Differential associations of cardiometabolic risk factors with liver-related events by alcohol consumption category: Results from a large population-based study

Background & Aims: The relative contributions of alcohol-associated and cardiometabolic drivers to liver-related events (LREs) remains unknown. We aimed to evaluate their relative contributions to LREs and examine possible interactions. Approach & Results: 329,526 UK Biobank participants were included. Alcohol consumption was self-reported and categorized by weekly consumption as low (<140 g for females, <210 g for males), intermediate (140-350 g for females, 210-420 g for males), and high (>350 g for females, >420 g for males). Five cardiometabolic risk factors (CMRFs) were identified using diagnostic criteria for metabolic dysfunction-associated steatotic liver disease. Over a median follow-up of 12.8 years, 1,809 LREs were documented. Alcohol consumption showed the strongest association with LREs. Among participants with low alcohol intake, pre-diabetes/diabetes (hazard ratio: 1.87, 95% confidence interval: 1.64-2.14), low HDL cholesterol (1.79, 1.53-2.10), overweight/obesity (1.68, 1.40-2.01), hypertension (1.27, 1.06-1.53), and overall CMRF burden (5.61, 3.66-8.62) were associated with increased risk of LREs. The corresponding values for intermediate alcohol consumption were 2.00 (1.64-2.43), 1.47 (1.16-1.86), 1.19 (0.92-1.54), 1.90 (1.36-2.64), 5.95 (2.84-12.45); and for high consumption, 1.48 (1.17-1.87), 1.47 (1.11-1.95), 0.88 (0.66-1.18), 1.30 (0.88-1.94), 1.17 (0.58-2.34), respectively. A multiplicative interaction was observed between high alcohol consumption and CMRFs, but not between intermediate consumption and CMRFs. Conclusions: Excessive alcohol use appears to be the strongest factor associated with LREs. Associations between CMRFs and LREs seem similar among individuals with low and intermediate alcohol intake. Reducing alcohol intake, alongside targeted management of CMRFs, may improve strategies for preventing severe liver disease.