Sarcopenia in the Cirrhotic Patient: Current Knowledge and Future Directions

Abstract

Cirrhosis predisposes to abnormalities in energy, hormonal, and immunological homeostasis. Disturbances in these metabolic processes create susceptibility to sarcopenia or pathological muscle wasting. Sarcopenia is prevalent in cirrhosis and its presence portends significant adverse outcomes including the length of hospital stay, infectious complications, and mortality. This highlights the importance of identification of at-risk individuals with early nutritional, therapeutic and physical therapy intervention. This manuscript summarizes literature relevant to sarcopenia in cirrhosis, describes current knowledge, and elucidates possible future directions.

Keywords: ACE, angiotensin-converting enzyme; ACE-I, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ALM, appendicular lean mass; ARB, angiotensin receptor blocker; ASM, appendicular skeletal mass; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; ATP, adenosine-5′-triphosphate; AWGS, Asian Working Group for Sarcopenia; BCAA, branched chained amino acids; BIA, bioelectrical impedance analysis; BMI, body mass index; CART, classification and regression tree; CKD, chronic kidney disease; CRP, C-reactive protein; DEXA, dual energy X-ray absorptiometry; EAA, essential amino acids; ESPEN-SIG, European Society for Clinical Nutrition and Metabolism Special Interests Groups; ESRD, end-stage renal disease; EWGSOP, European Working Group on Sarcopenia in Older People; FAD, flavin adenine dinucleotide; FADH2, flavin adenine dinucleotide +2 hydrogen; FNIH, Foundation for the National Institutes of Health; GTP, guanosine-5′-triphosphate; GnRH, gonadotrophin-releasing hormone; HCC, hepatocellular carcinoma; HPT, hypothalamic-pituitary-testicular; IFN-γ, interferon γ; IGF-1, insulin-like growth factor 1; IL-1, interleukin-1; IL-6, interleukin-6; IWGS, International Working Group on Sarcopenia; LH, luteinizing hormone; MELD, Model for End-Stage Liver Disease; MuRF1, muscle RING-finger-1; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide + hydrogen; NADPH, nicotinamide adenine dinucleotide phosphate; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NF-κβ, nuclear factor κβ; NHANES, National Health and Nutritional Examination Survey; PMI, psoas muscle index; PMTH, psoas muscle thickness; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; SARC-F, Strength, Assistance with walking, Rise from a chair, Climb stairs, and Falls; SHBG, sex hormone binding globulin; SMI, skeletal muscle index; SNS, sympathetic nervous system; SPPB, Short Performance Physical Battery; TNF-α, tumor necrosis factor α; UCSF, University of California, San Francisco; UNOS, United Network of Organ Sharing; cirrhosis; energy; mTOR, mammalian target of rapamycin; metabolism; muscle; sarcopenia.

Figure 1

Illustration of the citric acid cycle. Ammonia inhibits the citric acid cycle due to decrease in α-ketoglutarate, which leads to a diminished synthesis of GTP and other energy equivalents required for the electron transport chain and production of ATP. This can contribute to mitochondrial dysfunction that leads to muscle atrophy. ATP, adenosine-5′-triphosphate; FAD, flavin adenine dinucleotide; FADH₂, flavin adenine dinucleotide +2 hydrogen; GTP, guanosine-5′-triphosphate; NAD, nicotinamide adenine dinucleotide. NADH, nicotinamide adenine dinucleotide + hydrogen.

Figure 2

Illustration demonstrating stimuli promoting protein synthesis (testosterone, insulin, IGF-1, vitamin D, follistatin) via the Akt/mTOR pathway and protein breakdown (ammonia, myostatin glucagon, starvation, inflammation) mediated by the proteosome-ubiquitin pathway. IGF-1, insulin-like growth factor 1; mTOR, mammalian target of rapamycin; NF-κβ, nuclear factor κβ.

Figure 3

Flowchart of the diagnostic assessment of a patient suspected of having sarcopenia according to the EWGSOP. EWGSOP, European Working Group on Sarcopenia in Older People; SPPB, Short Performance Physical Battery.

Figure 4

Nutritional, exercise, and pharmacological approach to management of sarcopenia in cirrhosis.