Diagnostic Approach for Low IgA with Normal tTG IgG
Immediate Next Step
Order IgG-based celiac serology immediately, specifically IgG deamidated gliadin peptide (DGP-IgG), as low IgA levels render standard IgA-based celiac testing unreliable and may mask celiac disease. 1
Confirm IgA Deficiency
- Verify the total IgA level is truly deficient (typically <7 mg/dL or below age-specific reference ranges) to confirm that IgA-based testing is invalid 1, 2
- IgA deficiency occurs 10-15 times more frequently in celiac disease patients compared to healthy controls, affecting 1.7% of celiac patients 3, 4, 5
- The normal tTG IgG result is not reassuring in this context, as tTG IgG has poor diagnostic accuracy (sensitivity only 40.6-84.6%, specificity 78.0-89.0%) and should not be used to exclude celiac disease 1
Preferred IgG-Based Testing
- IgG deamidated gliadin peptide (DGP-IgG) is the preferred test in IgA-deficient patients, with superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to tTG IgG 1, 6
- If DGP-IgG is positive, proceed directly to upper endoscopy with duodenal biopsy to confirm diagnosis 1
- Ensure the patient is consuming adequate gluten (at least 10g daily) at the time of testing and biopsy to avoid false-negative results 1, 7
Biopsy Protocol if IgG Testing is Positive
- Obtain at least 6 biopsy specimens: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond 1, 7
- Request evaluation by an experienced gastrointestinal pathologist to confirm proper tissue orientation and assess for villous atrophy 3, 7
- If IgG-based serology is positive and villous atrophy is present, diagnose as selective IgA deficiency associated with celiac disease, not seronegative celiac disease 3
Additional Considerations
- Consider HLA-DQ2/DQ8 genetic testing if clinical suspicion remains high despite negative IgG serology, as absence of both alleles has >99% negative predictive value and effectively rules out celiac disease 3, 7
- If IgG and IgM levels are also low (not just IgA), refer to immunology for evaluation of common variable immunodeficiency, which can also cause villous atrophy 3, 5
- Screen for other autoimmune conditions commonly associated with IgA deficiency and celiac disease, including type 1 diabetes and autoimmune thyroid disease 6, 7
Monitoring After Diagnosis
- Use the same IgG-based antibody tests (DGP-IgG or tTG-IgG) for monitoring dietary compliance and disease activity at 6 months, 12 months, and annually thereafter 1
- Never rely on IgA-based testing for monitoring in patients with confirmed IgA deficiency 1
Critical Pitfall to Avoid
Do not exclude celiac disease based on normal tTG IgG alone in an IgA-deficient patient—this is a common diagnostic error that leads to missed celiac disease diagnoses. The tTG IgG has inadequate sensitivity and specificity for this purpose, and DGP-IgG must be ordered instead 1, 6