Muscle loss is a significant predictor of mortality in patients with LC and should be actively assessed in routine clinical practice [1]. In particular, it is important to identify patients at high risk of rapid muscle loss leading to sarcopenia [28]. Many studies focused on the incidence of sarcopenia [18], but our study, which comprehensively examined the longitudinal loss of muscle mass and its associated factors, revealed two important findings. The first is that ALD cirrhosis was associated with a two-fold faster decline in skeletal muscle mass than viral cirrhosis. Moreover, ALD cirrhosis, older age, male sex, and advanced liver disease were all independently associated with an increased risk of rapid muscle loss. The second finding was that ALD cirrhosis, rapid muscle loss, and low subcutaneous adipose tissue level were associated with an increased risk of mortality independently of well-established prognostic factors such as MELD and ALBI scores.

The annual rate of muscle loss in younger adults is about 0.5%, compared with 1.0% in older adults [29]. In patients with chronic liver disease, the annual rate of skeletal muscle loss increases with the severity of cirrhosis progression (from − 1.3% in Child–Pugh class A patients to − 3.5% in class B and − 6.1% in class C patients) [14, 16, 27]. Sarcopenia affects 30–70% of patients with LC, with the prevalence varying according to the underlying causes [1, 28]. For example, the prevalence of sarcopenia in cirrhosis due to ALD is 80%, compared with 10–40% in cirrhosis due to non-alcoholic steatohepatitis, viral hepatitis, or autoimmune hepatitis [16, 24]. The present findings, showing that the rate of skeletal muscle loss is significantly faster in ALD cirrhosis (− 5.7%) than in cirrhosis caused by HBV (− 2.8%) or HCV (− 3.1%) and that 70% of patients with ALD cirrhosis were in the poor prognosis group due to skeletal muscle loss, are in agreement with those of previous reports.

The present findings of close associations between rapid muscle loss and ALD cirrhosis, older age, male sex, and advanced liver dysfunction are also consistent with those of previous studies [16, 17]. Meta-analyses have also shown an association between ALD, male sex, and Child–Pugh class C cirrhosis and sarcopenia [4]. Patients with ALD cirrhosis often present with accelerated starvation, malnutrition, and severe liver dysfunction at the time of diagnosis [3, 28], suggesting a propensity for early muscle wasting and a higher susceptibility to sarcopenia. Excessive alcohol consumption may also lead to alcohol-related muscle myopathy [30], which potentially causes rapid muscle loss compared to other etiologies and affects the results of our study. Ethanol and acetaldehyde also increase the levels of inflammatory cytokines and endotoxins, impair hepatic ureagenesis and mitochondrial function, and increase autophagy and levels of muscle ammonia as well as myostatin, a negative regulator of skeletal muscle growth [31, 32]. These factors result in impaired protein synthesis and increased proteolysis, leading to accelerated muscle breakdown and subsequent sarcopenia. In addition, sarcopenia and liver dysfunction may also contribute to muscle loss in cirrhosis [22, 28]. In addition, HCC development and its treatment may affect skeletal muscle mass and prognosis [11, 12]. In this regard, we analyzed the impact of HCC development during the CT scan interval on the ΔSMA/year. Among the total cohort of patients, 85 (22%) developed HCC during this period. The results showed no significant difference in the ΔSMA/year between patients with and without HCC occurrence (P = 0.104). We hypothesize that the small number of patients with HCC had a limited impact on the ΔSMA/year.

In the present study, ALD was an independent predictor of mortality in patients with cirrhosis. ALD is the leading cause of cirrhosis, liver failure, and liver-related mortality worldwide [19]. Furthermore, mortality due to ALD could double by 2040 without effective interventions to reduce alcohol consumption [33], making alcohol management an important health issue. Rapid skeletal muscle mass loss (less than -3.1%/year) was also associated with mortality in patients with cirrhosis, which is consistent with a previous report [14]. A prospective cohort study has also suggested that changes in muscle mass may independently predict the development of cirrhosis complications [15]. Furthermore, the coexistence of sarcopenia and rapid muscle loss predicts long-term mortality in patients with cirrhosis, independent of liver function reserve and portal hypertension [14, 17]. Strategies to improve survival in patients with cirrhosis may therefore include treatment to ameliorate progressive muscle loss, improvement of nutritional status and liver functional reserves, and abstinence from alcohol. Clinical trials have shown that nalmefene, an opioid system modulator, reduces the total amount of alcohol consumption by over 60% [34] and improves liver stiffness and hepatic steatosis as measured by transient elastography [35]. Since alcohol reduction contributes to the improvement of liver‐related complications and mortality in patients with ALD cirrhosis, nalmefene may prevent muscle atrophy and improve prognosis [4, 36, 37].

Interventional studies have shown that exercise therapy improves physical ability and increases muscle mass and strength in patients with chronic liver disease, regardless of the presence of HCC [10,11,12,13]. A meta‑analysis of randomized controlled trials demonstrates that a combination of aerobic and resistance exercise reduces serious events, such as hepatic failure, HCC, or death, and improves the prognosis of patients with liver cirrhosis [10]. Indeed, a randomized, double-blind trial has shown that a combined nutrition- and exercise-based intervention improved muscle mass in patients with cirrhosis and sarcopenia [38]. As a nutritional therapy, BCAA supplementation has also been shown to improve skeletal muscle mass and liver function reserve and improve the prognosis of patients with cirrhosis [6, 38]. BCAAs not only serve as an energy substrate in patients with liver cirrhosis but also improve liver regeneration, immune function, albumin production, ammonia metabolism, and insulin sensitivity. Accumulating evidence demonstrates that these beneficial physiological effects may prevent hepatocarcinogenesis, inhibit sarcopenia, and improve the prognosis of patients with liver cirrhosis [8, 9]. Given this background, we further analyzed the data to investigate the effects of BCAA supplementation on the ΔSMA/year. Among the enrolled patients, 195 (51%) received BCAA supplementation. The results showed that the ΔSMA was − 4.2% in patients treated with BCAAs and − 3.7% in those without BCAA supplementation, with no statistically significant difference between the two groups (P = 0.21). This seemingly contradictory result may be attributed to more severe liver dysfunction (e.g., higher MELD score) in BCAA-treated patients compared with non-BCAA-treated patients (P < 0.001), and to unmeasured variables such as alcohol abstinence, dietary intake and habits, and daily physical activity levels [1].

The results of the present study clarified that loss of subcutaneous adipose tissue in addition to that of muscle mass increased the risk of mortality in patients with LC. Similar findings have been confirmed for patients with hematological malignancies and gastrointestinal, renal, and respiratory cancers [39, 40]. Recent studies also suggest that a low SATI can predict increased portal hypertension, liver-related decompensation, and mortality [26, 41]. As subcutaneous adipose tissue serves as the body’s main energy reserve, a low SATI could indicate a significant depletion of energy reserves due to cirrhosis, which could be one of the reasons for worse clinical outcomes [26].

The present study has several limitations. First, it was a single-center, retrospective study, and was thus limited with regard to the availability of accurate relevant information on skeletal muscle loss, such as regarding alcohol abstinence, alcohol-related muscle myopathy, eradication or suppression of the hepatitis virus infection by antiviral therapy, HCC development and its treatment, dietary intake and habits, and daily physical inactivity [1, 12, 42, 43]. Second, the limited etiologically relevant patient backgrounds may have introduced selection bias. Third, as age-related muscle loss is not uniform throughout the body—for example, the annual rate of leg muscle loss in chronic liver disease is faster than that of the trunk muscles [29]—the results of the present study may not accurately reflect the true rate of skeletal muscle loss in LC. Despite these limitations, the detailed quantification of muscle mass and adipose tissue in a large number of patients (n = 384), representation of the full spectrum of LC, use of CT, which is the gold standard for body composition assessment in cirrhosis [1, 28], long-term follow-up of the study cohort for more than 4 years, and the appropriate statistical estimation of the risk of muscle loss and mortality are major strengths of this study.

In conclusion, we provide convincing evidence that the rate of skeletal muscle loss in ALD cirrhosis is faster than that in viral cirrhosis. Our data also suggest a strong association between ALD and rapid skeletal muscle loss, both of which predict mortality in patients with LC, regardless of liver disease severity. However, further prospective studies on larger numbers of patients with various underlying etiologies from multiple centers are needed to validate our findings.