Association between nonalcoholic fatty liver disease and cardiovascular disease revealed after comprehensive control of metabolic risk factors: a nationwide population-based study in Korea

OBJECTIVES: Previous epidemiological studies have limitations in revealing whether cardiovascular disease (CVD) incidence is mediated by interim occurrence of other metabolic diseases in otherwise healthy nonalcoholic fatty liver disease (NAFLD) patients. METHODS: The study population consisted of 334 280 healthy subjects who had had the National Health check-ups in South Korea from 2009 to 2014. The fatty liver index (FLI) was used to identify subjects with NAFLD. CVD was defined as occurrence of a composite of cardiovascular death, myocardial infarction, ischemic stroke, or coronary revascularization. The association between FLI and CVD incidence was analyzed using time-dependent Cox regression analyses. RESULTS: The study population was categorized into quartile groups according to FLI (range: Q1, 0-4.9; Q2, 5.0-12.5; Q3, 12.6-31.0; Q4, >31.0). The median follow-up duration was 5.4 years, during which subjects with higher FLIs experienced CVD more frequently than did those with lower FLIs [Q1, 215 (0.3%); Q2, 498 (0.6%); Q3, 753 (0.9%); Q4, 981 (1.2%); P < 0.001]. Adjustment of baseline characteristics revealed that a higher FLI was independently associated with an increased risk for CVD [hazard ratio between Q4 and Q1, 1.86; 95% confidence interval (CI), 1.59-2.17; P < 0.001]. The association between them remained statistically significant (hazard ratio between Q4 and Q1, 1.92; 95% CI, 1.63-2.25; P < 0.001) after further adjustment for the interim events (diabetes, hypertension, heart failure, and atrial fibrillation). CONCLUSIONS: Otherwise healthy NAFLD patients progressed to develop CVD independently of the interim occurrence of other metabolic diseases, which emphasizes the importance of NAFLD as a potential therapeutic target for prevention of CVD.