What is the definitive diagnosis for celiac disease?

Definitive Diagnosis of Celiac Disease

The definitive diagnosis of celiac disease requires upper endoscopy with multiple duodenal biopsies (ideally 6 specimens: 1-2 from the duodenal bulb and at least 4 from the distal duodenum) demonstrating characteristic histologic changes—villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes—combined with positive serology (IgA tissue transglutaminase antibody) while the patient is consuming a gluten-containing diet. 1, 2

Diagnostic Algorithm

Step 1: Initial Serologic Testing (Patient Must Be on Gluten-Containing Diet)

• IgA tissue transglutaminase antibody (tTG-IgA) is the primary screening test with sensitivity of 90-96% and specificity >95% 2, 3
• The patient must be consuming at least 10g of gluten daily for 6-8 weeks before testing 2
• Measure total IgA level simultaneously to rule out IgA deficiency, which occurs with sufficient frequency in celiac disease to warrant checking 1, 2

Step 2: Confirmatory Serologic Testing (If Initial Test Positive)

• If tTG-IgA is >10× upper limit of normal, perform IgA endomysial antibody (EMA-IgA) as confirmatory testing with specificity of 99.6% 1, 2
• The combination of tTG-IgA >10× upper limit of normal plus positive EMA-IgA approaches 100% positive predictive value 2

Step 3: Intestinal Biopsy (Gold Standard—Required in Adults)

• Upper endoscopy with small bowel biopsy is mandatory for diagnosis in adults and cannot be replaced by serology alone 1
• Obtain multiple specimens: 1-2 biopsies from the duodenal bulb and at least 4 from the second part of the duodenum or beyond to account for patchy distribution 1, 2
• Characteristic histologic findings include:
  • Villous atrophy (partial to total) 1
  • Crypt hyperplasia with increased lamina propria 1
  • Increased intraepithelial lymphocytes (≥25 per 100 enterocytes) 1
• Villous atrophy is required to state a definite diagnosis 1

Step 4: Special Considerations for IgA Deficiency

• If IgA is low or absent, use IgG-based tests: IgG tissue transglutaminase (tTG-IgG) or IgG deamidated gliadin peptide (DGP-IgG) 1, 2
• IgG-based tests are markedly less sensitive and specific in patients with normal IgA levels and should not be used in that setting 2

When to Use HLA Testing

HLA-DQ2 and HLA-DQ8 testing should be reserved for specific clinical scenarios, not routine diagnosis 1, 2:

• When celiac disease is strongly suspected despite negative serology 2, 3
• In patients with equivocal small-bowel histologic findings 1, 2
• In patients already on a gluten-free diet who were never properly tested before diet initiation 1, 2
• When the original diagnosis is in question 1
• Negative HLA-DQ2 and HLA-DQ8 has >99% negative predictive value and essentially rules out celiac disease 1, 2, 4

Critical Pitfalls to Avoid

• Never initiate a gluten-free diet before completing diagnostic testing—this leads to false-negative serology and may reduce severity of histologic lesions, impacting pathologic interpretation 1, 2
• Do not rely on serology alone without biopsy confirmation in adults—this leads to misdiagnosis 2
• Do not use clinical response to gluten-free diet as diagnostic evidence—symptom improvement or exacerbation with gluten reintroduction has very low positive predictive value and should not be used for diagnosis without other supportive evidence 1
• Lymphocytic infiltration without villous atrophy is not specific for celiac disease—other causes must be excluded including H. pylori infection, small bowel bacterial overgrowth, and systemic autoimmune disorders 1
• Seronegative celiac disease can occur—if clinical suspicion remains high despite negative serology, proceed to biopsy 1, 2

Special Pediatric Exception

• In children with tTG-IgA ≥10× upper limit of normal, positive EMA-IgA, and positive HLA-DQ2/DQ8, biopsy may be avoided according to recent pediatric guidelines 2, 3
• This biopsy-avoidance approach does not apply to adults 2

For Patients Already on Gluten-Free Diet

• If a patient started a gluten-free diet before proper testing, they must resume normal diet with three slices of wheat bread daily for 1-3 months before repeat testing 2
• Some patients may require several years of gluten challenge for histologic relapse to occur 1, 2
• HLA testing can be performed first—if negative for both DQ2 and DQ8, celiac disease is essentially ruled out without need for gluten challenge 2