Can you have celiac disease with normal tissue transglutaminase (tTG) Immunoglobulin A (IgA) levels?

Can Celiac Disease Occur with Normal tTG IgA Levels?

Yes, celiac disease can occur with normal tissue transglutaminase (tTG) IgA levels, as false negatives can occur in approximately 3-19% of cases depending on the testing method used and patient factors.

Understanding Celiac Disease Testing Accuracy

The tTG-IgA test is the primary screening test for celiac disease, but it is not perfect:

• According to the American Gastroenterological Association (AGA), IgA-tTG has a sensitivity typically >90% and specificity slightly higher when using thresholds in the 7-15 AU/mL range 1
• A systematic review found that tTG-IgA sensitivity ranges from 64.3-100% in adults and 28.6-100% in children, depending on the study population and threshold used 1
• The European Society for Pediatric Gastroenterology reports tTG-IgA sensitivity of 97.7% in children, meaning about 2.3% of celiac cases may be missed 2

Reasons for False Negative tTG IgA Results

Several factors can lead to normal tTG IgA levels in patients with celiac disease:

1. IgA Deficiency:

   • IgA deficiency is the most common cause of false-negative tTG-IgA results 1, 2
   • Approximately 2-3% of celiac patients have IgA deficiency
   • The AGA recommends a second test to detect celiac disease in the setting of IgA deficiency 1

2. Early Disease Stage:

   • Patients with early or mild intestinal damage may have antibody levels below the detection threshold

3. Testing Method Variability:

   • Different assays have varying sensitivities and specificities 3
   • Fluorochrome-enzyme immunoassays (FEIA) and chemiluminescence immunoassays (CLIA) can yield different results 3

4. Already on Gluten-Free Diet:

   • Patients who have reduced or eliminated gluten prior to testing may have normal antibody levels 2

Recommended Diagnostic Approach

When celiac disease is suspected despite normal tTG IgA:

1. Check Total IgA Levels:

   • Measure total serum IgA to rule out IgA deficiency 1, 2
   • If IgA deficiency is present, proceed with IgG-based testing

2. Alternative Testing for IgA-Deficient Patients:

   • IgG-tTG or IgG deaminated gliadin peptides (DGP) testing 1, 2, 4
   • IgG-tTG has shown 100% discrimination between IgG-EMA positive and negative subjects with IgA deficiency 4
   • Combined IgA/IgG anti-TG2 testing has demonstrated 96% sensitivity and 99.5% specificity 5

3. HLA Testing:

   • HLA-DQ2/DQ8 testing has >99% negative predictive value 2
   • Useful when serology is negative but clinical suspicion remains high
   • A negative HLA result can effectively rule out celiac disease 2

4. Duodenal Biopsy:

   • Gold standard for diagnosis
   • Multiple biopsies (at least 6 specimens) are essential 2
   • 1-2 from duodenal bulb and at least 4 from distal duodenum

Important Clinical Considerations

• In a 2001 study, 4 out of 114 untreated celiac patients (3.5%) with normal total IgA were negative for all serological tests, including tTG-IgA 6
• Starting a gluten-free diet before testing reduces the sensitivity of both serology and biopsy 2
• For patients already on a gluten-free diet without prior diagnosis, resume normal diet with three slices of wheat bread daily for 1-3 months, then repeat serologic testing 2

Conclusion

While tTG-IgA is the recommended first-line test for celiac disease, normal levels do not definitively rule out the condition. When clinical suspicion is high despite normal tTG-IgA, further investigation with total IgA measurement, alternative antibody testing, HLA typing, and/or intestinal biopsy is warranted to avoid missing this important diagnosis.