What is the appropriate workup for a patient suspected of having celiac disease?

Workup for Celiac Disease

The workup for suspected celiac disease begins with IgA tissue transglutaminase (tTG-IgA) antibody testing plus total IgA level measurement while the patient is consuming adequate gluten, followed by upper endoscopy with multiple duodenal biopsies for histologic confirmation in those with positive serology. 1, 2

Critical Pre-Test Requirements

Patients must consume at least 10g of gluten daily (approximately 3 slices of wheat bread) for 6-8 weeks before any testing. 3, 4, 2 Starting a gluten-free diet before completing the diagnostic workup leads to false-negative serology and inconclusive biopsies, which is one of the most common diagnostic pitfalls. 3

• No fasting is required for serologic testing, as antibody levels are not affected by recent food intake. 4

Initial Serologic Testing

First-Line Test

• Order IgA tissue transglutaminase (tTG-IgA) as the preferred initial screening test, with sensitivity of 90.7% and specificity of 87.4% in adults at 15 U/mL threshold. 1, 2, 5
• Simultaneously measure total IgA level to identify selective IgA deficiency, which occurs in 1-3% of celiac patients and causes falsely negative IgA-based tests. 1, 3, 2

If IgA Deficiency is Present

• Order IgG-based tests immediately: IgG deamidated gliadin peptide (DGP-IgG) is preferred due to superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity). 3, 2
• IgG tissue transglutaminase (tTG-IgG) is an alternative but has lower accuracy with only 40.6-84.6% sensitivity. 3, 2

Confirmatory Serology

• If tTG-IgA is positive, consider adding IgA endomysial antibody (EMA-IgA) for confirmation, which has excellent specificity of 99.6% in adults. 3, 4, 2
• The combination of positive tTG-IgA (especially >10 times upper normal limit) plus positive EMA-IgA has virtually 100% positive predictive value for celiac disease. 3, 4

Confirmatory Histologic Testing

Upper endoscopy with small bowel biopsy is mandatory to confirm the diagnosis in adults with positive serology. 1, 2, 6

Biopsy Protocol

• Obtain at least 6 duodenal biopsy specimens: 1-2 from the duodenal bulb and 4-6 from the second part of the duodenum or beyond. 1, 3, 2
• Ensure specimens are properly oriented for histologic analysis using Marsh classification. 3, 2
• Request evaluation by a pathologist with gastroenterology expertise, as poorly oriented mucosa can lead to misinterpretation. 3

Histologic Findings

• Look for villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. 4, 7
• The diagnosis requires demonstration of these characteristic histologic changes. 1

Special Testing Scenarios

When to Consider HLA-DQ2/DQ8 Genetic Testing

HLA testing is not part of routine initial screening but should be considered in specific scenarios: 2

• Patients with equivocal serologic or histologic findings 2
• Patients already on a gluten-free diet before diagnostic workup 2
• When clinical suspicion remains high despite negative serology (negative predictive value >99% when both HLA-DQ2 and HLA-DQ8 are absent) 3, 2

Seronegative Celiac Disease

If clinical suspicion remains high despite negative serology: 3

• Verify the patient was consuming adequate gluten (≥10g daily for 6-8 weeks) when tested 3
• Confirm total IgA level was measured to exclude IgA deficiency 3
• Proceed directly to upper endoscopy with duodenal biopsies if suspicion remains high 3

High-Risk Populations Requiring Screening

Screen for celiac disease even without symptoms in: 2

• First-degree relatives of celiac patients 2
• Patients with type 1 diabetes 2
• Patients with Down syndrome 2
• Unexplained iron deficiency anemia (5% prevalence of celiac disease) 4, 2
• Unexplained elevated liver transaminases 2
• Premature osteoporosis 2
• Patients with irritable bowel syndrome symptoms 1

Common Clinical Presentations

Patients warranting testing include those with: 1

• Chronic diarrhea with weight loss 1
• Steatorrhea 1
• Postprandial abdominal pain and bloating 1
• Laboratory evidence of malabsorption 1
• Unexplained iron deficiency anemia 1, 2

Critical Pitfalls to Avoid

• Never start a gluten-free diet before completing the diagnostic workup, as this leads to false-negative results and inconclusive biopsies. 3, 4
• Never rely on symptoms alone or symptom response to gluten-free diet for diagnosis, as this cannot differentiate celiac disease from non-celiac gluten sensitivity. 1, 3
• Do not use anti-gliadin antibodies (native gliadin) for primary detection, as they are no longer recommended. 1
• Do not combine multiple serologic tests in low-risk populations, as this marginally increases sensitivity but reduces specificity. 1
• Do not skip biopsy confirmation in adults, even with highly positive serology, as intestinal biopsy remains the diagnostic gold standard. 1, 6