Causes of Colitis
Colitis has multiple etiologies that can be broadly categorized into infectious, inflammatory (immune-mediated), drug-induced, ischemic, and microscopic causes, with infections and inflammatory bowel disease being the most common in clinical practice.
Primary Categories of Colitis
1. Infectious Colitis
Infections are a critical cause that must be excluded in all patients presenting with colitis 1, 2. The major infectious agents include:
- Bacterial pathogens: Clostridium difficile, Campylobacter species, Salmonella, Shigella, Escherichia coli 1, 3, 4
- Viral pathogens: Cytomegalovirus (CMV), particularly in immunosuppressed patients 1
- Parasitic infections: Entamoeba histolytica, Giardia lamblia, Spirochaetosis 1
Critical clinical point: C. difficile testing should be performed with every disease flare in patients with known IBD, as pseudomembranes are present in only 50% of infected patients overall and just 13% in IBD patients 1, 2. Infections may trigger IBD onset, cause disease flares, and complicate the clinical picture 1.
2. Inflammatory Bowel Disease (IBD)
This represents chronic immune-mediated colitis with two main subtypes:
- Ulcerative colitis: Characterized by continuous mucosal inflammation starting from the rectum
- Crohn's disease: Can affect any part of the GI tract with transmural inflammation and skip lesions
- IBD-Unclassified (IBDU): Used when endoscopic biopsies show chronic colitis without definitive features of UC or CD 1
The pathogenesis involves complex interactions between genetic predisposition, environmental triggers, microbial dysbiosis, and immune dysregulation 5.
3. Microscopic Colitis
This clinicopathologic entity includes 1:
- Collagenous colitis
- Lymphocytic colitis
Defining features: Chronic watery (non-bloody) diarrhea, normal or near-normal endoscopic appearance, and distinct histologic patterns. The pathogenesis is multifactorial, representing a mucosal response in susceptible individuals to noxious luminal agents including drugs and enteric infections 1.
4. Drug-Induced Colitis
Key causative agents include:
- Non-steroidal anti-inflammatory drugs (NSAIDs): Can cause or exacerbate colitis 2
- Immune checkpoint inhibitors (ICIs): Cause colitis in up to 40% of patients, with severe cases in 2-5% on PD-1/PD-L1 inhibitors and ~10% on CTLA-4 inhibitors 6, 7
- Antibiotics: Can trigger C. difficile colitis 1, 2
5. Ischemic Colitis
Results from inadequate blood flow to the colon, typically affecting watershed areas 2.
6. Eosinophilic (Allergic) Colitis
Allergy-associated colitis, particularly relevant in pediatric populations 1.
Diagnostic Approach Algorithm
Step 1: Clinical Assessment
- Detailed history: onset, bloody diarrhea, frequency, urgency, tenesmus, abdominal pain, nocturnal symptoms
- Recent travel, antibiotic use, NSAID use, immunosuppression status
- Family history of IBD or colorectal cancer 2
Step 2: Initial Laboratory Testing
- Complete blood count, inflammatory markers (CRP), electrolytes, liver function
- Stool studies: Culture, C. difficile toxin assay, ova and parasites (if indicated)
- Fecal calprotectin (accurate marker of colonic inflammation) 2, 8
Step 3: Endoscopic Evaluation
- Flexible sigmoidoscopy or colonoscopy with biopsies from multiple sites
- Minimum of 2 biopsies from terminal ileum, 4 from different colonic segments, and rectum 8
- Histopathology is essential for diagnosis and differentiation 1, 8
Step 4: Additional Testing Based on Context
- CMV testing (H&E, immunohistochemistry, quantitative PCR) in active IBD or immunosuppressed patients 1
- Hepatitis B, tuberculosis screening if biologic therapy anticipated 7
- Tissue transglutaminase IgA for celiac disease in refractory cases 7
Critical Pitfalls to Avoid
Do not rely on histology alone for bacterial infections: Histology is not a good tool to identify bacterial infections, especially C. difficile 1.
Avoid diagnosing "indeterminate colitis" on endoscopic biopsies: This has high potential for diagnostic error; use "IBD-Unclassified" instead 1.
Always exclude infection before starting immunosuppression: This is mandatory in all suspected IBD cases and flares 2, 7.
Consider multiple concurrent pathogens: Particularly in immunosuppressed or high-risk populations 9.
Recognize that normal CRP/ESR does not exclude colitis: Laboratory markers may be normal in mild-moderate UC, especially proctitis 2.