What is the next step for a patient with a genetic testing result showing a variant of DQ2 (Deoxyribonucleic acid 2) and HLA-DQ2 (Human Leukocyte Antigen DQ2) positive for celiac disease?

Next Steps After HLA-DQ2 Positive Genetic Testing for Celiac Disease

When genetic testing shows a variant of DQ2 positive for celiac disease, the next recommended step is to perform serological testing with tissue transglutaminase IgA (tTG-IgA) antibodies along with total IgA levels, followed by duodenal biopsies if serology is positive or if clinical suspicion remains high despite negative serology. 1

Diagnostic Algorithm After Positive HLA-DQ2 Testing

1. Serological Testing

   • Primary test: Tissue transglutaminase IgA (tTG-IgA) antibodies
   • Simultaneously check total IgA levels to rule out IgA deficiency
   • If IgA deficient, use IgG-based testing (IgG DGP or IgG tTG)

2. Interpret Genetic Results Appropriately

   • HLA-DQ2 positivity supports the possibility of celiac disease but is not diagnostic
   • Present in approximately 25-30% of the general population 1
   • Different variants carry different risks:
     • DQ2.5 homozygous pattern makes celiac disease more likely
     • DQ2.2 heterozygous pattern makes celiac disease less likely 2
     • DQ2.5/DQ2.2 combination carries a high risk (1:10) 3

3. Endoscopic Evaluation

   • If serology is positive: Upper endoscopy with multiple duodenal biopsies
   • Take at least 6 biopsy specimens:
     • 4-6 from distal duodenum
     • 1-2 from duodenal bulb 1
   • Biopsies should be properly positioned, with Marsh classification and villus-crypt ratio documented 2

4. If Serology is Negative but Clinical Suspicion Remains High

   • Proceed with endoscopy and biopsies despite negative serology
   • Up to 2-3% of celiac patients may have negative serology 1

Important Considerations

• Ensure Adequate Gluten Exposure: Patient should maintain regular gluten consumption for at least 6 weeks prior to testing (1-3 slices of gluten-containing bread daily) 1

• Diagnostic Histological Findings:

  • Villous atrophy
  • Crypt hyperplasia
  • Increased intraepithelial lymphocytes (≥25 IELs/100 enterocytes)
  • Increased lamina propria lymphocytes 1

• Alternative Causes of Villous Atrophy:

  • Medications
  • Infections
  • Autoimmune enteropathy
  • Common variable immunodeficiency
  • Crohn's disease
  • Collagenous sprue 1

Common Pitfalls to Avoid

• Misinterpreting HLA Results: HLA-DQ2 positivity alone is insufficient for diagnosis, as it's present in approximately 30% of the general population 1

• Premature Exclusion Based on Negative Serology: Some celiac patients may have negative serology but still have the disease 1

• Inadequate Biopsy Sampling: Multiple biopsies from both duodenal bulb and distal duodenum are essential to avoid missed diagnoses 1

• Not Considering Family History: First-degree relatives of celiac patients have a 7.5% risk of celiac disease 2, and nearly 90% of relatives carry HLA-DQ2 and/or DQ8 4

By following this systematic approach after identifying a positive HLA-DQ2 variant, clinicians can effectively diagnose or exclude celiac disease while minimizing the risk of missed diagnoses or unnecessary interventions.