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Approach to the adult with chronic diarrhea in resource-abundant settings

Approach to the adult with chronic diarrhea in resource-abundant settings
Authors:
Peter A L Bonis, MD
J Thomas Lamont, MD
Section Editor:
Lawrence S Friedman, MD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Literature review current through: Dec 2022. | This topic last updated: May 02, 2022.

INTRODUCTION — Diarrhea is a common manifestation of gastrointestinal disease and is a leading cause of health care utilization [1,2]. Optimal strategies for the evaluation of patients with chronic diarrhea have not been established. The selection of specific tests, timing of referral, and the extent to which testing should be performed depend upon an appraisal of the likelihood of a specific diagnosis, the availability of treatment, the severity of symptoms, patient preference, and comorbidities. However, a specific diagnosis can be achieved in more than 90 percent of patients.

This topic review will provide an overview of the evaluation and treatment of chronic diarrhea. Individual disorders associated with chronic diarrhea and an approach to patients with acute diarrhea are presented separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management" and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Evaluation of the patient with HIV and diarrhea" and "Approach to the adult with acute diarrhea in resource-rich settings".)

DEFINITION — Chronic diarrhea is defined as a persistent alteration of stool consistency from the norm with loose stools (consistency between types 5 and 7 on the Bristol stool chart) and increased stool frequency of greater than three stools daily of at least four weeks' duration [3-7].

EPIDEMIOLOGY — The prevalence of chronic diarrhea in the general population in resource-abundant settings has not been well established. The variable rates observed in several studies reflect differences in study design, definitions, and characteristics of populations that have been sampled. Based upon a commonly used definition (ie, the presence of excessive stool frequency) a reasonable approximation is that chronic diarrhea affects approximately 3 to 7 percent of the population [4,8,9]. Chronic diarrhea can decrease quality of life. However, accurate assessment of the degree to which this occurs has not been established. Direct and indirect costs of chronic diarrhea in the United States are estimated to be at least $524 million per year and $136 million per year, respectively [10-12].

ETIOLOGY — The principal causes of diarrhea vary based upon the socioeconomic status of the population. In resource-abundant settings, common causes are irritable bowel syndrome (IBS), inflammatory bowel disease, malabsorption syndromes (such as lactose intolerance and celiac disease), and chronic infections (particularly in patients who are immunocompromised) (table 1). In resource-limited settings, chronic diarrhea is frequently caused by chronic bacterial, mycobacterial, and parasitic infections, although functional disorders, malabsorption, and inflammatory bowel disease are also common.

The following sections highlight important distinguishing clinical features of some the most prevalent disorders associated with chronic diarrhea. Other less prevalent causes are listed in the table (table 1). Detailed discussions on these and other disorders associated with chronic diarrhea are presented in the corresponding topic reviews.

Functional disorders — Patients with IBS complain of cramping lower-quadrant pain associated with altered bowel habits (diarrhea, constipation, alternating diarrhea and constipation). Diarrhea is usually characterized as frequent loose stools of small to moderate volume. Stools generally occur during waking hours, most often in the morning or after meals. Some bowel movements are preceded by extreme urgency and may be followed by a feeling of incomplete evacuation or tenesmus. Incontinence of liquid stool may occur during periods of disease activity. Approximately one-half of all patients with IBS complain of mucus discharge with stools. Symptoms of IBS often correlate with episodes of psychologic stress. Thus, patients often seek medical help for their chronic symptoms during such periods. Patients usually experience the onset of symptoms as young adults, but the prevalence is similar in older adults. Post-infectious IBS can occur following recovery from Clostridioides difficile and other bacterial infections. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults" and "Pathophysiology of irritable bowel syndrome".)

A number of related functional bowel disorders have also been described to include functional diarrhea, IBS with predominant diarrhea, and IBS with mixed bowel habits [13]. These disorders are considered to represent a continuum, rather than being independent entities, according to a consensus of experts [14,15]. Functional diarrhea is characterized by recurrent passage of loose or watery stools. Patients with functional diarrhea should not meet criteria for IBS. Patients with functional diarrhea may have abdominal pain and/or bloating, but unlike IBS, these are not predominant symptoms.

Organic disorders — Organic disorders are conditions that are associated with physiologic, structural, or biochemical abnormalities. Organic disorders are more likely in adults with "alarm" features (table 2). (See 'Evaluation for alarm features' below.)

Inflammatory bowel disease — Inflammatory bowel disease (IBD) primarily refers to ulcerative colitis and Crohn disease, although other intestinal disorders are also associated with intestinal inflammation. Most cases of ulcerative colitis and Crohn disease have their onset between ages 15 and 40. Many studies suggest a bimodal age distribution for both disorders with a second peak between age 50 and 80. IBD tends to run in families and is more common in individuals with Jewish ancestry. (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease".)

Crohn disease – Crohn disease may involve the entire gastrointestinal tract from mouth to perianal area. Diarrhea, abdominal pain, weight loss, and fever are the typical clinical manifestations for most patients with ileitis, ileocolitis, or Crohn colitis. Patients can have symptoms for many years prior to diagnosis. Although occult GI blood loss is common in Crohn disease, gross bleeding is much less frequent than in ulcerative colitis (except for some patients with Crohn colitis).

Ulcerative colitis – Patients with ulcerative colitis may present in a variable manner. The history is typically one of the gradual onset of symptoms, sometimes preceded by a self-limited episode of rectal bleeding that occurred weeks or months earlier. The initial episode is limited to the rectum or distal colon in one-third of patients, to the left colon up to the splenic flexure in one-third, and most of the remaining patients have pancolitis. Less than 10 percent present with fulminant disease. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)

Microscopic colitis — Microscopic colitis usually occurs in middle-aged and older adults, but it can also affect children. Microscopic colitis has two main histologic subtypes (lymphocytic colitis and collagenous colitis). Both subtypes have a similar clinical presentation. Patients with microscopic colitis usually have between four and nine watery stools per day, but in rare cases, bowel movements can exceed 1.5 or up to 2 liters per day. The clinical course is mainly intermittent. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations'.)

Colonoscopy usually reveals macroscopically normal colonic mucosa, although slight edema, erythema, and friability may be seen. Although specimens obtained by flexible sigmoidoscopy are frequently sufficient to establish the diagnosis, the severity of histologic changes declines from the proximal to the distal colon; thus, colonoscopic biopsies should be obtained from the entire colon. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management", section on 'Diagnostic approach' and 'Endoscopic evaluation' below.)

Malabsorption syndromes — The classic manifestations of malabsorption are pale, greasy, voluminous, foul-smelling stools, and weight loss despite adequate food intake. However, this spectrum of findings is relatively uncommon, even in generalized mucosal disease. The majority of patients with malabsorption have relatively mild gastrointestinal symptoms, which often mimic more common disorders such as IBS. In some cases, flatulence, abdominal distension, and borborygmi may be the only complaints suggesting malabsorption; other patients may be asymptomatic. (See "Approach to the adult patient with suspected malabsorption".)

The clinical and laboratory features of malabsorption depend upon the cause and severity of the disease (table 3). As an example, isolated forms of malabsorption may present solely with symptoms that are attributable to the particular nutrient in question (table 4). Iron deficiency anemia may be the only clue to the presence of celiac disease. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)

Relatively common disorders associated with malabsorption include:

Lactose intolerance (see "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management")

Chronic pancreatitis (see "Chronic pancreatitis: Clinical manifestations and diagnosis in adults")

Celiac disease (see "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults")

Bacterial overgrowth of the small intestine (see "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis")

Post-cholecystectomy diarrhea — The incidence of diarrhea following cholecystectomy has ranged from as low as 2 percent to as high as 50 percent in various reports reflecting the various populations, differences in study design, and the degree to which diarrhea was sought [16-18]. In many cases, the diarrhea will resolve or significantly improve over the course of weeks to months [19]. The diarrhea is related to excessive bile acids entering the colon [20,21]. In the absence of a gallbladder, bile drains directly and more continuously into the small bowel, which may overcome the terminal ileum's reabsorptive capacity. The increased bile acids in the colon lead to diarrhea (cholerheic diarrhea) [22]. Patients often respond to treatment with bile-acid binding resins such as cholestyramine or colestipol [23]. (See 'Empiric therapy in selected patients' below.)

Chronic infections — Some persisting infections (eg, C. difficile, Aeromonas, Plesiomonas, Campylobacter, Giardia, Amebae, Cryptosporidium, Whipple's disease, and Cyclospora) can be associated with chronic diarrhea [24]. Microsporidium should be a consideration in immunocompromised patients with persistent diarrhea. (See appropriate topic reviews).

Several other causes of chronic diarrhea caused by, or resulting from a presumed infection have been described:

An epidemic form of secretory diarrhea (Brainerd diarrhea) associated with patchy lymphocytic colonic inflammation can cause symptoms that persist for up to three years [25-30]. Risk factors include consumption of contaminated water and unpasteurized milk. An infectious agent is suspected but has not been identified.

The development of post-infectious irritable bowel syndrome has also been described in up to 30 percent of patients following documented acute bacterial enteric infections. (See "Pathophysiology of irritable bowel syndrome" and 'Functional disorders' above.)

It is possible that some patients with chronic diarrhea may have an infectious cause that may not be easily demonstrable. A case report described a woman with severe, debilitating diarrhea that was ultimately found to be due to Stenotrophomonas maltophilia, a Gram-negative rod that was only identifiable using molecular genetic techniques [31]. Further studies using such techniques will help determine whether other infectious agents can be implicated in chronic diarrhea.

Chronic diarrhea due to Candida albicans infection has been described in case reports [32]. Most patients had received immunosuppression (in some cases with antibiotics), were malnourished, or had an immune disorder [32]. Diagnosis was established by detection of large numbers of Candida in small bowel aspirates and stool specimens, and response to antifungal therapy. The presence of Candida in stool specimens has also been described in asymptomatic individuals, and thus, the clinical context is important in considering the diagnosis.

Chronic infection with Blastocystis hominis, an anaerobic protozoan parasite, has been implicated as a cause of chronic diarrhea in some reports. (See "Blastocystis species".)

Medications — Many drugs can cause diarrhea through a variety of mechanisms [33-37]. It can be challenging to identify the agent causing drug-induced diarrhea, particularly in patients taking multiple medications (table 5). The clinical setting and timing of the onset of symptoms relative to when the medications were started can be helpful.

INDICATIONS FOR REFERRAL TO A GASTROENTEROLOGIST — The need for gastroenterology evaluation and timing of referral depend upon the severity of symptoms, the diagnoses being considered, and the presence of alarm features (table 2). (See 'Evaluation for alarm features' below and 'Establishing a diagnosis' below.)

Indications for referral include anyone of the following:

Alarm features

Severe diarrhea

Suspected inflammatory bowel disease (see 'Inflammatory bowel disease' above)

Inconclusive diagnosis after initial evaluation (see 'Initial evaluation' below and 'Establishing a diagnosis' below)

Failure to respond to empiric therapy (see 'Empiric therapy in selected patients' below)

Referral to a gastroenterologist may also be appropriate in patients who require long-term management for the underlying cause (eg, inflammatory bowel disease, chronic pancreatitis).

INITIAL EVALUATION

Overview — The initial evaluation of patient with chronic diarrhea includes history, physical examination, and laboratory testing to determine whether the patient has any alarm findings which help to distinguish organic from functional diarrhea and characterizing the diarrhea in order to direct the need for additional evaluation.

Evaluation for alarm features — Alarm features in patients with chronic diarrhea may be suggestive of an underlying organic etiology (table 2). These features include the following (see 'Organic disorders' above):

Age of onset after age 50 years

Rectal bleeding or melena [6]

Nocturnal pain or diarrhea

Progressive abdominal pain

Unexplained weight loss, fever, or other systemic symptoms

Laboratory abnormalities (iron deficiency anemia, elevated C-reactive protein or fecal calprotectin)

Family history of inflammatory bowel disease (IBD) or colorectal cancer

Characterizing the diarrhea type — Information other than alarm features obtained in the initial evaluation helps to distinguish among organic etiologies. Characterizing the diarrhea (infectious, inflammatory, osmotic, secretory) is a useful way to guide evaluation and the diagnosis can then be confirmed by focused testing (table 6). The distinction between types of diarrhea can often be made based upon the medical history but in other cases may require additional laboratory evaluation. (See 'Laboratory evaluation' below.)

Watery diarrhea – The water content of chronic diarrhea can be caused by secretory or osmotic processes, or a combination of the two. These categories are useful to narrow the diagnostic possibilities. However, the clinical utility of these categories and their diagnostic markers is limited because some diarrheal diseases involve a combination of both processes. If needed, it is possible to distinguish between these processes by measurement of fecal electrolytes, pH, reducing substances, and calculation of the osmotic gap. (See 'Laboratory evaluation' below.)

Secretory – Secretory diarrhea is usually associated with large volumes of watery stools and persists during fasting. Consequently, it is helpful to assess the effects of fasting on stool output. Pure secretory diarrheas are uncommon, but can occur in the setting of certain enteric infections. Secretory diarrhea occurs in 80 percent of patients with carcinoid syndrome and is often the most debilitating component of the syndrome. Stools may vary from few to more than 30 per day, are typically watery and nonbloody, and can be explosive and accompanied by abdominal cramping. The abdominal cramps may be a consequence of mesenteric fibrosis or intestinal blockage by the primary tumor. The diarrhea is usually unrelated to flushing episodes.

Osmotic – Osmotic (or "substrate-induced" or "diet-related") diarrhea typically is less voluminous than secretory diarrhea (eg, <200 mL per day), and improves or resolves during 12- to 24-hours of fasting. The presence of reducing substances or low fecal pH (ie, pH <6) suggest carbohydrate malabsorption. Osmotic diarrheas are characterized by relatively low sodium concentration (<70 mEq/L) and a high osmotic gap (>75 mOsm/kg) but testing stool osmolality is not routinely required. (See 'Laboratory evaluation' below.)

Fatty diarrhea – Malabsorption is often accompanied by steatorrhea and the passage of bulky malodorous pale stools. However, milder forms of malabsorption may not result in any reported stool abnormality. (See "Approach to the adult patient with suspected malabsorption".)

Inflammatory diarrhea – Inflammatory forms of diarrhea typically present with liquid loose stools with blood. Elevation in fecal calprotectin (a protein found in neutrophil granulocytes) indicates an inflammatory diarrhea. The presence of occult blood also raises this possibility but is less specific. (See 'General laboratory tests' below.)

History — The initial evaluation of patients who present to medical care with chronic diarrhea should include a careful history to determine the duration of symptoms, the frequency and characteristics of the stool, and the presence of associated symptoms. Fecal incontinence is frequently misinterpreted as diarrhea. A thorough medical history can guide appropriate evaluation. Important components of the history include the following (table 7):

Symptom characteristics

A clear understanding of what led the patient to complain of diarrhea (eg, consistency or frequency of stools, the presence of urgency or fecal incontinence).

Stool characteristics (eg, greasy stools that float and are malodorous may suggest fat malabsorption, while the presence of visible blood may suggest an inflammatory cause of diarrhea). Patients with carbohydrate malabsorption (eg, lactose malabsorption) may be present with watery diarrhea, excess flatus, and bloating. (See 'Characterizing the diarrhea type' above and 'Malabsorption syndromes' above and "Approach to the adult patient with suspected malabsorption".)

Duration of symptoms, nature of onset (sudden or gradual).

Occurrence of diarrhea during fasting or at night suggests a secretory or inflammatory diarrhea. (See 'Characterizing the diarrhea type' above.)

The volume of the diarrhea (eg, voluminous watery diarrhea is more likely to be due to a disorder in the small bowel, while small-volume frequent diarrhea is more likely to be due to disorders of the colon).

The presence of bloody diarrhea favors a colonic versus small bowel disorder.

The presence of weight loss and other systemic symptoms may indicate IBD (eg, fevers, joint pains, mouth ulcers, eye redness).

Association of stress and depression with onset and severity of the diarrhea suggests a functional disorder such as irritable bowel syndrome. Irritable bowel syndrome (IBS) is characterized by chronic abdominal pain and altered bowel habits. Symptoms of IBS include diarrhea, constipation, alternating diarrhea and constipation, or normal bowel habits alternating with either diarrhea and/or constipation. (See 'Functional disorders' above and "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'History and physical examination'.)

Risk factors

Travel to a resource-limited setting increases the risk of bacterial diarrhea and also informs the risk of certain parasitic infections. (See 'Characterizing the diarrhea type' above.)

History of Clostridiodes (formerly Clostridium difficile) infection and risk factors for C. difficile. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Risk factors'.)

All medications (including over-the-counter drugs and supplements) (table 5) [2].

Dietary history should include possible use of sorbitol-containing products, food additives including fructose and other fermentable oligo-, di-, mono-saccharides and polyols, alcohol and association of symptoms with specific food ingestion (eg, dairy products or potential food allergens) (table 8).

Medical history:

-A history of or risk factors for sexually transmitted diseases. As examples, Neisseria gonorrhoeae and herpes simplex virus are associated with proctitis. HIV infection is associated with diarrhea due to infectious agents but may also be due to infiltrative diseases, such as lymphoma or Kaposi's sarcoma or antiretroviral medication use. (See "Evaluation of the patient with HIV and diarrhea".)

-A history of recurrent bacterial infections (eg, sinusitis, pneumonia), which may indicate a primary immunoglobulin deficiency. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

-A history of chronic diseases associated with amyloidosis (eg, chronic degenerative arthropathies, particularly rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis and plasma cell dyscrasias). (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management", section on 'Gastrointestinal tract amyloidosis'.)

-In patients with a history of an allogeneic hematopoietic cell transplant, graft versus host disease and among recipients of umbilical cord blood, cord colitis syndrome can cause diarrhea. Radiation enteritis can also cause chronic diarrhea, and in some cases can occur several years after treatment. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Gastrointestinal tract' and "Overview of gastrointestinal toxicity of radiation therapy", section on 'Enteritis' and "Diagnosis and management of chronic radiation enteritis", section on 'Management' and "Early complications of hematopoietic cell transplantation", section on 'Cord colitis syndrome'.)

-Prior gastrointestinal surgeries can lead to diarrhea due to intentional or inadvertent vagotomy, small intestinal bacterial overgrowth, and based on the length of small bowel resection, bile acid malabsorption, or short bowel syndrome. (See "Approach to the adult patient with suspected malabsorption" and "Overview of the treatment of malabsorption in adults" and "Pathophysiology of short bowel syndrome", section on 'Initial determinants of intestinal function' and "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis".)

-Diarrhea in patients with diabetes may also be due to visceral autonomic neuropathy, pancreatic exocrine insufficiency, bacterial overgrowth, or fecal incontinence (which may be confused with diarrhea). (See "Diabetic autonomic neuropathy of the gastrointestinal tract".)

Family history of colorectal cancer, celiac disease and inflammatory bowel disease (IBD)are associated with an increased risk of these disorders. (See "Diagnosis of celiac disease in adults", section on 'Individuals with high celiac disease probability' and "Genetic factors in inflammatory bowel disease".)

Physical examination — A comprehensive physical examination should be performed that includes a dermatologic examination and rectal examination. Physical examination rarely provides a specific diagnosis. However, a number of findings can provide clues (table 7).

General laboratory tests — We suggest the following initial tests for most patients with chronic diarrhea (table 7):

Complete blood count and differential.

Thyroid stimulating hormone and free thyroxine (T4) to identify patients with hyperthyroidism.

Celiac serologies (see "Diagnosis of celiac disease in adults", section on 'Overview').

Serum electrolytes in patients with severe diarrhea, or concern for dehydration or electrolyte abnormalities.

Stool occult blood – Gross or occult gastrointestinal bleeding is suggestive of organic disease (eg, chronic infection or IBD).

Stool test for giardia – Giardia stool antigen and nucleic acid detection tests are more sensitive for the diagnosis of giardiasis as compared to stool microscopy. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Fecal calprotectin or fecal lactoferrin – Fecal calprotectin levels are increased in intestinal inflammation and may be useful for distinguishing inflammatory from noninflammatory causes of chronic diarrhea [38,39]. Calprotectin is a zinc and calcium binding protein that is derived mostly from neutrophils and monocytes. It can be detected in tissue samples, body fluids, and stools, making it a potentially valuable marker of neutrophil activity [40]. The fecal lactoferrin test is an agglutination assay that is a marker for fecal leukocytes [41].

If fecal calprotectin and fecal lactoferrin are normal, a diagnosis of IBD is unlikely. If fecal calprotectin or fecal lactoferrin levels are above the reference range, we proceed with ileocolonoscopy and biopsy to confirm the diagnosis of IBD. (See 'Patients with alarm features' below and 'Inflammatory bowel disease' above.)

C-reactive protein – C-reactive protein levels have limited utility in differentiating IBS and IBD and should be performed in the evaluation of patients with chronic diarrhea if fecal calprotectin and fecal lactoferrin cannot be performed [42].

Additional laboratory evaluation may be warranted if specific organic conditions are suspected:

Other tests

Stool microbiologic evaluation – Patients with recent antibiotic therapy or suspected Clostridioides difficile infection should undergo testing for C. difficile associated diarrhea. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'When to suspect and test for C. difficile infection'.)

Additional testing may also be indicated based on other risk factors for infectious diarrhea. Persistent diarrhea following travel to certain locations, such as Russia, Nepal, or mountainous regions, is associated with Giardia, Cryptosporidium, or Cyclospora. Persistent diarrhea with exposure to infants in daycare centers has been associated with Giardia and Cryptosporidium. Microsporidium should be a consideration in immunocompromised patients with persistent diarrhea. (See "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Persistent diarrhea' and "Giardiasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Cyclospora infection", section on 'Diagnosis' and "Microsporidiosis", section on 'Diagnosis' and "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Fecal leukocytes – Fecal leukocyte evaluation is not an accurate test for inflammatory diarrhea [43]. A number of studies have evaluated the accuracy of fecal leukocytes alone or in combination with occult blood testing. The ability of these tests to predict the presence of an inflammatory diarrhea has varied greatly, with reports of sensitivity and specificity ranging from 20 to 90 percent [44-47]. A meta-analysis of diagnostic test accuracy estimated that at a peak sensitivity of 70 percent, the specificity of fecal leukocytes was only 50 percent [47].

ESTABLISHING A DIAGNOSIS

Patients with alarm features — Patients with alarm findings require endoscopic evaluation for organic disorders. Patients with abdominal pain as a major symptom in addition to chronic diarrhea often require abdominal imaging (table 2). (See 'Imaging in selected patients' below and 'Endoscopic evaluation' below.)

If an etiology is established, patients should be managed based on the underlying cause. If an etiology is not identified, additional evaluation should be guided by the initial evaluation similar to patients without alarm features. (See 'Treatment of the underlying etiology' below and 'Patients without alarm features' below.)

Patients without alarm features

Specific diagnosis suspected — If the initial evaluation points toward a specific diagnosis or type of diarrhea, further testing should be directed toward confirming the diagnosis. As examples, upper endoscopy with duodenal biopsies can establish the diagnosis of celiac disease in a patient with positive celiac serologies; breath test for bacterial overgrowth in a patient with risk factors; in a patient with suspected inflammatory bowel disease (IBD) due to a family history of IBD, the diagnosis can usually be established by colonoscopy. (See 'Initial evaluation' above and "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Etiology and risk factors'.)

Further testing in patients with osmotic diarrhea may be unnecessary if the osmotic agent can be identified based upon the history. An example is inadvertent ingestion of sorbitol (such as in sugar substitutes) or lactose in patients who have lactose intolerance. Temporary avoidance of lactose-containing foods can help establish the diagnosis of lactose intolerance in patients who were unaware of the diagnosis. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management", section on 'Management'.)

In other cases, empiric therapy may be indicated (eg, cholestyramine for bile acid malabsorption in a patient with a history of ileal resection). (See 'Empiric therapy in selected patients' below.)

Functional bowel disease suspected — A clinical diagnosis of irritable bowel syndrome (IBS) or functional diarrhea requires the fulfillment of symptom-based diagnostic criteria and a limited initial evaluation to exclude underlying organic disease. In patients with IBS, these include presence of recurrent abdominal pain at least three days per month in the last three months, associated with a change in stool frequency or form, and improvement with defecation. Functional diarrhea is defined as similar stool changes without prominent pain. (See 'Initial evaluation' above and 'Functional disorders' above and "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Diagnosis'.)

However, the presence of persistent symptoms despite treatment, atypical symptoms (eg, older age of onset), or progressive symptoms require additional evaluation for alternative etiologies. (See 'Additional testing in specific circumstances' below.)

Unclear diagnosis after initial evaluation — If the initial evaluation does not point toward a specific diagnosis, we perform additional testing. (See 'Overview' above and 'Additional testing in specific circumstances' below.)

ADDITIONAL TESTING IN SPECIFIC CIRCUMSTANCES — For patients with persistent diarrhea with no clear etiology after initial evaluation or diarrhea that does not respond to initial treatment, we perform additional testing to determine the underlying etiology. The order and extent of testing should be individualized based on the clinical presentation and results of initial evaluation. (See 'Initial evaluation' above.)

Laboratory evaluation

Blood tests for malabsorption – An initial screen for nutritional deficits can provide indirect evidence of malabsorption. This includes a complete blood count, red cell folate and serum iron, total iron binding capacity, vitamin B12, calcium, magnesium, albumin, carotene, and 25-hydroxyvitamin D. Blood tests can provide supportive evidence of malabsorption. Clinical or laboratory features suggesting malabsorption should prompt a specific evaluation (table 3 and table 4). (See "Approach to the adult patient with suspected malabsorption".)

Stool tests – Work-up for patients with persistent diarrhea should include evaluation for C. difficile and parasitic infections (eg, Giardia, Cryptosporidium, Cyclospora, E. histolytica), if not already performed. Microsporidium should be a consideration in immunocompromised patients with persistent diarrhea. (See 'General laboratory tests' above and "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Persistent diarrhea' and "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Immunocompromised patients'.)

Endoscopic evaluation — We generally perform colonoscopy and obtain mucosal biopsies in patients with chronic diarrhea, if not previously performed. Colonoscopy has the advantage of allowing evaluation of the terminal ileum and sampling of the right and left colon. Flexible sigmoidoscopy (to 60 cm) is less expensive, is associated with fewer risks as compared with colonoscopy and may be appropriate for selected patients [48-51]. However, colonoscopy should be performed in patients with iron deficiency anemia, those in whom inspection of the terminal ileum is needed (eg, to exclude Crohn disease), patients who require age appropriate screening for colorectal cancer, and those with suspected microscopic colitis. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management", section on 'Endoscopy and biopsy'.)

In patients with positive serologic testing for celiac disease and in patients at increased risk for celiac disease (regardless of celiac specific serology results), an upper endoscopy with small bowel biopsy should be performed. (See "Diagnosis of celiac disease in adults", section on 'Overview'.)

Imaging in selected patients — In patients with abdominal pain as a major symptom, systemic symptoms (fever, weight loss), or suspected Crohn or pancreatic disease based on history, we perform additional abdominal imaging with an abdominal computed tomography (CT) or magnetic resonance imaging (MRI). In patients with suspected chronic pancreatitis, we perform a magnetic resonance cholangiopancreatography. An MRE (magnetic resonance enterography) can be used to identify small bowel Crohn disease or small bowel tumors. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults", section on 'Imaging'.)

Plain abdominal films have limited utility in the evaluation of chronic diarrhea. Supine and upright position can provide evidence of bowel distention or air-fluid levels suggesting a motility disease, megacolon due to infectious or inflammatory processes, or partial mechanical obstruction due to strictures in Crohn disease or tumors such as carcinoid.

Tests to evaluate uncommon causes — Additional testing for uncommon disorders may be appropriate in the subset of patients with persistent symptoms in whom a diagnosis remains unclear (table 2).

We perform an upper endoscopy with mucosal biopsies, if not previously performed, to rule out small bowel enteropathies.

We reserve laboratory testing for hormone secreting tumors (eg, fasting serum gastrin, calcitonin, somatostatin, vasoactive intestinal polypeptide, 24-hour urine 5-HIAA) in patients where no other etiology if found (algorithm 1). (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "VIPoma: Clinical manifestations, diagnosis, and management".)

Testing for laxatives may occasionally be required if laxative abuse is suspected based on history or endoscopic evaluation (presence of melanosis coli). A screen for laxative abuse should include the detection of anthraquinones, bisacodyl and phenolphthalein in urine and magnesium and phosphate in stool. (See "Factitious diarrhea: Clinical manifestations, diagnosis, and management", section on 'Diagnosis'.)

MANAGEMENT

Treatment of the underlying etiology — Specific therapy should be directed to the underlying etiology in patients in whom the diagnosis has been established. The management of specific disorders associated with chronic diarrhea are presented in detail separately in the corresponding topic reviews.

Empiric therapy in selected patients — Empiric therapy may be appropriate when comorbidities limit diagnostic evaluation or when a diagnosis is strongly suspected. Examples include:

Empiric antibiotics for small intestinal bacterial overgrowth (SIBO) in patients with recurrent SIBO and predisposing risk factors. (See "Small intestinal bacterial overgrowth: Management", section on 'Inadequate response to initial therapy or recurrence'.)

Lactose restriction in a patient with suspected lactose intolerance in whom relief of symptoms is observed following a temporary trial of a lactose-free diet. (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management", section on 'Dietary lactose restriction'.)

Cholestyramine for bile acid diarrhea in a patient who develops diarrhea following limited (<100 cm) ileal resection, abdominal radiation therapy, or post-cholecystectomy diarrhea [16,22]. It is reasonable to start patients on a low dose (eg, 2 g once or twice daily) and titrate to a higher dose as needed. We have found that patients often prefer pill formulations (ie, colestipol) over the powder (ie, cholestyramine). (See "Overview of the treatment of malabsorption in adults", section on 'Directed therapy based on the underlying etiology'.)

Symptomatic therapy — Symptomatic therapy to reduce the frequency and severity of chronic diarrhea is indicated when the diagnosis has been made but definitive treatment is unavailable, when diagnosis has eluded diagnostic evaluation, and as a temporizing measure during evaluation. A variety of medications can help relieve diarrhea including loperamide, anticholinergic agents, and intraluminal adsorbents (such as clays, activated charcoal, bismuth, fiber and bile acid binding resins). Symptomatic therapy may also be used to manage diarrhea in specific disorders and is discussed in the corresponding topic reviews.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic diarrhea".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Chronic diarrhea in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Etiology – Chronic diarrhea is defined as a persistent alteration of stool consistency from the norm with loose stools (consistency between types 5 and 7 on the Bristol stool chart) and increased stool frequency of greater than four weeks' duration. In resource-abundant settings the most prevalent causes are irritable bowel syndrome, inflammatory bowel disease (IBD), malabsorption syndromes (such as lactose intolerance and celiac disease), and chronic infections (particularly in patients who are immunocompromised) (table 1). (See 'Etiology' above.)

Indications for gastroenterology referral The need for gastroenterology evaluation and timing of referral for chronic diarrhea depend upon the severity of symptoms, the diagnoses being considered, and the presence of alarm features (table 2). (See 'Indications for referral to a gastroenterologist' above.)

Indications for referral include anyone of the following:

Alarm features (table 2)

Severe diarrhea

Suspected inflammatory bowel disease (see 'Inflammatory bowel disease' above)

Inconclusive diagnosis after initial evaluation (see 'Initial evaluation' above and 'Establishing a diagnosis' above)

Failure to respond to empiric therapy (see 'Empiric therapy in selected patients' above)

Referral to a gastroenterologist may also be appropriate in patients who require long-term management for the underlying cause (eg, IBD, chronic pancreatitis).

Initial evaluation – The initial evaluation of patient with chronic diarrhea includes history, physical examination, and laboratory testing to determine whether the patient has any alarm features which help to distinguish organic from functional diarrhea and characterizing the diarrhea (infectious, inflammatory, osmotic, secretory) in order to direct evaluation (algorithm 1). (See 'Overview' above and 'History' above and 'Physical examination' above and 'General laboratory tests' above.)

Additional evaluation based on the presence of alarm features

Patients with alarm features Patients with alarm features require endoscopic evaluation for organic disorders. Patients with abdominal pain as a major symptom in addition to chronic diarrhea often require abdominal imaging. (See 'Endoscopic evaluation' above and 'Imaging in selected patients' above.)

Patients without alarm features In patients without alarm features, if the initial evaluation points toward a specific diagnosis or type of diarrhea, further testing should be directed toward confirming the diagnosis. However, in some cases, further testing may be unnecessary (eg, functional diarrhea or suspected lactose intolerance) and patients can be managed empirically (lactose restriction for lactose intolerance, cholestyramine for post-cholecystectomy diarrhea). (See 'Patients without alarm features' above.)

Patients with persistent symptoms – In patients with persistent diarrhea with no clear etiology after initial evaluation or diarrhea that does not respond to initial treatment, we perform additional testing to determine the underlying etiology. This evaluation is individualized based on the clinical presentation and can include screening for evidence of malabsorption, stool tests for evidence of an infection, and endoscopic evaluation if not previously performed. We perform imaging (abdominal computed tomography or magnetic resonance imaging) in patients with unexplained diarrhea and abdominal pain as a major symptom, systemic symptoms (fever, weight loss), or suspected Crohn or pancreatic disease based on history. (See 'Additional testing in specific circumstances' above.)

ACKNOWLEDGMENT — We are saddened by the death of Paul Rutgeerts, MD, who passed away in September 2020. UpToDate gratefully acknowledges Dr. Rutgeerts' work as our Section Editor for Gastroenterology.

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