What labs should be ordered to rule out celiac disease in a patient?

Laboratory Testing to Rule Out Celiac Disease

Order IgA tissue transglutaminase antibody (tTG-IgA) along with total IgA level as the first-line screening test while the patient is consuming at least 10g of gluten daily for 6-8 weeks prior to testing. 1, 2, 3

Primary Screening Tests

• IgA tissue transglutaminase (tTG-IgA) is the preferred first-line test with sensitivity of 90-96% and specificity >95% in adults 2, 4
• Total IgA level must be measured simultaneously to identify IgA deficiency, which occurs in 1-3% of celiac disease patients and causes falsely negative IgA-based tests 1, 5, 2
• Testing must be performed while the patient consumes adequate gluten (at least 10g daily, approximately 3 slices of wheat bread) for 6-8 weeks to avoid false-negative results 1, 2, 3

Confirmatory Testing When Initial Screen is Positive

• IgA endomysial antibody (EMA-IgA) should be added for confirmation when tTG-IgA is positive, with excellent specificity of 99.6% 5, 2, 3
• When tTG-IgA is >10 times the upper limit of normal plus positive EMA-IgA in a second blood sample, the positive predictive value approaches 100% for celiac disease 5, 2, 3

Special Testing Scenarios

If IgA Deficiency is Detected

• IgG deamidated gliadin peptide (DGP-IgG) is the preferred IgG-based test with superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to IgG tTG 1, 5
• IgG tTG has limited utility with sensitivity ranging only 40.6-84.6% and should not be the primary choice 5

If High Clinical Suspicion Despite Negative Serology

• HLA-DQ2 and HLA-DQ8 genetic testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 1, 5, 2
• This testing is useful when celiac disease is strongly suspected despite negative serology, in patients with equivocal findings, or in those already on a gluten-free diet who were never properly tested 2

Critical Testing Requirements

• No fasting is required for celiac serology, as antibody levels are not affected by recent food intake 3
• Gluten consumption is mandatory: Reduction or avoidance of gluten prior to testing significantly reduces sensitivity of both serology and biopsy 3
• Patients who have already started a gluten-free diet must resume normal diet with three slices of wheat bread daily for 1-3 months before testing 2

Diagnostic Algorithm for Negative Serology

When celiac disease is still suspected despite negative initial testing:

1. Confirm adequate gluten intake (≥10g daily for 6-8 weeks) when tested 5
2. Verify total IgA level was measured to exclude IgA deficiency 5
3. Perform HLA-DQ2/DQ8 testing—if positive, proceed to upper endoscopy with duodenal biopsies 2
4. If HLA testing is negative, celiac disease is effectively ruled out 1, 2

Common Pitfalls to Avoid

• Never initiate a gluten-free diet before completing diagnostic testing, as this leads to false-negative results and inconclusive biopsies 5, 2
• Do not rely on IgG-based tests in patients with normal IgA levels, as they are markedly less accurate in this setting 2
• Do not use serology alone without biopsy confirmation when results are positive, especially with discordant results 1, 5
• Approximately 19 per 10,000 adults and 5 per 10,000 children with actual celiac disease will have false-negative IgA tTG results, so clinical judgment remains essential 5

High-Risk Groups Warranting Testing

Consider celiac screening in:

• First-degree relatives of patients with celiac disease 2
• Patients with type 1 diabetes mellitus 2
• Unexplained iron deficiency anemia (5% prevalence of celiac disease) 2, 3
• Autoimmune thyroid disease 2
• Unexplained liver transaminase elevations 2
• Premature osteoporosis 2
• Down syndrome 2