How should I evaluate and manage colitis in an adult with no known etiology?

Evaluation and Management of Colitis in Adults with Unknown Etiology

Begin with colonoscopy and biopsies from at least five colonic sites plus ileum and rectum (two specimens per site) to establish the diagnosis, while simultaneously obtaining stool cultures for bacterial pathogens, Clostridioides difficile toxin, and parasites—but do not delay treatment if severe colitis is suspected. 1

Initial Diagnostic Evaluation

Immediate Laboratory and Stool Assessment

• Obtain complete blood count, ESR, CRP, albumin, liver function tests, and electrolytes to assess inflammatory activity and severity 1, 2
• Send stool samples for bacterial culture (including Campylobacter), C. difficile toxin, and ova/parasites to exclude infectious etiologies 3, 1
• Measure fecal calprotectin, which has excellent sensitivity for inflammatory bowel disease but poor specificity (infections and drugs also elevate it) 3
• Check for hypokalaemia and hypomagnesaemia, as these are risk factors for toxic megacolon 3

Endoscopic Evaluation

• Perform colonoscopy with segmental biopsies from all colonic regions, terminal ileum, and rectum (minimum two biopsies per site) 3, 1
• In patients presenting with acute severe colitis, unprepared flexible sigmoidoscopy is safer initially, with planned colonoscopy later to assess disease extent 3
• Endoscopic appearance may underestimate true extent, particularly in quiescent disease, so biopsies are essential 3

Imaging When Indicated

• Obtain plain abdominal radiograph if colonic dilatation is suspected; transverse colon diameter >5.5 cm indicates toxic megacolon requiring urgent intervention 3, 1
• Consider contrast-enhanced CT abdomen/pelvis if acute abdominal symptoms suggest complications (perforation, pneumatosis, abscess) 1

Differential Diagnosis Framework

Inflammatory Bowel Disease (Most Common in Young Adults)

• Ulcerative colitis: Diffuse mucosal inflammation starting in rectum, extending proximally in continuous fashion 3, 2
• Crohn's disease: Patchy, transmural inflammation affecting any GI tract segment; may spare rectum 3, 4
• IBD-Unclassified (IBDU): Use this term instead of "indeterminate colitis" when endoscopic biopsies show chronic colitis without definitive UC or CD features 3

The European consensus explicitly states pathologists should avoid diagnosing "indeterminate colitis" on preoperative biopsies due to high diagnostic error potential 3. IBDU is a temporary diagnosis requiring scheduled follow-up at 1 and 5 years, as most cases ultimately behave like UC 3.

Microscopic Colitis (Normal-Appearing Mucosa)

• Suspect when chronic watery non-bloody diarrhea occurs with normal or near-normal colonoscopy 3, 5
• Requires histologic diagnosis showing either collagenous colitis (subepithelial collagen band expansion) or lymphocytic colitis (increased intraepithelial lymphocytes) 3, 5, 6
• Incidence now exceeds UC and Crohn's disease in elderly populations in some countries 5
• Risk factors include older age, female sex, smoking, NSAIDs, proton pump inhibitors, and antidepressants 6

Infectious Colitis

• Always exclude before diagnosing IBD, as infections can trigger IBD onset or mimic flares 3, 7
• C. difficile is particularly important—histology is not a good tool for identifying bacterial infection 3
• Consider post-infectious irritable bowel syndrome, spirochaetosis, and atypical infections 3

Ischemic Colitis (Especially in Elderly)

• Presents with abdominal pain and bloody diarrhea; CT may show bowel wall thickening, pneumatosis, or portal venous gas 1
• Nongangrenous disease has <5% mortality with medical management; gangrenous disease has 50-85% mortality even with surgery 1

Initial Management Based on Severity

Mild-to-Moderate Disease (Outpatient)

If UC suspected:

• Start oral mesalamine 2-4 g daily (once-daily dosing preferred) as first-line therapy 3, 1, 8
• For distal disease (proctitis/proctosigmoiditis), add topical mesalamine suppositories 1 g daily or enemas 1-4 g daily 1, 8
• If inadequate response after 2-4 weeks, add oral prednisolone 40 mg daily with gradual 8-week taper 3, 1, 8

If Crohn's disease suspected:

• High-dose mesalamine 4 g daily for mild ileocolonic disease 1, 8
• Oral prednisolone 40 mg daily with 8-week taper for moderate disease or mesalamine failure 1, 8
• Budesonide 9 mg daily is alternative for isolated ileocecal disease, though marginally less effective 1, 8

Severe Disease (Hospitalization Required)

Immediate actions:

• Admit and start IV hydrocortisone 400 mg/day or IV methylprednisolone 60 mg/day immediately—do not wait for stool culture results 3, 1, 8
• Provide IV fluids, electrolyte replacement, blood transfusion to maintain hemoglobin >10 g/dL, and subcutaneous heparin for VTE prophylaxis 3, 1
• Monitor vital signs four times daily, stool frequency, and abdominal examination 3, 1
• Repeat labs (CBC, CRP, electrolytes, albumin) every 24-48 hours 1

For Crohn's disease specifically:

• Add IV metronidazole because active disease is difficult to distinguish from septic complications 1, 8

Rescue therapy criteria (by day 3):

• 8 stools/day or 3-8 stools/day with CRP >45 mg/L predicts ~85% colectomy rate 3, 1

• Options: infliximab 5 mg/kg IV at weeks 0,2,6 or ciclosporin 2 mg/kg/day IV 3, 1, 8
• Critical pitfall: Do not use infliximab in Crohn's disease with obstructive symptoms 1, 8

Surgical consultation:

• Involve colorectal surgery from admission; counsel that colectomy risk is 25-30% 3, 1, 8
• Urgent surgery indicated for: toxic megacolon not improving after 24-48 hours, perforation, massive hemorrhage, peritoneal signs, or rescue therapy failure after 4-7 days 3, 1

Critical Pitfalls to Avoid

• Never delay corticosteroids while awaiting stool cultures in suspected severe colitis 1, 8
• Never taper prednisolone faster than 8 weeks—rapid tapering causes early relapse 3, 1, 8
• Never use corticosteroids for long-term maintenance in either UC or Crohn's disease 1
• Never perform full colonoscopy in acute severe colitis—use flexible sigmoidoscopy to avoid perforation risk 8
• Always exclude C. difficile before attributing symptoms to IBD flare, as it can mimic or coexist with IBD 8
• Never use infliximab in Crohn's disease with obstructive symptoms or active sepsis 1, 8
• Do not overlook microscopic colitis—biopsy even normal-appearing mucosa in chronic watery diarrhea 3, 5, 6

Maintenance Therapy After Remission

For ulcerative colitis:

• Continue aminosalicylates (mesalamine ≥2 g daily) indefinitely to reduce relapse risk and potentially lower colorectal cancer risk 1, 8
• Consider azathioprine 1.5-2.5 mg/kg/day or mercaptopurine 0.75-1.5 mg/kg/day for steroid-dependent disease (>1 course/year) 3, 1, 8
• Discontinuation may be considered only for distal disease in remission ≥2 years in patients preferring to avoid medication 3, 1

For microscopic colitis:

• Budesonide is first-line therapy; maintenance often necessary 5, 6
• Antidiarrheal medications (loperamide, bismuth subsalicylate) may suffice for mild symptoms 5, 6

Follow-Up for Uncertain Diagnosis

When diagnosis remains unclear despite full workup, use the term IBD-Unclassified rather than "indeterminate colitis" 3. Schedule follow-up procedures at 1 and 5 years for diagnostic reconfirmation and review of previous biopsies, as most cases ultimately behave like UC 3.