In a patient with colitis evident on CT scan, persistent diarrhea and abdominal pain, but a normal colonoscopy and biopsies negative for microscopic colitis, what alternative diagnoses should be considered and what additional investigations are recommended?

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Bile Acid Diarrhea Should Be Your Primary Diagnostic Consideration

Test this patient for bile acid diarrhea (BAD) using SeHCAT scanning or serum C4 levels, as this is a frequently missed diagnosis that presents exactly like your clinical scenario and has simple, effective treatment. 1

Why Bile Acid Diarrhea is the Most Likely Diagnosis

The British Society of Gastroenterology guidelines emphasize that bile acid diarrhea is systematically underdiagnosed in patients presenting with chronic diarrhea and normal colonoscopy. A meta-analysis of 36 studies involving 5,028 patients found that 25% of patients previously diagnosed with functional diarrhea actually had primary bile acid diarrhea 1. This is precisely your clinical scenario—CT shows colitis, but colonoscopy and biopsies are negative.

Critical Diagnostic Pitfall to Avoid

Do NOT use a therapeutic trial of cholestyramine to diagnose or exclude bile acid diarrhea. 1 This is a common mistake. In a series of 264 patients with bile acid diarrhea, 44% failed to respond to cholestyramine alone, and half of these non-responders benefited from colesevelam. Lack of response to cholestyramine does not exclude the diagnosis 1.

Diagnostic Algorithm

First-Line Testing:

  • SeHCAT scanning (if available) - highest diagnostic yield
  • Serum C4 levels (alternative if SeHCAT unavailable)
  • Both tests are now readily available and should no longer allow this diagnosis to be missed 1

Second-Line Considerations:

1. Reconsider Microscopic Colitis Despite Negative Biopsies

While your biopsies were negative, consider:

  • Were biopsies taken from the right colon? Recent data shows that right-sided biopsies detect microscopic colitis in 100% of cases, while left-sided biopsies miss 10% 2
  • Were adequate numbers of biopsies obtained? Guidelines recommend biopsies from multiple sites 1
  • Microscopic colitis has a patchy distribution in 2% of cases 2
  • Importantly, bile acid diarrhea coexists with microscopic colitis in 41% of collagenous colitis cases and 29% of lymphocytic colitis cases 1

2. Celiac Disease Screening

  • Tissue transglutaminase IgA with total IgA levels 3
  • Celiac disease is associated with microscopic colitis in 5-7% of cases 1
  • Presents with large-volume diarrhea and weight loss 3

3. Small Intestinal Bacterial Overgrowth (SIBO)

  • Consider if large-volume diarrhea with weight loss or steatorrhea 3
  • Hydrogen breath testing

4. Carbohydrate Malabsorption

  • FODMAP intolerance (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols)
  • Lactose intolerance testing 1

Why CT Shows "Colitis" But Colonoscopy is Normal

This discrepancy is actually characteristic of several conditions:

  • Bile acid diarrhea can cause colonic wall thickening on CT without endoscopic abnormalities
  • Microscopic colitis by definition has normal or minimal endoscopic findings despite histologic inflammation 1, 4
  • CT findings of colitis have a 96% positive predictive value for histologic colitis when biopsies are adequate 5, suggesting your biopsies may have missed the diagnosis

Additional Workup to Consider

Inflammatory Markers:

  • Fecal calprotectin (elevated in microscopic colitis with excellent diagnostic validity at >64 mcg/g) 6
  • ESR (>14 mm/h has 0.94 AUC for microscopic colitis) 6
  • CRP levels 6

Medication Review: Look for drugs associated with microscopic colitis:

  • Proton pump inhibitors
  • NSAIDs
  • Selective serotonin reuptake inhibitors
  • Statins
  • Angiotensin receptor blockers 7, 8

Key Clinical Features That Guide Diagnosis

Favor Bile Acid Diarrhea if:

  • Frequent, low-volume stools
  • Urgency with excess mucus
  • Nocturnal diarrhea 1

Favor Small Bowel Pathology (Celiac/SIBO) if:

  • Large-volume diarrhea
  • Weight loss
  • Steatorrhea 3

Favor Microscopic Colitis if:

  • Age >60 years (though 25% are <45 years) 1
  • Female sex (68-77% of cases) 1
  • Nocturnal diarrhea and fecal incontinence 1
  • Associated autoimmune diseases 1

Bottom Line

Your immediate next step should be testing for bile acid diarrhea with SeHCAT or serum C4, as this is the most commonly missed diagnosis in this exact clinical presentation. 1 If negative, repeat colonoscopy with targeted right-sided biopsies (at least two sites from the right colon) 2, check celiac serology, and measure fecal calprotectin. The combination of CT-evident colitis with negative standard workup is classic for bile acid diarrhea, which affects up to 25% of patients with unexplained chronic diarrhea 1.

References

7
Research

Microscopic Colitis: A Concise Review for Clinicians.

Mayo Clinic proceedings, 2021

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.