What is the recommended testing approach for a patient suspected of having celiac disease?

Recommended Testing Approach for Suspected Celiac Disease

Begin with IgA tissue transglutaminase antibody (tTG-IgA) combined with total IgA level measurement as your first-line screening test—this combination has 90-96% sensitivity and >95% specificity while simultaneously identifying IgA deficiency that would cause false-negative results. 1, 2

Initial Serological Testing Algorithm

Step 1: Order tTG-IgA + Total IgA

• Measure both tests simultaneously to avoid missing IgA-deficient patients (occurs in 1-3% of celiac patients) who will have falsely negative IgA-based tests 1
• Patient must consume at least 10g of gluten daily for 6-8 weeks before testing—gluten avoidance causes false-negative results 1, 2
• tTG-IgA has 90.7% sensitivity and 87.4% specificity in adults at 15 U/mL threshold 3
• In children, tTG-IgA has 97.7% sensitivity and 70.2% specificity at 20 U/mL threshold 3, 4

Step 2: Interpret Results Based on Total IgA Status

If Total IgA is Normal:

• Positive tTG-IgA (especially >10× upper limit of normal): Order confirmatory IgA endomysial antibody (EMA-IgA) testing, which has 99.6% specificity in adults and 93.8% in children 1, 3, 4
• Negative tTG-IgA: Celiac disease is effectively ruled out in most cases 3

If Total IgA is Deficient:

• Order IgG-based tests instead: IgG deamidated gliadin peptide (DGP-IgG) is preferred with 93.6% sensitivity and 99.4% specificity—superior to IgG tTG 3
• Also consider IgG tTG or IgG EMA, though DGP-IgG performs best 1

Confirmatory Testing Strategy

When to Proceed to Endoscopy with Biopsy

In Adults:

• All seropositive adults require upper endoscopy with duodenal biopsy to confirm diagnosis 1, 2
• Obtain at least 6 biopsy specimens: 1-2 from duodenal bulb and at least 4 from distal duodenum 2
• Request histologic analysis with Marsh classification by a gastroenterology-specialized pathologist 1

In Children (Biopsy-Avoidance Criteria):

• Children can avoid biopsy if ALL criteria met: tTG-IgA ≥10× upper limit of normal, EMA-IgA positive, HLA-DQ2/DQ8 positive, and symptoms compatible with malabsorption 4, 2
• If criteria not met, proceed to biopsy as in adults 4

Special Testing Scenarios

High-Risk Populations Requiring Screening

• Type 1 diabetes patients: Screen at diagnosis, after 2 years, and after 5 years (prevalence 5-10%) 4
• First-degree relatives of celiac patients: Risk is 7.5% 4
• Down syndrome or Turner syndrome patients 4
• Unexplained iron deficiency anemia: Celiac disease present in 2-6% of cases 3

HLA-DQ2/DQ8 Genetic Testing

• Use HLA testing for its negative predictive value (>99%) when celiac disease is strongly suspected despite negative serology 1, 2
• Absence of both HLA-DQ2 and HLA-DQ8 essentially rules out celiac disease 1, 3
• Do not use as primary diagnostic tool—only to rule out disease in specific scenarios 3

Seronegative Enteropathy Workup

• If villous atrophy found but serology negative: Measure total IgA, repeat tTG-IgA, DGP-IgA, and EMA-IgA 1
• Consider HLA-DQ2/DQ8 testing—negative results rule out celiac disease 1
• Review medications (especially olmesartan causing villous atrophy) and travel history 1
• If seronegative with villous atrophy and positive HLA: Repeat endoscopy after 1-3 years on gluten-free diet to confirm histologic improvement 1

Critical Pitfalls to Avoid

Testing Errors

• Never start gluten-free diet before completing diagnostic workup—this causes false-negative serology and inconclusive biopsies 1, 2
• Never rely on IgG tTG in patients with normal IgA levels—it has poor sensitivity (40.6-84.6%) and specificity (78.0-89.0%) 3
• Never diagnose based on symptoms alone or symptom response to gluten-free diet—this cannot differentiate celiac disease from non-celiac gluten sensitivity 3

Interpretation Errors

• Do not assume negative serology rules out celiac disease in high-risk patients—proceed to biopsy if clinical suspicion remains high 1, 3
• Recognize that poorly oriented duodenal mucosa leads to misinterpretation—ensure pathologist has gastroenterology expertise 1
• Understand that tTG-IgA >10× upper limit of normal combined with positive EMA has virtually 100% positive predictive value for celiac disease 1, 3

Special Population Considerations

• In children under 2 years: Combine tTG-IgA with IgG and IgA deamidated gliadin peptides for improved sensitivity 4, 2
• In IgA-deficient patients: Use IgG DGP as first choice, not IgG tTG 3

Follow-Up Testing After Diagnosis

• Repeat tTG-IgA at 6 months, 12 months, then annually after starting gluten-free diet 1, 3, 2
• Persistently positive serology indicates ongoing gluten exposure and intestinal damage 1, 3
• Negative serology does NOT guarantee mucosal healing—consider follow-up biopsy in patients with persistent symptoms even with negative serology 1, 5
• Serology has only 50% sensitivity for detecting persistent villous atrophy in treated patients 5