Serologic Testing for Celiac Disease
For initial screening of celiac disease, order IgA tissue transglutaminase (TG2-IgA) antibody along with total serum IgA level. 1, 2
Primary Screening Tests
- IgA tissue transglutaminase (TG2-IgA) is the single best serologic test for detecting celiac disease, with the highest diagnostic accuracy 1, 3
- Total serum IgA must be measured concurrently to identify IgA deficiency, which occurs in approximately 2-3% of celiac patients and causes false-negative TG2-IgA results 1
Additional Testing Based on Initial Results
If IgA Deficient:
- Order IgG-based tests: IgG tissue transglutaminase (TG2-IgG), IgG endomysial antibodies (EMA-IgG), or IgG deamidated gliadin peptide (DGP-IgG) 1
- IgG testing is only specific and useful in the context of IgA deficiency 1
If Weakly Positive TG2-IgA (in adults):
- Add IgA endomysial antibodies (EMA-IgA) for confirmation 1, 4
- However, the 2025 ESsCD guidelines now de-emphasize routine EMA testing for confirmation, favoring high-performance validated ELISA assays 4
If Strongly Positive TG2-IgA:
- TG2-IgA levels >10× upper limit of normal combined with positive EMA in a second blood sample have virtually 100% positive predictive value for celiac disease 1
- This allows for potential biopsy-avoidance in select adults and children with appropriate confirmatory testing 1, 4
Tests NOT Routinely Recommended
- IgG tissue transglutaminase should not be ordered unless IgA deficiency is documented 1
- IgA endomysial antibodies are no longer recommended as routine confirmatory testing in the most recent 2025 guidelines, though they remain useful in specific scenarios 4
- Deamidated gliadin peptide antibodies can be considered but are not first-line 1, 5
Critical Pitfalls to Avoid
- Never start a gluten-free diet before testing, as this reduces sensitivity of both serology and biopsy 1, 6
- If patients have already eliminated gluten, they must consume gluten equivalent to three slices of wheat bread daily for 1-3 months before testing 1
- Always check total IgA levels with TG2-IgA to avoid missing celiac disease in IgA-deficient patients 1, 6
When to Consider HLA Testing
- HLA-DQ2/DQ8 genetic testing is useful when patients are already on a gluten-free diet, as negative results effectively rule out celiac disease without requiring gluten challenge 3, 4
- HLA testing helps clarify diagnosis in cases of seronegative villous atrophy or potential celiac disease 4
High-Risk Groups Requiring Screening
Screen individuals with: first-degree relatives of celiac patients, type 1 diabetes, autoimmune thyroid disease, Down syndrome, Turner syndrome, Williams syndrome, unexplained iron deficiency anemia, osteoporosis, elevated liver enzymes, IBS-like symptoms, microscopic colitis, or unexplained neurologic symptoms 3, 7