Sarcopenia: Ammonia metabolism and hepatic encephalopathy

Abstract

Sarcopenia (loss of muscle mass and/or strength) frequently complicates liver cirrhosis and adversely affects the quality of life; cirrhosis related liver decompensation and significantly decreases wait-list and post-liver transplantation survival. The main therapeutic strategies to improve or reverse sarcopenia include dietary interventions (supplemental calorie and protein intake), increased physical activity (supervised resistance and endurance exercises), hormonal therapy (testosterone), and ammonia lowering agents (L-ornithine L-aspartate, branch chain amino acids) as well as mechanistic approaches that target underlying molecular and metabolic abnormalities. Besides other factors, hyperammonemia has recently gained attention and increase sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Sarcopenia contributes to frailty and increases the risk of minimal and overt hepatic encephalopathy.

Keywords: Ammonia; Hepatic encephalopathy; Liver cirrhosis; Sarcopenia; Testosterone.

Figure 1.

Muscle regulation and potential therapeutic strategies. Solid arrows indicate activating pathways. Dashed lines indicate inhibitory pathways. IGF-1, insulin-like growth factor 1; PKB/AKT, protein kinase B; mTOR, mammalian target of rapamycin; FoxO, forkhead box transcription factor; UPP, ubiquitin-proteasome pathway.

Figure 2.

Overview of strategies to reverse sarcopenia in cirrhosis. The step-wise approach for management of sarcopenia are depicted. TIPS, transjugular intrahepatic portosystemic shunt; BCAA, branched-chain amino acid; IGF-1, insulin-like growth factor-1.