Cirrhosis is the advanced stage of chronic liver diseases and is mainly attributed to hepatitis B or C virus infection, alcohol consumption, non-alcoholic fatty liver disease, and autoimmune diseases (1). This disease has resulted in more than 1.3 million deaths, making it one of the leading global causes of mortality (2). With disease progression, many complications follow, including ascites, variceal bleeding, and hepatic encephalopathy (HE), which considerably affect the prognosis of patients with cirrhosis (3). HE is defined as a spectrum of nonspecific neurological or psychiatric abnormalities ranging from subclinical alterations to coma. It is typically induced by liver failure and/or portal vein-systemic shunting. As one of the primary complications of late-stage cirrhosis, HE has an incidence rate of about 20% to 80% (4). In patients with cirrhosis, elevated ammonia concentrations, brain edema, and increased intracranial pressure can contribute to varying degrees of HE (5, 6). HE is associated with a poor prognosis, often necessitating frequent hospitalization, imposing socio-economic and psychological burdens on patients and their families, and ultimately reducing the overall survival rate (7). Therefore, it is pressingly urgent to find more risk factors for cirrhosis.

Sarcopenia is a prevalent concern in individuals diagnosed with liver cirrhosis (8). Characterized by the decline in muscle mass, strength, and physical performance (9), sarcopenia has been detected in 14% to 55% of cirrhosis patients, prompting growing interest among researchers (10). The liver holds a central position in nutrient metabolism, and the diminishment of liver functional reserves can result in a range of complications, including malnutrition and the development of sarcopenia (11). Previous studies have revealed that sarcopenia in cirrhosis patients may be attributed to liver metabolic dysfunction, reduced appetite, increased muscle autophagy, elevated serum myostatin levels, catabolic effects of systemic inflammation induced by intestinal bacterial translocation, and low testosterone levels (10). Sarcopenia in cirrhosis patients is associated with a grim prognosis (12), such as reduced quality of life, elevated hepatic venous pressure gradients, complications related to portal hypertension (such as ascites and upper gastrointestinal varices), infections (including urinary tract infections and spontaneous peritonitis) and HE (10). Reduced extrahepatic ammonia clearance in patients with sarcopenia may contribute to HE to some extent (13).

It has been demonstrated that sarcopenia affects both hepatic encephalopathy and mortality in cirrhosis patients (13), and the decline in muscle mass in cirrhosis patients for more than a year also carries unfavorable prognostic implications (14). A meta-analysis of 22 studies has confirmed that sarcopenia is an independent predictor of increased mortality in cirrhosis patients (15). The progressive and systemic loss of skeletal muscle mass and strength in patients with sarcopenia also indicates, to some extent, the poor prognosis of LC patients (16). Therefore, we have embarked on an up-to-date and more exhaustive meta-analysis to comprehensively investigate the consequences of sarcopenia in individuals with cirrhosis. We aim to appraise the survival rates and mortality rates in cirrhotic patients with sarcopenia. The secondary objectives include appraising the prevalence of sarcopenia in cirrhotic patients and examining the impact of sarcopenia on LC and HE.

This meta-analysis followed the updated PRISMA (2020) and MOOSE guidelines (17–19), and the study protocol was registered with PROSPERO (CRD42023458935).

In this analysis of 40 studies involving 8,945 patients with cirrhosis, the prevalence of sarcopenia in the cirrhotic population was found to be higher (41%) than that (33%) reported in a previous study (60). A higher prevalence was observed in male patients (44%) and those with hepatic encephalopathy (48%). The findings also illustrated a robust correlation between sarcopenia and both the survival rate and mortality in cirrhosis patients. This correlation was substantiated by subgroup analyses based on study location, sample origin, diagnostic criteria, and methodologies. Furthermore, the analysis outcomes indicated a substantial connection between sarcopenia and hepatic encephalopathy in individuals with liver cirrhosis.

A previous systematic reviews and meta-analyses included four articles that assessed the relationship between sarcopenia and cirrhosis. However, one study only pooled retrospective cohorts of patients with sarcopenia and hepatic encephalopathy (61), another study did not include hepatic encephalopathy in the analysis (15), one study solely focused on the prevalence of sarcopenia in patients with cirrhosis (60). A different meta-analysis included a large number of patients after liver transplantation, but all included studies were retrospective observational cohort studies (62). In contrast, our study conducted a more comprehensive and extensive search, additionally analyzed hepatic encephalopathy in patients with liver cirrhosis, and incorporated approximately 50% prospective studies. To ensure the quality of the study, we rigorously controlled the inclusion and exclusion criteria for articles and performed subgroup and sensitivity analyses for all outcomes.

This research revealed that the general prevalence of sarcopenia in individuals with liver cirrhosis stood at 41%, with a notably elevated prevalence among male patients. This finding was in line with previous analyses (15, 60), which could be attributed to the predominance of males in the study samples (67.08%). Furthermore, we established a strong link between sarcopenia and an increased risk of death in cirrhotic patients. Patients with sarcopenia exhibited a higher mortality rate and a 2.13-fold elevated risk of death compared to those without sarcopenia. Sarcopenia posed a significant obstacle to survival. A previous study has demonstrated a higher incidence of complications and a reduced quality of life in patients with sarcopenia (27). The survival rate of patients with sarcopenia was 2.57 times lower than that of patients without sarcopenia. In a subgroup analysis of survival, the pooled HR was higher in patients receiving transjugular intrahepatic portocaval shunts (TIPS) than in the general population (3.71 vs. 2.35). This suggests that TIPS had a more significant impact on survival, and we hypothesized that sarcopenia played a role in worsening survival among cirrhotic patients receiving TIPS. The combined HR was also higher in the cohort containing hepatocellular carcinoma (HCC) patients compared to the cohort without HCC patients (3.38 vs. 2.31), indicating that HCC had a more pronounced effect on survival rates. This highlights the connection between sarcopenia and 5 years cumulative survival in cirrhotic patients.

From a pathophysiologic point of view, sarcopenia results from an imbalance between protein synthesis and degradation caused by multiple pathways. Chronic sarcopenia is characterized by loss of muscle mass, metabolic and biochemical abnormalities, and disruption of protein homeostasis throughout the body (63). Increased hepatic gluconeogenesis in cirrhotic patients is most likely due to limited hepatic glycogen content and insulin resistance, resulting in insufficient supply of branched-chain amino acids and glucose to muscle cells. In addition, recent clinical trials have found testosterone deficiency in cirrhotic patients, indicating increased muscle cell apoptosis and myogenic protein activity (64). Sarcopenia may be also induced by chronic catabolic conditions, such as cachexia due to cirrhosis, increased energy consumption, and decreased food intake due to loss of appetite. Maintaining muscle mass and avoiding rapid loss of muscle mass and transition to sarcopenia appear to be critical for the prognosis of patients with cirrhosis. Therefore, improving survival and quality of life by monitoring body composition and screening for sarcopenia should be a priority in the clinical management of cirrhosis.

Our analysis suggests that sarcopenia constitutes a risk factor for hepatic encephalopathy. In the context of hepatic encephalopathy, ammonia plays a pivotal role in the development of HE in individuals with liver cirrhosis. Previous studies have also demonstrated that the toxicity of ammonia impacts muscles and other organs. In chronic liver disease, muscles play a critical compensatory role in ammonia clearance. However, as the ammonia clearance rate decreases in cirrhotic patients, the compensatory function of patients with sarcopenia weakens. This results in the influx of ammonia into the blood in substantial quantities, greatly increasing the likelihood of hepatic encephalopathy. During hyperammonemia, the loss of muscle mass and subsequent impairment, induced by mitochondrial dysfunction and reduced adenosine triphosphate, or altered protein modification due to various factors, contribute to the onset of sarcopenia, creating a vicious cycle (65). Diagnosing hepatic encephalopathy is vital for the prognosis of patients with liver cirrhosis. However, due to equipment and personnel constraints, hepatic encephalopathy is not routinely examined in clinical practice (66). Therefore, medical staff should be attentive to such patients and implement more targeted screening and interventions for their benefit. The earlier sarcopenia is detected, the sooner the prevention and treatment programs can be initiated to prevent significant impact on HE.

The limitations of this article can be summarized as follows. First, the patient characteristics of the included studies were inconsistent, such as their demographics (i.e., the severity of and causes of cirrhosis) and methods used to determine sarcopenia. This inconsistency may have contributed to the observed heterogeneity. To address this issue, future studies should standardize diagnostic criteria as much as possible to include more patients with cirrhosis and/or sarcopenia with the same characteristics. Second, the majority of the studies included in our analysis were observational cohort studies, potentially introducing bias due to variations in statistical methods, diagnostic criteria, cut-off values for defining sarcopenia, and the distribution of viral liver disease, alcoholic liver disease, and the percentage of cases involving hepatocellular carcinoma (HCC). We attempted to mitigate these limitations through subgroup and sensitivity analyses. Nevertheless, it is imperative to adopt standardized definitions and criteria when conducting meta-analyses of individual sarcopenia data to better elucidate the prevalence of sarcopenia and provide a more comprehensive description of cirrhosis patients with sarcopenia. Finally, we only included studies published in English and may have excluded relevant studies published in other languages, so there may be biases.

In conclusion, this systematic review and meta-analysis establishes that patients with cirrhosis have a prevalence of sarcopenia of 41%, with up to half of these individuals developing cirrhosis due to either alcoholic liver disease or viral hepatitis. Moreover, sarcopenia is closely associated with the survival and mortality rates in patients with cirrhosis, the study reveals that sarcopenia is linked to a greater than twofold rise in the risk of mortality and a decline in survival rates across most subgroups. Hepatic encephalopathy may interact with sarcopenia in patients with cirrhosis. Based on our comprehensive analysis, sarcopenia should be included as an integral component of the initial assessment for all cirrhosis patients.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

YC: Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. MZ: Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. JG: Conceptualization, Formal analysis, Investigation, Writing – review & editing. JJ: Conceptualization, Formal analysis, Investigation, Writing – review & editing. HW: Conceptualization, Supervision, Writing – review & editing. XW: Conceptualization, Supervision, Writing – review & editing.