How to diagnose celiac disease in a patient with Immunoglobulin A (IgA) deficiency?

Testing for Celiac Disease in IgA Deficiency

In patients with IgA deficiency, immediately order IgG-based serologic tests—specifically IgG deamidated gliadin peptide (DGP-IgG)—as standard IgA-based celiac testing will be falsely negative and miss the diagnosis. 1, 2

Why IgA Deficiency Matters

• IgA deficiency occurs 10-15 times more frequently in celiac disease patients than in healthy controls, affecting approximately 1.7% of celiac patients 3, 4
• Standard IgA-based tests (tissue transglutaminase IgA, endomysial antibody IgA) will be falsely negative in IgA-deficient patients who actually have celiac disease 1, 5
• Celiac disease is found in approximately 1 in 6 IgA-deficient patients who are properly evaluated, making this a critical diagnostic consideration 5

Diagnostic Algorithm for IgA-Deficient Patients

Step 1: Confirm True IgA Deficiency

• Verify total IgA is truly deficient (typically <7 mg/dL or below age-specific reference ranges) 2
• Measure total IgA levels alongside any celiac serology to identify this issue 1, 6

Step 2: Order the Correct IgG-Based Tests

Preferred test:

• IgG deamidated gliadin peptide (DGP-IgG) is the test of choice, with superior diagnostic accuracy of 93.6% sensitivity and 99.4% specificity 2, 3, 7

Alternative (but inferior) test:

• IgG tissue transglutaminase (tTG-IgG) can be used but has significantly lower accuracy, with sensitivity only 40.6-84.6% and specificity 78.0-89.0% 2, 3
• Do not rely on tTG-IgG alone to exclude celiac disease due to its poor performance characteristics 3

Step 3: Additional Serologic Testing

• IgG endomysial antibody (EMG) testing can also be performed, though it detected celiac disease in only 60% of confirmed cases in one study 8
• All 15 IgA-deficient patients with biopsy-proven celiac disease in one cohort were positive for IgG endomysial antibodies 4

Step 4: Proceed to Biopsy Confirmation

When IgG serology is positive:

• Proceed directly to upper endoscopy with duodenal biopsy 2, 3
• 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, 3
• Ensure the patient is consuming adequate gluten (at least 10g daily) at the time of biopsy to avoid false-negative histology 2, 3

When IgG serology is negative but suspicion remains high:

• Consider HLA-DQ2/DQ8 genetic testing, as absence of both alleles has >99% negative predictive value and effectively rules out celiac disease 1, 3
• If clinical suspicion remains very high despite negative IgG serology and negative HLA testing, proceed to biopsy anyway 1

Critical Pitfalls to Avoid

• Never rely on standard IgA-based celiac panels alone—always measure total IgA levels concurrently 1, 6
• Do not use tTG-IgG as the sole test in IgA deficiency due to its poor sensitivity 3
• In one study, 46% of IgA-deficient patients with negative EMA received no further appropriate evaluation, leading to missed diagnoses 5
• Ensure the patient has not started a gluten-free diet before testing, as this causes false-negative results on both serology and biopsy 1

Monitoring After Diagnosis

• Use the same IgG-based antibody tests (DGP-IgG or tTG-IgG) for monitoring dietary compliance and disease activity 2, 3
• Follow-up testing should occur at 6 months, 12 months, and annually thereafter 2, 3
• Request evaluation by an experienced gastrointestinal pathologist for biopsy interpretation 3

Associated Conditions to Screen For

• Screen for other autoimmune conditions commonly associated with IgA deficiency and celiac disease, including type 1 diabetes and autoimmune thyroid disease 3