What is the best serological test for diagnosing celiac disease and what confirmatory testing is recommended?

Best Serological Test for Celiac Disease and Confirmatory Testing

The IgA tissue transglutaminase antibody (tTG-IgA) is the preferred serological test for diagnosing celiac disease in individuals older than two years, with confirmation requiring upper endoscopy and multiple duodenal biopsies. 1, 2

Diagnostic Approach

Initial Serological Testing

• First-line test: IgA tissue transglutaminase antibody (tTG-IgA)

  • High sensitivity (97.7%) and acceptable specificity (70.2%) 2
  • Must be performed while patient is on a gluten-containing diet 1, 2
  • Most cost-effective single test option 3

• Total IgA measurement:

  • Should be checked concurrently with tTG-IgA to rule out IgA deficiency 1, 2
  • Approximately 2-3% of celiac patients have IgA deficiency, which can lead to false-negative results 2

• For IgA-deficient patients:

  • Use IgG-based testing instead: IgG-tTG or IgG deamidated gliadin peptides (DGP) 2

• Special considerations for children:

  • In children under 2 years: Combine tTG-IgA with IgG and IgA deamidated gliadin peptides for improved sensitivity 1

Confirmatory Testing

• Upper endoscopy with multiple duodenal biopsies is mandatory for diagnosis 1, 2

  • Collect at least 6 specimens: 1-2 from the bulb and at least 4 from the distal duodenum 1
  • Histologic changes associated with celiac disease must be demonstrated for diagnosis

• Genetic testing (HLA-DQ2/DQ8):

  • Not recommended for routine diagnosis 1
  • Useful in specific situations:
    • Seronegative cases with suspected celiac disease
    • Equivocal small-bowel histologic findings
    • High-risk populations (e.g., Down syndrome)
  • Negative predictive value >99% (if both HLA-DQ2 and HLA-DQ8 are negative, celiac disease is highly unlikely) 1, 2

Important Clinical Considerations

Testing Pitfalls

• Avoid gluten-free diet before testing:

  • Serological tests and biopsies must be performed while the patient is consuming gluten 2
  • If already on a gluten-free diet, a gluten challenge (1-3 slices of bread daily for 1-3 months) is required before testing 2

• Beware of false negatives:

  • IgA deficiency causing false-negative tTG-IgA results
  • Inadequate gluten consumption prior to testing
  • Insufficient biopsy sampling (a common cause of missed diagnosis) 2

Differential Diagnosis

• Lymphocytic infiltration without villous atrophy is not specific for celiac disease 1

  • Consider other causes:
    • H. pylori infection
    • Small bowel bacterial overgrowth
    • Systemic autoimmune disorders

• Clinical symptoms alone cannot differentiate celiac disease from other GI disorders 1

  • Symptom improvement on a gluten-free diet has low positive predictive value without supportive evidence

Follow-up Testing

• Serological monitoring:

  • tTG-IgA at 6 months, 12 months, and annually thereafter 2
  • Note: Negative serology does not guarantee intestinal healing 4
  • Persistently positive serology usually indicates ongoing intestinal damage and gluten exposure 2

• Histological assessment:

  • The gold standard for evaluating mucosal healing
  • Serological tests have low sensitivity (<50%) for detecting persistent villous atrophy in patients on a gluten-free diet 4, 5

Special Populations

• High-risk groups requiring screening:

  • First-degree relatives (7.5% risk)
  • Type 1 diabetes
  • Autoimmune thyroid disease
  • Down syndrome, Turner syndrome
  • Unexplained iron deficiency anemia 2

• Patients with high tTG-IgA levels:

  • Very high tTG-IgA levels (>10-12 times upper limit of normal) correlate with higher grades of villous atrophy 6
  • Some research suggests that in symptomatic patients with very high tTG-IgA levels (>70 IU/ml), biopsy might be unnecessary, though this remains controversial 6