What to do with negative tissue transglutaminase (tTG) but gluten intolerance, is a colonoscopy (C scope) necessary?

Management of Negative tTG with Suspected Gluten Intolerance

Upper endoscopy with duodenal biopsy is necessary—not colonoscopy—to differentiate between seronegative celiac disease and non-celiac gluten sensitivity in patients with negative tTG who report gluten-related symptoms. 1, 2

Why Upper Endoscopy, Not Colonoscopy

• Colonoscopy evaluates the wrong anatomic location—celiac disease and gluten-related enteropathy affect the small intestine (duodenum and jejunum), not the colon. 1
• Upper endoscopy with at least 6 duodenal biopsies from the second part of the duodenum or beyond is the gold standard for diagnosing seronegative enteropathy. 2, 3
• The presence or absence of villous atrophy on small bowel biopsy determines the diagnostic pathway and management strategy. 1, 2

Complete Diagnostic Workup Before Endoscopy

Before proceeding to biopsy, ensure comprehensive serologic evaluation:

• Confirm the patient is consuming adequate gluten (at least 10g daily for 6-8 weeks) at the time of testing, as gluten avoidance causes false-negative results. 1, 2
• Measure total IgA level to rule out selective IgA deficiency, which occurs in 1-3% of celiac patients and causes falsely negative IgA-based tests. 1, 2
• Complete the full celiac panel: anti-tTG IgA, deamidated gliadin peptide (DGP) IgA, and endomysial antibody (EMA) IgA—not just tTG alone. 1, 2
• Order HLA-DQ2/DQ8 genetic testing—negative results effectively rule out celiac disease in seronegative patients (99.6% negative predictive value). 1, 2

Critical Medication and Travel History

• Review for angiotensin II receptor blockers (especially olmesartan), which cause villous atrophy mimicking celiac disease. 1, 2
• Document immunosuppressive medications that can mask serologic findings or cause enteropathy. 1
• Obtain travel history to identify infectious causes of villous atrophy. 1

Interpretation Algorithm Based on Biopsy Results

If Biopsy Shows Villous Atrophy + Positive HLA-DQ2/DQ8:

• Diagnose seronegative celiac disease. 1, 2
• Initiate strict gluten-free diet immediately. 2
• Perform follow-up endoscopy after 1-3 years to confirm histologic improvement, which validates the diagnosis. 1, 2

If Biopsy Shows Villous Atrophy + Negative HLA-DQ2/DQ8:

• Celiac disease is excluded—pursue alternative diagnoses including medication-induced enteropathy, autoimmune enteropathy, tropical sprue, or common variable immunodeficiency. 1, 2

If Biopsy is Normal + Negative Serology:

• Diagnose non-celiac gluten sensitivity (NCGS). 4
• Patients with negative serology who lack malabsorption symptoms (weight loss, diarrhea, nutrient deficiencies) and celiac risk factors (autoimmune diseases, family history) have a positive likelihood ratio of 80.9 for NCGS. 4
• No further invasive testing is required—manage with dietary modification based on symptoms. 4

Management of Persistent Symptoms Despite Gluten-Free Diet

• If symptoms persist after adequate gluten-free diet trial and no etiology is identified, treat empirically with budesonide. 1, 2
• Re-evaluate for complications including refractory celiac disease, enteropathy-associated lymphoma, microscopic colitis, or pancreatic exocrine dysfunction. 5

Common Pitfalls to Avoid

• Never start a gluten-free diet before completing the diagnostic workup—this renders serology and biopsy unreliable and prevents accurate diagnosis. 2, 3
• Do not rely on symptoms alone—67.3% of celiac patients present with malabsorption symptoms, but 24.8% of NCGS patients have similar presentations. 4
• Ensure pathology review by gastroenterology-specialized pathologists—poorly oriented duodenal mucosa leads to misinterpretation of villous architecture. 1, 2
• Colonoscopy has no role in the initial evaluation of suspected gluten-related disorders unless there are specific colonic symptoms suggesting alternative diagnoses like microscopic colitis in refractory cases. 5