We read with great interest the study by Han et al. [1], which reviewed the basic definition of non-alcoholic fatty liver disease (NAFLD) and its subtypes, including non-alcoholic fatty liver (NAFL), NAFL with inflammation, and non-alcoholic steatohepatitis (NASH). Conventional classification of NAFLD subtypes, classification by severity, and classification using scoring systems, such as the NAFLD activity score or fibrosis score, have provided an in-depth understanding of the disease status and the risk of liver cirrhosis and hepatocellular carcinoma [2,3]. However, none of the classifications targeted the risk of cardiovascular disease (CVD) and dementia according to NAFLD status.

In recent years, NAFLD has been found to increase the risk of several extrahepatic diseases, including CVD and dementia [4,5]. Previously, we used the Korean National Health and Nutrition Examination Survey-derived NAFLD (K-NAFLD) score, which was externally validated in an independent population using FibroScan, to evaluate the risk of CVD. We found that low-intermediate and high hepatic steatosis were associated with 30% and 55% higher risk of CVD, respectively [6,7]. Furthermore, high steatosis with at least two forms of metabolic dysfunction was associated with a 71% higher risk of CVD compared to high steatosis without metabolic dysfunction. Therefore, the use of the K-NAFLD score, along with metabolic dysfunction, may be useful in classifying NAFLD in terms of CVD risk.

NAFLD has also been found to be a risk factor for the development of dementia [5,8]. After independent propensity score matching between the low-intermediate and intermediatehigh fatty liver index (FLI) groups, we found a 4% lower and 5% higher risk of dementia for the low FLI group (FLI<30) and high FLI group (FLI≥60), respectively, compared with the intermediate FLI group (FLI≥30 and <60). Additionally, in a preclinical study, NAFLD-induced chronic hepatic inflammation was associated with the pathogenesis of Alzheimer’s disease through the induction of neurodegeneration [9]. Lipocalin-2, an adipokine that is exclusively produced in NASH liver and circulates in the bloodstream, has also been found to activate pro-inflammatory processes and weaken the blood-brain barrier [10,11]. Therefore, the severity of steatosis and the presence of NASH may be useful in classifying patients who are at higher NAFLD-associated risk of dementia.

Taken together, clinicians need to consider NAFLD-associated non-liver comorbidities as an important aspect of the management and classification of the disease [12]. The use of NAFLD scoring systems, metabolic dysfunction, and the severity of steatosis or the presence of NASH may provide insight into the development of NAFLD subtypes in terms of CVD and dementia risk.