In this large-scale, nationwide, longitudinal cohort study, we investigated the relationship between FLI, a validated surrogate marker of NAFLD, and future CV events in subjects without a history of CVD. We found that FLI was an independent predictor of CV events, even after adjusting for possible confounding factors including body weight and cholesterol levels, during a median follow-up period of 6 years. There was a linear association between the increase in FLI values and primary outcome measures. When this association was stratified by outcome, a higher FLI level was significantly associated with an increased risk of non-fatal MI, non-fatal ischemic stroke, and CV death. We also demonstrated a greater impact of FLI on subjects with other co-morbidities such as hypertension and diabetes. To our knowledge, the current study is the largest to date to evaluate the relationship between a clinical marker of NAFLD and future CV events in the general population.
NAFLD is recognized as a risk factor for CVD. A recent meta-analysis demonstrated that the presence of NAFLD was significantly associated with a 64% increased risk of a composite endpoint of CVD [16]. In addition, a cross-sectional study of 3,270 subjects who were referred for coronary angiography reported that high FLI levels were independently associated with increased all-cause, CV, and non-CV mortality, as well as cancers [17]. To determine the effect of NAFLD on CVD in the general population, we used FLI. The proportion of patients with newly developed CV events in our study gradually increased across FLI quartiles and FLI deciles, suggesting a quantitative relationship, with the amount of hepatic steatosis playing a major role in the development of CVD. Regarding the fact that FLI < 30 is suggested to rule out NAFLD, we identified that even the normal range of FLI (7.02-29) was associated with a higher risk of incident CVD. When this association was stratified by the presence or absence of various CV risk factors (e.g., old age, obesity, diabetes, hypertension, and use of anti-dyslipidemia agents), the relationship between higher FLI levels and future risk of CVD remained. Considering the fact that the NHIS database includes the entire South Korean population, our finding provides robust evidence of the association between FLI and risk of CVD events in the general population. This finding suggests that FLI would be a useful screening tool as a predictor of CVD incidence.
Despite the known close relationship between NAFLD and CVD, whether NAFLD independently increases the risk of CV death remains controversial. Several studies demonstrated unequivocally increased incidence of CV deaths in patients with NAFLD[18, 19]. Nevertheless, some meta-analyses failed to confirm this association[16, 20]. Moreover, Hwang et al. reported that the association between NAFLD and mortality caused by CVD was observed only in women and not in men[21]. In addition, in a 15-year follow-up study of 2,075 middle-aged Caucasian, FLI was not independently associated with CVD mortality, while it was a significant predictor of increased risk of liver-related mortality [22]. However, these previous studies were conducted in specific cohorts with relatively small numbers of patients. Consequently, the findings of these studies have limited generalizability to a general population. Conversely, the current study was a large-scale population-based study. We demonstrated that FLI is associated with mortality caused by CVD independent of traditional CV risk factors such as body weight, cholesterol levels, hypertension, diabetes, and medication for dyslipidemia. We also observed that the association between higher FLI values and CV death is significant in both sexes. It would be important to determine whether NAFLD also affects future CV deaths, and our study contributes supportive and confirmative data regarding this emerging issue.
Previously, NAFLD was regarded as a hepatic manifestation of metabolic syndrome, which is a traditional CVD risk factor. The specific contribution of NAFLD to increased CVD risk, especially in clinical studies, is difficult to assess separately from the combination of risk factors that are shared between NAFLD and CVD[23]. However, there has been increasing evidence suggesting NAFLD itself to be an independent risk factor of CVD. Apart from genetic factors, various hepatokines related to the liver-gut axis and systemic insulin resistance can also induce endothelial cell deterioration due to inflammatory reactions and oxidative stress, structural changes in blood vessels, and changes in blood coagulation factors[24]. Although these mechanisms plausibly link NAFLD to the development and progression of CVD, no study to date has proven a cause-and-effect relationship between these two entities, and further research is required to gain mechanistic insights into the pathophysiology linking NAFLD to the development and progression of these extrahepatic chronic diseases.
The major strength of the current study was the large sample size, consisting of more than 3,000,000 subjects, and longitudinal data. However, several limitations of this study should also be addressed. The mortality rate was assessed over a short follow-up period of 6 years, which may be a limitation. A further limitation of our study is the use of FLI as a surrogate measure for NAFLD instead of the histological assessment for NAFLD. Furthermore, because FLI comprises known CV risk factors (BMI, triglyceride, waist circumference), these variables account for the associations seen in the current study. However, to overcome this limitation, we conducted analysis stratified by the presence or absence of these CV risk factors. Second, because the NHIS database relies on physicians’ assignment of a diagnostic code for CVD, there is a possibility of misdiagnosis of CVD, which may lead to under or overestimation of disease prevalence. Third, we did not collect data on medications or interventions, including weight reduction, that may have affected liver fat accumulation during the follow-up period. In addition, other unreported confounders, including socioeconomic status and genetic factors, may have affected the association between NAFLD and mortality in our study participants. Lastly, as our study subjects were mostly Korean, the results might not be generalizable to other ethnic groups.