What is the unifying diagnosis for an adult with CT‑identified colitis, painful hematochezia, vitamin D and vitamin B12 deficiency, mild pancreatic exocrine insufficiency with elevated lipase, hyperuricemia, elevated κ‑light chains, low testosterone, pre‑diabetes, normal antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA), positive anti‑Saccharomyces cerevisiae antibodies (ASCA), normal colonoscopy, and a negative inflammatory bowel disease gene panel?

Unifying Diagnosis: Crohn's Disease with Atypical Presentation

The most likely unifying diagnosis is Crohn's disease, despite the normal colonoscopy and negative IBD gene panel, because the positive anti-Saccharomyces cerevisiae antibodies (ASCA), CT-documented colitis, vitamin B12 deficiency, and pancreatic exocrine insufficiency collectively point toward this diagnosis. 1, 2, 3

Diagnostic Reasoning

Why Crohn's Disease Fits Despite Normal Colonoscopy

The normal colonoscopy does not exclude Crohn's disease for several critical reasons:

• Microscopic disease can exist without macroscopic findings: Approximately 5-15% of IBD cases cannot be definitively classified on initial endoscopy and histology, leading to IBD-unclassified designation 2, 4
• Small bowel involvement may be missed: About one-third of Crohn's disease patients have small intestine involvement not detectable by colonoscopy, which explains why CT showed colitis while colonoscopy appeared normal 3
• Focal inflammation patterns: Crohn's disease characteristically shows patchy, discontinuous distribution with skip lesions that may be missed on random biopsies 2, 5
• Upper GI tract involvement: The elevated lipase and pancreatic exocrine insufficiency suggest proximal disease that would not be visible on colonoscopy 1, 6

Supporting Laboratory Evidence

The constellation of findings strongly supports Crohn's disease:

• Positive ASCA antibodies: While pANCA and ASCA have limited accuracy for differentiating colonic Crohn's from ulcerative colitis, positive ASCA in the context of other findings supports Crohn's disease diagnosis 3, 6
• Vitamin B12 deficiency: This occurs in 33% of Crohn's disease patients (versus 16% in ulcerative colitis) due to terminal ileal involvement or inflammation, even without resection 7
• Pancreatic exocrine insufficiency with elevated lipase: Approximately 30% of adults with exocrine pancreatic insufficiency develop vitamin B12 malabsorption, and this can occur in Crohn's disease with gastroduodenal involvement 8, 6
• Vitamin D deficiency: Common in IBD due to malabsorption and chronic inflammation 3

Negative Findings That Support Rather Than Refute Crohn's Disease

• Normal ANA and ANCA: These exclude autoimmune conditions but do not rule out Crohn's disease 3
• Negative IBD gene panel: Over 250 IBD-associated genetic variants exist, but genetic testing is not recommended for diagnosis because it lacks sufficient sensitivity and specificity 3
• Normal colonoscopy: As discussed above, this requires cross-sectional imaging and potentially capsule endoscopy for complete evaluation 1, 2

Recommended Diagnostic Algorithm

Immediate Next Steps

1. Obtain MRI or CT enterography: This is mandatory to evaluate small bowel involvement that colonoscopy cannot assess 1, 2, 3

   • Look specifically for: skip lesions, transmural inflammation, wall thickening, strictures, prestenotic dilatation
   • Active terminal ileal inflammation and disease burden (≥1 skip lesion, prestenotic dilatation >3 cm) correlate with B12 deficiency 7

2. Consider small bowel capsule endoscopy: If MR/CT enterography is inconclusive, capsule endoscopy can establish definitive diagnosis by demonstrating small bowel lesions in 17-70% of patients with unclassified IBD 2

   • Critical caveat: Use patency capsule first to avoid retention in suspected strictures 1, 2

3. Repeat ileocolonoscopy with systematic biopsies: Obtain at least two biopsies from five different sites including ileum and rectum, even from normal-appearing areas 1, 2

   • Look for: focal chronic inflammation without crypt atrophy, focal cryptitis, granulomas (present in 61-67% of untreated patients), rectal sparing 1, 2
   • Biopsies from unaffected areas document spared segments between inflammatory areas 2

4. Upper endoscopy with biopsies: Given the pancreatic involvement and elevated lipase, evaluate for gastroduodenal Crohn's disease 1, 6

   • Look for: focal inflammation, granulomas, perifoveolar/periglandular mononuclear infiltrate
   • Isolated gastric Crohn's disease is rare (<0.07%) but can occur 6

Additional Metabolic Workup

The constellation of metabolic abnormalities requires attention:

• Elevated kappa light chains: Investigate for plasma cell dyscrasia or monoclonal gammopathy, which can coexist with IBD but may represent separate pathology 3
• Hyperuricemia and prediabetes: Likely related to chronic inflammation and metabolic syndrome, common in IBD patients 3
• Hypotestosteronism: Can result from chronic inflammatory disease and malnutrition 3

Critical Pitfalls to Avoid

• Do not dismiss Crohn's disease based on normal colonoscopy alone: This represents inadequate evaluation without cross-sectional imaging 1, 2, 3
• Do not rely on genetic testing: The negative IBD gene panel is not diagnostically useful 3
• Do not ignore the pancreatic findings: Pancreatic exocrine insufficiency with B12 deficiency suggests proximal GI involvement requiring upper endoscopy 7, 8
• Do not assume IBS with focal inflammation: Documented inflammation on CT excludes IBS by definition and requires full IBD workup 4
• Do not overlook the need for systematic biopsies: Random or inadequate sampling misses focal disease patterns characteristic of Crohn's disease 1, 2

Treatment Implications

Once Crohn's disease is confirmed with appropriate imaging:

• Address vitamin B12 deficiency with supplementation (common in 33% of Crohn's patients) 7
• Correct vitamin D deficiency 3
• Manage pancreatic exocrine insufficiency with enzyme replacement 8
• Initiate appropriate IBD-specific therapy based on disease extent, location, and severity 1