The results of this study demonstrate a notable correlation between sarcopenia and the severity of liver fibrosis in patients with MASLD aged 18-59 years. Patients with sarcopenia exhibited a markedly elevated risk of significant liver fibrosis, advanced liver fibrosis, and cirrhosis in comparison to non-sarcopenia patients across both the Chinese and US cohorts. Moreover, the study demonstrated a significant inverse correlation between ASMI and the severity of liver fibrosis in patients with MASLD. In the Chinese cohort, the risk of liver fibrosis exhibited a gradual decline with increasing ASMI, and this relationship demonstrated a nonlinear feature in specific liver fibrosis indicators. In contrast, the potential of ASMI as an essential biomarker for predicting the progression of liver fibrosis in patients with MASLD was similarly supported in the US cohort. However, the relationship between ASMI and liver fibrosis was found to be closer to linear. These findings provide support for the hypothesis that sarcopenia represents an independent risk factor for the progression of liver fibrosis in patients with MASLD.

The findings of this study align with those of previous investigations into the relationship between sarcopenia and liver fibrosis, furthering our comprehension of this association. Prior research has demonstrated that sarcopenia is linked to the advancement of liver fibrosis in a multitude of chronic liver disorders [12, 14]. Some studies in patients with NAFLD have confirmed that sarcopenia is associated with the severity of liver fibrosis [15, 16, 23, 24]. Furthermore, several other studies have demonstrated that reduced ASMI is an independent risk factor for liver fibrosis [25, 26]. A recent meta-analysis that included 25 relevant studies also showed that sarcopenia is associated with an increased chance of liver fibrosis in patients with NAFLD [12]. These studies highlight sarcopenia’s crucial role in hepatic fibrosis in fatty liver disease.

This study represents the first investigation into the relationship between sarcopenia and hepatic fibrosis in patients with MASLD. Utilizing a cross-national cohort study design, the prevalence of sarcopenia was identified as an independent risk factor for the progression of hepatic fibrosis. Compared to previous studies, the present study not only included two large cohorts from disparate cultural backgrounds but also effectively controlled for potential confounding variables through meticulous data screening and multivariate adjustment modeling, thus enhancing the reliability and generalisability of the findings. Furthermore, the present study employed the RCS model to elucidate the potential non-linear relationship between ASMI and liver fibrosis severity, thereby offering a novel perspective on the role of sarcopenia in the pathogenesis of liver fibrosis. In conclusion, this study underscores the utility of ASMI as a valuable tool for evaluating the risk of hepatic fibrosis in patients with MASLD, offering a novel approach for the early identification of high-risk patients in clinical settings. These insights enhance our comprehension of the association between sarcopenia and hepatic fibrosis and illuminate promising avenues for future research.

The precise mechanisms through which sarcopenia is associated with liver fibrosis in patients with MASLD encompass a range of interrelated factors that collectively contribute to the advancement of liver fibrosis. Patients with sarcopenia frequently exhibit insulin resistance, which represents a crucial pathophysiological basis of MASLD [27, 28]. Insulin resistance results in hyperglycemia, hyperinsulinemia, and dyslipidemia, which can directly damage hepatocytes and promote hepatic fat deposition and oxidative stress. This, in turn, gives rise to an inflammatory response and fibrosis [29,30,31,32]. Furthermore, a reduction in muscle mass results in a decline in glucose uptake and utilization, thereby exacerbating systemic metabolic abnormalities and accelerating the onset and progression of liver fibrosis [33]. In this study, patients with sarcopenia exhibited higher levels of metabolic abnormalities, including BMI, waist circumference, blood glucose, and lipid levels, compared to patients without sarcopenia. These findings also demonstrate a robust correlation between sarcopenia and metabolic abnormalities. The elevated glucose and lipid levels observed in sarcopenia patients may serve to further exacerbate the metabolic burden on the liver, thereby promoting the occurrence and development of liver fibrosis.

Patients with sarcopenia frequently present with a chronic, low-grade inflammatory state within their bodies. This may be associated with releasing inflammatory factors and cellular debris during muscle tissue degeneration [34]. The levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and C-reactive protein (CRP), are typically elevated in patients with sarcopenia [34, 35]. These inflammatory factors enter the liver via the circulatory system, thereby activating inflammatory pathways within the liver. This results in hepatocyte damage and repair responses that ultimately lead to liver fibrosis [27, 35].

In patients with sarcopenia, there is a reduction in the body’s antioxidant capacity and an increase in oxidative stress, elevating the level of lipid peroxidation products. These peroxidation products can directly damage hepatocyte membranes and organelles and activate hepatic stellate cells (HSC), prompting their transformation into myofibroblasts and secretion of large amounts of extracellular matrix (ECM). The latter process promotes the formation of liver fibrosis [36, 37]. Moreover, mitochondrial dysfunction in muscle and liver cells has been identified as a contributing factor in the development of sarcopenia and liver fibrosis [37]. Mitochondria play a crucial role in energy metabolism and cell death. Such dysfunction may result in cell injury and death, which in turn may contribute to developing liver fibrosis [38].

Muscle represents a significant source of several adipokines and cytokines, including leptin, lipocalin, and IL-6. The levels of these factors are frequently dysregulated in patients with sarcopenia [27]. Leptin resistance and diminished lipocalin levels are associated with insulin resistance and adipose accumulation in the liver [39,40,41]. Concurrently, elevated pro-inflammatory factors, such as IL-6, exacerbate the liver’s inflammatory response and fibrotic process [42]. In conclusion, the relationship between sarcopenia and liver fibrosis in patients with MASLD can be attributed to a complex interplay of mechanisms, including insulin resistance and metabolic abnormalities, chronic low-grade inflammation, oxidative stress and lipid peroxidation, mitochondrial dysfunction, and dysregulation of adipokines and cytokines. These mechanisms interact with one another and collectively contribute to the onset and progression of liver fibrosis.

In subgroup analyses, we further investigated the influence of diverse demographic factors, including gender, age, smoking status, alcohol, physical activity, BMI, DM, and hypertension, on the relationship between sarcopenia and liver fibrosis. While the impact of sarcopenia on liver fibrosis was more pronounced in specific subgroups, the overall negative effect of sarcopenia on liver fibrosis remained consistent across all subgroups. This finding highlights the prevalence and stability of sarcopenia as a significant risk factor for liver fibrosis while also providing a scientific foundation for the development of tailored intervention strategies for diverse patient subgroups.

While the present study has yielded meaningful findings regarding the relationship between sarcopenia and hepatic fibrosis, it is essential to acknowledge its limitations. First, this study focused on the 18-59 age group, which may limit the generalizability of the findings to a broader age range, particularly the elderly population. The elderly population is at an elevated risk of both sarcopenia and hepatic fibrosis. Furthermore, the relationship between sarcopenia and hepatic fibrosis may vary by age. Consequently, future studies must include a more extensive age range to gain a deeper understanding of the influence of sarcopenia on liver fibrosis across different life stages. Secondly, although the present study controlled for some confounding factors, other factors that may influence liver fibrosis, such as genetic background and dietary habits, were not explored sufficiently. Genetic factors may play a significant role in the pathogenesis of sarcopenia and hepatic fibrosis, while dietary habits directly impact muscle mass and liver health. Failure to control for these factors may limit our ability to understand the relationship between sarcopenia and liver fibrosis fully. Future studies should consider these factors to more fully elucidate the complex mechanisms of hepatic fibrosis in patients with MASLD. Furthermore, this study employed the use of ASMI as a diagnostic tool for sarcopenia. While this is one of the standard diagnostic procedures, it may not fully account for the decline in muscle function, which is also a crucial aspect of the definition of sarcopenia. It would be beneficial for future studies to consider incorporating additional assessment methods, such as muscle strength testing and functional testing, to gain a more comprehensive understanding of sarcopenia. Finally, although the use of two cohorts from different geographic and ethnic backgrounds increased the generalizability and representativeness of the study, it is important to note that differences between the cohorts may affect the interpretation of the results. For example, the U.S. and Chinese cohorts exhibited notable differences in socioeconomic status, healthcare systems, and lifestyle factors. These discrepancies may indirectly influence the incidence and risk factors for sarcopenia and liver fibrosis. It would be beneficial for future studies to explore these potential differences further and consider adjusting analytic methods to minimize their impact on the results.