What are the diagnostic steps and treatment options for celiac disease?

How to Know if Someone Has Celiac Disease

Begin with IgA tissue transglutaminase antibody (tTG-IgA) testing while the patient is consuming gluten, followed by upper endoscopy with multiple duodenal biopsies for histologic confirmation—both steps are essential for diagnosis in adults. 1, 2

Initial Serological Testing

The tTG-IgA test is your first-line screening tool, with sensitivity of 90-96% and specificity exceeding 95%. 2, 3 This test must be performed while the patient is actively eating gluten—at least 10 grams daily for 6-8 weeks—or results will be falsely negative. 2, 3

Simultaneously measure total IgA levels to identify IgA deficiency, which occurs more frequently in celiac disease and causes false-negative IgA-based testing. 1, 2 If IgA deficiency is present, switch to IgG-based tests (IgG deamidated gliadin peptide or IgG tTG). 1, 3

When Serology is Strongly Positive

If tTG-IgA exceeds 10 times the upper limit of normal, obtain IgA endomysial antibody (EMA-IgA) testing on a second blood sample as confirmation. 1 When both tests are positive at these levels, the positive predictive value for celiac disease approaches 100%. 1 Even with this near-certainty, proceed to endoscopy in adults for differential diagnosis and to exclude other conditions. 1

Confirmatory Intestinal Biopsy

Upper endoscopy with duodenal biopsies remains the diagnostic gold standard in adults. 1, 2 Obtain at least 6 biopsy specimens total: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond. 1, 2 This sampling strategy accounts for patchy distribution of mucosal changes. 1

The characteristic histologic findings you're looking for include:

• Villous atrophy (partial to total)
• Crypt hyperplasia with lengthening
• Increased intraepithelial lymphocytes
• Increased lamina propria inflammatory cells 1

Important caveat: Lymphocytic infiltration alone without architectural changes is not diagnostic of celiac disease and requires evaluation for other causes such as H. pylori infection, small bowel bacterial overgrowth, or systemic autoimmune disorders. 1

Special Testing Scenarios

For IgA-Deficient Patients

Use IgG-based tests: IgG deamidated gliadin peptide (DGP-IgG) and IgG tTG. 1, 3 Note that IgG tTG testing is not specific in patients with normal IgA levels and should not be used in that setting. 1

For Children Under 2 Years

Combine tTG-IgA with both IgG and IgA deamidated gliadin peptides to improve sensitivity in this age group. 1, 3

When Serology is Negative but Suspicion Remains High

Order HLA-DQ2 and HLA-DQ8 genetic testing. 1, 2 The absence of both alleles has a negative predictive value exceeding 99%, essentially ruling out celiac disease. 2, 3 If either allele is present, proceed to biopsy despite negative serology, as seronegative celiac disease exists. 2, 4

HLA testing is also valuable for:

• Patients with equivocal biopsy findings
• Patients already on a gluten-free diet who were never properly tested
• First-degree relatives of celiac patients
• Patients with Down syndrome 1, 2

Who Should Be Tested

Test these high-risk populations even without classic symptoms:

• First-degree relatives of celiac patients 2
• Patients with type 1 diabetes mellitus 2
• Unexplained iron deficiency anemia 2
• Premature osteoporosis 2
• Autoimmune thyroid disease 2
• Unexplained liver transaminase elevations 2
• Down syndrome 2
• Chronic diarrhea with weight loss, steatorrhea, or postprandial bloating 1

Critical Pitfalls to Avoid

Never allow patients to start a gluten-free diet before completing diagnostic testing. 2, 3 This is the most common diagnostic error and leads to false-negative serology and potentially normalized or less severe histology. 1, 2

Do not diagnose celiac disease based on serology alone without biopsy confirmation in adults. 1, 2 While pediatric guidelines allow biopsy avoidance in children with tTG-IgA ≥10× upper limit of normal plus positive EMA-IgA and positive HLA, this approach is not standard for adults. 2, 3

Do not rely on symptom improvement with gluten avoidance as diagnostic evidence. 1 This has very low positive predictive value, as many gastrointestinal conditions improve with dietary modification. 1

If a patient has already started a gluten-free diet, they must resume eating gluten (three slices of wheat bread daily) for 1-3 months before repeat testing, though some patients may require several years for histologic relapse to occur. 2

Diagnostic Algorithm for Unclear Cases

When celiac disease is strongly suspected despite negative serology:

1. Confirm adequate gluten intake during testing (at least 10g daily for 6-8 weeks) 2, 4
2. Verify total IgA level was measured and is normal 2, 4
3. Perform HLA-DQ2/DQ8 testing—if positive, proceed to biopsy 2, 4
4. If HLA is negative, celiac disease is effectively ruled out (>99% negative predictive value) 2, 3

Treatment Confirmation

Once diagnosed, refer to a dietitian experienced in celiac disease management for strict lifelong gluten-free diet education. 2 Perform follow-up serology at 6 and 12 months, then yearly thereafter. 2 Persistently positive serology usually indicates ongoing gluten exposure and continued intestinal damage. 2, 3

Remember: Negative serology after treatment does not guarantee mucosal healing—patients with persistent or relapsing symptoms require repeat endoscopic biopsies to assess healing, even with negative tTG-IgA. 2