Tests to Order for Celiac Disease Diagnosis
The initial diagnostic workup for celiac disease should include IgA tissue transglutaminase antibody (tTG-IgA) plus total IgA level, performed while the patient is consuming a gluten-containing diet, followed by upper endoscopy with multiple duodenal biopsies for confirmation in adults. 1, 2
Initial Serological Testing
First-line test:
- IgA tissue transglutaminase antibody (tTG-IgA) is the preferred screening test with sensitivity of 90-96% and specificity >95% 1, 2
- Total IgA level must be measured simultaneously to rule out IgA deficiency, which occurs in 1-3% of celiac patients and causes false-negative results 1, 2
Critical requirement: Testing must be performed while the patient consumes at least 10g of gluten daily for 6-8 weeks—starting a gluten-free diet before testing leads to false-negative results 1, 2
Confirmatory Serological Testing
When tTG-IgA is elevated (especially >10× upper limit of normal):
- IgA endomysial antibody (EMA-IgA) should be performed as confirmatory testing with excellent specificity of 99.6% 1, 2
- The combination of tTG-IgA >10× upper limit of normal plus positive EMA-IgA approaches 100% positive predictive value for celiac disease 1
Testing in IgA-Deficient Patients
If total IgA is low or absent:
- IgG deamidated gliadin peptide (DGP-IgG) is the preferred IgG-based test with sensitivity of 93.6% and specificity of 99.4% 1, 3
- IgG tissue transglutaminase (tTG-IgG) is an alternative but has inferior accuracy compared to DGP-IgG 3
Important pitfall: IgG-based tests should NOT be used in patients with normal IgA levels, as they are markedly less accurate in this setting 1
Biopsy Confirmation (Gold Standard in Adults)
Upper endoscopy with duodenal biopsies:
- Obtain at least 6 biopsy specimens total: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond 1, 2
- Characteristic histologic findings include villous atrophy, crypt lengthening, and increased intraepithelial lymphocytes 1, 2
Biopsy remains mandatory in adults despite high antibody levels, as it establishes the diagnosis definitively and rules out other causes of villous atrophy 4, 1
HLA Genetic Testing (Second-Line)
HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 1, 2
Specific indications for HLA testing:
- Celiac disease strongly suspected despite negative serology 1, 2
- Equivocal biopsy findings 1
- Patient already on gluten-free diet without prior proper testing 1
- Discrepant serology and histology results 2
HLA testing is NOT useful for diagnosis confirmation when tTG-IgA is highly elevated, as it adds no diagnostic value in this scenario 4
Pediatric Biopsy-Avoidance Protocol
In children only, biopsy may be avoided when ALL of the following are present:
Special Population Testing
Children under 2 years:
Tests That Should NOT Be Ordered
Avoid these tests as they add no diagnostic value:
- Non-deamidated gliadin antibodies (IgA/IgG) have no additional benefit in adults 4, 5
- IgG tTG in patients with normal IgA levels (poor accuracy) 1, 3
- Point-of-care tests may have quality control issues and rarely change management 4
Common Diagnostic Pitfalls
Never initiate gluten-free diet before completing diagnostic testing—this is the most common error and leads to false-negative serology and inconclusive biopsies 1, 2
If patient already started gluten-free diet: They must resume normal diet with three slices of wheat bread daily for 1-3 months (sometimes longer) before repeat testing 1
Relying solely on serology without biopsy in adults can lead to misdiagnosis, especially with discordant or weakly positive results 1, 2
Seronegative celiac disease exists—approximately 5-10% of patients with biopsy-proven celiac disease have negative serology, requiring biopsy for diagnosis 1
High-Risk Groups Requiring Testing
Screen the following populations even without symptoms: