Why do we check tissue transglutaminase antibody (TTG)?

Why We Check Tissue Transglutaminase Antibody (TTG)

We check TTG primarily to diagnose celiac disease, as IgA tissue transglutaminase (TTG-IgA) is the preferred first-line screening test with excellent diagnostic accuracy (sensitivity 90-97%, specificity 96-100%), and serves as the cornerstone for identifying this treatable autoimmune condition that, if left undiagnosed, leads to malabsorption, nutritional deficiencies, and increased risk of complications including lymphoma. 1

Primary Diagnostic Purpose

TTG-IgA is the gold standard screening test for celiac disease because tissue transglutaminase-2 is the major autoantigen recognized in celiac disease, making antibodies against it highly specific for the condition. 1

Key Diagnostic Characteristics:

• Sensitivity ranges from 90.7% to 97% in adults and children, making it highly effective at detecting celiac disease 1, 2, 3
• Specificity ranges from 96% to 100%, meaning positive results are highly reliable 1, 3
• Superior to older tests like anti-gliadin antibodies, which are no longer recommended for primary detection 1
• Well-suited for automation through ELISA platforms, allowing high-throughput, standardized testing 1

Who Should Be Tested

Symptomatic Patients:

• Gastrointestinal symptoms: chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain, bloating, or constipation 1
• Malabsorption indicators: unexplained iron deficiency anemia (celiac disease present in 2-6% of these patients), failure to thrive in children, unexplained weight loss 1
• Extra-intestinal manifestations: dermatitis herpetiformis, fatigue, osteoporosis 1

High-Risk Asymptomatic Patients (5-10% prevalence):

• First-degree relatives of celiac patients (7.5% risk) 1
• Type 1 diabetes (5-10% prevalence of celiac disease) 1
• Autoimmune conditions: autoimmune thyroid disease, autoimmune liver disease 1
• Chromosomal abnormalities: Down syndrome, Turner syndrome 1

Testing in these populations increases pre-test probability from 1% (general population) to 5-10% or higher, significantly improving positive predictive value. 1

Critical Testing Requirements

Must Test While on Gluten-Containing Diet:

All diagnostic serologic testing must be performed before initiating a gluten-free diet, as gluten withdrawal causes antibody levels to decline and produces false-negative results. 1, 2 Patients need adequate gluten intake (at least 10g daily for 6-8 weeks) before testing. 2

Measure Total IgA Simultaneously:

Total IgA levels must be documented because IgA deficiency occurs in 1-3% of celiac disease patients (compared to 0.2% in general population), which causes falsely negative TTG-IgA results. 1, 2 If IgA deficiency is confirmed, use IgG-based tests (IgG deamidated gliadin peptide or IgG TTG). 1, 2

Monitoring Treatment Response

TTG-IgA serves as the primary marker for monitoring adherence to gluten-free diet and assessing treatment response. 4, 5

Follow-up Testing Schedule:

• 6 months after starting gluten-free diet 2, 4
• 12 months after diagnosis 2
• Annually thereafter 2, 4

Interpretation During Monitoring:

• Persistently elevated TTG-IgA indicates ongoing gluten exposure or poor dietary compliance 2, 4, 5
• TTG-IgA levels typically decline within months of starting gluten-free diet, with most significant drops in the first year 2
• Different assays have varying sensitivity for detecting suboptimal treatment response—some assays detect ongoing intestinal damage better than others 5

Confirmatory Testing Strategy

When TTG-IgA is elevated, proceed to confirmatory testing to establish diagnosis before initiating lifelong dietary restrictions. 1, 2

Two-Step Approach:

1. Endomysial antibody (EMA) testing as second-line confirmation with excellent specificity (99.6% in adults) 1, 2
2. Upper endoscopy with duodenal biopsy (at least 6 specimens from second part of duodenum) remains the gold standard for diagnosis confirmation 1, 2

The concordance rate between TTG-IgA and EMA is 95-100% in untreated celiac disease. 1, 6

Common Pitfalls to Avoid

• Never start gluten-free diet before completing diagnostic workup, as this leads to false-negative serology and inconclusive biopsies 2
• Do not rely solely on symptoms for diagnosis—gastrointestinal symptoms alone cannot differentiate celiac disease from other disorders 1
• Avoid using point-of-care tests as primary diagnostic tools due to quality control difficulties with inexperienced users 1
• Do not combine multiple antibody tests in low-risk populations, as this marginally increases sensitivity but reduces specificity 1
• Recognize that TTG-IgA levels >10 times upper limit of normal correlate strongly with severe intestinal damage and have virtually 100% positive predictive value when combined with positive EMA 1, 2