Combined Effects of Smoking and Bilirubin Levels on the Risk of Lung Cancer in Korea: The Severance Cohort Study

Abstract

BackgroundSmoking is a major risk factor for lung cancer. Bilirubin, an antioxidant, is inversely associated with the risk of diseases related to oxidative stress. This study was conducted to determine the influence of smoking and bilirubin levels on the risk of lung cancer in the Severance cohort study.MethodsThis study included 68,676 Korean who received a health examination at Severance Health Promotion Center from 1994 to 2004. Serum bilirubin measurements within normal range were divided into tertiles whereas smoking states were divided as never-smokers, former smokers and current smokers. A diagnosis of lung cancer was coded as occurring based on the report from the National Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using Cox proportional hazards model.ResultsAt the end of the study period, 240 patients (men: 181, women: 59) developed lung cancer. Compared to those with bilirubin levels ≥1.0 mg/dL, HRs (95% CI) for lung cancer were 2.8 (1.8–4.2) for subjects having bilirubin levels from 0.2 to 0.7 mg/dL in men. When we stratified our analysis by smoking status, bilirubin consistently showed a protective effect on the risk of lung cancer on both never- and current smokers. Current smokers having bilirubin levels from 0.2 to 0.7 mg/dL had a risk of lung cancer by 6.0-fold higher than never-smokers with bilirubin levels ≥1.0 mg/dL in men.ConclusionIn this large prospective study, higher baseline bilirubin level in the normal range was associated with low risk of lung cancer. Smoking and low bilirubin levels were cumulatively associated with a higher risk of lung cancer.

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

“…10 Population-based cohort studies have also linked moderately raised serum bilirubin levels with lower rates of respiratory diseases and lung cancer with the strongest associations in cigarette smokers. [11][12][13][14] Although these observations are consistent with an endogenous antioxidant function for bilirubin, the relationships with lung cancer could reflect residual confounding or reverse causation. For instance, liver diseases, infections, acute events such as heart attacks, certain drugs and environmental exposures can influence bilirubin levels.…”

Total antioxidant status in lung cancer is associated with levels of endogenous antioxidants and disease stage rather than lifestyle factors – preliminary study

“…smoking, while others, e.g. alcohol consumption, may increase its concentration [ 29 ]. During smoking, which is the main risk factor of lung cancer, the bilirubin is wasted.…”

Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non‐small‐cell lung cancer patients with EGFR mutations

“…Bilirubin, a bile pigment, is the major end product of heme degradation and cleared from liver, and has potential properties of anti‐inflammation, antioxidation and anticancer . As reported by previous studies, bilirubin was inversely associated with an increased risk of lung cancer . Similarly, dysfunctional metabolism of cholesterol in circulation was also proposed to be related with the development of lung cancer .…”