How are celiac disease Immunoglobulin A (IgA) and Immunoglobulin G (IgG) levels interpreted?

Interpretation of Celiac Disease IgA and IgG Antibody Levels

IgA tissue transglutaminase (tTG-IgA) is the preferred first-line test for celiac disease screening, with sensitivity of 90.7% and specificity of 87.4% in adults at 15 U/mL threshold, while IgG-based tests are primarily reserved for patients with confirmed IgA deficiency. 1, 2

Initial Testing Strategy

IgA-Based Testing (Standard Approach)

• Always measure total IgA level simultaneously with tTG-IgA to rule out IgA deficiency, which occurs in 1-3% of celiac disease patients and causes falsely negative IgA-based results 3, 2
• tTG-IgA interpretation thresholds:
  • Levels >10× upper limit of normal have virtually 100% positive predictive value for celiac disease and correlate strongly with severe intestinal damage 3, 2
  • Levels of 21-118 U combined with IgA endomysial antibody (EMA) titer ≥1:160 have 83% positive predictive value 4
  • Levels <20 U combined with EMA titer <1:10 have 92% negative predictive value 4
• IgA EMA serves as confirmatory testing with excellent specificity of 99.6% in adults and should be performed when tTG-IgA is elevated 1, 3

IgG-Based Testing (Special Populations Only)

• IgG tests are NOT useful when total IgA is normal - a negative tTG-IgA effectively excludes celiac disease in most cases when IgA levels are adequate 3
• IgG deamidated gliadin peptide (DGP-IgG) is the preferred IgG test in IgA-deficient patients, with superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to tTG-IgG 3
• IgG tTG has limited utility: sensitivity ranges from only 40.6-84.6% and specificity 78.0-89.0%, making it less reliable than DGP-IgG 1

Algorithmic Interpretation Based on Results

Scenario 1: Elevated tTG-IgA with Normal Total IgA

• If tTG-IgA >10× upper limit of normal: Proceed directly to upper endoscopy with at least 6 duodenal biopsies for confirmation 3, 2
• If tTG-IgA 1-10× upper limit of normal: Add IgA EMA testing for confirmation before proceeding to biopsy 3, 2
• Ensure patient is consuming adequate gluten (at least 10g daily for 6-8 weeks) before biopsy to avoid false-negative results 3, 2

Scenario 2: Normal tTG-IgA with Normal Total IgA

• Celiac disease is effectively ruled out in most cases - consider alternative diagnoses 3
• Exception: In high-risk populations (first-degree relatives with celiac disease, type 1 diabetes, autoimmune thyroid disease), consider biopsy despite negative serology if clinical suspicion remains high 3

Scenario 3: IgA Deficiency Confirmed (Low Total IgA)

• Immediately switch to IgG-based testing: Order IgG DGP and IgG tTG 3, 2
• Do not rely on tTG-IgA results in IgA-deficient patients as they will be falsely negative 5
• IgG-tTG shows 100% concordance with IgG-EMA in IgA-deficient subjects and can discriminate between positive and negative cases effectively 5

Scenario 4: Discordant Results (Positive tTG-IgA, Negative EMA)

• Proceed with upper endoscopy and biopsy as the gold standard - discordant results may represent early or developing celiac disease 3
• tTG-IgA has higher sensitivity but lower specificity than EMA, so positive tTG-IgA with negative EMA requires histologic confirmation 3

Critical Pitfalls to Avoid

• Never start a gluten-free diet before completing diagnostic workup - this leads to false-negative serology and inconclusive biopsies 3, 2
• Never rely solely on serology without biopsy confirmation in adults - biopsy remains the gold standard except in specific pediatric protocols 3, 2
• Do not order IgG tests when IgA levels are normal - this adds no diagnostic value and increases false positives 3
• Do not interpret isolated positive IgG tTG as diagnostic when IgA is normal - this has poor specificity and requires alternative diagnosis consideration 3

Monitoring After Diagnosis

• Follow-up tTG-IgA testing schedule: at 6 months after starting gluten-free diet, at 12 months, then annually thereafter 3, 6
• Persistently elevated antibodies indicate ongoing gluten exposure or poor dietary compliance 3, 6
• Antibody levels typically decline within months of starting gluten-free diet, with most significant drops in the first year 3
• Negative serology after treatment does not guarantee mucosal healing - consider follow-up biopsy in 1-3 years for severe initial presentations 3, 2