What are the diagnostic tests for celiac disease?

Diagnostic Tests for Celiac Disease

Initial Screening Test

The IgA tissue transglutaminase antibody (tTG-IgA) is the single best initial screening test for celiac disease, with sensitivity of 90-96% and specificity >95%. 1, 2, 3

• Total serum IgA level must be measured simultaneously to rule out IgA deficiency, which occurs in 1-3% of celiac patients and causes false-negative tTG-IgA results 2, 3, 4
• Testing must be performed while the patient consumes at least 10g of gluten daily for 6-8 weeks before testing, as starting a gluten-free diet leads to false-negative results 2, 3, 4
• The older IgA/IgG antigliadin antibody tests are not recommended due to poor diagnostic performance compared to tTG-IgA 1, 5

Confirmatory Serologic 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, 3

• The combination of tTG-IgA >10× upper limit of normal plus positive EMA-IgA approaches 100% positive predictive value for celiac disease 2, 4
• EMA-IgA has sensitivity of 88-94.5% and specificity of 93.8-99.6%, making it useful for ruling in disease 1
• There is no advantage to using a panel of multiple serologic tests over the two-step tTG-IgA followed by EMA-IgA approach 1, 5

Gold Standard: Intestinal Biopsy

Upper endoscopy with multiple duodenal biopsies remains the gold standard for diagnosis in adults, even when antibody levels are highly elevated 1, 2, 4

• At least 6 biopsy specimens total should be obtained: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond 1, 2, 4
• Multiple biopsies are necessary because mucosal changes can be patchy 1
• Characteristic histologic findings include villous atrophy, crypt lengthening, and increased intraepithelial lymphocytes 1, 2, 3
• Isolated intraepithelial lymphocytosis without villous atrophy is not diagnostic of celiac disease and requires consideration of other causes 3

Testing in IgA-Deficient Patients

In patients with IgA deficiency, IgG-based tests must be used instead: IgG deamidated gliadin peptide (DGP-IgG) or IgG tissue transglutaminase (tTG-IgG) 1, 2, 3

• IgG-based tests have excellent sensitivity and specificity in IgA-deficient patients 1
• IgG-based tests are markedly less accurate in patients with normal IgA levels and should not be used in that setting 2

HLA Genetic Testing

HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 2, 3, 4

HLA testing is useful in specific scenarios:

• When celiac disease is strongly suspected despite negative serology 1, 2, 4
• In patients with equivocal biopsy findings 2, 3
• In patients already on a gluten-free diet who were never properly tested 2, 3
• HLA testing is NOT useful for diagnosis confirmation when tTG-IgA is highly elevated, as it adds no diagnostic value in this scenario 4

Special Population Considerations

In children under 2 years of age, tTG-IgA should be combined with IgG and IgA deamidated gliadin peptides for improved sensitivity 2, 3, 4

Biopsy may be avoided in children (but not adults) with all three criteria: tTG-IgA ≥10× upper limit of normal, positive EMA-IgA, and positive HLA-DQ2/DQ8 2, 3

Critical Pitfalls to Avoid

Starting a gluten-free diet before completing diagnostic testing is the most common error and leads to false-negative serologic and histologic results 2, 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 repeat testing 2, 3
• Some patients may require several years of gluten challenge for histologic relapse to occur 2

Relying solely on serology without biopsy confirmation in adults leads to misdiagnosis 2, 3

Negative serology after treatment does not guarantee intestinal mucosal healing—approximately 50% of patients with persistent villous atrophy on gluten-free diet have normal tTG-IgA levels 6, 7

• Follow-up serology should be performed at 6 and 12 months after diagnosis, then yearly 2, 3
• Patients with persistent or relapsing symptoms require repeat endoscopic biopsies to determine healing, even with negative tTG-IgA 2

Diagnostic Algorithm for Negative Serology with High Clinical Suspicion

When serology is negative but clinical suspicion remains high:

1. Confirm patient is consuming adequate gluten (at least 10g daily for 6-8 weeks) 2
2. Verify total IgA level is normal 2
3. Perform HLA-DQ2/DQ8 testing—if positive, proceed to biopsy 2
4. If HLA is negative, celiac disease is essentially ruled out 2, 3