What is the diagnostic approach for celiac disease?

Diagnosis of Celiac Disease

The diagnosis of celiac disease requires serological testing with IgA tissue transglutaminase antibody (tTG-IgA) followed by duodenal biopsy showing characteristic histological changes in patients on a gluten-containing diet. 1

Diagnostic Algorithm

Step 1: Initial Serological Testing

• Primary test: IgA tissue transglutaminase antibody (tTG-IgA)
  • Sensitivity: 90-96% in adults, 97.7% in children
  • Specificity: >95% in adults 1
• Simultaneously measure: Total serum IgA levels to rule out IgA deficiency (occurs in 1-3% of celiac patients) 1

Step 2: Follow-up Based on Initial Results

If tTG-IgA is positive:

• If weakly positive: Order IgA endomysial antibody (EMA-IgA) as confirmatory test
  • Sensitivity: 88% in adults
  • Specificity: 99.6% in adults 1
• Proceed to duodenal biopsy for definitive diagnosis 2

If tTG-IgA is negative but celiac disease still suspected:

• Check total IgA level
• If IgA deficient: Order IgG-based tests (IgG-tTG, IgG-EMA, or IgG-DGP) 2, 1
• Consider HLA-DQ2/DQ8 testing - absence of these virtually excludes celiac disease 2, 1

Step 3: Duodenal Biopsy

• Gold standard for diagnosis in adults 2
• Obtain multiple biopsy specimens (ideally 6) from the second part of duodenum or beyond 2, 1
• Characteristic histological findings:
  • Villous atrophy (partial to total)
  • Crypt hyperplasia/lengthening
  • Increased intraepithelial lymphocytes (≥25 IELs per 100 enterocytes)
  • Increased lamina propria lymphocytes 2

Critical Considerations

Patient Preparation

• Maintain regular gluten consumption before testing:
  • At least 1-3 slices of gluten-containing bread daily
  • For at least 6 weeks prior to testing 1
• Warning: Premature gluten restriction can reduce lesion severity and lead to false negatives 2, 1

Special Diagnostic Scenarios

1. High tTG-IgA levels (≥10x upper limit of normal) AND positive EMA-IgA:

   • In children, may diagnose without biopsy 3
   • Adults still require biopsy confirmation 2

2. tTG-IgA positive but EMA-IgA negative:

   • Exercise caution - high variability among anti-tTG methods
   • Lower probability of true celiac disease 4
   • Consider testing with multiple anti-tTG assays

3. Seronegative celiac disease:

   • If strong clinical suspicion despite negative serology:
     • Test for HLA-DQ2/DQ8
     • If positive, proceed to biopsy 1

Populations to Consider Testing

• Unexplained gastrointestinal symptoms
• Unexplained iron deficiency anemia
• Premature osteoporosis
• Unexplained elevated liver enzymes
• First-degree relatives of celiac patients
• Associated conditions: Type 1 diabetes, autoimmune thyroid disease, Down syndrome 1

Pitfalls to Avoid

1. Relying on antigliadin antibodies (AGA) as primary screening - inferior accuracy compared to tTG-IgA and EMA-IgA 2, 5

2. Using at-home celiac tests - lower accuracy and no professional oversight 1

3. Inadequate biopsy sampling - celiac disease can be patchy; multiple samples are essential 2

4. Biopsy while on gluten-free diet - can lead to false negatives 2, 1

5. Misinterpreting increased intraepithelial lymphocytes without architectural changes - may represent latent celiac disease but not diagnostic 2

By following this structured approach to diagnosis, clinicians can accurately identify celiac disease, allowing for prompt initiation of treatment with a gluten-free diet to prevent complications such as osteoporosis, infertility, and small bowel cancer 1, 6.