What are the steps to diagnose celiac disease?

Celiac Disease Diagnostic Algorithm

Begin with IgA tissue transglutaminase antibody (tTG-IgA) testing while the patient is actively consuming gluten (at least 10g daily for 6-8 weeks), followed by intestinal biopsy for confirmation in adults. 1

Step 1: Initial Serologic Testing

• Order tTG-IgA as the first-line test with sensitivity of 90-96% and specificity >95% 1, 2
• Simultaneously measure total IgA level to rule out IgA deficiency, which occurs in 1-3% of celiac disease patients and causes false-negative results 1, 2
• Critical requirement: Patient must be on a gluten-containing diet at time of testing—starting a gluten-free diet before testing leads to false-negative results and diagnostic failure 1, 2

Step 2: Interpret Initial Results

If tTG-IgA is >10x upper limit of normal:

• Order IgA endomysial antibody (EMA-IgA) as confirmatory test with specificity of 99.6% 3, 1
• The combination of tTG-IgA >10x upper limit plus positive EMA-IgA approaches 100% positive predictive value 1
• Still proceed to biopsy in adults despite high predictive value, to confirm diagnosis and rule out differential diagnoses 1

If tTG-IgA is positive but <10x upper limit of normal:

• Proceed directly to intestinal biopsy without additional serologic testing 1

If tTG-IgA is negative but clinical suspicion remains high:

• Verify total IgA level is normal (if not already done) 1
• Order HLA-DQ2 and HLA-DQ8 testing—absence of both alleles has >99% negative predictive value and essentially rules out celiac disease 1, 2
• If HLA-DQ2/DQ8 positive, proceed to biopsy 1

If IgA deficiency is detected:

• Switch to IgG-based tests: IgG deamidated gliadin peptide (DGP-IgG) or IgG tissue transglutaminase (tTG-IgG) 1, 2
• Do not use IgG tests in patients with normal IgA levels—they are markedly less accurate in this setting 1

Step 3: Intestinal Biopsy (Gold Standard)

• Obtain multiple specimens: ideally 6 total biopsies—1-2 from duodenal bulb and at least 4 from second part of duodenum or beyond 1, 4
• Timing is critical: Perform biopsy promptly after positive serology while patient is still consuming gluten 3
• Characteristic histologic findings: Villous atrophy, crypt lengthening, and increased intraepithelial lymphocytes 1, 2

Common biopsy pitfalls to avoid:

• Taking too few specimens or only from duodenal bulb—mucosal changes can be patchy 3, 1
• Allowing patient to reduce gluten intake before biopsy—this reduces lesion severity and impacts interpretation 3
• Misinterpreting increased intraepithelial lymphocytes alone without villous atrophy as diagnostic—this is not specific for celiac disease 3, 2

Step 4: Special Scenarios

Patient already on gluten-free diet without prior testing:

• Resume normal diet with three slices of wheat bread daily for 1-3 months before repeat testing 1, 4
• Some patients require several years of gluten challenge for histologic relapse 3, 1
• Alternatively, order HLA-DQ2/DQ8 testing first—if negative, celiac disease is ruled out without gluten challenge 1

Discordant results (positive tTG-IgA, negative EMA):

• Proceed with biopsy as gold standard 4
• May represent early or developing celiac disease 4
• Consider other causes of villous atrophy if biopsy abnormal but serology discordant 4

Children under 2 years:

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

Pediatric biopsy-avoidance protocol:

• 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 does not apply to adults—biopsy remains mandatory 1

High-Risk Groups Requiring Proactive Testing

Screen the following populations even without symptoms:

• First-degree relatives of celiac disease patients 1, 5
• Type 1 diabetes mellitus patients 1, 5
• Autoimmune thyroid disease (Hashimoto's, Graves') 1, 5
• Unexplained iron deficiency anemia 1, 5
• Down syndrome, Turner syndrome, Williams syndrome 1, 5
• Unexplained liver enzyme elevations or autoimmune hepatitis 1, 5
• IgA deficiency 5
• Dermatitis herpetiformis 5

Critical Diagnostic Pitfalls

• Never start gluten-free diet before completing diagnostic workup—this is the most common error leading to inconclusive results 1, 2
• Never rely solely on serology without biopsy in adults—positive serology alone can lead to misdiagnosis 1, 2
• Never use IgG antigliadin antibody or IgA antigliadin antibody—these add no diagnostic value in adults 3
• Never assume symptom improvement on gluten-free diet confirms diagnosis—this has low positive predictive value 2
• Seronegative celiac disease exists—proceed to biopsy if clinical suspicion high despite negative serology 1

Post-Diagnosis Monitoring

• Follow-up serology at 6 months, 12 months, then yearly 1, 2
• Negative serology does not guarantee mucosal healing—44% of patients with persistent villous atrophy have normal tTG levels 4, 6
• Persistently positive serology indicates ongoing gluten exposure and intestinal damage 1, 2
• Consider repeat biopsy at 1-3 years to confirm mucosal healing, especially in severe initial presentation 4