What is the best course of action for an adult patient with chronic diarrhea lasting greater than a month, normal stool studies, and a complex medical history, including potential underlying conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or malabsorption disorders?

Chronic Diarrhea with Normal Stool Studies: Next Steps

When initial stool studies are normal in chronic diarrhea, proceed with colonoscopy with biopsies from the right and left colon (not rectum) to exclude microscopic colitis, followed by testing for bile acid diarrhea and celiac disease if not already done. 1

Immediate Next Steps

Verify Initial Workup Completion

• Confirm that basic blood tests were performed: complete blood count, C-reactive protein, tissue transglutaminase IgA with total IgA, thyroid function, and fecal calprotectin 1, 2
• If celiac serology was not done or IgA deficiency exists, test with IgG tissue transglutaminase or IgG deaminated gliadin peptides 1
• Ensure Giardia testing was completed, as this is a strong recommendation even in chronic presentations 1

Colonoscopy with Strategic Biopsies

Perform colonoscopy with biopsies from the right and left colon (specifically avoiding rectal biopsies) to diagnose microscopic colitis, which is frequently missed without histologic examination. 1

• Microscopic colitis causes chronic watery diarrhea with completely normal-appearing mucosa on endoscopy, making biopsies essential 1
• This is a common cause of chronic diarrhea that cannot be diagnosed without tissue sampling 1

Testing for Bile Acid Diarrhea

Test for bile acid diarrhea using SeHCAT scanning or serum 7α-hydroxy-4-cholesten-3-one, depending on local availability. 1

• The British Society of Gastroenterology specifically recommends against empirical treatment trials without making a positive diagnosis first 1
• This contrasts with the AGA's conditional recommendation suggesting testing is reasonable, though empirical bile acid sequestrant trials may be used when tests are unavailable 1
• Bile acid diarrhea accounts for 20-30% of IBS-D cases and is a treatable cause 3

Malabsorption Evaluation

Small Bowel Assessment

• If fat malabsorption is suspected (greasy, floating stools), order fecal elastase testing to evaluate for pancreatic insufficiency 1
• Consider MR enterography or video capsule endoscopy for small bowel evaluation if symptoms suggest small bowel pathology 1
• Do not order small bowel barium studies due to poor sensitivity and specificity 1

Carbohydrate Malabsorption

• If lactose intolerance is suspected, perform hydrogen breath testing or implement a dietary lactose elimination trial 1
• Consider broader FODMAP restriction if functional symptoms predominate 1

Small Intestinal Bacterial Overgrowth (SIBO)

Use an empirical trial of antibiotics rather than breath testing for suspected SIBO, as breath tests lack sufficient diagnostic accuracy. 1

• The British Society of Gastroenterology explicitly states insufficient evidence supports routine hydrogen or methane breath testing 1
• SIBO accounts for approximately 15-20% of IBS-D presentations 3

Special Populations and Considerations

Immunocompromised or Elderly Patients

• Test for HIV in immunocompromised patients with chronic diarrhea 1
• Recheck for chronic infections including Cryptosporidium and norovirus in immunodeficient states 1
• Consider repeat C. difficile testing with both PCR and toxin assays if recent antibiotic exposure occurred 1

Medication Review

• Systematically review for diarrheogenic medications: magnesium supplements, ACE inhibitors, NSAIDs, DPP-4 inhibitors (gliptins), metformin, antineoplastic agents 1, 2
• Up to 4% of chronic diarrhea cases are medication-induced 1

Surgical History

• Ileal resection or right colectomy can cause bile acid malabsorption 1, 2
• Gastric bypass procedures predispose to bacterial overgrowth 1, 2

When to Consider IBS-D Diagnosis

Make a positive diagnosis of IBS-D only after excluding microscopic colitis, bile acid diarrhea, celiac disease, and inflammatory conditions. 1

• IBS-D requires abdominal pain associated with altered bowel habits, not diarrhea alone 3
• Functional diarrhea (without pain) is a separate entity from IBS-D 4
• Food intolerances account for 30-40% of IBS-D symptoms and warrant systematic evaluation 3
• Currently available serologic tests for IBS-D (anti-CdtB and anti-vinculin antibodies) lack sufficient diagnostic accuracy for routine use 1

Common Pitfalls to Avoid

• Do not skip colonic biopsies even when mucosa appears normal—microscopic colitis requires histologic diagnosis 1
• Do not biopsy the rectum for microscopic colitis evaluation; use right and left colon samples 1
• Do not use empirical bile acid sequestrant therapy as a diagnostic test without attempting objective testing first 1
• Do not order endocrine tumor markers (VIP, gastrin, chromogranin) unless other causes are excluded, as these tumors are extremely rare and false positives exceed true positives 1, 5
• Do not diagnose IBS-D in patients with isolated diarrhea without abdominal pain 3

Rare Causes: When to Consider

Test for hormone-secreting tumors only after excluding all common causes of chronic diarrhea 1

• These represent less than 1% of chronic diarrhea cases 5
• Testing prematurely leads to false-positive results and unnecessary workup 5