Approach to the patient with diarrhea

Overview

Chronic diarrhea is frequently associated with an increase in stool frequency (i.e., >3 bowel movements per day) and/or volume (i.e., >200 cc per day), as well as a decrease in stool consistency. Clinical presentation, however, can vary significantly. The American Gastroenterological Association has defined chronic diarrhea as at least 4 weeks with a decrease in stool consistency.

What disease states can produce this sign or symptom?

Chronic diarrhea can be the manifestation of a number of causes. In developing countries, the leading cause is infectious, whereas in developed countries – which is the focus of this section – the most common causes are irritable bowel syndrome (IBS), carbohydrate malabsorption (e.g., lactose intolerance), celiac disease, inflammatory bowel disease, and, rarely, chronic infections.

Often, the history and physical exam can provide clues as to the underlying cause. For example, patients with short bowel syndrome will report a prior history of bowel resection. Patients with carbohydrate malabsorption will report symptoms after ingesting particular foods containing lactose (e.g, dairy), fructose (e.g., candy, fruit juices, etc.), or artificial sugars (e.g., diet sodas). Patients with inflammatory bowel disease (IBD) frequently will report abdominal pain with fever, a palpable abdominal mass, a positive fecal occult blood test, as well as other extra-intestinal manifestations (e.g., mouth ulcers, skin rashes, anal fissures, or perianal fistulas). Patients who are immunocompromised (e.g., affected by HIV or on immunosuppressants) are at increased risk for infectious diarrhea. Diarrhea is reported to occur in up to 12% of cases, following cholecystectomy from bile salt malabsorption. Finally, patients with malabsorbtion may have evidence of weight loss, muscle wasting, anemia, and, possibly, vitamin deficiencies.

Epidemiological history can be useful in eliciting clues supporting the presence of chronic infection, such as C. difficile, Campylobacter, Aeromonas, Giardia, ameba, Cryptosporidium, and Cyclospora.

The use of many medications is also associated with diarrhea. A nonexhaustive list of medication categories commonly associated with diarrhea is presented in Table I. Careful medication history should be obtained, and appropriate attempts at treatment tapering and discontinuation should be attempted, compatible with the relevance and severity of the comorbidities in question.

It is important to evaluate patients for “alarm” features that could suggest an underlying organic disease. Common alarm features that suggest the need for further diagnostic testing such as a colonoscopy include age above 50 years, blood in the stools, the presence of nocturnal symptoms, a recent change in symptoms, recent use of antibiotics, and a strong family history of organic GI disease, such as IBD.

Patients with functional bowel disorders such as IBS frequently have had symptoms for more than 1 year and report abdominal discomfort of pain, typically relieved or exacerbated by episodes of diarrhea. The Rome III criteria (Table II) are used for clinical practice and research to diagnose IBS. IBS frequently occurs after a bout of infectious gastroenteritis.

What urgent or emergent measures should be initiated even before the diagnosis is established?

Sigmoidoscopy/colonoscopy

(Sigmoidoscopy for colitis, viral, parasitic.) Even in patients whose mucosa appears normal random biopsies from the colon (particularly the ascending colon) should be considered in patients with chronic diarrhea to exclude microscopic colitis.

Upper endoscopy

This test allows the performance of biopsies of the proximal small bowel that allow characterization of the mucosa.It can rule out the presence of celiac sprue, giardiasis, Crohn’s disease, eosinophilic enteritis, lymphoma, hypogammaglobulinemia, lymphangectasia, Whipple’s, amyloidosis, and conditions with bacterial, fungal, and parasitic etiology.

Computed tomography/magnetic resonance imaging

CT/MRI, radiological tests, can be performed in chronic diarrhea to rule out pancreatic cancer, chronic pancreatitis, and other intra-abdominal malignancies. With the use of IV contrast, angiography can reveal the presence of critical mesenteric stenoses. CT or MRI enterography is performed with administration of a specific oral contrastcan to assess for small bowel inflammation/strictures in Crohn’s disease or other inflammatory conditions. .

Plasma and serum tests

Antitissue transglutaminase antibodies are useful to rule out underlying celiac disease; elevated C-reactive protein suggests underlying inflammation; HIV immunoassay can make the diagnosis.

Stool tests

Clostridium difficile (C. difficile) toxin assay. C. difficilediarrhea, a condition linked to antibiotic administration once believed almost exclusive to hospitalized and institutionalized patients, is increasingly present in the community. The ELISA assays for toxin A and B are specific, but their sensitivity is limited and often need to be repeated (at least three times, according to most institutional guidelines) prior to reaching a diagnosis, although recent data suggest a single sample is sufficient in the routine clinical setting. Real time PCR testing is also available.

Occult blood. This test can be used to screen for inflammatory, neoplastic causes as well as for celiac sprue, although there are no reliable data on its sensitivity and specificity in chronic diarrhea.

Stool leukocytes. This test helps in identifying inflammatory causes. The use of stool lactoferrin, a product of neutrophils, appears to improve the test performance. This test is useless in bloody diarrhea.

Sudan stain for fat in stool. Helps identifying underlying pancreatic insufficiency with fat malabsorption. It is dependent on the amount of fat intake. A 48- or 72-hour stool collection while on a 100-g fat diet is a more reliable test for assessing steatorrhea.

Stool cultures. The yield of stool cultures is low in immune competent patients with chronic diarrhea. Campylobacter and Salmonella are potential causes of chronic diarrhea in the immune-compromised host. Testing for ova and parasites is routinely done in refractory diarrhea and can direct toward a positive diagnosis for certain agents, such as Strongyloides, although some parasites (e.g.,
Entamoeba histolytica) are endemic in developing countries. Colonic biopsies, not stools, are used for the diagnosis of chronic viral infections (e.g., cytomegalovirus).

Quantitative stool analyses. A 48-hour stool collection may be useful in selected cases to quantify stool output and to test for stool pH, electrolytes, laxatives, fat, and carbohydrates. For practical reasons, these tests are more easily performed on inpatients.

Stool weight. A stool weight of less than 500 mg/day is likely to orient toward less severe causes of diarrhea, such as IBS, whereas stool weights above 1500 mg/day can be seen with pancreatic insufficiency and severe involvement of the small bowel, mandating aggressive intravenous fluid replacement. Persistence of diarrhea after 24 to 48 hour fasting would also orient toward a secretory, rather than osmotic process, although neither continuation nor cessation of diarrhea with fasting is not specific to individual underlying diagnoses.

pH. Isolated carbohydrate malabsorption is generally associated with fecal pH lower than 5.4. Combined multinutrient malabsorbtion, including carbohydrate, can be present with pH higher than 6.

Stool electrolytes and osmotic gap. After measurement of electrolytes in the stool, the osmotic gap can be calculated using the formula 290-2([Na+] +[K+]). In osmotic diarrhea, the osmotic gap is more than 100 mOsm/kg, whereas in secretory diarrhea, the gap is less than 50 mOsm/kg. If both secretory and osmotic pathophysiologies are significantly contributing, measuring the osmotic gap is less useful.

Fecal carbohydrates. Tests for the presence in the stool of individual carbohydrates (reducing and nonreducing) are available and can orient toward sugar malabsorption.

Urine tests

Urine can be tested for laxatives and for 5-hydroxyindoleacetic acid (which can orient to diagnosis of carcinoid syndrome).

Other serum and blood assays

Vasoactive intestinal peptide (VIP) in large volume, secretory diarrhea, can support the diagnosis of VIPoma. An elevated serum gastrin (at least >300 in presence of concomitant proton pump inhibitor use) suggests underlying gastrinoma. Elevated calcitonin may be present with diarrhea due to underlying medullary thyroid cancer and elevated glucagon with underlying glucagonoma.

Routine performance of these peptide assays is not recommended unless there is reasonable underlying clinical suspicion, as their yield is acceptable only with high pretest probability of disease.

Breath tests

H2 lactose breath test. This test supports the presence of lactose malabsorption. However, lactose malabsorption is often acquired in chronic, ongoing diarrhea, and a positive test has often limited pathophysiological implications.

H2 lactulose and glucose breath tests. These tests support the diagnosis of small intestinal bacterial overgrowth (SIBO). Their performance is poor as the lactulose test is prone to false positives (especially in presence of accelerated small bowel transit) and the glucose test is prone to false negatives. Nonetheless, they are more practical than jejunal aspirate cultures, once believed the gold standard for diagnosing SIBO, which have now fallen out of favor due to invasiveness and limited reliability.

What is the appropriate initial diagnostic approach to identify the specific underlying disease?

A diagnostic algorithm for chronic diarrhea is presented in Figure 1. A battery of investigation that can be performed in the initial evaluation of chronic diarrhea can orient relatively early toward the underlying diagnosis. If these tests fail to identify the underlying process, more rigorous categorization of the diarrhea with stool analysis can further help to identify the causative process.

Figure 1a

Figure 1b

What is the right therapy for the patient with chronic diarrhea?

Whenever possible, therapy is directed toward the underlying cause of diarrhea (e.g., gluten-free diet in patients with celiac disease, anti-inflammatory medications for inflammatory bowel diseases, etc.).

A list of therapeutic intervention useful in specific conditions presenting with chronic diarrhea is presented in Table III.

Initial therapeutic options, including guidelines for use (including expected result of therapy)

Mu-opioid agonists. Loperamide and diphenoxylate are available opioids that are not controlled substances. Loperamide has limited penetration into the central nervous system and therefore is available over-the-counter. In contrast, diphenoxylate, which can cross into the central nervous system, is combined with atropine to reduce the potential for abuse. Mu-opioid agonists are relatively contraindicated in the presence of untreated C. difficile infection or bloody diarrhea as its overuse might hasten complications such as toxic megacolon.

Bismuth subsalicylate. Can be used, although there is better evidence to support its use in acute rather than in chronic diarrhea.

Bile acid sequestrants. Cholestyramine 4g q.i.d. is used as empiric treatment for presumed bile acid malabsorption, post-cholecystectomy diarrhea. A therapeutic trial of this agent can be done in all other diarrheas. Cholestyramine also works as toxin binders and might work on symptoms of C. difficile diarrhea.

Colestipol and colesevelam. Also bile acid sequestrants that may be more palatable than cholestyramine and can be used as alternatives to it.

What is the diagnostic approach if this initial evaluation fails to identify the cause?

Narcotic opioids. Codeine, tincture of opium are controlled substances, although chronic diarrhea patients rarely abuse them. They remain a “last resort” approach.

Clonidine. Alpha2-adrenoreceptor agonist, used in secretory and hypermotility diarrhea, 0.1 mg twice daily dose and 0.3 mg patch.

Alosetron. 5-HT3 receptor antagonist, used in women with severe refractory IBS with diarrhea, its use is restricted to women with severe IBS with diarrhea due to the potential of ischemic colitis in 1/750 users.

Antibiotics. Rifaximin, a nonabsorbable agent, has been used in bacterial overgrowth and in mild to moderate nonconstipated irritable bowel syndrome. Other antibiotics such as metronidazole, neomycin, and ciprofloxacin have also been used to treat bacterial overgrowth and diarrhea.

Octreotide. This somatostatin analog binding to somatostatin receptors 2 and 5 and its long-acting depot forms delay small bowel transit time and reduce intestinal secretion. Octreotide controls diarrhea and flushing in carcinoid syndrome, and at the 50 to 150 mcg t.i.d. dose is used in many forms of noninfectious, noninflammatory diarrhea with pathophysiology involving the small bowel motility and secretion.

Monitoring side effects from second-line therapies

Non-narcotic opioids. Watch for abdominal distention, megacolon in patients with chronic infectious and inflammatory diarrhea (e.g., C. difficile, ulcerative colitis).

Narcotic opioids. As above, plus sedation, central effects, tolerance, withdrawal.

Clonidine. Watch for changes in blood pressure, drowsiness, dizziness, dry mouth.

Alosetron. Severe constipation causing impaction, ischemic colitis.

Antibiotics. Antibiotic-associated diarrhea, secondary C. difficile.

Octreotide. Monitor sugar levels, watch for pancreatitis, especially with long-term use.

Monitoring the patient with chronic diarrhea

The treatment endpoints in chronic diarrhea are maintenance and re-establishment of adequate fluid balance and nutrition status, and improvement of quality of life through reduction of volume improvement of frequency and form of bowel movements. Often, especially when treatment is empiric and diarrhea is functional, these endpoints are achieved over months or years or are only partially met, and a combination of treatment agents is needed to reach acceptable symptom control.

As patients with diarrhea due to functional disorders (i.e., IBS) remain prone to most other conditions manifesting with diarrhea, abrupt change in symptoms or the new occurrence of alarm symptoms should be promptly investigated with adequate testing (e.g., obtain a colonoscopy in a 55-year-old woman who has had IBS with diarrhea for 30 years and has worsening in her diarrhea with new-onset rectal bleeding).

What's the evidence?

Fine, KD, Schiller, LR. “AGA technical review on the evaluation and management of chronic diarrhea”. Gastroenterology. vol. 116. 1999. pp. 1464(Classical authoritative review on the general approach to the patient with chronic diarrhea.)

Longstreth, GF, Thompson, WG, Chey, WD. “Functional bowel disorders”. Gastroenterology. vol. 130. 2006. pp. 1480(Landmark guideline paper on diagnostic criteria for functional bowel disorders.)

Schiller, LR. “Chronic diarrhea”. Gatroenterology. vol. 127. 2004. pp. 287(An exhaustive review of treatment options for patients with chronic diarrhea.)

Headstrom, PD, Surawicz, C. “Chronic diarrhea”. Clin Gastroenterol Hapatol. vol. 3. 2005. pp. 734-7. (An up to date, high-quality clinical review.)

Robayo-Torres, CC, Quezada-Calvillo, R, Nichols, BL. “Disaccharide digestion: clinical and molecular aspects”. Clin Gastroenterol Hepatol. vol. 4. 2006. pp. 276-97. (An informative review on carbohydrate malabsorption.)

Kelly, CP, LaMont, JT. “Clostridium difficile: more difficult than ever”. N Engl J Med. vol. 359. 2008. pp. 1932-40. (Comprehensive discussion of pathogenesis, clinical manifestation, diagnosis, and treatment of C. difficile infection.)

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