Associations between Prediagnostic Circulating Bilirubin Levels and Risk of Gastrointestinal Cancers in the UK Biobank

SIMPLE SUMMARY: Evidence from experimental studies suggests that bilirubin, a metabolic by-product of hemoglobin breakdown, has anticancer activity and may, therefore, reduce the risk of gastrointestinal (GI) cancers. We conducted a prospective study among 440,948 participants in the UK Biobank and found that higher prediagnostic circulating bilirubin levels were robustly associated with a lower risk of developing esophageal adenocarcinoma, which is compatible with the antioxidant hypothesis of bilirubin. We further observed negative associations between bilirubin and risk of colorectal cancer, which were less robust and could be due to reverse causality, whereby undiagnosed cancer affects bilirubin levels. The observed positive associations between bilirubin and risk of hepatobiliary cancers may indicate underlying liver disease processes. No associations were found for cancers of the mouth, stomach, and pancreas. Bilirubin is a novel biomarker for disease development that is routinely measured in clinical settings. Provided that our findings are replicated in further studies, circulating bilirubin could serve as a future risk stratification marker for certain GI cancers. ABSTRACT: We investigated associations between serum levels of bilirubin, an endogenous antioxidant, and gastrointestinal cancer risk. In the UK Biobank, prediagnostic serum levels of total bilirubin were measured in blood samples collected from 440,948 participants. In multivariable-adjusted Cox proportional hazard regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between bilirubin levels and gastrointestinal cancer risk (colorectum, esophagus, stomach, mouth, pancreas, and liver). After a median follow-up of 7.1 years (interquartile range: 1.4), 5033 incident gastrointestinal cancer cases were recorded. In multivariable-adjusted models, bilirubin levels were negatively associated with risk of esophageal adenocarcinoma (EAC, HR per 1-SD increment in log-total bilirubin levels 0.72, 95%CI 0.56–0.92, p = 0.01). Weak and less robust negative associations were observed for colorectal cancer (CRC, HR per 1-SD increment in log-total bilirubin levels 0.95, 95%CI 0.88–1.02, p = 0.14). Bilirubin levels were positively associated with risk of hepatocellular carcinoma (HCC, HR per 1-SD increment in log-total bilirubin levels 2.07, 95%CI 1.15–3.73, p = 0.02) and intrahepatic bile duct (IBD) cancer (HR per 1-SD increment 1.67, 95%CI 1.07–2.62, p = 0.03). We found no associations with risks of stomach, oral, and pancreatic cancers. Prediagnostic serum levels of bilirubin were negatively associated with risk of EAC and positively associated with HCC and IBD cancer. Further studies are warranted to replicate our findings for specific GI cancers.