Sarcopenia in cirrhosis: from pathogenesis to interventions

Abstract

Sarcopenia (severe muscle depletion) is a prevalent muscle abnormality in patients with cirrhosis that confers poor prognosis both pre- and post-liver transplantation. The pathogenesis of sarcopenia is multifactorial and results from an imbalance between protein synthesis and breakdown. Nutritional, metabolic, and biochemical abnormalities seen in chronic liver disease alter whole body protein homeostasis. Hyperammonemia, increased autophagy, proteasomal activity, lower protein synthesis, and impaired mitochondrial function play an important role in muscle depletion in cirrhosis. Factors including cellular energy status, availability of metabolic substrates (e.g., branched-chain amino acids), alterations in the endocrine system (insulin resistance, circulating levels of insulin, insulin-like growth factor-1, corticosteroids, and testosterone), cytokines, myostatin, and exercise are involved in regulating muscle mass. A favored atrophy of type II fast-twitch glycolytic fibers seems to occur in patients with cirrhosis and sarcopenia. Identification of muscle biological abnormalities and underlying mechanisms is required to plan clinical trials to reverse sarcopenia through modulation of specific mechanisms. Accordingly, a combination of nutritional, physical, and pharmacological interventions might be necessary to reverse sarcopenia in cirrhosis. Moderate exercise should be combined with appropriate energy and protein intake, in accordance with clinical guidelines. Interventions with branched chain amino acids, testosterone, carnitine, or ammonia-lowering therapies should be considered individually. Various factors such as dose, type, duration of supplementations, etiology of cirrhosis, amount of dietary protein intake, and compliance with supplementation and exercise should be the focus of future large randomized controlled trials investigating both prevention and treatment of sarcopenia in this patient population.

Keywords: Interventions; Mechanisms; Muscle loss; Pathways.

Fig. 1

Summary of factors and pathways contributing to sarcopenia in cirrhosis. Numerous factors such as portal hypertension complications, pro-inflammatory cytokines, hyperammonemia, loop diuretics, hypotestosteronemia, physical inactivity, elevated hepatic gluconeogenesis, impaired insulin/IGF-1 signaling and alcoholic cirrhosis associate with sarcopenia in cirrhosis. Several signaling pathways including ubiquitin–proteasome degradation, myostatin activation, impaired mitochondrial function, NFκB signaling, mTOR inhibition, apoptosis and elevated eIF2 phosphorylation are involved in sarcopenia in cirrhosis. BCAA branched-chain amino acids, eIF2 eukaryotic initiation factor 2, IGF-1 insulin-like growth factor 1, NFκB nuclear factor κB

Fig. 2

Computed tomography images used for the muscle radiodensity assessment in patients with cirrhosis. Comparison of two patients with cirrhosis and similar BMI. Attenuation ranges used for the analysis of normal attenuation (red), low attenuation region 1 (yellow), and low attenuation region 2 (dark blue) muscle, as well as intermuscular adipose tissue (IMAT; teal), are shown. In patient with low muscle attenuation (34 HU) or myosteatosis, less than half of the muscle cross-sectional area falls within the normal attenuation range whereas in patient with normal muscle attenuation (47 HU, no-myosteatosis), muscle with the normal attenuation range is predominant

Fig. 3

Abdominal computed tomography images taken at the 3rd lumbar vertebra to quantify total muscle cross-sectional area and rectus abdominis muscle morphological characteristics. Reduction in skeletal muscle mass in sarcopenia, identified by CT images, is detectable at the microscopic level by reduction in muscle fiber size and muscle fiber type transformation. a Red color designates skeletal muscles. Sarcopenic patient had had low SMI (43 cm²/m²) whereas in non-sarcopenic patient, SMI was 51 cm²/m². b Muscle fiber boundaries were demarked using laminin and dystrophin stain (cell membrane) for muscle fiber size calculation. c Fiber types were identified in rectus abdominis muscle by using immunofluorescence myosin heavy-chain staining technique. Sarcopenic patient has mostly type IIA/IIX fibers (blue/green) whereas type IIA fibers (blue) were more frequent in non-sarcopenic patient. Scale bar = 130 µm