Which serologic and immunologic tests should be ordered when total immunoglobulin A (IgA) is low but tissue transglutaminase IgA (tTG‑IgA) and tissue transglutaminase IgG (tTG‑IgG) are normal?

Laboratory Testing for Low Total IgA with Normal Celiac Serology

Order IgG deamidated gliadin peptide (DGP-IgG) immediately, as this is the preferred test for evaluating celiac disease in patients with low IgA levels, demonstrating superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to tTG-IgG. 1, 2

Understanding the Clinical Context

Your patient has low total IgA with normal tTG-IgA and normal tTG-IgG results. This scenario requires careful interpretation because:

• Selective IgA deficiency occurs 10-15 times more frequently in celiac disease patients (affecting 1.7-2.6% of celiac patients) compared to the general population (0.1-0.3%), making false-negative IgA-based serology a significant concern. 3, 1

• The normal tTG-IgG result is not reassuring in this context, as tTG-IgG has poor diagnostic accuracy with sensitivity of only 40.6-84.6% and specificity of 78.0-89.0%, and should not be used to exclude celiac disease. 1, 2, 4

• The normal tTG-IgA result may be falsely negative due to the low total IgA level, rendering standard IgA-based celiac testing unreliable. 1, 2

Recommended Testing Algorithm

Step 1: Confirm True IgA Deficiency

• Measure quantitative IgG and IgM levels to verify selective IgA deficiency versus common variable immunodeficiency (CVID). 1
• Selective IgA deficiency is defined as IgA below age-specific reference ranges with normal IgG and IgM levels. 1
• If IgG or IgM are also low, this suggests CVID rather than isolated IgA deficiency, requiring different management. 1

Step 2: Order IgG-Based Celiac Serology

• IgG deamidated gliadin peptide (DGP-IgG) is the test of choice, with 93.6% sensitivity and 99.4% specificity in IgA-deficient patients. 1, 2, 5
• This test significantly outperforms tTG-IgG and should replace it as the primary screening tool in this population. 1, 2
• Do not rely on the previously obtained tTG-IgG result to exclude celiac disease, as its poor sensitivity makes it inadequate for ruling out disease. 1, 2

Step 3: Verify Adequate Gluten Intake

• Confirm the patient has consumed at least 10g of gluten daily for 6-8 weeks prior to any serologic testing to avoid false-negative results. 2
• If the patient has reduced gluten intake, testing must be deferred until adequate gluten challenge is completed. 2

If DGP-IgG is Positive

Proceed directly to upper endoscopy with duodenal biopsy to confirm the diagnosis:

• 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, 2
• Request evaluation by an experienced gastrointestinal pathologist to assess for villous atrophy and confirm proper tissue orientation. 1, 2

If DGP-IgG is Negative but Clinical Suspicion Remains High

Consider the following additional steps:

• HLA-DQ2/DQ8 genetic testing can be valuable, as absence of both alleles has >99% negative predictive value and effectively rules out celiac disease. 1, 2
• If genetic testing shows DQ2 or DQ8 positivity and symptoms are highly suggestive, proceed to endoscopy with biopsy despite negative serology, as seronegative celiac disease exists. 1, 2

Common Pitfalls to Avoid

• Never rely solely on tTG-IgG in patients with low IgA—its poor sensitivity (40.6-84.6%) means it will miss a substantial proportion of celiac disease cases. 1, 2, 4
• Do not start a gluten-free diet before completing the diagnostic workup, as this leads to false-negative serology and inconclusive biopsies. 1, 2
• Avoid ordering IgG endomysial antibodies (EMA) as a first-line test—while highly specific, DGP-IgG is preferred due to its superior sensitivity and ease of standardization. 1

Monitoring After Diagnosis

If celiac disease is confirmed in an IgA-deficient patient:

• Use IgG-based antibody tests (DGP-IgG or tTG-IgG) for ongoing monitoring, not IgA-based tests. 1
• Follow-up testing should occur at 6 months, 12 months, and annually thereafter using the same IgG-based test. 1
• Never switch back to IgA-based monitoring in IgA-deficient patients. 1

Additional Screening Considerations

• Screen for other autoimmune conditions commonly associated with IgA deficiency and celiac disease, including type 1 diabetes and autoimmune thyroid disease. 1, 2
• Consider evaluation for other IgA-related disorders (IgA nephropathy, IgA vasculitis) based on clinical context if symptoms suggest these conditions. 2