What are the next steps for a patient with a normal tissue transglutaminase (tTG) Immunoglobulin A (IgA) result, potentially indicating no celiac disease?

Normal tTG IgA: Celiac Disease is Effectively Ruled Out

A normal tTG IgA result effectively excludes celiac disease in patients with normal total IgA levels, and no further celiac-specific workup is needed unless clinical suspicion remains exceptionally high. 1, 2

Confirm Test Validity

• Measure total IgA level to ensure the negative tTG IgA is not falsely negative due to selective IgA deficiency, which occurs in 1-3% of celiac disease patients and causes falsely negative IgA-based antibody tests 1, 3
• If total IgA is normal, the negative tTG IgA has a negative predictive value of virtually 100% for celiac disease 2
• If IgA deficiency is confirmed, repeat testing using IgG-based assays (IgG deamidated gliadin peptide or IgG tTG), as IgG deamidated gliadin peptide has superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to tTG IgG 1

Verify Adequate Gluten Consumption

• Confirm the patient was consuming at least 10g of gluten daily for 6-8 weeks prior to testing to avoid false-negative results 1, 3
• If the patient had already reduced or eliminated gluten before testing, the negative result is unreliable and gluten must be reintroduced for 6-8 weeks before repeat testing 1

When to Pursue Further Testing Despite Negative Serology

• If clinical suspicion remains exceptionally high (unexplained iron deficiency anemia, chronic diarrhea with weight loss, family history of celiac disease, type 1 diabetes, or autoimmune thyroid disease), proceed to upper endoscopy with at least 6 duodenal biopsies 1, 3
• Consider HLA-DQ2/DQ8 genetic testing, which has >99% negative predictive value—absence of both alleles essentially rules out celiac disease and can avoid unnecessary endoscopy 1
• The American Gastroenterological Association recognizes seronegative celiac disease as a rare subset of patients with characteristic intestinal damage but negative antibody testing, requiring biopsy for diagnosis 1

Test Performance Characteristics

• tTG IgA has 90.7% sensitivity and 87.4% specificity in adults at 15 U/mL threshold 1, 3
• In children, tTG IgA has 97.7% sensitivity and 70.2% specificity at 20 U/mL threshold 1
• Approximately 19 patients with actual celiac disease would have false-negative results out of 10,000 adults tested, and approximately 5 out of 10,000 children 1

Common Pitfall to Avoid

• Never start a gluten-free diet based on symptoms alone without confirmed celiac disease, as this can lead to nutritional deficiencies, unnecessary dietary restrictions, and makes future diagnostic testing unreliable 1, 3
• If symptoms persist, investigate alternative diagnoses such as irritable bowel syndrome, inflammatory bowel disease, small intestinal bacterial overgrowth, or non-celiac gluten sensitivity 1

Follow-Up Recommendations

• If new gastrointestinal symptoms develop, growth failure occurs, or unexplained iron deficiency anemia develops, repeat celiac serology while maintaining adequate gluten intake 1
• In high-risk populations (first-degree relatives of celiac disease patients, type 1 diabetes, autoimmune thyroid disease), consider periodic screening every 2-3 years even with initial negative serology 1