Persistently Elevated Gamma-Glutamyl Transferase and Hepatobiliary Malignancies: A Real-World Cohort Study

Background: Gamma-glutamyl transferase (GGT) has been associated with increased risks of multiple cancers and mortality. Because GGT is also a marker of hepatobiliary injury, metabolic dysfunction, and alcohol exposure, this study evaluated associations between persistently elevated GGT and hepatobiliary and pancreatic outcomes. Materials and Methods: This retrospective cohort study used TriNetX data from the US Collaborative Network to compare adults aged 40 years or older with persistently elevated GGT against those with normal GGT using a 65 U/L threshold on two occasions 6–12 months apart. Outcomes were assessed from 180 to 1095 days after the index event. Following 1:1 propensity score matching, 14,590 patients per cohort were analyzed. Cox proportional hazards analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Elevated GGT was associated with increased hazards of cholangiocarcinoma (HR 3.715, 95% CI 1.899–7.268), hepatocellular carcinoma (HR 2.260, 95% CI 1.677–3.045), acute pancreatitis (HR 3.359, 95% CI 2.284–4.941), chronic pancreatitis (HR 3.086, 95% CI 1.975–4.821), pancreatic cysts (HR 2.160, 95% CI 1.493–3.127), hospitalization (HR 1.363, 95% CI 1.236–1.503), and all-cause mortality (HR 2.250, 95% CI 2.051–2.467). No statistically significant association was observed with pancreatic cancer (HR 1.591, 95% CI 0.766–3.303; log-rank p = 0.209). Mean follow-up after matching was 799.722 ± 391.071 days in the elevated GGT cohort and 844.685 ± 374.676 days in controls. Conclusions: Persistent GGT elevation was associated with hepatobiliary malignancies, pancreatic inflammatory diseases, pancreatic cysts, hospitalization, and all-cause mortality, but not pancreatic cancer. These results suggest that persistent GGT elevation may be a non-specific clinical marker of underlying hepatobiliary and metabolic risk.