Alcohol, Cardiometabolic Risk Factors, and Cirrhosis: Ten-Year Risk Estimates from a Population-based Danish Cohort.

BACKGROUND & AIMS: The combined effects of alcohol consumption and cardiometabolic risk factors on cirrhosis risk are increasingly recognized. We examined their separate and combined effects. METHODS: We included 354,624 participants from the Danish National Health Surveys 2010-2017 without a diagnosis of cirrhosis. We estimated 10-year absolute and relative cirrhosis risks, population attributable fractions (PAFs), and supra-additive interactions according to alcohol consumption and cardiometabolic risk factors. RESULTS: Participants had a median age of 55 years; 12% reported ≥15 drinks/week, 17% had a body mass index (BMI) ≥30 kg/m2, 5% diabetes, 28% hypertension, 18% dyslipidemia, and 21% smoked. During 3.3 million person-years of observation, 1211 developed cirrhosis. Alcohol consumption strongly affected the risk of cirrhosis (10-year absolute risks of 0.14%, 0.29%, 0.68%, 2.0% and 4.6% for 1-7, 8-14, 15-28, 29-42, and >42 drinks per week, respectively). BMI ≥30 kg/m2, diabetes, hypertension, and smoking were each associated with two- to threefold higher risk. Dyslipidemia was not associated with cirrhosis risk overall, but was associated with increased risk among participants drinking 8-14 drinks/week. BMI ≥30 kg/m2, diabetes, and hypertension increased risk among consumers of 1-28 drinks per week, but not among heavier drinkers. Smoking increased risk across all alcohol levels, with indications of supra-additive interaction. PAFs were 59.9% for alcohol consumption, 29.3% for hypertension, 21.2% for smoking, 13.8% for BMI ≥30 kg/m2, and 9.0% for diabetes; dyslipidemia had no statistically significant PAF. CONCLUSIONS: Obesity, diabetes, hypertension, and smoking, but not dyslipidemia, increased cirrhosis risk, with modest effects compared to heavy alcohol use. The impact of cardiometabolic risk factors was non-significant above 28 drinks per week, underscoring alcohol as the principal driver of cirrhosis risk in heavy drinkers. IMPACT AND IMPLICATIONS: The introduction of the MetALD nomenclature has highlighted the need to understand how alcohol consumption and cardiometabolic risk factors jointly contribute to cirrhosis risk, but whether these interactions differ by level of alcohol intake has remained unclear. In this population-based cohort, alcohol consumption was the dominant modifiable risk factor, with approximately 60% of cirrhosis cases attributable to drinking above the minimum-risk reference range, whereas the attributable fractions for individual cardiometabolic and lifestyle risk factors were substantially smaller. Supra-additive associations were observed for obesity, diabetes, and hypertension mainly at alcohol intakes up to 28 drinks per week, while smoking showed supra-additivity with alcohol across alcohol consumption levels; dyslipidemia showed no clear contribution. These findings support alcohol reduction as the primary prevention priority, while indicating that smoking cessation and cardiometabolic risk management should be considered complementary prevention targets, particularly among people who drink alcohol.