Is a low Immunoglobulin A (IgA) level in celiac disease testing concerning for other immunology issues, such as selective IgA deficiency or common variable immunodeficiency?

Low IgA in Celiac Testing: Immunologic Implications

Yes, low IgA levels during celiac disease testing are highly concerning for selective IgA deficiency, which occurs 10-15 times more frequently in celiac patients than in the general population and warrants immediate IgG-based celiac testing plus evaluation for other immunologic conditions. 1, 2

Prevalence and Clinical Significance

• Selective IgA deficiency occurs in 1.7-2.3% of celiac disease patients, compared to approximately 0.1-0.3% in the general population 3, 2, 4
• Among patients screened for celiac disease, IgA deficiency is found in approximately 1 in 131 patients tested 5
• The critical issue is that low IgA renders standard IgA-based celiac serology (IgA-tTG, IgA-EMA) falsely negative, potentially missing celiac disease diagnosis in these patients 1, 2, 5

Immediate Diagnostic Actions Required

When total IgA is low or absent during celiac testing, you must immediately order IgG-based celiac serology 1, 2:

• IgG deamidated gliadin peptide (DGP-IgG) is the preferred test, with superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) in IgA-deficient patients 1, 2
• IgG tissue transglutaminase (tTG-IgG) can be used but has lower sensitivity (40.6-84.6%) and specificity (78.0-89.0%) 1, 2
• Do not rely on tTG-IgG alone to exclude celiac disease due to its poor diagnostic performance 2

Confirming Selective IgA Deficiency

Verify true IgA deficiency by checking IgG and IgM levels 1:

• Selective IgA deficiency is defined as IgA below age-specific reference ranges (typically <7 mg/dL) with normal IgG and IgM levels 1, 6
• If IgG or IgM are also low, this suggests common variable immunodeficiency (CVID) rather than selective IgA deficiency 3, 4
• CVID requires referral to immunology for comprehensive evaluation and management 6

Associated Immunologic and Clinical Concerns

Patients with selective IgA deficiency have increased risk of 3, 4:

• Recurrent sinopulmonary infections (upper and lower respiratory tract infections)
• Autoimmune diseases including autoimmune thyroid disease, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus 3, 4
• Allergic disorders and anaphylactic reactions to blood products containing IgA 4
• Gastrointestinal infections including giardiasis 3

Diagnostic Algorithm for Celiac Disease with Low IgA

Follow this stepwise approach 1, 2:

1. Confirm IgA deficiency: Measure IgG and IgM to distinguish selective IgA deficiency from CVID 1
2. Order IgG DGP-IgG immediately (preferred) or IgG-tTG 1, 2
3. If IgG serology is positive: Proceed directly to upper endoscopy with duodenal biopsy 1, 2
4. Obtain at least 6 biopsy specimens: 1-2 from duodenal bulb and ≥4 from second part of duodenum or beyond 1, 2
5. Ensure adequate gluten intake (≥10g daily) at time of biopsy to avoid false-negative histology 1, 2

Common Pitfalls in Clinical Practice

A major study found that 46% of IgA-deficient patients with negative IgA-EMA received inadequate evaluation, resulting in missed celiac disease diagnoses 5:

• Administrative errors, inappropriate management, or patient/physician refusal led to failure to pursue IgG-based testing 5
• Among IgA-deficient patients properly evaluated with biopsy, 18% had celiac disease 5
• 76% of IgA-deficient patients who underwent endoscopy had gastrointestinal pathology, emphasizing the importance of complete evaluation 5

Monitoring After Diagnosis

Use IgG-based antibody tests for ongoing monitoring 1, 2:

• Follow-up testing at 6 months, 12 months, and annually thereafter using the same IgG-based tests (DGP-IgG or tTG-IgG) 1, 2
• Do not switch back to IgA-based monitoring in IgA-deficient patients 1, 2

When to Refer to Immunology

Refer to immunology when 6, 4:

• IgG or IgM levels are also low (suggesting CVID rather than selective IgA deficiency) 6
• Recurrent infections are present 6, 4
• Multiple autoimmune conditions coexist 4
• Patient requires blood product transfusions (risk of anaphylaxis to IgA in donor blood) 4

Additional Genetic Testing Consideration

If clinical suspicion for celiac disease remains high despite negative IgG serology, consider HLA-DQ2/DQ8 genetic testing 2:

• Absence of both alleles has >99% negative predictive value and effectively rules out celiac disease 2
• This can help avoid unnecessary biopsies in low-probability cases 2