What tests can rule out Crohn's disease (Crohn's disease)?

Diagnostic Testing to Rule Out Crohn's Disease

To rule out Crohn's disease, perform ileocolonoscopy with systematic biopsies from at least five sites (including terminal ileum and rectum), obtain fecal calprotectin, exclude infectious causes with stool cultures and C. difficile testing, and perform MR enterography to evaluate small bowel disease beyond endoscopic reach. 1

Essential Diagnostic Tests

Endoscopic Evaluation with Histology

• Complete ileocolonoscopy with systematic biopsies is mandatory, taking at least two biopsies from five different sites including the terminal ileum and rectum, even from normal-appearing mucosa 1, 2
• Biopsies from unaffected areas are critical to document histologically the spared segments between inflammatory areas, as discontinuous (skip) lesions are a key feature of Crohn's disease 2
• In acute severe colitis, sigmoidoscopy alone may be sufficient 2
• The majority of initial biopsies (96%) in Crohn's disease show abnormal findings with active chronic ileocolitis, with 80% demonstrating the classic combination of abnormal mucosal architecture, epithelial abnormalities, and active chronic inflammation 3

Cross-Sectional Imaging

• MR enterography is the preferred imaging modality to detect small bowel involvement beyond endoscopic reach, assess transmural disease, identify strictures and fistulae, and evaluate extraluminal complications 1, 2
• MRI is preferred over CT as first-line imaging due to lack of radiation exposure and superior ability to detect active inflammation 1, 2
• CT enterography has similar accuracy but should be reserved for situations where MRI is contraindicated or unavailable 4
• Both CTE and MRE have moderately high accuracy for detecting penetrating Crohn's disease complications (fistulas, inflammatory mass, abscess) 4

Laboratory Testing

Comprehensive blood work should include: 1, 5

• Complete blood count (to assess for anemia from chronic inflammation or blood loss)
• C-reactive protein and erythrocyte sedimentation rate (CRP is more sensitive and correlates better with endoscopic disease activity) 5
• Comprehensive metabolic panel including electrolytes, liver function tests, and renal function
• Serum albumin and pre-albumin (to assess nutritional status)
• Iron studies (serum iron, ferritin, total iron-binding capacity)
• Vitamin B12 level (commonly deficient in terminal ileal disease)

Critical caveat: Approximately 20% of patients with active Crohn's disease have normal CRP levels, so normal inflammatory markers do not exclude active disease 1, 5

Stool Studies

• Fecal calprotectin is highly valuable with pooled sensitivity of 93-95% and specificity of 91-96% for diagnosing IBD, using a cutoff of 100 μg/g for greater diagnostic precision 1, 5, 2
• Mandatory stool cultures to exclude bacterial pathogens (Salmonella, Shigella, Campylobacter, Yersinia) 5, 2
• C. difficile toxin testing is essential to rule out this infectious trigger which can precipitate or mimic Crohn's disease flares 5, 2
• Loose stools for more than 6 weeks usually discriminate IBD-associated colitis from most infectious diarrhea 2

Diagnostic Integration

• No single test serves as a gold standard—diagnosis requires a combination of clinical, biochemical, endoscopic, radiological, and histological investigations 1, 2
• The combination of elevated CRP and fecal calprotectin provides the most reliable assessment of inflammatory activity 1, 5
• At initial diagnosis, all four assessment modalities should be used where resources allow: symptom assessment, endoscopic evaluation, laboratory markers, and cross-sectional imaging 5

Key Histologic Features

The most sensitive histologic feature is lamina proprial chronic inflammation (sensitivity 92.7%), followed by active inflammation (87.8%), basal plasmacytosis (82.1%), architectural changes (80.5%), and epithelial abnormalities (70.7%) 3

Granulomas are not required for diagnosis—they are seen in only 10 of 41 Crohn's disease cases at initial presentation, and when present, small, tight, well-defined granulomata characterize Crohn's disease 3

Important Mimics to Exclude

Tuberculosis and diverticular disease-associated colitis are two important mimics that can show similar histologic features to Crohn's disease, including the classic combination of abnormal architecture, epithelial abnormalities, and active chronic inflammation 3

Large coalesced granulomata suggest tuberculosis over Crohn's disease, which typically shows smaller, tighter granulomata 3

Tests NOT Recommended

Genetic testing should NOT be used for diagnosing Crohn's disease in routine clinical practice, as NOD2/CARD15 testing lacks adequate sensitivity and specificity for diagnosis 5

Limited exception: Genetic testing may be considered in very early onset inflammatory bowel disease, patients with family history suggesting Mendelian inheritance, or severe refractory disease 5