First-Line Blood Tests for Suspected Celiac Disease
Order IgA tissue transglutaminase antibody (tTG-IgA) together with total IgA level as your first-line screening panel for suspected celiac disease. 1
Initial Screening Strategy
The combination of tTG-IgA plus total IgA represents the most efficient initial screening approach because it simultaneously detects celiac-specific antibodies while identifying IgA deficiency, which occurs in 1-3% of celiac patients and causes falsely negative IgA-based results. 1
tTG-IgA demonstrates strong diagnostic performance: 90.7% sensitivity and 87.4% specificity in adults (at 15 U/mL threshold), and 97.7% sensitivity with 70.2% specificity in children (at 20 U/mL threshold). 1
Critical Pre-Test Patient Preparation
Ensure your patient is consuming at least 10g of gluten daily for 6-8 weeks before testing to avoid false-negative results—this is roughly equivalent to three slices of wheat bread per day. 1
If the patient has already reduced or eliminated gluten, they must resume regular gluten intake for 1-3 months before serologic testing, as gluten avoidance markedly lowers the sensitivity of both antibody assays and subsequent duodenal biopsy. 1
Interpretation Algorithm Based on Initial Results
If tTG-IgA is Positive AND Total IgA is Normal:
Order IgA endomysial antibody (EMA) as confirmatory testing because EMA provides superior specificity of 99.6% in adults and 93.8% in children. 1
When tTG-IgA exceeds 10 times the upper limit of normal AND a repeat sample shows positive EMA, the positive predictive value for celiac disease approaches 100%. 1
Proceed to upper endoscopy with at least 6 duodenal biopsies (from the second part of duodenum or beyond) for definitive diagnosis—in adults, diagnosis must not rely on serology alone. 1
If tTG-IgA is Negative BUT Total IgA is Low or Absent:
Immediately order IgG-based serologic tests because IgA deficiency renders standard IgA-based celiac testing falsely negative in patients who may actually have celiac disease. 2
IgG deamidated gliadin peptide (DGP-IgG) is the preferred test in IgA-deficient patients, demonstrating superior diagnostic accuracy with 93.6% sensitivity and 99.4% specificity compared to IgG tTG (which has only 40.6-84.6% sensitivity and 78.0-89.0% specificity). 2, 1
IgG EMA can also be used in IgA-deficient patients and shows excellent performance, but DGP-IgG remains the first choice. 1
If Both tTG-IgA and Total IgA are Normal:
Celiac disease is effectively ruled out in most cases, and alternative diagnoses should be pursued. 3
If clinical suspicion remains very high (e.g., first-degree relatives with celiac disease, type 1 diabetes, autoimmune thyroid disease, unexplained iron deficiency), consider proceeding directly to endoscopy with duodenal biopsies despite negative serology. 1
Common Pitfalls to Avoid
Never order IgG tTG as a primary screening test when total IgA is normal—it lacks specificity in that setting and should only be used in confirmed IgA deficiency. 1
Do not start a gluten-free diet before completing the diagnostic workup, as this leads to false-negative serology and inconclusive biopsies, making definitive diagnosis impossible. 1
Recognize that approximately 19 out of 10,000 adults tested with tTG-IgA will have false-negative results despite having actual celiac disease, so maintain clinical suspicion in high-risk populations. 1
Be aware that only 52-57% of established celiac patients with ongoing gluten exposure will show positive serology, demonstrating that negative antibodies do not exclude dietary transgressions or early disease. 1, 4
Additional Testing Considerations
Do not routinely order HLA-DQ2/DQ8 genetic testing as part of initial screening—its primary value is its negative predictive value (>99%) to rule out celiac disease in ambiguous cases, not for diagnosis. 1, 3
Isolated positive DGP antibodies (IgA or IgG) with negative tTG-IgA can identify celiac disease in approximately 15.5% of cases, but the low positive predictive value means most will not have celiac disease on biopsy. 5