Total serum bilirubin levels as mediators of anti-atherosclerosis mechanisms with consideration of smoking status

Introduction: Cigarette smoking is a significant risk factor for atherosclerotic cardiovascular diseases (ASCVDs). Mildly elevated total serum bilirubin (TSB) levels can exert anti-atherosclerotic effects and may regulate inflammation. We explore the relationship between TSB levels, smoking, and inflammation.

Methods: This cross-sectional study evaluated health screening participants with no history of ASCVD between 1 April 2019 and 31 March 2020. TSB was compared between non-smokers and smokers using the Kruskal-Wallis test, and the influencing factors of TSB levels were identified using multivariable logistic regression with TSB levels above the 75th percentile set as the dependent variable. Mediation analysis was performed to determine whether TSB levels mediated the association between smoking and inflammation.

Results: A total of 8337 participants (mean age: 46.6 ± 13.0 years; 58.9% men) were included. TSB levels were significantly lower in smokers (n=1353) than in non-smokers (n=6984) [median (IQR): 0.72 (0.56-0.92) vs 0.76 (0.60-0.97) mg/dL, p<0.0001]. Multivariable logistic regression analysis demonstrated that smoking was an independent determinant of lower TSB levels (adjusted odds ratio, AOR=0.81; 95% CI: 0.70-0.93, p=0.003). Leukocyte counts and C-reactive protein levels significantly decreased as TSB levels increased (p<0.0001). Moreover, the relationship between the duration of smoking cessation and TSB levels showed a positive correlation. Mediation analysis indicated that cigarette smoking had significant indirect effects on higher leukocyte counts and higher CRP levels (coefficient=0.014; 95% CI: 0.008-0.021; and coefficient=0.002; 95% CI: 0.001-0.003, respectively].

Conclusions: Lower TSB levels related to a smoking habit may be associated with higher inflammation, thereby increasing the ASCVD risk. TSB may regulate inflammation and exert antioxidant effects. Furthermore, smoking cessation may lead to higher TSB levels and lower inflammation.