Liver diseases, transaminases, and hepatobiliary–pancreatic cancer risk: a cohort and Mendelian randomisation study using data from UK Biobank

Objective Liver diseases are established risk factors for hepatobiliary and pancreatic cancers. This study explores the relationship between liver disease and hepatobiliary–pancreatic cancers, focusing on transaminase levels and genetic susceptibility. Methods We conducted a large cohort study using data from 449 815 participants in the UK Biobank. Logistic regression models assessed cancer risks in liver disease versus control groups. The association between transaminase levels, polygenic risk scores (PRS), and hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), biliary tract cancer, and pancreatic cancer was examined. Two-sample Mendelian randomisation (MR) investigated the causal relationships between liver diseases and the four cancers. Results Liver disease and elevated transaminase levels were significantly associated with increased cancer risks (p<0.001). Higher alanine transaminase and aspartate transaminase PRS were linked to increased HCC risk (HR=1.69, 95% CI 1.38 to 2.08; HR=1.79, 95% CI 1.46 to 2.19). MR analysis revealed a causal link between alcohol-associated liver disease (ALD) and both HCC (OR=1.379, 95% CI 1.109 to 1.714) and ICC (OR=1.429, 95% CI 1.130 to 1.807), while metabolic dysfunction-associated steatotic liver disease showed no significant associations. Conclusion Patients with liver diseases have a significantly higher risk of hepatobiliary and pancreatic cancers, and individuals with elevated transaminase levels also exhibit a genetic predisposition to HCC. ALD demonstrates significant causal relationships with HCC and ICC.