What are the diagnostic tests for gluten intolerance?

Diagnostic Tests for Gluten Intolerance (Celiac Disease)

Begin with IgA tissue transglutaminase antibody (tTG-IgA) testing while the patient is consuming a gluten-containing diet, followed by upper endoscopy with multiple duodenal biopsies for definitive diagnosis. 1, 2

Initial Serological Testing

The tTG-IgA test is the first-line screening test with sensitivity of 90-96% and specificity exceeding 95%. 1, 3, 2 This test must be performed while the patient is actively consuming gluten (at least 10g daily for 6-8 weeks) to avoid false-negative results. 1, 2

Critical First Step: Check Total IgA Level

• Always measure total IgA levels simultaneously with tTG-IgA to identify IgA deficiency, which occurs in approximately 2-3% of celiac patients and causes false-negative results. 1, 2
• If IgA deficiency is detected, switch to IgG-based tests (IgG deamidated gliadin peptide or IgG tissue transglutaminase). 1, 2

Confirmatory Serology for High-Positive Results

• When tTG-IgA levels exceed 10 times the upper limit of normal, perform IgA endomysial antibody (EMA-IgA) testing as confirmation, which has excellent specificity of 99.6%. 1, 2
• The combination of very high tTG-IgA (>10x ULN) plus positive EMA-IgA approaches 100% positive predictive value. 1

Definitive Diagnostic Testing: Intestinal Biopsy

Upper endoscopy with duodenal biopsy remains the gold standard for diagnosis in adults and cannot be replaced by serology alone. 4, 1 The only exceptions are patients with coagulation disorders and pregnant women. 4

Biopsy Technique Requirements

• Obtain multiple biopsies: 1-2 samples from the duodenal bulb and at least 4 samples (ideally 6 total) from the distal duodenum or beyond. 4, 1, 2
• Look for characteristic histologic findings: villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (≥25 IELs per 100 enterocytes). 4, 1, 2
• Definite diagnosis requires villous atrophy, though lesser degrees of damage with elevated IELs may indicate celiac disease. 4

Important Caveat About Lymphocytic Duodenosis

Lymphocytic infiltration without villous atrophy is not specific for celiac disease. 4, 2 Consider alternative causes including H. pylori infection, small bowel bacterial overgrowth, and systemic autoimmune disorders before concluding the diagnosis. 4

Genetic Testing: HLA-DQ2 and HLA-DQ8

Do not perform HLA testing routinely as it has limited positive predictive value (HLA-DQ2 is present in 25-30% of the general white population). 4

When HLA Testing Is Useful

HLA-DQ2 and HLA-DQ8 testing has excellent negative predictive value (>99%) and should be reserved for specific scenarios: 4, 1, 2

• Patients with equivocal small-bowel histologic findings
• Patients already following a gluten-free diet without prior diagnostic testing
• Patients with discrepant serology and histology results
• First-degree relatives being evaluated for celiac disease risk
• Patients with Down syndrome
• When celiac disease is strongly suspected despite negative serology

Special Population Considerations

IgA-Deficient Patients

• Use IgG-based antibody tests: IgG deamidated gliadin peptide (DGP-IgG) and IgG tissue transglutaminase (tTG-IgG). 1, 2

Children Under 2 Years

• Combine tTG-IgA with both IgG and IgA deamidated gliadin peptides for improved sensitivity. 3, 2

Pediatric Biopsy-Avoidance Protocol

• 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, 3, 2
• This does not apply to adults, who still require biopsy confirmation. 1, 2

Critical Pitfalls to Avoid

The Gluten-Free Diet Trap

Never start a gluten-free diet before completing diagnostic testing. 1, 2 This is the most common diagnostic error and leads to false-negative results in both serology and biopsy. 1, 2

• If a patient has already started a gluten-free diet, they must resume consuming gluten (three slices of wheat bread daily) for 1-3 months before repeat testing. 1
• Serologic and histologic features may still be abnormal if the diet has been followed for less than one month. 4

Don't Rely on Serology Alone in Adults

Biopsy confirmation is essential in adults despite positive serology, as relying solely on antibody tests can lead to misdiagnosis. 1, 2

Symptom Response Is Not Diagnostic

Improvement on a gluten-free diet has low positive predictive value and should never be used for diagnosis without supportive serologic and histologic evidence. 2

Tests That Should NOT Be Used

The following tests are not recommended for celiac disease diagnosis: 4

• Stool studies
• Small-bowel follow-through
• Intestinal permeability testing
• D-xylose testing
• Salivary testing

Differentiating Celiac Disease from Non-Celiac Gluten Sensitivity

Non-celiac gluten sensitivity is a diagnosis of exclusion that can only be considered after celiac disease has been definitively ruled out with appropriate serology, biopsy, and potentially HLA testing. 4 Symptoms alone or symptom response to a gluten-free diet cannot reliably differentiate these conditions. 4

High-Risk Groups Requiring Testing

Screen the following populations even without typical symptoms: 1, 3

• First-degree relatives of celiac patients
• Patients with type 1 diabetes mellitus
• Patients with unexplained iron deficiency anemia
• Patients with premature osteoporosis
• Patients with autoimmune thyroid disease
• Patients with unexplained liver transaminase elevations
• Patients with Down syndrome