Approaching the Sarcopenic Patient with Nonalcoholic Steatohepatitis-related Cirrhosis

Abstract

Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.

Keywords: Cirrhosis; MASLD; NAFLD; Sarcopenia; Sarcopenic obesity.

Fig. 1. Summary of the main relevant players contributing to sarcopenia in cirrhosis:

hormonal dysregulation, metabolic alterations and pro-inflammatory status. ↑, increase; ↓, decrease; BCAA, branched chain amino acid; IGF-1, insulin-like growth factor-1.

Fig. 2. Liver-muscle-adipose tissue axis deregulation as the trigger of sarcopenia during the natural history of NAFLD.

Insulin resistance is a key determinant of proteolysis and BCAAs catabolism; obesity, through the associated pro-inflammatory status, and physical inactivity contribute to disturbance of muscle metabolism. When liver disease progresses to advanced fibrosis/cirrhosis, hyperammonemia contributes to myostatin axis deregulation and muscle catabolism. Dysbiosis and endotoxemia foster chronic inflammation, oxidative stress, and insulin resistance. BCAA, branched chain amino acid; IL-1β, interleukin-1 beta; IL-6, interleukin-6; NAFLD, nonalcoholic fatty liver disease; MAP-kinase, mitogen-activated protein kinase; mTORC, mammalian target of rapamycin complex; TNF-α, tumor necrosis factor-alpha.

Fig. 3. Myokines and sarcopenia in CLD: A summary of the principal derangements in myokine axis observed in patients with NAFLD.

Throughout the natural history of NAFLD-related CLD, insulin resistance, inflammation and finally hyperammonemia increase myostatin and reduce irisin levels. Myostatin negatively regulates proliferation and differentiation of satellite cells, favoring muscle loss and adipogenesis. Concurrently, reduced irisin levels contribute to sarcopenia development and to alterations in glucose metabolism. ↑, increase; ↓, decrease; CLD, chronic liver disease; NAFLD, nonalcoholic fatty liver disease.

Fig. 4. Treatment of sarcopenia in the cirrhotic patient:

a multicentered approach, including weight loss but guaranteeing lean mass preservation, optimal management of liver disease, and specific nutrient oral supplementations. BCAA, branched chain amino acid.