Abstract
BACKGROUND AND AIMS: This large-scale, population-based cohort study examined the associations between metabolic syndrome and cholangiocarcinoma risk, including its intrahepatic and extrahepatic forms. APPROACH AND RESULTS: A total of 4,932,211 adults aged ≥40 years participated in a government-initiated health checkup program (2012-2017), which collected lifestyle data, anthropometric measurements, and biochemical tests. Follow-up continued until 2021, with data linkage to National Cancer and Death Registries to ascertain the occurrence of cholangiocarcinoma and obtain vital status information. Fine and Gray models accounted for competing risks. During 35,879,371 person-years of follow-up, 6117 cholangiocarcinoma cases were identified, with an incidence rate of 17.05 (95% CI: 15.90-18.20) per 100,000 person-years. Individuals with metabolic syndrome had significantly higher incidences of both intrahepatic and extrahepatic cholangiocarcinoma ( p <0.0001). The multivariate-adjusted HR for cholangiocarcinoma among those with metabolic syndrome was 1.20 (1.14-1.27). Stratification analyses by age, sex, liver enzyme levels, and comorbidities consistently demonstrated an increased cholangiocarcinoma risk among individuals with metabolic syndrome. A dose-response relationship was observed, with a higher number of metabolic components correlating with an elevated cholangiocarcinoma risk, even after accounting for all-cause mortality as a competing risk. The adjusted subdistribution HRs ranged from 1.16 (95% CI: 1.02-1.32) for individuals with one metabolic component to 1.67 (95% CI: 1.45-1.94) for those with five ( p for trend <0.0001). CONCLUSIONS: The positive association between metabolic syndrome and cholangiocarcinoma risk suggests that managing metabolic risk factors might reduce the occurrence of both intrahepatic and extrahepatic cholangiocarcinoma.