What serologic blood tests should be ordered to screen for celiac disease while the patient is consuming a normal gluten‑containing diet?

Blood Testing for Celiac Disease

Order IgA tissue transglutaminase (IgA-TG2) as the primary screening test, along with total IgA level to rule out IgA deficiency. 1, 2

Primary Serologic Testing Approach

The most efficient initial blood test panel consists of:

• IgA tissue transglutaminase (IgA-TG2): This is the single most sensitive and specific serological test for celiac disease, with both sensitivity and specificity exceeding 95% in most studies 1, 3
• Total IgA level: Must be measured concurrently because IgA deficiency occurs in approximately 2-3% of celiac patients and will cause false-negative IgA-based testing 1, 2

The patient must be consuming a normal gluten-containing diet at the time of testing (ideally at least 3 slices of wheat bread daily for 1-3 months) because gluten avoidance reduces test sensitivity 1

If IgA Deficiency is Detected

When total IgA is low or absent, switch to IgG-based testing 1, 2:

• IgG tissue transglutaminase (IgG-TG2)
• IgG deamidated gliadin peptide (IgG-DGP)

Important caveat: IgG-TG2 testing is NOT specific in the absence of IgA deficiency and should not be used routinely 1

Additional Testing Considerations

Endomysial Antibody (EMA-IgA)

• The 2019 AGA guidelines indicate that when IgA-TG2 is strongly positive (>10× upper normal limit) combined with positive EMA in a second blood sample, the positive predictive value approaches 100% 1
• However, the most recent 2025 European guidelines no longer recommend routine EMA testing for confirmation, as validated high-performance IgA-TG2 ELISAs are sufficiently accurate 4
• EMA testing is more labor-intensive and operator-dependent than automated TG2 assays 3

Antigliadin Antibodies (AGA)

Do not order traditional antigliadin antibodies (IgA-AGA or IgG-AGA) for celiac disease diagnosis—these tests are outdated, highly variable, and provide no additional diagnostic benefit 5, 6, 3

The deamidated gliadin peptide (DGP) tests are superior to traditional AGA but are primarily reserved for IgA-deficient patients 1, 2

What NOT to Order Initially

• HLA-DQ2/DQ8 typing: This has limited diagnostic utility and should NOT be part of initial screening 1. Its value lies primarily in its negative predictive value to rule out celiac disease in complex cases (seronegative patients with histologic changes, or those already on a gluten-free diet without prior serologic confirmation) 1, 4
• IgG-TG2 in IgA-sufficient patients: Not specific and will generate false positives 1
• Traditional antigliadin antibodies: Poor sensitivity and specificity 5, 3

Clinical Pitfalls to Avoid

1. Testing patients already avoiding gluten: This is the most common error—serology and biopsy sensitivity both decrease significantly with gluten restriction 1
2. Ordering IgA-TG2 without checking total IgA: You will miss IgA-deficient celiac patients who test falsely negative 1, 2
3. Relying on serology alone for diagnosis: In adults, duodenal biopsy remains essential for confirmation in most cases (the 2025 European guidelines conditionally allow a no-biopsy approach only for highly selected adults with IgA-TG2 ≥10× ULN) 2, 4
4. Using panels of multiple antibody tests: There is no advantage to testing multiple antibodies simultaneously—IgA-TG2 alone (with total IgA) is sufficient for initial screening 3

Summary Algorithm

For immunocompetent patients on a gluten-containing diet:

• Order: IgA-TG2 + Total IgA 1, 2

If total IgA is low/absent:

• Order: IgG-TG2 and/or IgG-DGP 1, 2

If IgA-TG2 is positive:

• Proceed to upper endoscopy with duodenal biopsies for confirmation 2, 4