What does a negative tissue transglutaminase antibody IgA (tTG‑IgA) result indicate regarding celiac disease?

Negative Tissue Transglutaminase Antibody IgA (tTG-IgA) Result

A negative tTG-IgA result effectively rules out celiac disease with a negative predictive value approaching 100%, provided the patient has been consuming adequate gluten and does not have IgA deficiency. 1

What This Means Clinically

• No further celiac-specific workup is needed in most cases when tTG-IgA is negative and total IgA is normal. 1
• The test performs exceptionally well at excluding disease, with 90.7% sensitivity and 87.4% specificity in adults at standard thresholds. 1
• In children, the performance is even better with 97.7% sensitivity and 70.2% specificity. 1

Critical Caveats That Could Invalidate This Result

1. Gluten Intake Must Be Adequate

• The patient must have consumed at least 10g of gluten daily for 6-8 weeks before testing to avoid false-negative results. 1, 2
• If the patient has already reduced or eliminated gluten, the test is unreliable and should be repeated after resuming adequate gluten intake for 1-3 months. 2

2. IgA Deficiency Must Be Ruled Out

• Total IgA levels should always be measured alongside tTG-IgA because selective IgA deficiency occurs in 1-3% of celiac patients and causes falsely negative IgA-based tests. 1, 2
• If IgA deficiency is present (total IgA <0.06 g/L), the negative tTG-IgA is meaningless and IgG-based testing must be performed instead (IgG deamidated gliadin peptide or IgG tTG). 1, 2

When to Pursue Further Testing Despite Negative Serology

High Clinical Suspicion Scenarios

• Proceed to upper endoscopy with at least 6 duodenal biopsies if clinical suspicion remains very high despite negative serology, particularly with: 1, 2
  • Chronic diarrhea with weight loss
  • Malabsorption symptoms
  • Strong family history of celiac disease
  • Associated autoimmune conditions (type 1 diabetes, autoimmune thyroid disease)

HLA Genetic Testing

• HLA-DQ2/DQ8 testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease and can be useful when seronegative celiac is suspected. 1, 2
• This is particularly valuable in patients with persistent symptoms who have negative serology but cannot undergo biopsy. 1

False-Negative Rates in Real-World Practice

• Approximately 2-10% of patients with actual celiac disease could have false-negative results, but this occurs primarily in: 1

  • Patients who have already reduced gluten intake
  • Very early or mild disease
  • IgA-deficient patients (if total IgA not checked)

• In absolute terms, only about 19 out of 10,000 adults with celiac disease would have false-negative tTG-IgA when properly tested. 2

Repeat Testing Considerations

• Repeat celiac screening may be warranted in high-risk populations even with previously negative serology if: 1
  • New gastrointestinal symptoms develop
  • Unexplained iron deficiency anemia appears
  • Growth failure occurs (in children)
  • Patient has type 1 diabetes, first-degree relatives with celiac disease, or autoimmune thyroid disease

Bottom Line Algorithm

1. Confirm adequate gluten intake (≥10g daily for 6-8 weeks before testing) 1, 2
2. Verify total IgA level was measured to exclude IgA deficiency 1, 2
3. If both conditions met and tTG-IgA negative → celiac disease effectively ruled out 1
4. If gluten intake inadequate → repeat after gluten challenge 2
5. If IgA deficient → perform IgG-based testing (IgG DGP preferred) 1, 2
6. If very high clinical suspicion persists → proceed to endoscopy with biopsies 1, 2
7. If symptoms but low suspicion → consider HLA testing to definitively exclude celiac disease 1