What are the diagnostic steps and treatment for celiac disease?

Diagnosing Celiac Disease

Initial Serological Testing

Begin with IgA tissue transglutaminase antibody (tTG-IgA) testing while the patient is actively consuming gluten—this is the single most efficient and accurate screening test for celiac disease. 1, 2

• The tTG-IgA test has excellent diagnostic performance with sensitivity of 90-96% and specificity >95% 1, 2
• Always measure total IgA levels simultaneously to identify IgA deficiency, which occurs in 1-3% of celiac patients and causes false-negative tTG-IgA results 1, 2
• Testing must be performed while consuming at least 10g of gluten daily for 6-8 weeks—never start a gluten-free diet before completing diagnostic testing 1, 2

For Patients with IgA Deficiency

• Use IgG-based tests instead: IgG deamidated gliadin peptide (DGP-IgG) or IgG tissue transglutaminase (tTG-IgG) 1, 2
• IgG tests are markedly less accurate in patients with normal IgA levels and should not be used in that setting 3

Special Pediatric Considerations

• In children under 2 years, combine tTG-IgA with IgG and IgA deamidated gliadin peptides to improve sensitivity 3, 2

Confirmatory Serological Testing

• If tTG-IgA is >10× the upper limit of normal, perform IgA endomysial antibody (EMA-IgA) testing as confirmation with excellent specificity of 99.6% 1, 2
• The combination of tTG-IgA >10× upper limit plus positive EMA-IgA approaches 100% positive predictive value for celiac disease 1

Intestinal Biopsy: The Gold Standard

Upper endoscopy with small bowel biopsy remains mandatory for diagnosis in adults, regardless of antibody levels. 1, 2

Biopsy Technique

• Obtain multiple specimens—ideally 6 biopsies total: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond 3, 1
• Mucosal changes can be patchy, and Brunner's glands in the bulb can interfere with interpretation if only bulb biopsies are taken 3
• Visual endoscopic appearance alone is insufficient—villous atrophy may not be visible, so biopsies must be obtained even if mucosa appears normal 3

Diagnostic Histologic Findings

• Characteristic features include villous atrophy, crypt lengthening with increased lamina propria, and increased intraepithelial lymphocytes 3, 1
• Lymphocytic infiltration alone without villous atrophy is NOT diagnostic of celiac disease—consider other causes like H. pylori infection, bacterial overgrowth, or autoimmune disorders 3, 2

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 per pediatric guidelines 1, 2
• This strategy does NOT apply to adults 1

HLA Genetic Testing

• HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease 3, 1, 2
• Do NOT use HLA testing for routine diagnosis—25-30% of the general white population carries HLA-DQ2, making it a poor positive predictor 3

When HLA Testing Is Useful

• When celiac disease is strongly suspected despite negative serology 3, 1
• In patients with equivocal biopsy findings 3, 2
• In patients already on a gluten-free diet who were never properly tested 3, 2
• In patients with discrepant serology and histology results 3, 2
• In Down syndrome patients where testing is recommended 3, 1

Diagnostic Algorithm for Specific Scenarios

Negative Serology but High Clinical Suspicion

1. Confirm patient is consuming adequate gluten (at least 10g daily for 6-8 weeks) 1, 2
2. Verify total IgA level is normal 1, 2
3. Perform HLA-DQ2/DQ8 testing—if positive, proceed to biopsy 3, 1
4. If HLA negative, celiac disease is effectively ruled out 1, 2

Patient Already on Gluten-Free Diet

• Resume normal diet with three slices of wheat bread daily for 1-3 months before repeat testing 1
• Some patients may require several years of gluten challenge for histologic relapse to occur 3
• A 4-week challenge with sufficient gluten to reproduce symptoms is adequate in most cases 3

Discordant Results (Positive tTG-IgA, Negative EMA)

• Proceed directly to upper endoscopy with biopsy—this may represent early or developing celiac disease 4
• Do not rely on serology alone when results are discordant 3, 4

High-Risk Groups Requiring Testing

Screen the following populations even without symptoms:

• First-degree relatives of celiac patients 1, 5
• Type 1 diabetes mellitus 1, 5
• Autoimmune thyroid disease (Hashimoto's or Graves') 1, 5
• Unexplained iron deficiency anemia 1, 5
• Premature osteoporosis 1
• Unexplained liver transaminase elevations 1, 5
• Down syndrome, Turner syndrome, Williams syndrome 1, 5
• Autoimmune hepatitis or primary biliary cholangitis 5
• Sjögren's syndrome 5
• Dermatitis herpetiformis 6, 5
• Unexplained ataxia or peripheral neuropathy 5

Treatment Approach

Initiate a strict, lifelong gluten-free diet immediately after biopsy confirmation—this is the only effective treatment. 1, 7

• Refer to a registered dietitian experienced in celiac disease management 1
• Follow-up serology at 6 months, 12 months, then yearly thereafter 1, 2
• Negative serology after treatment does NOT guarantee mucosal healing—persistently positive antibodies indicate ongoing gluten exposure 1, 2
• For persistent or relapsing symptoms despite negative serology, perform repeat endoscopic biopsies to assess mucosal healing 1

Critical Pitfalls to Avoid

• Never initiate a gluten-free diet before completing diagnostic workup—this leads to false-negative serology and inconclusive biopsies 1, 2
• Do not rely solely on symptom improvement with gluten avoidance—this has very low positive predictive value for celiac disease 3, 2
• Do not use IgG antigliadin antibodies for primary detection—these are no longer recommended 3
• Do not skip biopsy in adults based on high antibody levels alone—biopsy remains mandatory for differential diagnosis 1, 7
• Do not assume normal-appearing mucosa on endoscopy rules out celiac disease—always obtain biopsies 3