Main findings of this study
In this large-scale, nationwide, longitudinal cohort study, we investigated the relationship between the FLI, a validated surrogate marker of NAFLD, and future CV events for subjects without pre-existing MI and ischemic stroke. We found that the 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 value 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 the 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.
FLI is correlated with the CVD incidence in the general population
NAFLD is recognized as a risk factor for CVD [18]. A recent meta-analysis demonstrated that the presence of NAFLD was significantly associated with a 64% increased risk of a composite endpoint of CVD [19]. Furthermore, a cross-sectional study of 3,270 subjects who were referred for coronary angiography reported that high FLI values were independently associated with increased risk of all-cause mortality, CV death, non-CV mortality, and cancer [20]. To determine the effect of NAFLD on CVD incidence in the general population, we used the FLI. The proportion of patients with newly developed CV events in our study gradually increased across FLI quartiles and FLI deciles. We also observed that a one standard deviation increase in the FLI values was associated with increased risks of CV events. Moreover, we found that linear relationship between hepatic steatosis index (HSI), other previously validated index for hepatic steatosis [21], and the CVD incidence (Additional file 5). These findings suggest a quantitative relationship, and the extent of hepatic steatosis had a major role in the development of 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 close relationship between higher FLI values and future risk of CVD remained. Because the NHIS database includes the entire South Korean population, our findings provide robust evidence regarding the association between the FLI and risk of CVD events in the general population, thereby suggesting that the FLI could be applied as a useful screening tool for predicting the CVD incidence in the general population.
FLI, a surrogate marker of NAFLD, is associated with CV death
Despite the known close relationship between NAFLD and CVD [22], whether NAFLD independently increases the risk of CV death remains controversial. Several studies demonstrated unequivocally increased incidence of CV deaths among patients with NAFLD [23, 24]. Nevertheless, some meta-analyses failed to confirm this association [19, 25]. Moreover, Hwang et al. reported that the association between NAFLD and mortality caused by CVD was observed only for women [26]. Furthermore, in a 15-year follow-up study of 2,075 middle-aged Caucasian subjects, the FLI was not independently associated with CVD mortality; however, it was a significant predictor of an increased risk for liver-related mortality [27]. However, previous studies involved 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 the FLI is associated with mortality caused by CVD independent of traditional CV risk factors such as body weight, cholesterol levels, hypertension, diabetes, and use of medication for dyslipidemia. We also observed that the association between higher FLI values and CV death is significant for both sexes. It is important to determine whether NAFLD also affects future CV deaths, and our study contributes supportive and confirmative data regarding this emerging issue.
Possible mechanisms of the independent association between FLI and CVD
Previously, NAFLD was regarded as a hepatic manifestation of metabolic syndrome, which is a traditional CVD risk factor [28, 29]. 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 by NAFLD and CVD [30]. However, increasing evidence has suggested that NAFLD is an independent risk factor for CVD. In addition to genetic factors, various hepatokines related to the liver-gut axis and systemic insulin resistance can induce endothelial cell deterioration due to inflammatory reactions and oxidative stress, structural changes in blood vessels, and changes in blood coagulation factors [31]. 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. Therefore, further research is required to gain mechanistic insights regarding the pathophysiology linking NAFLD to the development and progression of these extrahepatic chronic diseases.
Limitations
The major strengths of the current study were its large sample size, with more than 3,000,000 subjects, and longitudinal data. However, several limitations of this study should be addressed. The mortality rate was assessed during a short follow-up period of 6 years, which may have been a limitation. Another limitation of our study was the use of the FLI as a surrogate measure of NAFLD instead of histological assessment of NAFLD. Furthermore, because FLI comprises known CV risk factors (BMI, triglyceride levels, waist circumference) [28, 32], these variables account for the associations observed in the current study. However, to overcome this limitation, we conducted analyses stratified by the presence or absence of these CV risk factors. Because the NHIS database relies on the assignment of a diagnostic code for CVD by physicians, there is the possibility of misdiagnoses of CVD, which may lead to under or overestimation of the disease prevalence. We did not collect data regarding medications or interventions, including weight reduction, that may have affected liver fat accumulation during the follow-up period. Moreover, other unreported confounders, including socioeconomic status and genetic factors, may have affected the association between NAFLD and mortality in our study participants. Finally, because our study subjects were mostly Korean, the results might not be generalizable to other ethnic groups.