What is the significance of low Immunoglobulin A (IgA), in a normal celiac disease panel?

From the Guidelines

Low Immunoglobulin A (IgA) levels in a normal celiac disease panel are significant because they may indicate IgA deficiency, which can lead to false negative results in IgA-based serological tests for celiac disease.

Key Points to Consider

• IgA deficiency is present in 1 in 500 in the general population, but in 1-3% of patients with celiac disease 1
• IgA deficiency can lead to false negative results in IgA-based serological tests, such as IgA anti-tissue transglutaminase (tTG) and IgA endomysial antibodies (EMA) 1
• In cases of suspected IgA deficiency, measuring total IgA levels, IgG deamidated gliadin antibody tests, and TG2-IgG testing is recommended 1
• The prevalence of IgA deficiency in celiac disease is sufficiently low that routine measurement of serum IgA levels is not warranted as a first step towards diagnosis, unless IgA deficiency is strongly suspected 1

Diagnostic Approach

• If celiac disease is strongly suspected despite negative serologic test results, one can test for the presence of the disease-associated HLA alleles and, if present, proceed to small intestinal mucosal biopsy 1
• Alternatively, it is reasonable to proceed directly to upper intestinal endoscopy and small bowel biopsy if the signs and symptoms that suggested celiac disease would otherwise warrant those procedures 1

Important Considerations

• IgG-based tests, such as IgG EMA and IgG tTGA, have excellent sensitivity and specificity in cases of selective IgA deficiency, but are less sensitive and specific than IgA-based tests in those with normal levels of IgA 1
• Measurement of the serum IgA level is an appropriate next step in individuals with a negative IgA EMA or IgA tTGA in whom celiac disease is still suspected 1

From the Research

Significance of Low Immunoglobulin A (IgA) in Celiac Disease Panel

• Low IgA levels can lead to false-negative results in serological tests for celiac disease, such as IgA-endomysial antibody (EMA) and IgA-tissue transglutaminase (TG) tests 2, 3, 4
• IgA deficiency is more common in patients with celiac disease, with a prevalence of 2-3% in celiac patients 3, 5
• Patients with selective IgA deficiency have a 10- to 20-fold increased risk of celiac disease 6
• In patients with IgA deficiency, alternative tests such as IgG-based assays (e.g., IgG-EMA, IgG-TG) may be used to diagnose celiac disease, but their reliability is limited 2, 6, 4
• Intestinal biopsy is often necessary to confirm the diagnosis of celiac disease in patients with IgA deficiency 2, 3, 4

Clinical Implications

• IgA deficiency can lead to underdiagnosis of celiac disease, as serological tests may be negative or inconclusive 2, 3, 4
• Patients with IgA deficiency and suspected celiac disease should undergo intestinal biopsy to confirm the diagnosis 2, 3, 4
• Clinicians should be aware of the potential for IgA deficiency in patients with celiac disease and use alternative diagnostic approaches when necessary 2, 3, 6, 4

Association with Autoimmune Diseases

• IgA deficiency is associated with an increased risk of autoimmune diseases, including celiac disease 5
• Patients with IgA deficiency and celiac disease may have a lower incidence of autoimmune diseases compared to those without IgA deficiency 3