In a patient with selective IgA deficiency, how should I interpret a positive tissue transglutaminase IgG, negative tissue transglutaminase IgA, and negative gliadin antibodies, and what are the next steps?

Interpretation of Celiac Panel with Positive TTG IgG, Negative TTG IgA, and Negative Gliadin Antibodies in Selective IgA Deficiency

In a patient with selective IgA deficiency, a positive TTG IgG should prompt immediate ordering of IgG deamidated gliadin peptide (DGP-IgG) testing, as TTG IgG alone has poor diagnostic accuracy and cannot reliably diagnose or exclude celiac disease. 1, 2

Understanding the Test Results

Why TTG IgG Is Unreliable

• TTG IgG has poor diagnostic performance with sensitivity ranging only 40.6-84.6% and specificity 78.0-89.0%, making it inadequate as a standalone test for celiac disease 2, 3
• The positive TTG IgG in your patient cannot be interpreted as diagnostic because this test was never designed to be the primary screening tool 2
• IgA deficiency occurs 10-15 times more frequently in celiac disease patients (affecting 1.7% of celiac patients) compared to healthy controls, which is why your patient's low IgA levels render standard IgA-based testing unreliable 2, 4

The Problem with Negative Gliadin Antibodies

• Traditional gliadin antibodies (IgA or IgG) are outdated markers with inferior diagnostic accuracy compared to modern tests 5
• Negative gliadin antibodies do not exclude celiac disease, particularly in IgA-deficient patients 6

Immediate Next Steps

Order the Correct IgG-Based Test

• IgG deamidated gliadin peptide (DGP-IgG) is the preferred test in IgA-deficient patients, with superior diagnostic accuracy showing 93.6% sensitivity and 99.4% specificity 5, 2
• DGP-IgG significantly outperforms TTG IgG and should replace it as the diagnostic test of choice in this clinical scenario 2
• If DGP-IgG testing is unavailable, IgG endomysial antibody (EMA-IgG) is an alternative, as all IgA-deficient celiac patients tested positive for EMA-IgG in research studies 6, 4

Proceed to Duodenal Biopsy

• If DGP-IgG is positive, proceed directly to upper endoscopy with duodenal biopsy to confirm the diagnosis 2
• Even if DGP-IgG is negative but clinical suspicion remains high (chronic diarrhea, weight loss, malabsorption, iron deficiency anemia), biopsy should still be performed because seronegative celiac disease exists 1, 7
• 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

Critical Pre-Test Considerations

Confirm Adequate Gluten Intake

• Verify the patient consumed at least 10g of gluten daily for 6-8 weeks before the original testing 5, 1
• If the patient has reduced gluten intake, gluten must be reintroduced (equivalent to 3 slices of wheat bread daily) for 1-3 months before repeat testing or biopsy 1, 7
• Inadequate gluten exposure is a common cause of false-negative results in both serology and biopsy 1

Additional Diagnostic Testing

HLA-DQ2/DQ8 Genetic Testing

• Consider HLA-DQ2/DQ8 testing if clinical suspicion remains high despite negative IgG serology 1, 7, 2
• Absence of both HLA-DQ2 and HLA-DQ8 alleles has >99% negative predictive value and effectively rules out celiac disease 1, 7
• All IgA-deficient patients with celiac disease who underwent genetic screening tested positive for celiac-related HLA markers 6

Screen for Associated Conditions

• Screen for other autoimmune conditions commonly associated with IgA deficiency and celiac disease, including type 1 diabetes and autoimmune thyroid disease 1, 2
• Check for iron deficiency anemia with CBC and iron studies, as celiac disease is present in 2-6% of patients with unexplained iron deficiency 1

Diagnostic Algorithm Summary

1. Confirm selective IgA deficiency with quantitative total IgA level 5
2. Order IgG deamidated gliadin peptide (DGP-IgG) immediately—this is the gold standard IgG test 2
3. Verify adequate gluten intake (≥10g daily for 6-8 weeks) 1
4. If DGP-IgG is positive: proceed to upper endoscopy with ≥6 duodenal biopsies 2
5. If DGP-IgG is negative but clinical suspicion high: proceed to biopsy anyway and consider HLA testing 1, 7
6. Request evaluation by an experienced GI pathologist to confirm proper tissue orientation and assess for villous atrophy 2

Common Pitfalls to Avoid

Do Not Rely on TTG IgG Alone

• Never use TTG IgG as the sole basis for diagnosis or exclusion of celiac disease in IgA-deficient patients 2, 3
• A study of 233 patients with isolated positive TTG IgG and negative TTG IgA found only 3% (6/178) had confirmed celiac disease on biopsy 3
• The low positive predictive value of TTG IgG means most positive results are false positives when used in isolation 3

Do Not Start Gluten-Free Diet Before Completing Workup

• Never initiate a gluten-free diet before biopsy confirmation, as this leads to false-negative serology and inconclusive biopsies 1, 7
• Patients who have already reduced gluten must resume adequate intake before diagnostic testing 1

Do Not Ignore Seronegative Celiac Disease

• Approximately 15.5% of patients with negative TTG but positive DGP antibodies had celiac disease on biopsy in one study 8
• Seronegative celiac disease is a recognized entity requiring biopsy for diagnosis when clinical suspicion is high 1, 7

Monitoring After Diagnosis

• If celiac disease is confirmed, use the same IgG-based antibody tests (DGP-IgG or TTG-IgG) for monitoring dietary compliance at 6 months, 12 months, and annually thereafter 2
• IgA-based tests cannot be used for monitoring in IgA-deficient patients 2