What is the diagnostic approach for a patient suspected of having celiac disease?

Diagnostic Testing for Celiac Disease

Begin with IgA tissue transglutaminase antibody (tTG-IgA) plus total IgA level while the patient is consuming a gluten-containing diet, followed by upper endoscopy with multiple duodenal biopsies for confirmation in adults. 1, 2

Initial Serological Testing

• Measure serum IgA tTG-IgA and total IgA simultaneously as the first-line screening approach, with tTG-IgA demonstrating 90-96% sensitivity and >95% specificity 1, 2
• Total IgA measurement is mandatory to identify IgA deficiency, which occurs in 1-3% of celiac patients and causes falsely negative IgA-based antibody tests 1, 2
• Testing must be performed while consuming at least 10g of gluten daily for 6-8 weeks to avoid false-negative results 1, 2

Critical Pre-Test Requirements

• Patients who have already started a gluten-free diet must resume normal diet with three slices of wheat bread daily for 1-3 months before testing 1
• Never initiate a gluten-free diet before completing the diagnostic workup, as this leads to false-negative serology and inconclusive biopsies 1

Confirmatory Serological Testing

• When tTG-IgA is elevated (especially >10× upper limit of normal), perform IgA endomysial antibody (EMA-IgA) as confirmatory testing with excellent 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 for celiac disease 1, 2

Testing in IgA-Deficient Patients

• If IgA deficiency is identified, use IgG-based tests: IgG deamidated gliadin peptide (DGP-IgG) or IgG tTG 3, 1
• IgG DGP has superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to IgG tTG 1
• If IgG-based testing is positive with villous atrophy present, diagnose as selective IgA deficiency associated with celiac disease rather than seronegative enteropathy 3

Intestinal Biopsy Confirmation

Upper endoscopy with at least 6 biopsy specimens remains the gold standard for diagnosis in adults: obtain 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond 1, 2

Histologic Criteria

• Characteristic findings include villous atrophy, crypt lengthening, and increased intraepithelial lymphocytes 1
• Villous atrophy must be present for diagnosis; patients with only increased intraepithelial lymphocytes and normal villi should not be considered to have celiac disease 3
• Have experienced pathologists review biopsies to confirm proper orientation and exclude other etiologies such as Crohn's disease, autoimmune enteropathy, or common variable immunodeficiency 3

HLA Genetic Testing

• HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 1, 2
• HLA testing is most useful when results are negative, as this excludes the possibility of celiac disease 3, 1
• Use HLA testing when celiac disease is strongly suspected despite negative serology, in patients with equivocal biopsy findings, or in patients already on a gluten-free diet who were never properly tested 1

Biopsy-Avoidance Strategy in Children

• Children with tTG-IgA ≥10× upper limit of normal, positive EMA-IgA, and positive HLA-DQ2/DQ8 may avoid biopsy according to recent pediatric guidelines 1
• This approach is not currently recommended for adults, who should undergo biopsy confirmation 1, 2

Seronegative Celiac Disease Evaluation

Seronegative celiac disease represents 1.7-5% of celiac cases and requires all IgA/IgG antibodies (tTG, DGP, EMA) to be negative in the presence of villous atrophy and compatible HLA genetics. 3

Diagnostic Approach for Seronegative Cases

• Confirm patient was consuming adequate gluten when tested 3
• Review serum total IgA levels to exclude IgA deficiency 3
• Perform HLA-DQ2/DQ8 testing—if negative, this excludes seronegative celiac disease 3
• Ensure experienced pathologists review biopsies to exclude other etiologies of villous atrophy 3
• Diagnosis requires clinical and histologic response to gluten-free diet after other etiologies have been examined 3

High-Risk Populations Requiring Testing

Screen the following groups even without symptoms:

• First-degree relatives of celiac patients 1
• Type 1 diabetes mellitus patients 1
• Autoimmune thyroid disease patients 1
• Unexplained iron deficiency anemia 1
• Premature osteoporosis 1
• Unexplained liver transaminase elevations 1
• Down syndrome 1

Common Diagnostic Pitfalls

• Relying solely on serology without biopsy confirmation in adults leads to misdiagnosis, especially with discordant or weakly positive results 1
• IgG isotype testing for tTG antibody is not specific in the absence of IgA deficiency and should not be used in patients with normal IgA levels 1
• Different tTG-IgA assays have varying sensitivity, which can affect interpretation of treatment response 1
• A normal tTG level does not guarantee intestinal mucosal healing in patients on a gluten-free diet—44% of patients with persistent villous atrophy had normal tTG levels in one study 4