Celiac Disease Diagnosis with Negative IgG and tTG
A patient with low IgA levels and negative IgG and tTG tests cannot be definitively ruled out for celiac disease without first measuring total IgA levels to exclude IgA deficiency, which occurs in 1-3% of celiac disease patients and causes falsely negative IgA-based tests. 1, 2
Critical First Step: Assess for IgA Deficiency
The most important consideration is whether "low IgA" means IgA deficiency (typically <7 mg/dL or <0.07 g/L):
- If IgA deficiency is confirmed, the negative tTG IgA result is unreliable and meaningless, as IgA-based tests will be falsely negative regardless of whether celiac disease is present 1, 3, 4
- IgA deficiency occurs in 1:131 patients tested for celiac disease, and among properly evaluated IgA-deficient patients, 1 in 6 has celiac disease 3
- All 15 IgA-deficient patients with confirmed celiac disease in one study were positive for IgG endomysial antibodies, demonstrating the necessity of IgG-based testing in this population 4
Appropriate Testing Algorithm for IgA-Deficient Patients
If IgA deficiency is present, the diagnostic approach must shift entirely to IgG-based testing:
- IgG deamidated gliadin peptide (DGP-IgG) is the preferred test, with superior diagnostic accuracy of 93.6% sensitivity and 99.4% specificity in adults 1
- IgG tTG has limited utility with only 40.6-84.6% sensitivity and 78.0-89.0% specificity, making it less reliable than DGP-IgG 1
- IgG endomysial antibody testing is highly effective in IgA-deficient patients, with all IgA-deficient celiac patients testing positive in research studies 4
If Total IgA is Normal (Not Deficient)
When total IgA levels are normal, negative tTG IgA effectively excludes celiac disease in most cases:
- Negative tTG IgA has a negative predictive value approaching 100% when the patient has consumed adequate gluten 2
- In adults, tTG IgA demonstrates 90.7% sensitivity and 87.4% specificity at 15 U/mL threshold 5, 2
- Approximately 2-10% of patients with actual celiac disease could have false-negative results, primarily those who have reduced gluten intake or have very early/mild disease 2
Essential Pre-Test Requirements
Before accepting negative serology as definitive, verify:
- The patient consumed at least 10g of gluten daily for 6-8 weeks prior to testing to avoid false-negative results 1, 6, 2
- Reduction or avoidance of gluten significantly reduces sensitivity of both serology and biopsy 6
When to Pursue Further Testing Despite Negative Serology
Proceed to upper endoscopy with at least 6 duodenal biopsies if: 1, 2
- Clinical suspicion remains very high (chronic diarrhea, weight loss, malabsorption, family history) 2
- Patient is in a high-risk population: first-degree relatives of celiac patients, type 1 diabetes, autoimmune thyroid disease 1, 2
- Seronegative celiac disease is recognized as a subset of patients with characteristic intestinal damage but negative antibody testing 1
HLA Genetic Testing for Definitive Exclusion
- HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 1, 2
- HLA testing should not be used as a primary diagnostic tool, only to rule out disease when serology is negative but suspicion remains 1
Common Diagnostic Pitfall
The most critical error is inadequate evaluation of IgA deficiency during celiac testing, which occurred in 46% of IgA-deficient patients in one study, resulting in underdiagnosis of both IgA deficiency and celiac disease 3. Among 35 IgA-deficient patients tested for celiac disease, only 54% were diagnosed appropriately with either biopsy or IgG-based testing 3.