Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is a risk factor for significant hepatic fibrosis [1, 2]. Since there are multiple pathogeneses for NAFLD, various subgroups are seen in patients with NAFLD [3]. “Non-obese NAFLD with metabolic syndrome (MS)” is one subgroup, and a noteworthy fact is that this subgroup is growing increasingly prevalent [4, 5]. However, limited information is available regarding the prevalence and risk factors for non-alcoholic steatohepatitis (NASH) and significant fibrosis in non-obese patients with NAFLD.

In this issue of the Journal of Gastroenterology, Kim et al. investigated the prevalence of NASH and significant fibrosis in non-obese patients with NAFLD and MS [6]. They found that NASH and significant fibrosis were seen in approximately 60% and 55% of non-obese patients with NAFLD and MS, respectively, and its prevalence did not significantly differ from those in obese patients with NAFLD and without MS. Thus, metabolic disorders promote progression to NASH and significant fibrosis in non-obese patients with NAFLD. Furthermore, they showed that the ratio of visceral adipose tissue area-to-subcutaneous adipose tissue area (VAT/SAT) was an independent factor for NASH or significant fibrosis in a dose-dependent fashion [6]. Thus, this study revealed an important pathogenesis of non-obese NAFLD with MS. Even in non-obese patients with NAFLD, a metabolically unhealthy phenotype can promote progression to NASH and significant fibrosis through an increase in the VAT/SAT ratio.

Non-obese patients with NAFLD have been reported to have a lower risk of steatohepatitis and advanced fibrosis [7], and a patatin-like phospholipase domain-containing 3 (PNPLA3) variant (rs738409 C>G) was the only factor associated with NASH or significant fibrosis in non-obese patients with NAFLD [8]. Thus, genetic alteration has been thought to be the main pathogenesis of progression to NASH and significant fibrosis in non-obese patients with NAFLD [9]. However, in this issue of the Journal of Gastroenterology, Kim et al. revealed that the VAT/SAT ratio was an independent factor for NASH or significant fibrosis in a dose-dependent fashion [6]. Tobari et al. reported that the prevalence of PNPLA3 risk alleles did not differ between non-obese and obese patients with NAFLD [10]. Li et al. reported that non-obese patients with NAFLD had comparable lifestyle habits, including overeating, sleep disturbances, and overtime work, as obese patients with NAFLD [11]. Moreover, Wong et al. recently reported that a reduction in body weight and waist circumference by lifestyle intervention was an independent factor associated with the remission of NAFLD in non-obese patients [12]. Taken together, along with genetic alterations, metabolic syndrome with visceral obesity seems to be an important pathogenesis even in non-obese NAFLD.

Non-obese NAFLD and obese NAFLD are classified based on BMI, which is mainly affected by adipose tissue and skeletal muscle mass. Therefore, patients with NAFLD and adiposis and muscle atrophy can be classified as non-obese NAFLD. In fact, physical inactivity is an independent predictor of NAFLD in non-obese subjects [13]. Skeletal muscle mass is also significantly lower in non-obese patients with NAFLD than in obese patients with NAFLD [10]. In addition, sarcopenia exacerbates obesity-associated insulin resistance [14], which is a potent risk factor for NASH and advanced hepatic fibrosis in patients with NAFLD. Recently, Vila et al. reported that the muscle-specific ubiquitin-conjugating E2O causes diet-induced insulin resistance and metabolic syndrome in mice [15]. Thus, loss of skeletal muscle mass could be a pathogenesis for NASH and advanced fibrosis in non-obese patients with NAFLD and metabolic syndrome.

In this issue of the Journal of Gastroenterology, Kim et al. clearly demonstrated that, regardless of BMI, metabolic syndrome was associated with the progression to NASH and significant fibrosis in patients with NAFLD [6]. However, there are limitations in this study. First, this study was designed as a cross-sectional study, and the causal relationship between metabolic syndrome and the progression to NASH and significant fibrosis remains unclear. Second, metabolic syndrome was defined by elevation of blood pressure, fasting blood glucose level, and serum triglyceride level, and reduction of high-density lipoprotein cholesterol level. It remains unclear which metabolic disorder has the most significant impact on the progression to NASH and significant fibrosis. Third, lifestyle-related factors including energy intake, mild alcoholic consumption, and physical activity, as well as the skeletal muscle mass of the trunk, were not analyzed in this study. These limitations should be examined in a future study to reveal further the pathogenesis of and establish therapeutic strategies for non-obese NAFLD.