Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses

Abstract

Malnutrition is the most common, reversible complication of cirrhosis that adversely affects survival, response to other complications, and quality of life. Sarcopenia, or loss of skeletal muscle mass, and loss of adipose tissue and altered substrate use as a source of energy are the 2 major components of malnutrition in cirrhosis. Current therapies include high protein supplementation especially as a late evening snack. Exercise protocols have the potential of aggravating hyperammonemia and portal hypertension. Recent advances in understanding the molecular regulation of muscle mass has helped identify potential novel therapeutic targets including myostatin antagonists, and mTOR resistance.

Fig. 1

Regulation of skeletal muscle mass. The protein synthesis and satellite cell (myogenically committed stem cells) contribute to muscle growth and reversal of atrophy. These are regulated primarily by myostatin and IGF1. The proteolysis is mediated primarily by the ubiquitin proteasome pathway with a variable contribution by the lysosomal cathepsin mediated autophagy pathway.

Fig. 2

Integration of the 3 major pathways that regulate skeletal muscle mass. Myostatin and IGF1 regulate muscle growth via transcriptional and posttranslational regulation of myogenic genes. The ubiquitin proteasome pathway is responsible for proteolysis. All 3 pathways crosstalk at multiple levels, including Akt, mTOR, AMP kinase, and FOXO. PIP2, phosphatidyl inositor bisphosphate; PIP3, phosphatidylinositol 3 phosphate; IGF1R, IGF1 receptor; Alk5, activinlike kinase 5, forms a heterodimeric complex with generic TGFβ receptor for myostatin; Act IIbr, activin II b receptor; GSK, 3β glycogen synthase kinase; eIF, eukaryotic initiation factor; 4E BP1, 4 E binding protein 1; IRS 1, insulin receptor substrate that is downstream of both insulin and IGF1 receptor; MURf, muscle ring finger protein, final component in the ubiquitin proteasome pathway with atrogin; PCNA, proliferating cell nuclear antigen, a marker of satellite cell proliferation.