What is the next step in diagnosis and management if a celiac panel shows low Immunoglobulin A (IgA) levels?

Low IgA on Celiac Panel: Diagnostic Approach

When a celiac panel shows low IgA levels, you must immediately order IgG-based serologic tests—specifically IgG deamidated gliadin peptide (DGP-IgG) or IgG tissue transglutaminase (tTG-IgG)—because IgA deficiency renders standard IgA-based celiac testing falsely negative in patients who may actually have celiac disease. 1, 2

Immediate Next Steps

Confirm IgA Deficiency Status

• Verify the total IgA level is truly deficient (typically <7 mg/dL or below age-specific reference ranges) 1, 2
• Measure IgG and IgM levels to determine if this is selective IgA deficiency (SIgAD) versus combined immunodeficiency 3
• If IgG and IgM are normal, this confirms selective IgA deficiency, which occurs in 1.2% of patients screened for celiac disease 3

Order Appropriate 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 2
• IgG tissue transglutaminase (tTG-IgG) can also be used, though it has lower sensitivity (40.6-84.6%) and specificity (78.0-89.0%) than DGP-IgG 2
• IgG endomysial antibody (EMA-IgG) testing is highly effective, with all IgA-deficient celiac patients testing positive in validation studies 4

Critical Clinical Context

Why This Matters

• IgA deficiency is 10-15 times more common in celiac disease patients than in the general population 4
• Standard IgA-based tests (tTG-IgA, EMA-IgA) will be falsely negative in IgA-deficient patients with celiac disease 1, 5
• Among IgA-deficient patients properly evaluated for celiac disease, approximately 1 in 6 (18%) actually have the condition 5

Common Diagnostic Pitfall

• In one study, 46% of IgA-deficient patients with negative IgA-based serology received no further evaluation to exclude celiac disease, resulting in significant underdiagnosis 5
• This occurs due to inappropriate management, administrative errors, or failure to recognize the implications of IgA deficiency 5

Confirmatory Testing Algorithm

If IgG-Based Serology is Positive

• Proceed directly to upper endoscopy with duodenal biopsy to confirm the diagnosis 1, 2
• 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 2, 6
• Ensure the patient is consuming adequate gluten (at least 10g daily) at the time of biopsy to avoid false-negative histology 2, 6

If IgG-Based Serology is Negative but Clinical Suspicion Remains High

• Consider HLA-DQ2/DQ8 genetic testing, which has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 2, 6
• If HLA-DQ2 or DQ8 is positive and clinical suspicion persists, proceed to duodenal biopsy despite negative serology 2
• Verify the patient has been consuming adequate gluten for 6-8 weeks before testing 2, 6

Additional Considerations

Immunologic Evaluation

• Refer to an immunologist if IgG/IgM levels are also low or if the patient has recurrent infections, as this suggests combined immunodeficiency rather than selective IgA deficiency 3
• Selective IgA deficiency itself may be asymptomatic or associated with recurrent infections, but does not preclude celiac disease diagnosis 3

Monitoring After Diagnosis

• Use the same IgG-based antibody tests (DGP-IgG or tTG-IgG) for monitoring dietary compliance and disease activity 4
• Follow-up testing should occur at 6 months, 12 months, and annually thereafter 2, 6
• IgG antibody levels can reliably monitor patient dietary compliance in IgA-deficient celiac patients 4

Key Takeaway for Clinical Practice

The detection of low IgA on a celiac panel is not a dead end—it is a critical finding that mandates switching to IgG-based testing strategies. Failure to recognize this and order appropriate IgG-based tests results in missed diagnoses in a population with significantly elevated celiac disease prevalence. 1, 5