What is the recommended approach for testing for celiac disease?

Recommended Approach for Testing Celiac Disease

The primary diagnostic approach for celiac disease should begin with IgA tissue transglutaminase antibody (tTG-IgA) testing along with total serum IgA measurement to rule out IgA deficiency. 1

Initial Diagnostic Testing

1. First-line serological testing:

   • tTG-IgA (sensitivity 97.7%, specificity 70.2% in children) 1
   • Total serum IgA levels (to rule out IgA deficiency) 1

2. For patients with IgA deficiency:

   • Use IgG-based tests: IgG-tTG or IgG-DGP (deamidated gliadin peptides) 1
   • Note: Isolated positive tTG-IgG with negative tTG-IgA has low utility (only 3% diagnostic yield) 2

3. Special considerations for children under 2 years:

   • Combine tTG-IgA with IgG and IgA deamidated gliadin peptides for improved sensitivity 1

Confirmatory Testing

1. Upper endoscopy with multiple duodenal biopsies:

   • Gold standard for diagnosis when serology is positive 1
   • Collect at least 6 specimens: 1-2 from duodenal bulb and at least 4 from distal duodenum 1
   • Characteristic histological findings include:
     • Increased intraepithelial lymphocytes (≥25/100 enterocytes)
     • Crypt hyperplasia
     • Villous atrophy 1

2. 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 1
   • Negative HLA-DQ2 and HLA-DQ8 results have >99% negative predictive value 1

Diagnostic Algorithm

1. Step 1: Measure tTG-IgA and total serum IgA

   • If tTG-IgA positive → Proceed to endoscopy with biopsy
   • If tTG-IgA negative but high clinical suspicion → Consider EMA-IgA testing (specificity 93.8%) 1
   • If IgA deficient → Use IgG-based tests

2. Step 2: Confirm with duodenal biopsy

   • Positive histology + positive serology = Celiac disease diagnosis
   • Note: Some research suggests very high tTG-IgA titers (>100 U) may have sufficient diagnostic accuracy to potentially avoid biopsy in select pediatric populations (sensitivity 98%, specificity 97.2%) 3

3. Step 3: For unclear cases, consider genetic testing

   • If HLA-DQ2/DQ8 negative → Celiac disease highly unlikely (<1% chance) 1

Monitoring After Diagnosis

• Serological monitoring with anti-TG2 antibodies at 6,12 months, and annually thereafter 1
• Important caveat: Serological tests have low sensitivity (<50%) for detecting persistent villous atrophy in patients on a gluten-free diet 4, 5
• Normal tTG level does not guarantee intestinal healing - up to 44% of patients with persisting villous atrophy may have normal tTG levels 5

High-Risk Groups for Screening

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

Common Pitfalls to Avoid

1. Relying solely on serological tests for monitoring:

   • Serology has poor sensitivity (<50%) for detecting ongoing villous atrophy in patients on gluten-free diets 4
   • Consider follow-up biopsy for patients with persistent symptoms despite negative serology

2. Missing IgA deficiency:

   • Always check total IgA when testing for celiac disease
   • IgA deficiency will lead to false-negative tTG-IgA results

3. Using gliadin antibodies as primary screening:

   • Traditional gliadin antibodies (especially IgG-AGA) have poor sensitivity and specificity 6
   • No additional diagnostic benefit when used alongside tTG-IgA 5

4. Overlooking seronegative celiac disease:

   • Characterized by villous atrophy with negative serology
   • Requires exclusion of other causes of atrophy and evaluation of response to gluten-free diet 1