In this nationwide study of 8 million middle-aged population under routine health screening, the CVD risk increased in the following order: non-MAFLD, OW-MAFLD, lean-MAFLD, and DM-MAFLD. Even after appropriate adjustment for confounders, the order of the CVD risk was maintained. Similar trends were observed for the risk of liver cancer development and all-cause death.
Our study had several clinical implications. First, we confirmed that patients with MAFLD, with any subtype, were at a higher risk of CVD events than those without MAFLD. Previous observational studies have shown that NAFLD is significantly associated with a higher risk of CVD development , and that CVD, rather than liver-related complications or extrahepatic malignancies, is the primary cause of death in patients with NAFLD . Despite this close association between NAFLD and CVD, the NAFLD criteria might have a potential pitfall of including “metabolically healthy” subjects, not having DM, hypertension, dyslipidemia, or obesity, with negligible risk of CVD. Such patients with NAFLD who do not satisfy the new MAFLD criteria are at a significantly lower risk of CVD . we focused on subjects with MAFLD with “metabolically unhealthy” status and found that CVD incidence rates are much higher in MAFLD subgroups than those in the control group. In addition, extending this prior knowledge, we further evaluated the overlapping components between MAFLD subtypes by dividing them into seven mutually exclusive groups. In the OW-MAFLD, OW with MA conferred a higher CVD risk than OW without MA, whereas in the DM-MAFLD subtype, the presence of MA was associated with a higher CVD risk in both OW and non-OW patients. Our results suggest that the presence of MA in patients with OW-MAFLD and DM-MAFLD further increases the CVD risk.
Second, among the MAFLD subtypes, DM-MAFLD conferred the highest risk for CVD events. This is not surprising as DM has been recognized as a major risk factor for CVD . DM is associated with inflammatory and thrombotic condition, and endothelial cell dysfunction and oxidative stress due to insulin resistance and hyperglycemia; such processes can, in turn, lead to the development of atherosclerosis and CVD . Several studies using a large claims database reported that DM increases CVD risk in patients with NAFLD or MAFLD [4, 16]. Our study extends this prior knowledge by demonstrating that the DM-MAFLD subtype may be a strong predictor of future CVD events.
Third, lean-MAFLD was associated with a higher CVD risk than OW-MAFLD. There have been controversies regarding the different prognoses between obese and non-obese patients with NAFLD. A meta-analysis reported that obesity in NAFLD could predict worse long-term outcomes , while others reported that non-obese NAFLD increased CVD risk and CVD-related mortality [18, 19]. Another study showed similar event-free survival between obese and lean patients with NAFLD . In our study, the high CVD risk of lean-MAFLD compared to OW-MAFLD might be due to the influence of fibrotic burden. Several previous studies have revealed that advanced liver fibrosis in patients with FLD is not only a major risk factor for liver cancer or liver-specific mortality but is also closely related to CVD risk [21, 22]. Indeed, in this study, lean-MAFLD with advanced fibrosis had an increased CVD risk compared to OW-MAFLD without advanced fibrosis, whereas lean MAFLD without advanced fibrosis did not. This result supports the hypothesis that the extent of liver fibrosis may play a role in CVD risk. Although our data could not provide information regarding muscle mass, the prevalence of sarcopenia might have also influenced the CVD risk difference between lean and OW-NAFLD. A recent study proved the independent associations among NAFLD, fibrosis, sarcopenia, and CVD . “Metabolically unhealthy” lean patients may have less lean body mass, especially muscle mass, which may have an impact on poor CVD outcome [21, 23]. In addition, it is known that, unlike visceral fat, subcutaneous fat plays a role in protecting organs against lipotoxicity, and leg fat is associated with a low CVD risk . Therefore, obese patients with a large muscle mass and little visceral fat tissue may have a good prognosis.
Fourth, in our study, the risk for liver cancer and all-cause death varied across MAFLD subtypes similarly as for CVD events. DM is known to be a major risk factor for liver cancer development . In addition, a recent study revealed that the risk of advanced liver fibrosis increased in the order of OW, lean, and DM-MAFLD subtypes . Therefore, in our study, differences in fibrotic burden between each MAFLD subtype may affect the differences in liver cancer risk. In this study, all-cause mortality was lowest in OW-MAFLD and similarly higher in lean- and DM-MAFLD in most adjusted models. This finding is supported by a recent study based on the National Health and Nutrition Examination Survey III data , which showed that both lean- and DM-MAFLD might have higher risk of all-cause death than OW-MAFLD. This may be because OW-MAFLD subtype includes “metabolically healthy” patients except for high BMI .
Our study has several strengths. To the best of our knowledge, this is the first study to evaluate the long-term risk of CVD events, liver cancer development, and all-cause death according to the MAFLD subtypes. Based on the NHIS database, the single provider of universal healthcare coverage in Korea, with a large sample size of approximately 8 million subjects, and a median follow-up period of 10 years, we could compare the CVD risk among MAFLD subtypes with adequate statistical power and minimized risk of selection bias, which was further confirmed after adjustment for various confounders. Additionally, the large sample size allowed us to investigate the influence of fibrotic burden on CVD risk in each MAFLD subtype. Despite the strengths of our study, we are also aware of its limitations. First, in this study, FLD was defined by FLI without histology or imaging techniques. However, recent guidelines suggest that non-invasive markers such as FLI are acceptable alternatives for defining FLD in large epidemiologic studies [2, 7]. Second, only the BARD score was used to evaluate advanced liver fibrosis due to the limited availability of variables in the Korean NHIS database required to calculate other noninvasive surrogates such as fibrosis-4 index or NAFLD fibrosis score [4, 28]. Third, our study included only middle-aged Koreans; caution should be exercised when applying the results of this study to other populations or age groups. Finally, since there was no insulin and high-sensitivity C-reactive protein values in this database, MA were defined only with the remaining five factors; however, sensitivity analysis showed similar trends of CVD risk according to MAFLD subgroups.
In conclusion, long-term CVD outcomes differed across the MAFLD subtypes. Further studies are warranted to investigate whether preventive or therapeutic interventions should be optimized according to the MAFLD subtypes.