What does a positive Tissue Transglutaminase (TTG) Immunoglobulin A (IgA) test result indicate?

What TTG IgA Tells You

A positive TTG IgA test indicates active celiac disease with high diagnostic accuracy, serving as the preferred first-line screening test with 90.7% sensitivity and 87.4% specificity in adults. 1

Primary Diagnostic Significance

• TTG IgA is the gold standard initial screening test for celiac disease, recommended by the American Gastroenterological Association as the preferred first-line serologic marker 1
• The test detects IgA antibodies against tissue transglutaminase, the main autoantigen in celiac disease, with sensitivity of 90-96% in adults and 97.7% in children 1, 2
• A TTG IgA level >10 times the upper limit of normal has >98% positive predictive value for celiac disease and correlates strongly with severe intestinal villous atrophy 1
• Strongly positive results (≥100 units) occur almost exclusively with Marsh 3 histopathology (villous atrophy) in 96% of cases 3

Critical Testing Requirements

• The patient MUST be consuming at least 10g of gluten daily for 6-8 weeks before testing to avoid false-negative results 1
• Total IgA levels must be measured simultaneously because selective IgA deficiency occurs in 1-3% of celiac patients and causes falsely negative TTG IgA results 1, 4
• If IgA deficiency is present, IgG-based tests (particularly IgG deamidated gliadin peptide with 93.6% sensitivity and 99.4% specificity) should be used instead 1

Test Performance in Real-World Practice

• At the 15 U/mL threshold in adults: sensitivity 90.7%, specificity 87.4% 5
• At the 20 U/mL threshold in children: sensitivity 97.7%, specificity 70.2% 5
• The test performs better at ruling OUT celiac disease than ruling it IN due to lower specificity than sensitivity 1
• In a hypothetical cohort of 10,000 adults tested, approximately 19 patients with actual celiac disease would have false-negative results 1

Confirmatory Testing Strategy

• Positive TTG IgA should be confirmed with endomysial antibody (EMA) testing, which has superior specificity of 99.6% in adults and 93.8% in children 5, 1
• The combination of positive TTG IgA and positive EMA has virtually 100% positive predictive value for celiac disease 1
• Upper endoscopy with at least 6 duodenal biopsies from the second part of the duodenum remains the gold standard for definitive diagnosis before starting treatment 1

Monitoring Treatment Response

• TTG IgA levels should be rechecked at 6 months after starting a gluten-free diet, again at 12 months, then annually to assess treatment adherence 1, 2
• Antibody levels typically decline within months of starting a gluten-free diet, with most significant drops in the first year 1
• Persistently elevated TTG IgA despite dietary treatment indicates ongoing gluten exposure or poor dietary compliance 1, 2
• Different TTG IgA assays have varying sensitivity for detecting suboptimal treatment response—chemiluminescence assays appear more sensitive than fluorochrome-enzyme assays in detecting residual intestinal damage 6

Common Pitfalls to Avoid

• Never start a gluten-free diet before completing the diagnostic workup (serology AND biopsy), as this leads to false-negative results and inconclusive biopsies 1
• Do not confuse elevated total IgA with celiac disease risk—elevated total IgA actually strengthens confidence in negative TTG IgA results 1
• False-positive TTG IgA can occur in inflammatory bowel disease, liver disease, and other autoimmune conditions, though typically at lower titers 7
• Negative TTG IgA does not absolutely exclude celiac disease if the patient was not consuming adequate gluten or has IgA deficiency 1

When Negative TTG IgA Requires Further Investigation

• If clinical suspicion remains high despite negative serology, proceed directly to upper endoscopy with duodenal biopsies 1
• Consider HLA-DQ2/DQ8 genetic testing, which has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 1
• Seronegative celiac disease exists as a subset of patients with characteristic intestinal damage but negative antibody testing 1