Cause and management of muscle wasting in chronic liver disease

Abstract

Purpose of review Sarcopenia or loss of skeletal muscle loss is the major component of malnutrition and occurs in the majority of patients with liver disease. Lower muscle contractile function also contributes to the adverse consequences of sarcopenia. There are no effective therapies to prevent or reverse sarcopenia in liver disease. This review will discuss the advances in diagnosis, pathogenesis and treatment options for sarcopenia in liver disease. Recent findings Sarcopenia increases mortality, risk of development of other complications of cirrhosis, and post liver transplant outcomes while quality of life is decreased. Unlike other complications of cirrhosis that reverse after liver transplantation, sarcopenia may not improve and actually worsens. Impaired skeletal muscle protein synthesis and increased proteolysis via autophagy contribute to sarcopenia. Hyperammonemia is the best-studied mediator of the liver-muscle axis. Molecular studies show increased expression of myostatin while metabolic studies show impaired mitochondrial function and tricarboxylic acid cycle intermediates due to cataplerosis of α-ketoglutarate. Impaired skeletal muscle pyruvate and fatty acid oxidation during hyperammonemia suggest amino acids are diverted to acetyl CoA and potentially aggravate hyperammonemia. Nutritional supplementation is of limited or no benefit and suggests that cirrhosis is a state of anabolic resistance. Exercise maybe beneficial but whether it overcomes anabolic resistance is not known. Summary The high clinical significance of sarcopenia is well established. Current approaches to nutritional supplementation have not been effective in reversing sarcopenia because of anabolic resistance. Myostatin antagonists, specific amino acid supplementation, mitochondrial protection and combination endurance-resistance exercise are potential future therapeutic options.

Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis

“…The current study revealed that ammonia‐induced up‐regulation of myostatin and the consequent decreased protein synthesis are partially reversible in vitro and in vivo . Increased myostatin expression was not fully reversed by ammonia‐lowering therapy, which may be due to incomplete reduction in muscle ammonia concentrations or additional ammonia‐independent mechanisms of myostatin regulation in vivo . Targeting ammonia alone may also not be adequate to reverse myostatin expression as our in vitro data suggest that after 48 hours of ammonia withdrawal there is nearly complete reversal of the molecular perturbations but that in vivo ammonia reduction does not completely reverse these alterations.…”

“…Despite compelling evidence that hyperammonemia induces skeletal muscle metabolic and molecular perturbations, it is not known if lowering ammonia will reverse these responses and consequent sarcopenia. Current options to reverse sarcopenia have focused on nutritional and amino acid supplementation, with limited benefits …”

Validity of Japanese version of SARC‐F questionnaire in patients with chronic liver disease

“…However, in the present study, the positive predictive value of SARC‐F‐J was higher, whereas the negative predictive value was lower compared with previous studies. In patients with chronic liver disease, muscle atrophy due to physiological aging, increase in inflammation and oxidative stress, diet low in protein and energy, myostatin, decline in branched‐chain amino acids, hyperammonemia, cachexia, and other factors may lead to sarcopenia. Thus, the prevalence of sarcopenia in patients with chronic liver disease may be higher than that observed in the general elderly population and patients with diabetes.…”

Sarcopenia from mechanism to diagnosis and treatment in liver disease

“…Interventions that focus only on deficiency replacement have generally been ineffective while targeted therapies have the potential to reverse muscle loss[1, 18–20, 26, 66, 87]. The major strategies that have been used to improve muscle mass include supplemental calorie and protein intake, increased physical activity, supplemental hormone therapy, and mechanistic targeted treatments[17, 26, 109–111]. The critical outcome measures include survival, hospitalization, quality of life, development of and recovery from other complications of cirrhosis.…”