Can a person still develop celiac disease (CD) if they have a negative genetic test result for human leukocyte antigen (HLA) genotyping?

Negative HLA Genotyping Rules Out Celiac Disease

A negative HLA-DQ2 and HLA-DQ8 genetic test definitively excludes the possibility of developing celiac disease. 1, 2

Understanding HLA Genetics in Celiac Disease

HLA genotyping plays a crucial role in celiac disease diagnosis due to its exceptionally high negative predictive value:

• Nearly all celiac disease patients (>95%) carry either HLA-DQ2 or HLA-DQ8 genetic markers 1, 3
• The absence of both HLA-DQ2 and HLA-DQ8 effectively rules out celiac disease 1, 2, 4
• HLA testing is most valuable when results are negative, as this excludes the possibility of celiac disease 1

Important Considerations for HLA Testing Interpretation

When interpreting HLA test results, several factors must be considered:

• Complete allele assessment: Ensure all relevant alleles are evaluated, including:

  • HLA-DQ2.5 (DQA10501, DQB10201)
  • HLA-DQ8 (DQA103, DQB10302)
  • HLA-DQ2.2 (DQA10201, DQB10202)
  • HLA-DQ7.5 (DQA105, DQB10301) 1

• Laboratory reporting variations: Commercial labs may not report all celiac-associated alleles, so clinicians should review the specific alleles tested 1

• Half heterodimers: Check for the presence of half heterodimers compatible with celiac disease before confirming a negative result 1

Clinical Applications of Negative HLA Testing

Negative HLA testing is particularly valuable in several clinical scenarios:

1. Seronegative enteropathy evaluation: Rules out celiac disease in patients with villous atrophy but negative serology 1, 2

2. Gluten-free diet initiation without prior diagnosis: Prevents unnecessary dietary restrictions in patients who started a gluten-free diet without proper diagnostic confirmation 1

3. Avoiding gluten challenge: Prevents unnecessary gluten challenge in patients reporting severe symptoms with gluten exposure 1

4. Historical diagnosis confirmation: Validates or refutes historical diagnoses made before modern serological testing was available 1, 2

Limitations of HLA Testing

While negative HLA testing excludes celiac disease, positive results have limited diagnostic value:

• Approximately 30% of the general population carries HLA-DQ2 or HLA-DQ8 1
• Only 2-3% of genetically at-risk individuals will develop celiac disease during their lifetime 1
• Positive HLA results indicate risk but cannot independently diagnose celiac disease 1, 2

Alternative Diagnoses for Seronegative Enteropathy

When HLA testing is negative in patients with enteropathy, consider these alternative diagnoses:

• Infectious causes: Giardiasis, tropical sprue, Whipple's disease, SIBO, tuberculosis, HIV enteropathy 1, 5
• Immune-mediated conditions: Common variable immune deficiency, autoimmune enteropathy, intestinal lymphoma 1
• Medication-induced enteropathy: Olmesartan, azathioprine, methotrexate, mycophenolate mofetil 1
• Inflammatory conditions: Crohn's disease, collagenous sprue, eosinophilic enteritis 1

Conclusion

HLA genotyping provides definitive exclusion of celiac disease when negative. This makes it a valuable tool in clinical practice, particularly in cases with diagnostic uncertainty. When HLA testing is negative, clinicians should pursue alternative diagnoses for enteropathy symptoms rather than continuing to pursue celiac disease as a diagnosis.