epidemiology
The prevalence of functional diarrhea in the population is poorly studied. Most available surveys on the epidemiology of chronic diarrhea have not systematically distinguished D-IBS from other types of chronic diarrhea, and in a condition with such a broad differential diagnosis, symptom-based criteria are insufficient to exclude several organic causes. Nevertheless, a telephone survey in the United States found that 26.9% of 1017 respondents reported symptoms of diarrhea or loose stools in the prior month, with similar prevalences in both genders. The definition used in this survey, however, was less stringent than the Rome III consensus definitions.
A recent survey in Olmsted County, Minnesota, studied the prevalence of chronic diarrhea and excluded irritable bowel syndrome (IBS) based on Rome III criteria. In a questionnaire mailed to 892 eligible subjects, 73% responded, with 28% reporting chronic diarrhea. In 60% of these, the diarrhea was painless, and this was associated with self-reported food intolerance and with stress and was less prevalent in women and in those with a higher education. Chronic diarrhea was not associated with age, marital status, body mass index, smoking history, acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs, coffee use, alcohol use, pets, or water supply. The definition used (≥3 bowel movements a day, loose or watery stools, or fecal urgency on at least 25% of the occasions), however, was still less stringent than the Rome III definition for functional diarrhea. In addition, the study could not correct for identifiable causes, such as lactose intolerance and celiac disease, although their impact is likely low.
Diagnostic approach
History taking should evaluate the ingestion of poorly absorbed carbohydrates (fructose, sorbitol, and so forth), which may cause diarrhea, or a link between symptoms and ingestion of dairy products, suggestive of lactose intolerance. The Bristol stool form scale can be used as a visual aid to confirm a patient’s usual stool consistency. Medication use needs to be assessed, because several drugs (magnesium-containing antacids; lipase inhibitors, such as orlistat; prokinetics, such as erythromycin and metoclopramide; colchicine; misoprostil; and broad-spectrum antibiotics) may cause diarrhea as an adverse effect.
The presence of abdominal pain (suggestive of IBS or other causes), weight loss (suggestive of malabsorption), steatorrhea-like stools or nocturnal diarrhea, recent intake of antibiotics or a history of abdominal surgery all argue in favor of other specific diagnoses and should be evaluated. Similarly, a family history of inflammatory bowel disease, celiac disease, or colorectal cancer should increase suspicion of organic disorders. Physical examination should evaluate abdominal or rectal masses, signs of anemia, and signs of malnutrition (edema, skin or nail abnormalities, and so forth). Digital rectal examination should assess anal sphincter tone.
Chronic diarrhea generally requires additional technical examinations, including blood work with assessment of C-reactive protein, signs of malabsorption, thyroid function, and celiac disease screening. Colonoscopy is recommended in those above 50 years old and those with a recent onset of symptoms, but the threshold for ordering ileocolonoscopy (exclusion of polyps or inflammatory bowel disease) with biopsies (exclusion of microscopic colitis) and upper endoscopy with duodenal biopsies (exclusion of giardiasis and villous atrophy) is low in patients with chronic diarrhea. In refractory cases, analysis of 3-day stool collection volume and composition, tests for bile acid malabsorption, and small bowel radiograph can be considered. Additional evaluations include tests for small intestinal bacterial overgrowth and screening for secretive (factitious) laxative use. Several diagnostic algorithms have been published, which allow identifying organic or specific causes of chronic diarrhea through a cost-effective sequence of investigations.
Pathophysiologic mechanisms in functional diarrhea
Although many studies have addressed pathophysiologic mechanisms in D-IBS, functional diarrhea is poorly studied. The stool consistency, which is a key feature in the Rome III definition of functional diarrhea, suggests that rapid bowel transit is present in patients with chronic diarrhea. In keeping with an underlying motility disorder, a colonic manometry study found increased propagating colonic contractions and decreased nonpropagating contractions in functional diarrhea patients.
Epidemiologic research found an association between chronic diarrhea and self-reported stress in the general population. A study in healthy volunteers confirmed that acute dichotomous listening stress enhances small bowel transit whereas gastric emptying times were not affected. Chronic diarrhea, with or without abdominal pain, may be precipitated by an acute gastroenteritis, and in these patients falls within the spectrum of postinfectious bowel disorders.
Treatment approach
Clear explanation of the symptoms and diagnosis and reassurance about the benign nature of chronic functional diarrhoea are important. It is worthwhile to discuss potential triggering factors, such as specific foods, stress, and anxiety. Dietary restrictions of food components, such as fructose, sorbitol, caffeine, or other precipitating foods, are generally proposed as a first approach. A trial of lactose elimination can be advocated in those who consume milk products on a regular basis. In addition, restrictions of alcohol, which may precipitate diarrhea in susceptible subjects, and foods rich in fiber are recommended. A diet-and-stool diary may help identify aggravating factors.
Pharmacotherapy can be considered as a first-line treatment in those who have symptoms with major impact on their quality of life or can be added in those who fail to respond sufficiently to reassurance and dietary measures. Antidiarrheal agents may be classified as intestinal transit inhibitors (opioids, tricyclic antidepressants, and 5-HT 3 antagonists), intraluminal agents (cholestyramine, medicinal fiber, clays, activated charcoal, and bismuth), proabsorptive agents (clonidine), and antisecretory drugs (octreotide).
Intestinal transit inhibitors
Opioid Agonists
Opioid receptor ligands are the most frequently used agents in the (symptomatic) treatment of diarrhea. Morphine is well known to slow gastrointestinal transit and codeine, a μ-opioid receptor agonist, is less potent but also has antidiarrheal properties. Because of their central effects and risk of habituation, these opioids are usually avoided in the treatment of chronic diarrhea. Diphenoxylate and loperamide, especially, are preferentially used because they lack central nervous system effects.
The drug most commonly used in clinical practice is loperamide, a peripherally acting μ-receptor agonist without addictive properties. Loperamide inhibits peristalsis and slows intestinal and colonic transit times, thereby allowing more complete absorption of electrolytes and water. In addition, loperamide increases anal sphincter pressure and reduces the sensitivity of the rectum to distention, which is beneficial in cases of associated urge incontinence. Starting doses of loperamide are 2 mg to 4 mg, with titration to patient symptoms and stool pattern. A high interindividual dose variation exists, and in some patients with large volumes of liquid stool, doses may be increased up to 24 mg in divided doses over 24 hours. Loperamide can also be taken prophylactically before meals or when leaving the house.
Diphenoxylate is another μ-opioid agonist with peripheral actions similar to loperamide but which does cross the blood-brain barrier. To prevent overdosage, atropine is added to diphenoxylate capsules in some countries. In a crossover study with placebo in patients with chronic diarrhea, diphenoxylate with atropine significantly reduced stool frequency and daily stool weight. Adverse effects related to diphenoxylate or to atropine have been reported.
One trial comparing the efficacy of loperamide, codeine, and diphenoxylate plus atropine in patients with chronic diarrhea showed that loperamide or codeine were more efficacious and better tolerated than diphenoxylate. Another study compared loperamide to the α 2 -agonist, lidamidine, and to placebo in chronic diarrhea and found superior symptomatic responses to loperamide compared with lidamidine and placebo. A placebo-controlled trial in fecal incontinence showed that loperamide improved urgency and urgency incontinence. This was associated with increased anal sphincter pressure and an improved capacity for rectal retention of fluids.
5-HT 3 Receptor Antagonists
5-HT 3 receptor antagonists increase colonic transit times. Clinical studies with the 5-HT 3 receptor antagonist, alosetron, showed improved stool pattern and relief of pain/discomfort in women with D-IBS at a dose of 1 mg twice a day. The drug also improved symptoms of urgency and urgency incontinence in D-IBS. Data regarding its efficacy in functional diarrhea not related to IBS are lacking, but based on the mode of action and based on clinical experience, the drug seems efficacious in this condition. Shortly after its introduction to the US market, however, alosetron was withdrawn because of side effects of colonic ischemia. The drug was subsequently reintroduced in a restricted access program in the United States and follow-up reports have shown a good safety profile in this limited-use setting. In Japan, the 5-HT3 receptor antagonist, ramosetron, has been approved for the treatment of D-IBS in men.
Tricyclic Antidepressants
Tricyclic antidepressants have some anticholinergic and, therefore, antidiarrheal actions. In an uncontrolled study in patients with fecal incontinence, amitryptiline prolonged colonic transit time, improved stool consistency, suppressed rectal motor events, and improved fecal incontinence. Desipramine was investigated in a large, multicenter, placebo-controlled study of IBS but showed only beneficial effects in a per protocol analysis, whereas the intention-to-treat failed to show benefit due to poor tolerance with a high number of discontinuations. Because the study did not report details on stool pattern and urgency, it is unclear how well diarrhea symptoms responded.
Racecadotril
Racecadotril is an enkephalinase inhibitor, developed for the treatment of diarrhea. Clinical efficacy has mainly been established in acute infectious diarrhea. Studies comparing racecadotril to loperamide in adults with acute infectious diarrhea or in elderly patients residing in nursing homes with diarrhea reported rapid and complete resolution of diarrhea, with fewer symptoms of abdominal pain or constipation. It is unclear whether the drug affects intestinal transit; a study with acetorphan, another enkephalinase inhibitor, showed no effect on transit. Studies of enkephalinase inhibitors in functional diarrhea are lacking.
Related posts:
Colorectal Normal Histology and Histopathologic Findings in Patients with Chronic Diarrhea
Bacterial Flora as a Cause or Treatment of Chronic Diarrhea
Diarrhea in the Immunocompromised Patient
Diarrhea Caused By Carbohydrate Malabsorption
Celiac Disease
Diarrhea in Chronic Inflammatory Bowel Diseases
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