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

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.

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).

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.

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.