What are the initial lab tests for diagnosing celiac disease, specifically the recommended serological tests, such as tissue transglutaminase antibody (tTGA) test and endomysial antibody (EMA) test?

Initial Laboratory Testing for Celiac Disease

The IgA tissue transglutaminase antibody (tTG-IgA) is the single best initial screening test for celiac disease and should be ordered alongside a total IgA level in all patients being evaluated for this condition. 1, 2

Primary Screening Test

• Order IgA tTG as the first-line serological test, which demonstrates sensitivity of 90-96% and specificity greater than 95% in detecting celiac disease 1, 2
• Always measure total IgA level simultaneously with the tTG-IgA test, as IgA deficiency occurs in 1-3% of celiac patients and causes falsely negative results on IgA-based antibody tests 1, 2
• The patient must be consuming at least 10 grams of gluten daily for 6-8 weeks before testing to avoid false-negative results 1, 3

Confirmatory Serological Testing

• If tTG-IgA is positive (especially >10× upper limit of normal), order IgA endomysial antibody (EMA-IgA) as confirmatory testing 1, 2
• EMA-IgA has slightly lower sensitivity than tTG-IgA but excellent specificity of 99.6%, making it ideal for confirmation 1
• The combination of tTG-IgA >10× upper limit of normal plus positive EMA-IgA approaches 100% positive predictive value for celiac disease 3

Critical Pitfall: Do Not Order Gliadin Antibodies

• Avoid ordering IgA or IgG antigliadin antibodies (AGA), as these tests have poor diagnostic performance compared to tTG-IgA and EMA-IgA and are not warranted in the initial workup 1

Special Situations Requiring Modified Testing

If IgA Deficiency is Detected

• Switch to IgG-based testing if total IgA is low or absent 1, 2
• Order IgG deamidated gliadin peptide (DGP-IgG) as the preferred IgG test, which has superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to IgG tTG 4
• IgG tTG has limited utility with sensitivity ranging only 40.6-84.6% and should not be relied upon 4

In Children Under 2 Years

• Combine tTG-IgA with both IgG and IgA deamidated gliadin peptides for improved sensitivity in this age group 2, 3

When to Consider HLA Testing

• Order HLA-DQ2 and HLA-DQ8 genetic testing only when celiac disease is strongly suspected despite negative serology, as the absence of both alleles has >99% negative predictive value and essentially rules out celiac disease 2, 3
• HLA testing is not useful for confirming diagnosis when antibodies are already elevated, as it adds no diagnostic value in that scenario 3

Essential Pre-Test Requirements

• Never allow the patient to start a gluten-free diet before completing all diagnostic testing, as gluten restriction causes positive serologic results to resolve and histologic findings to improve, leading to false-negative results 1, 3
• If the patient has already reduced gluten intake, gluten must be reintroduced at ≥10g daily for 6-8 weeks before proceeding with testing 4, 3

Next Steps After Positive Serology

• All adults with positive serology require upper endoscopy with at least 6 duodenal biopsy specimens (1-2 from duodenal bulb, at least 4 from second part of duodenum or beyond) to confirm the diagnosis, as intestinal biopsy remains the gold standard 1, 3
• Positive serologic tests alone are supportive but not diagnostic of celiac disease without histologic confirmation in adults 1

High-Risk Populations Warranting Testing

Consider celiac serological testing even without classic symptoms in patients with: 1, 2

• Unexplained iron deficiency anemia
• Premature onset of osteoporosis
• Down syndrome or Turner syndrome
• Unexplained elevations in liver transaminase levels
• Type 1 diabetes mellitus
• Autoimmune thyroid disease
• First-degree relatives of patients with celiac disease