What is the diagnosis and treatment for a patient with positive t-Transglutaminase (tTG) Immunoglobulin G (IgG) antibodies, indicating an immune response to gluten?

Diagnosis and Management of Positive tTG IgG Antibodies

Primary Recommendation

Isolated positive tTG IgG with negative tTG IgA has extremely limited diagnostic utility for celiac disease (only 3% positive predictive value) and should not be used to diagnose celiac disease when IgA-based testing is negative. 1

Diagnostic Algorithm

Step 1: Verify Total IgA Level

• Measure total IgA level immediately to determine if IgA deficiency is present, which occurs in 1-3% of celiac disease patients and causes falsely negative tTG IgA results 2, 3, 4
• If total IgA is normal, the negative tTG IgA effectively excludes celiac disease in most cases, and the isolated positive tTG IgG should be disregarded 2
• If IgA deficiency is confirmed, proceed to IgG-based testing with deamidated gliadin peptide IgG (DGP-IgG), which has superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to tTG IgG 2

Step 2: Interpretation Based on IgA Status

If IgA is Normal:

• The isolated positive tTG IgG has minimal clinical significance 1
• In a study of 178 patients with isolated positive tTG IgG and negative tTG IgA who underwent biopsy, only 6 cases (3%) were confirmed as celiac disease 1
• Alternative diagnoses should be pursued rather than celiac disease 2

If IgA Deficiency is Present:

• Switch to IgG-based testing with DGP-IgG, not tTG IgG 2
• tTG IgG has poor diagnostic performance with sensitivity ranging only 40.6-84.6% and specificity 78.0-89.0% 2

Step 3: Consider High-Risk Populations

Proceed to endoscopy with duodenal biopsy despite negative tTG IgA only if:

• First-degree relatives with celiac disease 2
• Type 1 diabetes or autoimmune thyroid disease 2, 3
• Clinical suspicion remains extremely high with classic malabsorptive symptoms 2

Critical Testing Requirements

• All serologic testing must be performed while consuming at least 10g of gluten daily for 6-8 weeks to avoid false-negative results 2, 4
• tTG IgA is the gold standard screening test with sensitivity of 90-97% and specificity of 96-100% 4
• Never initiate a gluten-free diet before completing diagnostic workup, as this leads to false-negative serology and inconclusive biopsies 2

Common Pitfalls to Avoid

• Do not rely on isolated tTG IgG for diagnosis when tTG IgA is negative and total IgA is normal 1
• Do not proceed to biopsy based solely on positive tTG IgG without confirming IgA deficiency 2
• Do not confuse tTG IgG with DGP-IgG—they have vastly different diagnostic accuracies 2

When Biopsy is Indicated

Obtain at least 6 duodenal biopsy specimens from the second part of the duodenum if: 2, 3

• IgA deficiency is confirmed and IgG-based testing (DGP-IgG) is positive 2
• Patient belongs to high-risk population with strong clinical suspicion despite negative serology 2
• Ensure specimens are properly oriented for Marsh classification by a pathologist with gastroenterology expertise 2, 3