What is the next step in managing a patient with chronic diarrhea and negative stool tests?

Next Steps in Managing Chronic Diarrhea with Negative Stool Tests

After negative stool studies in chronic diarrhea, test for celiac disease with IgA tissue transglutaminase plus a second test for IgA deficiency, and specifically test for Giardia using antigen detection or PCR, as these are common treatable causes that must not be missed. 1

Priority Testing After Negative Initial Stool Studies

Celiac Disease Screening (Mandatory)

• Perform IgA tissue transglutaminase (IgA-tTG) as the primary test, with sensitivity and specificity >90% when using thresholds of 7-15 AU/mL 1, 2
• Always include a second test to detect IgA deficiency, as selective IgA deficiency occurs in 2.6% of celiac patients and causes false-negative IgA-tTG results 1, 2
• Two strategies for IgA deficiency detection: measure quantitative IgA level (if normal, confirms accuracy of negative IgA-tTG), or use IgG tissue transglutaminase or IgG deaminated gliadin peptides 1
• Celiac disease prevalence ranges from 3-10% in patients with chronic diarrhea referred to secondary care 1
• A positive test warrants confirmation by duodenal biopsy 1

Giardia Testing (Strongly Recommended)

• Test specifically for Giardia even without travel history, as it is a common cause of chronic watery diarrhea throughout the United States that can be readily treated 1, 2
• Use Giardia antigen detection or PCR, which have sensitivity and specificity >95% 1
• Standard ova and parasite examination has only 60-90% sensitivity and is labor-intensive 1
• Do not rely on routine ova and parasite testing alone—specific Giardia antigen or PCR testing is superior 1

Inflammatory Bowel Disease Screening

• Use fecal calprotectin (threshold 50 mg/g) or fecal lactoferrin (threshold 4.0-7.25 mg/g) to screen for IBD if not already done 1, 2
• Pooled sensitivity 0.81 and specificity 0.87 for calprotectin 2
• These markers have higher sensitivity than ESR/CRP for detecting intestinal inflammation 2

Comprehensive Blood Panel (If Not Already Completed)

• Full blood count to detect anemia suggesting malabsorption, IBD, or celiac disease 2
• ESR and CRP have high specificity but low sensitivity for organic disease; abnormal results warrant aggressive investigation 2
• Thyroid function tests to exclude thyrotoxicosis 2
• Vitamin B12, folate, and iron studies to identify malabsorption patterns 2
• Liver function tests, calcium, urea and electrolytes to screen for hepatobiliary disease, electrolyte disturbances, and metabolic abnormalities 2

Consider Bile Acid Diarrhea

• Bile acid diarrhea is common but testing is limited in North America 1
• Available tests include 48-hour stool bile acid collection and serum fibroblast growth factor 19, though neither is widely available 1
• Consider empiric trial of bile acid binder (cholestyramine) when bile acid diarrhea is suspected, particularly in patients with terminal ileum resection or post-cholecystectomy 1, 2

Additional Considerations Based on Clinical Context

Laxative Screen

• Perform laxative screen if factitious diarrhea is suspected, including detection of anthraquinones, bisacodyl, and phenolphthalein in urine, and magnesium and phosphate in stool 2
• Repeat testing may be necessary as patients may ingest laxatives intermittently 2

Microscopic Colitis

• If above testing is negative and diarrhea persists, consider colonoscopy with random colonic biopsies to evaluate for microscopic colitis, which requires histological diagnosis 3

Avoid These Common Pitfalls

• Do not skip Giardia-specific testing even in patients without travel history—it remains a common treatable cause 1, 2
• Do not overlook IgA deficiency when interpreting negative celiac serology; always include quantitative IgA level or alternative testing 1, 2
• Do not order broad ova and parasite testing in patients without travel to high-risk areas (other than Giardia)—the yield is extremely low 1
• Do not rely on ESR/CRP alone for IBD screening; use fecal calprotectin or lactoferrin instead 2

Empiric Therapy Considerations

If all testing remains negative and functional diarrhea or IBS-D is suspected:

• Loperamide can be used for symptomatic management of watery diarrhea 4, 5
• Cholestyramine can be tried empirically for suspected bile acid diarrhea when testing is unavailable 1, 2
• Rifaximin is FDA-approved for IBS-D treatment (550 mg three times daily for 14 days) 6