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

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.

Correlation between pre-treatment serum total blood bilirubin and unconjugated bilirubin and prognosis in patients with colorectal cancer

“…Studies have reported inconsistent results regarding the relationship between circulating bilirubin levels and risk of CRC. In a Mendelian randomization study (67878 cases), TBIL levels were not associated with the risk of CRC[ 11 ], which was similar to the findings of a meta-analysis and a prospective survey[ 12 , 13 ]. In an approximately 10-year follow-up study by He et al [ 14 ], baseline TBIL levels were found to be negatively correlated with the risk of CRC.…”

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer

“…In contrast, both PC1 and PC3, except for PC3 among women, were inversely associated with total bilirubin, indicating a less favorable metabolic health ( 31 ). Total bilirubin itself could potentially also play a causal role in CRC development, whereby higher circulating levels tended to be inversely associated with CRC risk in UK Biobank ( 32 ).…”

Development and Validation of Pretreatment Serum Total Bilirubin as a Biomarker to Predict the Clinical Outcomes in Primary Central Nervous System Lymphoma: A Multicenter Cohort Study

“…Various studies have suggested that serum bilirubin is associated with the occurrence and development of tumors [ 30 , 31 , 32 , 33 , 34 ]. To the best of our knowledge, this is the first study on the relationship between pretreatment STB and the prognosis of patients newly diagnosed with PCNSL who received HD-MTX-based combination immunochemotherapy.…”

“…In a retrospective study, Cao et al found that pretreatment STB and direct bilirubin were independent prognostic factors in patients with CRC [ 33 ]. In a large-scale prospective study based on data from the UK Biobank, higher levels of pre-diagnostic circulating total bilirubin were significantly inversely associated with the risk of esophageal adenocarcinoma [ 34 ]. In a two-sample Mendelian randomization study, researchers found an inverse association between genetically raised bilirubin levels and the risk of squamous cell lung cancer and HL [ 35 ].…”