Combined effects of smoking and alcohol consumption on the risk of liver cancer according to metabolic syndrome: A nested case-control study in South Korea

Tobacco and alcohol may interact to increase the risk of liver cancer, which might be modified by other risk factors. Their combined effects in the context of metabolic syndrome (MetS) remain unclear. Given the increasing prevalence of MetS, this nested case-control study was conducted to evaluate the combined effects of smoking and alcohol consumption on liver cancer risk with stratification by MetS. We included 15,352 liver cancer patients and 92,112 matched controls who attended the nationwide general health examination during 2009-2019, using a customized database (N = 5,545,835) from the Korean National Health Insurance Service. Liver cancer risk according to smoking and alcohol consumption was estimated using conditional multivariable logistic regression. Additive and multiplicative interactions between these two factors were assessed. Results showed that in men, dual current users were at a significantly higher risk of liver cancer compared with dual nonusers, adjusted odds ratio (aOR) = 1.61, 95% confidence interval: (1.50, 1.72). Interactions were detected between light-to-moderate alcohol consumption (0.1-28 g/day) and heavy smoking (>20 pack-years) on additive scale, relative excess risk due to interaction = 0.34 (0.16, 0.51), attributable proportion = 0.22 (0.11, 0.33), synergy index = 2.75 (1.85, 3.66), and multiplicative scale, aOR for the product term = 1.28 (1.11, 1.49). An additive interaction was also revealed between light-to-moderate drinking and light-to-moderate smoking in the MetS subgroup. In women, light-to-moderate drinking/nonsmoking was negatively associated with the risk in the non-MetS subgroup. In conclusion, a holistic health promotion program should target male dual users of tobacco cigarettes and alcohol, including light-to-moderate users, especially those with MetS.