Differential Diagnosis of Crohn's Disease
The differential diagnosis of Crohn's disease must systematically exclude infectious colitis (especially C. difficile, Yersinia, and CMV), ulcerative colitis, ischemic colitis, NSAID-induced colitis, intestinal tuberculosis, and malignancy before confirming the diagnosis.
Primary Inflammatory Bowel Disease Distinction
Ulcerative Colitis vs. Crohn's Disease
Distinguishing Crohn's disease from ulcerative colitis is the most critical differential, as management and prognosis differ fundamentally. 1
Endoscopic features favoring Crohn's disease include:
- Discontinuous (skip) lesions with intervening normal mucosa 1
- Aphthous ulcers and cobblestoning 2
- Strictures with upstream dilation 1
- Perianal fistulas or abscesses 1
- Rectal sparing in untreated patients 1
Endoscopic features favoring ulcerative colitis include:
- Continuous inflammation extending proximally from the rectum with clear demarcation 1, 3
- Rectal involvement (present in >97% of untreated cases) 3
- Confluent mucosal inflammation without skip lesions 1
Histologic features favoring Crohn's disease include:
- Non-caseating granulomas (present in minority of biopsies but highly specific) 1
- Discontinuous architectural changes with variation in intensity within and between biopsies 1
- Transmural inflammation 4, 5
Histologic features favoring ulcerative colitis include:
- Diffuse basal plasmacytosis 1, 3
- Continuous crypt architectural distortion 1
- Mucosal-only inflammation 3
Colonoscopy with biopsies distinguishes Crohn's disease from ulcerative colitis in 89% of cases, with 7% remaining indeterminate colitis and 4% requiring diagnostic revision over time. 1
Infectious Etiologies
Infectious colitis must be excluded first because treatment differs fundamentally and misdiagnosis leads to inappropriate immunosuppression. 2
Bacterial Infections
Test for Clostridioides difficile in every patient with suspected Crohn's disease or disease flare, regardless of antibiotic exposure, as it mimics Crohn's symptoms and carries higher mortality. 2, 3
Obtain stool cultures for Salmonella, Shigella, Campylobacter, and enterohemorrhagic E. coli O157:H7 before diagnosing inflammatory bowel disease. 2, 3
- Salmonella, Shigella, and Campylobacter produce endoscopic features similar to ulcerative colitis 1
- Yersinia enterocolitis resembles Crohn's disease with terminal ileal involvement 1, 3
Infectious colitis typically preserves crypt architecture with acute inflammation only, whereas Crohn's disease shows crypt distortion and chronic changes. 2, 3
Viral and Parasitic Infections
Cytomegalovirus (CMV) infection should be tested (PCR or immunohistochemistry) in severe or treatment-refractory cases, as CMV enterocolitis resembles Crohn's disease. 1, 2, 3
Perform ova and parasite examination (especially for Entamoeba histolytica) when travel history or endemic exposure is present. 2, 6
Intestinal Tuberculosis
Intestinal tuberculosis is a critical mimic of Crohn's disease, particularly in endemic regions, presenting with ileocecal involvement, strictures, and granulomas. 7
Vascular Disease
Ischemic Colitis
Ischemic colitis is a key consideration in patients >60 years presenting with acute bloody diarrhea and abdominal pain. 2, 3
Typical presentation includes sudden-onset cramping abdominal pain followed by bloody diarrhea. 2
Contrast-enhanced CT reveals segmental colonic wall thickening in watershed areas (splenic flexure, rectosigmoid junction). 2, 3
Ischemic colitis affects watershed areas and spares the rectum, contrasting with ulcerative colitis which involves the rectum. 3
Drug-Induced Colitis
NSAID-Induced Colitis
NSAID-induced colitis mimics Crohn's disease and must be excluded by careful medication history. 1, 2
Non-selective NSAIDs may exacerbate existing Crohn's disease or provoke de novo colitis with bloody diarrhea and endoscopic inflammation. 2
Discontinue NSAIDs before confirming Crohn's diagnosis when recent NSAID use is documented. 2
Other medications causing colitis include immunosuppressants and chemotherapy agents. 3
Segmental Colitis Associated with Diverticulosis (SCAD)
In elderly patients with left-sided segmental colitis and known diverticulosis, SCAD must be distinguished from Crohn's disease. 2
Endoscopy shows segmental inflammation confined between diverticula, lacking the continuous pattern of ulcerative colitis or the transmural/fistulizing features of Crohn's disease. 2
Histology may show chronic inflammation difficult to separate from inflammatory bowel disease. 2
Malignancy
Colorectal Cancer and Lymphoma
Exclude colorectal cancer in patients ≥50 years or those with alarm features (unexplained weight loss, anemia). 2, 6
Colonoscopy with targeted biopsies definitively distinguishes malignancy from inflammatory conditions. 2
Intestinal lymphoma can mimic Crohn's disease with strictures, ulceration, and transmural inflammation. 7
Other Mimics
Radiation Colitis
Radiation colitis occurs in patients with prior pelvic radiation and presents with rectal bleeding and diarrhea. 1
History of radiation therapy is essential for diagnosis. 1
Microscopic Colitis
Microscopic colitis (collagenous or lymphocytic) presents with chronic watery diarrhea without visible blood, making it less likely when hematochezia is prominent. 2
Endoscopic appearance is usually normal; diagnosis requires histologic examination of colonic biopsies. 2
Behçet's Disease
Behçet's disease causes intestinal ulceration resembling Crohn's disease but is distinguished by oral/genital ulcers, uveitis, and skin lesions. 7
Diagnostic Approach to Confirm Crohn's Disease
Clinical Assessment
Document bloody or non-bloody diarrhea, abdominal pain (often right lower quadrant), weight loss, fever, and perianal symptoms. 4, 5
Record medication use (especially NSAIDs and antibiotics), travel history, smoking status, and family history of inflammatory bowel disease. 2
Laboratory Investigations
Obtain complete blood count (anemia, thrombocytosis, leukocytosis), C-reactive protein (>10 mg/L correlates with severity), serum albumin (hypoalbuminemia indicates severe disease), and iron studies. 2
Fecal calprotectin >250 μg/g warrants urgent gastroenterology referral; <100 μg/g makes inflammatory bowel disease unlikely. 6, 3
Microbiological Exclusion
Perform stool cultures, C. difficile toxin assay, ova and parasite examination, and CMV testing (in severe cases) before diagnosing Crohn's disease. 2, 3
Endoscopic Evaluation
Ileocolonoscopy with biopsies is the gold standard for Crohn's disease diagnosis. 1
Obtain at least two biopsies from the terminal ileum, at least four different colonic segments, and the rectum, clearly identifying the sites of origin. 1, 3
Biopsy both inflamed and uninflamed segments, as early Crohn's disease may show preserved architecture. 1, 3
Histopathologic Confirmation
Characteristic Crohn's histology includes crypt architectural distortion, transmural inflammation, and non-caseating granulomas (when present). 1, 4, 5
Crypt distortion typically appears after ≥4 weeks of symptoms; early disease may show preserved architecture. 2, 3
Absence of granulomas does not exclude Crohn's disease, as they are present in only a minority of biopsies. 1
Cross-Sectional Imaging
CT enterography is the preferred first-line radiologic study for assessing small bowel Crohn's disease, identifying strictures, fistulas, and abscesses. 1, 5
MR enterography is preferred for young patients (<35 years) to avoid radiation exposure and can detect mural edema and inflammation. 1, 6
Strictures are defined as small bowel segments with luminal narrowing and unequivocal upstream dilation (>3 cm). 1
When strictures are found, describe the length, location, and presence of concurrent inflammation. 1
Common Diagnostic Pitfalls
Do not diagnose Crohn's disease without first excluding C. difficile infection, as it mimics inflammatory bowel disease and requires distinct therapy. 2
Do not rely on normal C-reactive protein to exclude Crohn's disease; 15-20% of active patients have normal inflammatory markers. 2
Do not accept a Crohn's diagnosis without histologic confirmation; endoscopic appearance alone is insufficient. 1, 2
Consider repeat endoscopy with biopsies if diagnostic uncertainty persists, especially in early disease when crypt architecture may be preserved. 2
Do not overlook upper gastrointestinal involvement; 20-40% of patients with ileocolitis have radiologic evidence of upper gastrointestinal Crohn's disease. 8