What are the steps for testing and treating celiac disease?

Testing for Celiac Disease

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

Initial Serologic Testing

The IgA tTG is the single most efficient screening test for celiac disease, with sensitivity of 90-96% and specificity >95%. 3, 1

• Measure total IgA level simultaneously with tTG-IgA to identify IgA deficiency, which occurs in 1-3% of celiac patients and causes false-negative results 1, 2, 4
• Testing must be performed while the patient consumes at least 10g of gluten daily for 6-8 weeks—starting a gluten-free diet before testing leads to false-negative results 1, 2, 4
• Do NOT use IgA or IgG antigliadin antibody tests, as their diagnostic performance is inferior and adds no value 3, 5

Confirmatory Serologic 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% 3, 1, 2
• The combination of tTG-IgA >10× upper limit of normal plus positive EMA-IgA approaches 100% positive predictive value for celiac disease 2, 4

Testing in IgA Deficiency

• If IgA deficiency is confirmed, use IgG-based tests: IgG deamidated gliadin peptide (DGP-IgG) or IgG tissue transglutaminase (tTG-IgG) 3, 1, 2
• Critical pitfall: IgG-based tests are markedly less accurate in patients with normal IgA levels and should NOT be used in that setting 2

Intestinal Biopsy Confirmation

Upper endoscopy with small bowel biopsy remains the gold standard for establishing the diagnosis of celiac disease in adults. 3, 2, 4

• 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 3, 2, 4
• Multiple biopsies are essential because mucosal changes can be patchy, and Brunner's glands or peptic changes in the bulb may hamper diagnosis 3
• Characteristic histologic findings include villous atrophy (partial to total), crypt lengthening with increased lamina propria, and increased intraepithelial lymphocytes 3, 1
• Biopsy remains mandatory in adults despite high antibody levels to establish definitive diagnosis and rule out other causes of villous atrophy 2, 4

Important Histologic Pitfall

• Increased intraepithelial lymphocytes without architectural changes (villous atrophy) should NOT be considered diagnostic of celiac disease—this may represent latent disease or other conditions 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, 4

When to Use HLA Testing

• When celiac disease is strongly suspected despite negative serology 3, 1, 2
• In patients with equivocal small-bowel histologic findings 1, 2
• In patients already on a gluten-free diet without prior testing 1, 2
• In patients with discrepant celiac-specific serology and histology 1

When NOT to Use HLA Testing

• HLA testing adds no diagnostic value when tTG-IgA is highly elevated, as it does not confirm diagnosis 4

Diagnostic Algorithm for Negative Serology with High Clinical Suspicion

1. Confirm the patient is consuming adequate gluten (at least 10g daily for 6-8 weeks) 2, 4
2. Verify total IgA level 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 essentially ruled out 1, 2, 4

Special Population Considerations

Children Under 2 Years

• Combine tTG-IgA with IgG and IgA deamidated gliadin peptides for improved sensitivity 1, 2, 4

Pediatric Biopsy-Avoidance Strategy

• In children with tTG-IgA ≥10× upper limit of normal, positive EMA-IgA, and positive HLA-DQ2/DQ8, biopsy may be avoided according to pediatric guidelines 1, 2
• This strategy does NOT apply to adults—biopsy remains mandatory 2, 4

Testing Patients Already on a Gluten-Free Diet

This is a common and problematic scenario that requires gluten rechallenge. 1, 2

• Resume normal diet with three slices of wheat bread daily for 1-3 months before repeat testing 1, 2
• Some patients may require several years of gluten challenge for histologic relapse to occur 2
• If gluten rechallenge is not feasible, HLA-DQ2/DQ8 testing can help: negative results rule out celiac disease 1, 2

High-Risk Groups Requiring Testing

Test these populations even without typical symptoms: 3, 2, 4

• First-degree relatives of celiac patients 3, 2, 4
• Type 1 diabetes mellitus 3, 2, 4
• Unexplained iron deficiency anemia 3, 2, 4
• Premature osteoporosis 3, 2, 4
• Autoimmune thyroid disease 3, 2, 4
• Down syndrome 3, 2, 4
• Turner syndrome 3, 2
• Unexplained liver transaminase elevations 3, 2, 4
• Primary biliary cirrhosis and autoimmune hepatitis 3
• Unexplained recurrent fetal loss 3
• Sjögren's syndrome 3

Follow-Up Testing After Diagnosis

• Perform follow-up serology at 6 and 12 months after diagnosis, then yearly thereafter 1, 2
• Critical limitation: Negative serology after treatment does NOT guarantee intestinal mucosal healing 1, 2, 6, 7
• Serologic tests (tTG-IgA and EMA-IgA) have only 50% and 45% sensitivity respectively for detecting persistent villous atrophy in patients on a gluten-free diet 6
• Persistently elevated antibodies usually indicate ongoing gluten exposure and continued intestinal damage 1, 2
• Patients with persistent or relapsing symptoms should undergo repeat endoscopic biopsies to determine healing, even with negative tTG-IgA 2

Critical Pitfalls to Avoid

• Never initiate a gluten-free diet before completing diagnostic testing—this leads to false-negative results and diagnostic uncertainty 1, 2, 4
• Never rely solely on serology without biopsy confirmation in adults—this leads to misdiagnosis 1, 2, 4
• Never use symptom improvement on a gluten-free diet as diagnostic evidence—this has low positive predictive value and is not specific for celiac disease 1
• Never assume negative follow-up serology means mucosal healing—44% of patients with persistent villous atrophy have normal tTG levels 6, 7