What is the diagnosis and management for a patient of European descent with a family history of autoimmune diseases, presenting with a negative Immunoglobulin A (IgA) result and a positive tissue transglutaminase IgA result?

Diagnosis: IgA Deficiency with Positive Tissue Transglutaminase IgA Result

This patient has selective IgA deficiency, which makes the positive tissue transglutaminase IgA result invalid and unreliable for diagnosing celiac disease. 1

Understanding the Test Result Discordance

The "negative IgA" refers to low or absent total IgA levels, which occurs in 1-3% of celiac disease patients—a rate 10-15 times higher than in the general population. 1, 2 This creates a critical diagnostic pitfall:

• When total IgA is deficient, all IgA-based antibody tests (including tissue transglutaminase IgA) become unreliable and can produce falsely low results in true celiac disease or paradoxically elevated results that are difficult to interpret 1
• IgA-based serologic tests should never be used as the sole diagnostic tool in IgA-deficient patients 1

Immediate Next Steps: Correct Serologic Testing

Order IgG-based celiac antibody testing immediately, as these are the appropriate tests for IgA-deficient patients: 1

1. IgG deamidated gliadin peptide (DGP-IgG) - This is the preferred IgG test with superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) 3
2. IgG tissue transglutaminase (tTG-IgG) - Less reliable than DGP-IgG, with sensitivity ranging only 40.6-84.6% and specificity 78.0-89.0% 3
3. IgG endomysial antibody (EMA-IgG) - Highly specific for celiac disease in IgA-deficient patients (100% specificity in one study of 15 IgA-deficient celiac patients) 2

Critical requirement: The patient must be consuming at least 10g of gluten daily (approximately 3 slices of wheat bread) for 6-8 weeks before testing to avoid false-negative results. 1, 4

Diagnostic Algorithm for IgA-Deficient Patients

If IgG-based antibodies are positive:

Proceed directly to upper endoscopy with duodenal biopsy to confirm the diagnosis: 1

• Obtain at least 6 biopsy specimens from the second part of the duodenum or beyond, as mucosal changes can be patchy 1, 3
• Request histologic analysis with Marsh classification, counting of intraepithelial lymphocytes per high-power field, and morphometry 1
• Look for villous atrophy (partial to total) with crypt hyperplasia and increased intraepithelial lymphocytes (≥25 IELs per 100 enterocytes) 3

If IgG-based antibodies are negative but clinical suspicion remains high:

Consider HLA-DQ2/DQ8 genetic testing: 3, 5

• Negative HLA-DQ2 and HLA-DQ8 effectively rules out celiac disease with >99% negative predictive value 3, 5
• If HLA testing is positive, proceed to upper endoscopy with duodenal biopsies despite negative serology, as seronegative celiac disease exists 3, 5

Clinical Context Considerations

Given the family history of autoimmune diseases and European descent, this patient has elevated pre-test probability for celiac disease: 3

• First-degree relatives of celiac patients have 10-20% risk of developing the disease 3
• European ancestry (particularly Northern European) carries higher celiac disease prevalence 1
• Autoimmune disease clustering is common in celiac disease families 1

Assess for clinical manifestations that would increase suspicion: 1, 3

• Gastrointestinal symptoms: chronic diarrhea, weight loss, abdominal pain, bloating, steatorrhea 1
• Extraintestinal manifestations: unexplained iron deficiency anemia, premature osteoporosis, elevated liver enzymes, dermatitis herpetiformis, neurologic symptoms 1, 3
• Associated autoimmune conditions: type 1 diabetes, autoimmune thyroid disease, Sjögren's syndrome 1, 3

Common Pitfalls to Avoid

Never rely on the positive tissue transglutaminase IgA result in this IgA-deficient patient—it is diagnostically meaningless. 1 The AGA guidelines explicitly state that "IgG isotype testing for TG2 antibody is not specific in the absence of IgA deficiency," emphasizing that IgG tests are specifically designed for IgA-deficient patients. 1

Do not initiate a gluten-free diet before completing the diagnostic workup (IgG serology and biopsy if indicated), as this will cause false-negative results and make diagnosis impossible. 1, 3

Do not diagnose celiac disease based on symptoms alone or symptom response to gluten elimination—this cannot differentiate celiac disease from non-celiac gluten sensitivity. 1, 3

If Celiac Disease is Confirmed

Initiate strict lifelong gluten-free diet immediately after biopsy confirmation: 3

• Refer to a registered dietitian experienced in celiac disease management 3
• Monitor IgG-based antibodies (not IgA-based) at 6 months, 12 months, and annually thereafter 3
• Screen for nutritional deficiencies (iron, vitamin D, calcium, B12, folate) and associated autoimmune conditions 3
• Consider bone density screening if risk factors present 3