Gamma-glutamyltransferase independently predicts mortality and heart failure hospitalization in cardiac transthyretin amyloidosis

Background: Transthyretin cardiac amyloidosis (ATTR-CA) is a leading cause of heart failure (HF). Although transthyretin is synthesized in the liver, overt liver disease is uncommon in ATTR-CA. We characterised hepatic involvement in patients with ATTR-CA, and identified the correlates and prognostic value of elevated gamma-glutamyl transferase (GGT), the most prominently deranged biomarker. Methods: We examined 528 patients from four centers, using scintigraphy, cardiovascular magnetic resonance, and circulating biomarkers to assess liver function. The primary endpoint was all-cause mortality; secondary endpoints included HF hospitalization alone or combined with all-cause mortality. Results: The cohort comprised predominantly older men (86 % male; median age 81 years). Scintigraphy showed no abnormal hepatic uptake, but liver extracellular volume was elevated (median 0.69; clinically significant cutoff 0.40). Median GGT was 49 U/L, with 48 % exceeding sex-specific upper reference limits. By comparison, elevated aspartate and alanine transaminases, total bilirubin, and alkaline phosphatase were observed in 26 %, 9 %, 33 %, and 1 % of patients, respectively. Patients with GGT ≥82 U/L displayed indicators of more advanced cardiac disease, hepatic injury, and venous congestion. During a median follow-up of 2.6 years, 39 % died and 33 % were hospitalized for HF. In multivariable analysis, GGT remained predictive of all-cause mortality and HF hospitalization beyond the National Amyloidosis Centre score (hazard ratio [HR] 1.15, 95 % confidence interval [CI] 1.01–1.31; p = 0.045, and HR 1.17, 95 % CI 1.03–1.32; p = 0.016, respectively). Conclusions: Elevated GGT is associated with greater disease severity and predicts worse outcomes in ATTR-CA. GGT measurement may improve risk stratification and guide treatment decision-making.