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Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

Sarcopenia in Chronic Liver Disease: A Metabolic Perspective

  • Ramesh Kumar1,* ,
  • Sabbu Surya Prakash1,
  • Rajeev Nayan Priyadarshi2  and
  • Utpal Anand3 
 Author information
Journal of Clinical and Translational Hepatology   2022;10(6):1213-1222

doi: 10.14218/JCTH.2022.00239

Abstract

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with chronic liver disease (CLD) and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and complications. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover wherein changes in various metabolic factors such as hyperammonemia, amino acid deprivation, hormonal imbalance, gut dysbiosis, insulin resistance, chronic inflammation, etc. have important roles. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to 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. Skeletal muscle is a major organ of insulin-induced glucose metabolism, and sarcopenia is closely linked to insulin resistance and metabolic syndrome. Patients with liver cirrhosis are in a hypermetabolic state that is associated with catabolism and depletion of amino acids, particularly branched-chain amino acids. Sarcopenia can have significant implications for nonalcoholic fatty liver disease, the most common form of CLD worldwide, because of the close link between metabolic syndrome and sarcopenia. This review discusses the potential metabolic derangement as a cause or effect of sarcopenia in CLD, as well as interorgan crosstalk, which that might help identifying a novel therapeutic strategies.

Graphical Abstract

Keywords

Sarcopenia, Liver cirrhosis, Chronic liver disease, Metabolism, Hyperammonemia

Introduction

Skeletal muscle is one of the largest organs in the body. It is not just a part of our locomotor system; but is also, an important secretory organ.1 Muscle fibers produce and release a variety of cytokines and other peptides known as myokine that which have autocrine, paracrine, and endocrine effects. Myokines regulate metabolism in organs including the liver and adipose tissues, in addition to maintaining muscle mass and strength.2,3 Myokines affect glucose and lipid metabolism as well as systemic inflammation.2 Crosstalk between myokines and other organokines, such as hepatokines and adipokines, has a critical role in orchestrating systemic metabolic alterations that lead to insulin resistance (IR), diabetes mellitus (DM), obesity, and metabolic syndrome (MetS).2,4 Because both the liver and the muscles are involved in metabolism, simultaneous loss of muscle and liver function can have a major influence on overall metabolism. In patients with chronic liver disease (CLD), loss of skeletal muscle mass, quality, and strength, defined as sarcopenia, is being increasingly recognized.5,6 Sarcopenia is thought to affect between 25% and 70% of CLD patients, with higher rates in men and in Western populations.6 In patients with liver cirrhosis (LC), sarcopenia causes significant clinical complications and has been linked to higher mortality, lower quality of life, longer hospital stays, and the development of complications such as infections, hepatic encephalopathy (HE), and hepatogenous diabetes (HD), putting a significant financial burden on the patient.7–11

A common link between sarcopenia and CLD is metabolic imbalance (Table 1). In fact, MetS is a key risk factor for sarcopenia, and nonalcoholic fatty liver disease (NAFLD), also known as metabolic associated fatty liver disease, the most prevalent cause of CLD worldwide.12,13 Skeletal muscle is a major organ of insulin-induced glucose metabolism, and thus sarcopenia is closely linked to IR and MetS.14 Sarcopenia is caused by a complex equilibrium between protein synthesis and breakdown. Hyperammonemia, amino acid deficiency, hormone imbalance, chronic inflammation, and other metabolic variables all appear to play a part in the pathophysiology.15,16 Patients with LC are in a hypermetabolic state characterized by catabolism and amino acid deficiency. Reduced levels of branched-chain amino acids (BCAAs) are associated with sarcopenia in LC.15,17 Despite the extensive data supporting the predictive relevance of sarcopenia in patients with LC, research on metabolic dysregulation as a cause or effect of sarcopenia in such patients is still evolving. The goal of this review is to summarize what is currently known about sarcopenia in cirrhotic patients, with a focus on metabolic dysregulation and its possible impact on clinical outcomes, molecular pathophysiology, and targeted therapeutic approaches.

Table 1

Metabolic alterations involved in the pathogenesis of sarcopenia in liver cirrhosis

Metabolic alterationImplication
Decreased hepatic glycogen; Decreased body fat to muscles volume; Increased gluconeogenesisMuscles protein breakdown
Muscle anabolic resistance; Altered lipid and amino acid metabolism; Reduced BCAA; Decreased bile production; Pancreatic insufficiencyDecreased muscles protein synthesis
Decreased anabolic hormones (IGF-1 and testosterone)Decreased muscles protein synthesis; Muscles protein breakdown
Hyperammonemia: Increased myostatin expression; Cataplerosis of α-ketoglutarate; Increased phosphorylation of eukaryotic initiation factor 2a; Altered integrated stress response; Mitochondrial dysfunctionDecreased muscles protein synthesis; Muscles protein breakdown
Insulin resistance; Myosteatosis; Pro-inflammatory cytokinesDecreased muscles protein synthesis; Muscles protein breakdown

BCAA, branch chain amino acid; IGF-1, insulin-like growth factor-1.

Metabolic functions of skeletal muscles

Skeletal muscle is the largest metabolic organ in terms of size and is an important site of glucose, protein, and lipid metabolism.18 In order to meet energy demands and maintain nutritional homeostasis, skeletal muscle alters metabolic pathways in response to varying physiologic needs.

Glucose metabolism

Skeletal muscle has a significant role in glucose metabolism and insulin sensitivity, clearing roughly 80% of postprandial glucose via insulin-dependent glucose uptake.14,19 In a fed state, glucose is actively transported across the plasma membrane of skeletal muscle in an insulin-dependent manner by specialized carrier proteins known as glucose transporters (GLUTs). GLUT1 is primarily found on the plasma membrane and is involved in basal glucose absorption, whereas GLUT4 is found in intracellular vesicles and is transported to the plasma membrane in response to stimuli. GLUT4 is the most abundant and is also known as the insulin-regulated glucose transporter.20 Inside the cell, hexokinase phosphorylates glucose, which is then be stored as glycogen, used as a substrate in glycolysis, used as a substrate for protein synthesis via the hexosamine pathway, or used as a substrate in the pentose phosphate pathway, depending on the metabolic demands of the cell.21

Protein metabolism

Muscle is important for whole-body protein metabolism because it serves as a primary storage site for amino acids, allowing protein synthesis in various tissues as well as providing precursors for hepatic gluconeogenesis.22 The needs for amino acids in all tissues do not alter greatly from the post-absorptive to the fed stage because an excess of protein is stored. Ingested amino acids are mostly consolidated into muscle protein in order to replenish the amino acid reserves lost during fasting. Thus, gains in muscle protein mass in the fed state generally offset losses in protein mass in the post-absorptive state.23

Lipid metabolism

Skeletal muscle is also an essential regulator of lipid metabolism in the body. Individuals with skeletal muscle diseases including muscular dystrophy and sarcopenia have a much increased risk of developing NAFLD.24,25 Increased intramyocellular triacylglycerol concentrations are linked to IR in skeletal muscle. This lipid accumulation is most likely caused by increased uptake and decreased mitochondrial oxidation of fatty acids in the muscle.26 Increased fatty acid levels in obese subjects contribute to accumulation of toxic lipid molecules, oxidative stress, and muscle autophagy.27

Muscle protein homeostasis and interorgan crosstalk

Muscle mass homeostasis is tightly regulated, requiring a balance between muscle protein synthesis and proteolysis. The exercise-activated mammalian target of rapamycin (mTOR) pathway is the most important regulator of protein synthesis.28 Variables that influence protein turnover, include cellular energy status, physical activity, substrate availability, insulin, insulin-like growth factor-1 (IGF-1), corticosteroids, testosterone, myostatin, and cytokines including interleukin-4 and interleukin-6 (IL6).29 Muscle degradation is driven by three pathways, the ubiquitin-proteasome pathway (UPP), caspase-mediated protein cleavage, and the autophagy system.30 the UPP is a key proteolysis process in which muscle protein is ubiquitinated and then degraded and eliminated by the 26S proteasome. Inactivity, glucocorticoids, tumor necrosis factor (TNF), and poor insulin/IGF-1 transmission can all activate UPP.31 Autophagy involves removal of misfolded proteins and damaged organelles by the formation of autophagosome, with subsequent degradation by lysosomes. Muscle replacement requires the activation and recruitment of muscle satellite cells, which are adult stem cells found in skeletal muscle.

Skeletal muscle, liver, and adipose tissue all function as endocrine organs, releasing myokines, hepatokines, and adipokines to perform interorgan crosstalk via autocrine, paracrine, and endocrine pathways.2,4 Myokines are peptides released by myocytes in response to muscle contraction.32 There are around 600 myokines known to date, with myostatin being the first to be identified as a myokine. In mature myofibers, myostatin forms complexes with Smad4 and activates protein degradation pathways such as UPP and autophagy while suppressing the Akt-mediated mTOR signaling pathway, resulting in suppression of protein synthesis and sarcopenia.33 Myostatin also prevents myogenesis by blocking satellite cell activation.34 In order to maintain muscle homeostasis, myostatin levels are regulated by follistatin, another glycoprotein. Follistatin promotes satellite cell recruitment while inhibiting Smad2/3, hence negating the action of myostatin. Follistatin infusions stimulate muscle protein synthesis in experimental models, resulting in muscle growth.35 However, the follistatin was recently found to be increased in human NAFLD, where it induced lipolysis in adipose tissue, but was not associated with skeletal muscle mass.36 Organokines are associated with obesity, IR, type 2 DM, MetS, and cardiovascular health. The presence of IL6-mediated muscle-liver crosstalk promotes glucose homeostasis during exercise, in which glucose absorption in muscle is followed by enhanced glucose release from the liver.37 Hepatokines are novel hormones produced by the liver that have a stronger interaction with adipose and skeletal muscle tissue, indicating an endocrine dependent crosstalk linkage.38,39 Among the hepatokines, fetuin-A was identified early on to be released from the fatty liver and found to induce subclinical inflammation and IR.39 Adipokines are a type of cell signaling molecule produced by adipocytes and are involved in lipid metabolism, insulin sensitivity, hepatic steatosis, and fibrogenesis.40

Sarcopenia in CLD

According to several observational studies, sarcopenia and CLD have a significant association.5–9 Sarcopenia appears early in the course of CLD and worsens as the disease progresses. Within CLD, NAFLD shares multiple risk factors with sarcopenia, and hence sarcopenia is linked to an increased risk of NAFLD and NAFLD progression, regardless of the presence of obesity, MetS, or IR.41–43 Sarcopenia is one of the most common complications of LC and is associated with poor clinical outcomes as well as metabolic consequences.7–11 The prevalence of sarcopenia ranges from 25–70% in cirrhotic patients.3,6 The prevalence depends on ethnicity, severity of underlying liver disease, and diagnostic criteria and tools used to define sarcopenia. Indians are expected to have high prevalence of sarcopenia because the lean muscle mass is 15% lower compared with Western populations of the same height.44 According to a meta-analysis conducted by Kim G et al.,6 the global prevalence of sarcopenia in LC is 48.1%, with men being more commonly involved (61.6%) than women (36%).

Recently, the European Working Group on Sarcopenia in Older People has proposed a new definition of sarcopenia giving more importance to muscle function than muscle mass, which is difficult to screen in patients with sarcopenia.5 The diagnosis of probable sarcopenia can be made when muscle strength is low. It is confirmed when there is additional documentation of low muscle quantity or quality. Severe sarcopenia is accompanied by low muscle strength, low muscle quantity/quality, and low physical performance.5 Patients with sarcopenia in the presence of obesity, a body mass index of ≥2 5 kg/m2, is defined as sarcopenic obesity. Sarcopenic obesity has greater metabolic implications than sarcopenia alone.45

Metabolic changes and pathophysiology of sarcopenia in CLD

Sarcopenia in CLD is a multifactorial disorder with a complex pathophysiology (Fig. 1). Its pathogenesis is more complex than simple protein and calorie malnutrition. Metabolic alterations in cirrhosis, such as depleted glycogen stores, hyperammonemia, and endocrine dysfunctions, cause excessive protein catabolism, increased UPP activation, inappropriate muscle autophagy, and diminished satellite cell proliferation. A combination of elevated myostatin levels, low IGF-1, hypogonadism, IR, and chronic inflammation appear to have important roles in the development of sarcopenia.

Schematic explanation main drivers and mechanism contributing to sarcopenia in patients with liver cirrhosis.
Fig. 1  Schematic explanation main drivers and mechanism contributing to sarcopenia in patients with liver cirrhosis.

Sarcopenia in chronic liver disease is a multifactorial disorder with a complex pathophysiology associated with a dysregulated muscle protein turnover. Numerous factors such as hyperammonemia, hypogonadism, impaired insulin/IGF-1 signaling, pro-inflammatory cytokines, and depleted glycogen stores are involved in the pathophysiology of sarcopenia in cirrhosis. Hyperammonemia contributed by decreased hepatic mass, portosystemic shunt, and gut dysbiosis lead to an increased myostatin expression, cataplerosis of α-ketoglutarate, altered integrated stress response, and mitochondrial dysfunction, resulting in impaired muscles protein synthesis as well as increased muscles autophagy. Hypogonadism and impaired insulin/IGF-1 signaling in cirrhosis also result in increased myostatin expression. Depleted glycogen stores and an accelerated starvation in patients with liver cirrhosis lead to increased gluconeogenesis resulting in a low concentration of skeletal muscle amino acids (BCAA) contributing to sarcopenia. Physical inactivity, pro-inflammatory cytokines and poor insulin/IGF-1 transmission can all activate UPP, causing increased muscles protein breakdown. BCAA, branch chain amino acid; GH, growth hormone; IGF-1, insulin-like growth factor-1; IL-interleukin; LPS, lipopolysaccharide; Mt, mitochondrial; NH3, ammonia; O2, oxygen; TNF, tumor necrotic factor; UPP, ubiquitin-proteasome pathway.

Altered protein, carbohydrate, and lipid metabolism

Alteration of protein turnover is an important contributor to sarcopenia in chronic illness. In general, body protein levels are maintained at the expense of carbohydrate and fat utilization as an energy source. Cirrhotic patients have a reduced ability to utilize carbohydrate as an energy source because of the diminished capacity of hepatocytes to synthesize, store, and break down glycogen.46 In the early stages of LC, muscle depletion may coexist with normal or even increased body fat, particularly visceral fat. Advanced cirrhosis, however, has more pronounced fat depletion.47,48 As a result, fat that may protect muscles in the early stages of cirrhosis is no longer available as the disease progresses, causing increased muscle protein breakdown. Increased mobilization of amino acids for gluconeogenesis and energy results in skeletal muscle loss.47 Thus, dysregulated muscle protein turnover underpins the pathogenesis of sarcopenia in LC patients. However, studies on muscle protein turnover have yielded inconsistent results in cirrhosis, with significant decreases in protein synthesis and contradictory reports of protein breakdown.49 These variations could be the result of differences in methodology and patient characteristics. Cirrhotic patients are thought to have anabolic resistance, which refers to reduced synthesis of muscle protein in response to dietary protein or exercise.50,51 One of the primary drivers of muscle anabolic resistance in patients with LC is increased myostatin expression.3 In patients with NAFLD, one of the key proinflammatory cytokines, TNF-alpha, inhibits muscle protein synthesis by interfering with mTORC and promotes muscle protein breakdown by increasing UPP activity.52 In alcoholic liver disease, ethanol contributes to sarcopenia by increasing myostatin levels and inhibiting mTORC1 activation.53

Hyperammonemia

Every day, adult humans produce roughly 1,000 mmol of ammonia from amino acids and other nitrogen containing compounds. The intestines and kidneys are the primary ammonia producers, while the liver and muscle are the primary ammonia consumers. Some ammonia is used in the synthesis of proteins, amino acids, and nucleic acids, but the rest is waste, neurotoxic, and is largely eliminated in the urine as urea.54 The liver is involved in ammonia detoxification via the urea cycle and glutamine synthesis, although that is hampered in patients with LC, resulting in hyperammonemia. During a state of hyperammonemia, muscle has an important role in detoxifying ammonia to nontoxic glutamine.55

In patients with LC, hepatocellular dysfunction, reduced ureagenesis, and portosystemic shunting, all contribute to hyperammonemia.55 Gut dysbiosis, infection with urease-positive bacteria, gastrointestinal hemorrhage, and constipation also contribute to hyperammonemia. Increased ammonia absorption by skeletal muscle secondary to hyperammonemia contributes to the development of sarcopenia, which further reduces the muscle mass available to eliminate excess ammonia, setting up a vicious cycle.56–58 Skeletal muscle hyperammonemia leads to an increase in myostatin expression and reduced NF-B activation, resulting in impaired synthesis of muscle protein as well as increased muscle autophagy.56–58 Myostatin also influences muscle satellite cell function. In an animal model study, myostatin expression was associated with a decrease in satellite cell function, which was mediated by a decrease in myogenic transcription factors myoD, myf5, and myogenin.17 Hyperammonemia potentially contributes to a reduction in muscle protein synthesis by interfering with tricarboxylic acid (TCA) cycle intermediate metabolism. Normally glutamate and glutamine are converted to ammonia and alpha-ketoglutarate in the TCA cycle.59 However, because of hyperammonemia in LC, removal of TCA intermediates may be favored, resulting in decreased availability of alpha-ketoglutarate and reduced adenosine triphosphate synthesis, which may limit muscle protein synthesis.59,60 Hyperammonemia has also been linked to an increase in reactive oxygen species, which can cause tissue damage and muscle loss.60

Substrate availability and energy expenditure

Anorexia, malabsorption, and altered macronutrient metabolism contribute to malnutrition and substrate availability in patients with LC.61 Moreover, LC is a state of accelerated starvation.62 An overnight fast causes a greater increase in fat oxidation, gluconeogenesis, and ketogenesis in LC patients than in healthy people.62,63 Increased gluconeogenesis often leads to increased amino acid use, resulting in a low concentration of skeletal muscle BCAA.63,64 Decreased BCAA levels in cirrhosis also result from increased use of BCAA as a donor of amino groups to alpha-ketoglutarate for synthesis of glutamate, which in muscles is involved in ammonia detoxification.65 Because of a limited supply of BCAA in cirrhosis patients, synthesis of other essential proteins such as albumin takes precedence over muscle protein synthesis, resulting in sarcopenia.64 BCAAs are involved in the metabolism of carbohydrates, proteins, and fats, as well as IR and cell proliferation.64 BCAAs have been demonstrated to increase glucose uptake in skeletal muscle via activating PI3K and protein kinase C.66

Generally, amino acid deficiency causes activation of the integrated stress response (ISR) via an amino acid deficiency sensor, i.e. general control nondepressed 2.67 That causes eukaryotic initiation factor 2 to be phosphorylated, resulting in a decrease in protein synthesis and an increase in activating transcription factor 4 (ATF4) mRNA. Activated ATF4 lowers the need for amino acids and inhibits mTORC1 signaling to promote autophagy in an attempt to preserve amino acid levels.68 LC patients have increased general control nondepressed 2 activation and eukaryotic initiation factor 2 phosphorylation, as well as reduced mTORC1 signaling, similar to the ISR that results from amino acid deficiency.17,69 Hyperammonemia, on the other hand, affects the ISR by preventing the expression of ATF4 mRNA, which results in an increase in autophagy and a reduction in muscle protein synthesis.17 Moreover, in a second route, an amino acid exchanger is activated in LC patients in response to hyperammonemia, resulting in an increase in leucine uptake.17,69 Leucine is used in the mitochondria to produce acetyl-CoA to generate energy.66 Leucine transport relies on glutamine transfer via the glutamine exchanger, while glutamine is largely used for ammonia detoxification in hyperammonemia.17,70 Overall, these metabolic alterations result in a negative protein balance that contributes to sarcopenia development.

Endocrine dysfunction

Changes in the hypothalamic-pituitary-gonadal axis in male patients with LC can result in a decrease in testosterone production and an increase in aromatase activity, an enzyme that converts testosterone to estrogen.71 Testosterone inhibits myostatin expression and signaling, and low testosterone levels promote sarcopenia in male patients with LC.72 The growth hormone (GH)/IGF-1 axis is disturbed in patients with CLD, and endogenous GH secretion is elevated.73,74 Because the liver is the principal source of IGF-1, LC patients with lower levels of IGF-1 produce more GH because of a loss of feedback inhibition. As a result, patients with LC have a state of hepatic GH resistance. Derangement of the GH/IGF axis may contribute to sarcopenia because GH and IGF-I are potent regulators of anabolism. Because IGF-1 and testosterone repress myostatin, lower levels of these growth hormones in LC patients result in increased myostatin expression.74,75 IGF-1 promotes muscle growth by stimulating the mTORC1 signaling pathway and prevents muscle atrophy by inhibiting ubiquitin ligase activity.76

Insulin resistance

Hyperinsulinemia and IR are prevalent in LC patients.77,78 Reduced hepatic insulin extraction and portosystemic shunting are thought to cause hyperinsulinemia, with hyperglucagonemia and pancreatic islet hypertrophy also having a role. As a result of persistent hyperinsulinemia, insulin receptors are downregulated on target cell membranes, leading to IR.79 Clamp studies on whole-body glucose utilization revealed that IR in LC patients was associated with a decrease in nonoxidative glucose disposal, mainly in skeletal muscles.80,81 Thus, sarcopenia also contributes to the development of IR as skeletal muscle is the predominant site of post-prandial glucose uptake.82 On the other hand, IR promotes sarcopenia by causing an increase in muscle protein breakdown and a decrease in muscle protein synthesis. IR increases lipolysis and the release of free fatty acids in adipose tissue, which inhibits IGF-1 signaling.83 IR leads to an increase in lipogenesis and suppression of beta-oxidation in muscles, resulting in myosteatosis.83 Reduced circulation levels of adiponectin and vitamin D may cause IR, resulting in sarcopenia.84 IR is a common link between sarcopenia and NAFLD.13,14 However, there are different major pathways inducing NAFLD, and the one with a strong hepatic genetic component is only weakly associated with IR and dysregulated hepatokine release.85 Thus, stratification of NAFLD by major metabolic pathways, may be done while investigating the relationship of fatty liver with metabolism and also skeletal muscle mass and function.

Gut dysbiosis

Changes in the composition and function of the gut microbiota are common in LC patients, influencing host immunity and many metabolic activities. The intestinal translocation of lipopolysaccharide, a gut-derived endotoxin, is associated with the pathogenesis of IR.86 Obesity, metabolic disorders, and diabetes have all been linked to intestinal dysbiosis.87 In LC patients, gut dysbiosis contributes to hyperammonemia, which has a role in the development of sarcopenia and peripheral IR.88 Furthermore, the gut microbiota produces a number of compounds, including BCAA, whose levels in the blood have been associated to the risk of IR and DM.89 A recent study demonstrated that the gut microbiome of CLD patients with sarcopenia was prodiabetogenic, with a high abundance of gram-negative bacteria and a low Firmicutes/Bacteroidetes ratio.90 As a result, gut dysbiosis could play a role in sarcopenia and diabetes in LC patients.

Clinical and metabolic implications of sarcopenia

In patients with LC, sarcopenia is linked to a wide range of consequences, such as HE, worse quality of life, infection risk, and increased mortality (Table 2).7–11,42,91–98 Notably, the impact of sarcopenia on survival has been found mainly in early stages of cirrhosis, with no such association found in patients with high MELD scores, Child-Pugh class C, and hepatic venous pressure gradient >20 mmHg, implying that sarcopenia has little additive impact on mortality prediction for patients who are severely ill.91,99 Other clinical effects of sarcopenia include decreased functional independence, such as difficulty walking and doing daily basic activities, as well as an increased risk of falls and fractures.100 From a metabolic standpoint, sarcopenia influences glucose tolerance, ammonia metabolism, amino acid metabolism, and bone production. Osteosarcopenia, defined as sarcopenia and osteoporosis occurring at the same time, is also common in CLD patients.101 In cirrhosis patients, sarcopenia impairs creatinine production, affecting renal evaluation.

Table 2

Studies on clinical implications of sarcopenia in CLD

Author, yearDesignAims/objectivesPopulationMain outcomes
Koo et al., 201742Cross-sectionalAssociation between sarcopenia and histological severity of NAFLD309 patients (240 with NAFLD)Sarcopenia was significantly associated with NASH, OR 2.28 (1.12–4.30), and significant fibrosis, OR 2.05 (1.01–4.16)
Tandon et al., 201211RetrospectivePrevalence and clinical impact of sarcopenia in LC patients142 LC patients listed for LTSarcopenia was independent predictor of mortality, HR 2.36 (1.23–4.53), after adjustments for age and MELD scores
Montano-Loza et al., 20127Cross-sectionalIncidence and association of sarcopenia with prognosis of LC112 patients with LCThe incidence of sarcopenia was 40%. Sarcopenia was associated with mortality in patients with LC, HR 2.21, p=0.008
Montano-Loza et al., 201591RetrospectiveImpact of sarcopenia on mortality prediction in LC669 patients with LCSarcopenia was independently associated with mortality, HR 0.97 (0.96–0.99). Inclusion of sarcopenia in MELD further improved the prediction
Merli et al., 201392ProspectiveRelationship between sarcopenia and HE300 LC patientsHE were significantly higher in LC patients with muscle depletion or decreased muscle strength. (30% vs. 15%, and 29% vs. 16%, respectively)
Kim et al., 201494RetrospectiveAssociation between sarcopenia and mortality in LC patients with ascites65 patients with LCSarcopenia is an independent predictor for long-term mortality in LC patients with ascites, HR 0.812 (0.684–0.965)
Durand et al., 20148RetrospectivePrognostic value of muscle atrophy in cirrhosis562 patients with LCTransversal psoas muscle thickness
/height on computed tomography independently predicted mortality in LC patients, HR 0.86 (0.78–0.94)
Masuda et al., 201495RetrospectiveImpact of sarcopenia on mortality and sepsis after LDLT204 LC patientsSarcopenia was an independent predictor of mortality (HR 2.06) and sepsis (HR 5.31) after LDLT
Fujiwara et al., 201596RetrospectiveImpact of sarcopenia and adiposity on HCC1,257 patients with HCCSarcopenia (HR 1.52) and myosteatosis (HR 1.34) independently predicted mortality in patients with HCC
Nardelli et al., 201793ProspectiveAssociation between sarcopenia and post-TIPS HE46 LC patientsSarcopenia independently predicted the development of HE after TIPS (HR, 31.3 (4.5–218.07)
Kaido et al., 201397RetrospectiveImpact of sarcopenia on pot-LT survival124 LC patientsSarcopenia was an independent risk factor for mortality after LT (OR 4.846 (2.092–11.790))
Montano-Loza et al., 201498RetrospectiveImpact of sarcopenia on outcomes after LT248 LC patientsSarcopenia was associated with longer hospital stays (40 vs. 25 days) and a higher risk of bacterial infection (26% vs. 15%) after LT

HR, hazard ratio; HCC, hepatocelluar carcinoma; HE, hepatic encephalopathy; LC, liver cirrhosis; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, model for end-stage liver disease; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio; TIPS, transjugular intrahepatic portosystemic shunt.

Sarcopenia and HE

Hyperammonemia is a common in LC and has been linked to the development of sarcopenia. Sarcopenia, in turn, tends to exacerbate hyperammonemia by limiting muscle ammonia consumption. Ammonia is a neurotoxic chemical that has been linked to the development of HE and minimal hepatic encephalopathy (MHE). Furthermore, skeletal muscle proteolysis compensates for high amino acid consumption in patients with advanced LC, allowing for enhanced gluconeogenesis. Both BCAAs and aromatic amino acids (AAAs) are produced in this process. In skeletal muscle, however, the localized branched-chain keto dehydrogenase preferentially catabolizes BCAAs.48,102 As a result, BCAA levels drop while AAA levels rise, lowering the Fischer ratio. A decreased Fischer ratio has been linked to HE via increasing AAA uptake in the brain and altering neurotransmission.103

Several studies have found an independent link between sarcopenia and HE.92,93,104 Merli et al.92 reported that sarcopenia was independently linked with overt HE during hospitalization in a multivariate logistic regression analysis of 300 cirrhotic patients.92 A Japanese group of researchers revealed that handgrip strength stratifies LC patients at high risk of developing overt HE.104 In a study of 46 LC patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), Nardelli et al.93 found that all patients who developed post-TIPS-HE (46%) had sarcopenia, and only MELD score and sarcopenia were independently linked with the development of HE.93 In a prospective study, 84% of LC patients with MHE had sarcopenia, compared with only 31% in those without MHE. Sarcopenia also independently predicted the occurrence of MHE in the multivariate analysis.105

Sarcopenia and HD

LC has long been known to have diabetogenic potential, and the term hepatogenous diabetes was coined to describe the condition.106 Although the pathophysiology of HD is complex and poorly understood, sarcopenia, sarcopenic obesity, gut dysbiosis, and hyperammonemia have been linked to the abnormal glucose metabolism in LC.10,107 The majority of postprandial glucose consumption occurs in skeletal muscle, making it an important insulin target organ for glucose uptake and utilization.14 As a result, skeletal muscle loss can lead to significant IR.14,107 Patients with HD often have abnormal oral glucose tolerance tests despite having normal fasting blood glucose levels, prompting us to believe that cirrhosis-related sarcopenia may play a role in HD pathophysiology. Sarcopenia is commonly accompanied by myosteatosis, macrophage infiltration, inflammatory cytokine production, and mitochondrial dysfunction, all of which contribute to IR and reduced glucose uptake and utilization.15 Moreover, skeletal muscles release a number of cytokines, including irisin and IL6, that control insulin sensitivity.108,109 As a result, sarcopenia-related reduction of muscle secretary function may contribute to the glucose intolerance in LC patients. Sarcopenic obesity has even greater impact on metabolic profile than sarcopenia alone.45

Sarcopenia and serum creatinine

Creatinine is a low-molecular-weight endogenous molecule generated from creatine and creatine phosphate, both of which are present mainly (95%) in muscle. Because serum creatinine levels correlate with muscle mass, it has been used as marker to measure muscle mass.110 Creatinine is a useful agent for estimating glomerular filtration rate (GFR) because it is uncharged, unbound to serum proteins, and filtered freely by the glomerulus without tubal reabsorption. However, creatinine production is reduced in cirrhosis patients with sarcopenia, which may lead to an overestimation of GFR and consequently an underestimation of renal impairment.111

Therapeutic perspective of metabolic correction

Sarcopenia is treated with a multifaceted strategy that includes lifestyle, nutrition, exercise, and adjunct medicine to treat metabolic imbalance. Several therapeutic options have been explored for sarcopenia, but only a handful have focused on CLD patients, with the majority of them being nutritional. A caloric energy intake of 3.0–35 kcal/kg/day should be advised, with a target protein consumption of 1.2–1.5 g/kg/day.112 Eating 3–5 meals each day and a late evening snack is also recommended to keep the starvation period short and improve protein turnover.112 Alcohol and smoking cessation should also be recommended. Recent studies have looked into ways to minimize ammonia, replenish BCAA, address hormonal imbalances, and use myostatin antagonists.

In a preliminary study, ammonia-lowering treatment using L-ornithine L-aspartate improved skeletal muscle mass and strength, along with lowered circulation and skeletal muscle ammonia levels.113 Ammonia-lowering strategies for the treatment of sarcopenia in CLD need to be proven in large, well-controlled clinical trials. The use of BCAAs to promote muscle protein synthesis appears to be supported by research.69,114–119 Long-term BCAA supplementation has been reported to improve protein metabolism in LC patients, resulting in increased muscle mass and MHE (Table 3).69,114–119 However, despite the positive results, a formal recommendation on the use of BCAA for sarcopenia in CLD is still in the works. Testosterone treatment has been found to help LC patients gain muscle and bone mass.120 Testosterone increases IGF-1 and decreases myostatin, both of which are beneficial to muscle growth. However, in patients with CLD, adverse events such as cardiovascular disease, fluid retention, gynecomastia, and prostatic disease progression have been reported, and long-term safety has yet to be proven. Similarly, while GH replacement therapy can increase muscle mass, it is associated with a high rate of adverse effects, such as increasing ascites and edema, as well as expensive cost.121 Because of the deleterious effects of myostatin on muscle protein turnover, many myostatin inhibitors (e.g. stamulumab, landogrozumab, and trevogrumab) are now being investigated for their safety and efficacy.122 Furthermore, glucose-lowering medications such as metformin and thiazolidinedione have been shown to improve skeletal muscle mass, strength, and performance in diabetes patients, indicating the need for their evaluation in a long-term, well-designed study in CLD patients.

Table 3

Studies on BCAA treatment for sarcopenia in patients with liver cirrhosis

Author, year, countryStudy typeStudy subjectsInterventionMain results
Tsien, 2015, Canada69Prospective study06 compensated, alcoholic cirrhosis patients and 08 controlsSingle dose of BCAAs mixture enriched with leucineAcute reversal of Impaired mTOR1 signaling and skeletal muscle autophagy by BCAA/leucine
Hiraoka, 2017, Japan114Prospective study33 patients with LCBCAA supplementation (protein 13.5 g) as a late evening snack and walking exercise for average of 2.7±0.7 monthsAverage daily steps, muscle volume, leg strength, and handgrip strength were increased at 3 months
Uojima, 2017, Japan115Prospective study82 patients with LC24-week, twice a day, treatment with oral BCAAs supplement powderBCAAs improved low muscle strength without any positive effect on muscle mass
Kitajima, 2018, Japan116Prospective study21 patients with LC48 weeks of supplementation with BCAAsAmelioration of hypoalbuminemia associated with BCAAs was correlated with decreased myosteatosis with better survival rates, maintained skeletal muscle mass, and improved glucose sensitivity
Ruiz-Margáin, 2018, Mexico117Randomized trial, open label37 LC patients in the intervention group and 35 in the controlsBCAAs (110 g daily) plus HPHF (1.2 g/kg protein and 30 g fibers). Controls were given only HPHF; For 6 monthsBCAA group had an increased muscle mass and a decreased fat mass, compared with the control group
Marchesini, 2003, Italy118Randomized study, double-blind174 patients with advanced cirrhosis.1-year BCAAs against lactoalbumin or maltodextrinsBCAAs prevented progressive hepatic failure and improved or maintained nutritional parameters and liver function tests
Les, 2011, Spain119Randomized study, double-blind,116 patients with cirrhosis30 g of BCAA or maltodextrin during 56 weeksBCAA supplementation improved muscle mass and minimal hepatic encephalopathy

BCAA, branched-chain amino acid; HPHF, high-protein, high-fiber diet; LC, liver cirrhosis.

Conclusions

In conclusion, sarcopenia is common in patients with CLD and is associated with a number of metabolic dysregulations. The decreased endocrine activity of both the liver and the skeletal muscles in such patients has reciprocal implications that necessitate special attention. Hyperammonemia, amino acid depletion, hormonal imbalance, and IR are among the key pathophysiological changes seen in LC patients that contribute to sarcopenia development. Given the clinical implications, a thorough metabolic evaluation in LC patients with sarcopenia should be performed for improved risk stratification and therapeutic guidance. However, therapy for sarcopenia that targets potential risk factors is still evolving, and more study in this field is needed.

Abbreviations

AAAs: 

aromatic amino acids

ATF4: 

transcription factor 4

BCAAs: 

branched-chain amino acids

CLD: 

chronic liver disease

DM: 

diabetes mellitus

GLUTs: 

glucose transporters

GH: 

growth hormone

HD: 

hepatogenous diabetes

HE: 

hepatic encephalopathy

ISR: 

integrated stress response

IL6: 

interleukin-6

IR: 

insulin resistance

IGF-1: 

insulin-like growth factor-1

LC: 

liver cirrhosis

MHE: 

minimal hepatic encephalopathy

mTOR: 

mammalian target of rapamycin

MetS: 

metabolic syndrome

NAFLD: 

nonalcoholic fatty liver disease

TNF: 

tumor necrosis factor

TCA: 

tricarboxylic acid

TIPS: 

transjugular intrahepatic portosystemic shunt

UPP: 

ubiquitin-proteasome pathway

Declarations

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Study concept and design (RK, SSP), data acquisition (RK, SSP, RNP, UA), and drafting of manuscript (RK, SSP, RNP), Critical revision and technical support (UA, RNP). All authors have made a significant contribution and have approved the final manuscript.

References

  1. Pedersen BK. Muscle as a secretory organ. Compr Physiol 2013;3(3):1337-1362 View Article PubMed/NCBI
  2. Ahima RS, Park HK. Connecting Myokines and Metabolism. Endocrinol Metab (Seoul) 2015;30(3):235-245 View Article PubMed/NCBI
  3. Nishikawa H, Enomoto H, Ishii A, Iwata Y, Miyamoto Y, Ishii N, et al. Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis. J Cachexia Sarcopenia Muscle 2017;8(6):915-925 View Article PubMed/NCBI
  4. de Oliveira Dos Santos AR, de Oliveira Zanuso B, Miola VFB, Barbalho SM, Santos Bueno PC, Flato UAP, et al. Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions. Int J Mol Sci 2021;22(5):2639 View Article PubMed/NCBI
  5. Shah Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 2019;48(1):16-31 View Article PubMed/NCBI
  6. Kim G, Kang SH, Kim MY, Baik SK. Prognostic value of sarcopenia in patients with liver cirrhosis: A systematic review and meta-analysis. PLoS One 2017;12(10):e0186990 View Article PubMed/NCBI
  7. Montano-Loza AJ, Meza-Junco J, Prado CM, Lieffers JR, Baracos VE, Bain VG, et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin Gastroenterol Hepatol 2012;10(2):166-173.e1 View Article PubMed/NCBI
  8. Durand F, Buyse S, Francoz C, Laouénan C, Bruno O, Belghiti J, et al. Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography. J Hepatol 2014;60(6):1151-1157 View Article PubMed/NCBI
  9. Ohashi K, Ishikawa T, Imai M, Suzuki M, Hoshii A, Abe H, et al. Relationship between pre-sarcopenia and quality of life in patients with chronic liver disease: a cross-sectional study. Eur J Gastroenterol Hepatol 2019;31(11):1408-1413 View Article PubMed/NCBI
  10. Orsi E, Grancini V, Menini S, Aghemo A, Pugliese G. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes?. Liver Int 2017;37(7):950-962 View Article PubMed/NCBI
  11. Tandon P, Ney M, Irwin I, Ma MM, Gramlich L, Bain VG, et al. Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value. Liver Transpl 2012;18(10):1209-1216 View Article PubMed/NCBI
  12. Nishikawa H, Asai A, Fukunishi S, Nishiguchi S, Higuchi K. Metabolic Syndrome and Sarcopenia. Nutrients 2021;13(10):3519 View Article PubMed/NCBI
  13. Kim SH, Jeong JB, Kang J, Ahn DW, Kim JW, Kim BG, et al. Association between sarcopenia level and metabolic syndrome. PLoS One 2021;16(3):e0248856 View Article PubMed/NCBI
  14. Merz KE, Thurmond DC. Role of Skeletal Muscle in Insulin Resistance and Glucose Uptake. Compr Physiol 2020;10(3):785-809 View Article PubMed/NCBI
  15. Ebadi M, Bhanji RA, Mazurak VC, Montano-Loza AJ. Sarcopenia in cirrhosis: from pathogenesis to interventions. J Gastroenterol 2019;54(10):845-859 View Article PubMed/NCBI
  16. Nishikawa H, Enomoto H, Nishiguchi S, Iijima H. Liver Cirrhosis and Sarcopenia from the Viewpoint of Dysbiosis. Int J Mol Sci 2020;21(15):E5254 View Article PubMed/NCBI
  17. Davuluri G, Krokowski D, Guan BJ, Kumar A, Thapaliya S, Singh D, et al. Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis. J Hepatol 2016;65(5):929-937 View Article PubMed/NCBI
  18. Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L. Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease. J Am Med Dir Assoc 2016;17(9):789-796 View Article PubMed/NCBI
  19. Ferrannini E, Simonson DC, Katz LD, Reichard G, Bevilacqua S, Barrett EJ, et al. The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism 1988;37(1):79-85 View Article PubMed/NCBI
  20. James DE, Brown R, Navarro J, Pilch PF. Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature 1988;333(6169):183-185 View Article PubMed/NCBI
  21. Bouché C, Serdy S, Kahn CR, Goldfine AB. The cellular fate of glucose and its relevance in type 2 diabetes. Endocr Rev 2004;25(5):807-830 View Article PubMed/NCBI
  22. Biolo G, Zhang XJ, Wolfe RR. Role of membrane transport in interorgan amino acid flow between muscle and small intestine. Metabolism 1995;44(6):719-724 View Article PubMed/NCBI
  23. Wolfe RR. The underappreciated role of muscle in health and disease. Am J Clin Nutr 2006;84(3):475-482 View Article PubMed/NCBI
  24. Moon JS, Yoon JS, Won KC, Lee HW. The role of skeletal muscle in development of nonalcoholic Fatty liver disease. Diabetes Metab J 2013;37(4):278-285 View Article PubMed/NCBI
  25. Kim G, Lee SE, Lee YB, Jun JE, Ahn J, Bae JC, et al. Relationship Between Relative Skeletal Muscle Mass and Nonalcoholic Fatty Liver Disease: A 7-Year Longitudinal Study. Hepatology 2018;68(5):1755-1768 View Article PubMed/NCBI
  26. Corcoran MP, Lamon-Fava S, Fielding RA. Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. Am J Clin Nutr 2007;85(3):662-677 View Article PubMed/NCBI
  27. Morales PE, Bucarey JL, Espinosa A. Muscle Lipid Metabolism: Role of Lipid Droplets and Perilipins. J Diabetes Res 2017;2017:1789395 View Article PubMed/NCBI
  28. Egerman MA, Glass DJ. Signaling pathways controlling skeletal muscle mass. Crit Rev Biochem Mol Biol 2014;49(1):59-68 View Article PubMed/NCBI
  29. Wing SS, Lecker SH, Jagoe RT. Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks. Crit Rev Clin Lab Sci 2011;48(2):49-70 View Article PubMed/NCBI
  30. Han HQ, Mitch WE. Targeting the myostatin signaling pathway to treat muscle wasting diseases. Curr Opin Support Palliat Care 2011;5(4):334-341 View Article PubMed/NCBI
  31. Bilodeau PA, Coyne ES, Wing SS. The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. Am J Physiol Cell Physiol 2016;311(3):C392-C403 View Article PubMed/NCBI
  32. Görgens SW, Eckardt K, Jensen J, Drevon CA, Eckel J. Exercise and Regulation of Adipokine and Myokine Production. Prog Mol Biol Transl Sci 2015;135:313-336 View Article PubMed/NCBI
  33. Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol 2013;45(10):2333-2347 View Article PubMed/NCBI
  34. McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R. Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol 2003;162(6):1135-1147 View Article PubMed/NCBI
  35. Castonguay R, Lachey J, Wallner S, Strand J, Liharska K, Watanabe AE, et al. Follistatin-288-Fc Fusion Protein Promotes Localized Growth of Skeletal Muscle. J Pharmacol Exp Ther 2019;368(3):435-445 View Article PubMed/NCBI
  36. Wu C, Borné Y, Gao R, López Rodriguez M, Roell WC, Wilson JM, et al. Elevated circulating follistatin associates with an increased risk of type 2 diabetes. Nat Commun 2021;12(1):6486 View Article PubMed/NCBI
  37. Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 2004;53(7):1643-1648 View Article PubMed/NCBI
  38. Oh KJ, Lee DS, Kim WK, Han BS, Lee SC, Bae KH. Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines. Int J Mol Sci 2016;18(1):E8 View Article PubMed/NCBI
  39. Stefan N, Häring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol 2013;9(3):144-152 View Article PubMed/NCBI
  40. Frithioff-Bøjsøe C, Lund MAV, Lausten-Thomsen U, Hedley PL, Pedersen O, Christiansen M, et al. Leptin, adiponectin, and their ratio as markers of insulin resistance and cardiometabolic risk in childhood obesity. Pediatr Diabetes 2020;21(2):194-202 View Article PubMed/NCBI
  41. Lee YH, Jung KS, Kim SU, Yoon HJ, Yun YJ, Lee BW, et al. Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES 2008-2011). J Hepatol 2015;63(2):486-493 View Article PubMed/NCBI
  42. Koo BK, Kim D, Joo SK, Kim JH, Chang MS, Kim BG, et al. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis. J Hepatol 2017;66(1):123-131 View Article PubMed/NCBI
  43. Gan D, Wang L, Jia M, Ru Y, Ma Y, Zheng W, et al. Low muscle mass and low muscle strength associate with nonalcoholic fatty liver disease. Clin Nutr 2020;39(4):1124-1130 View Article PubMed/NCBI
  44. Puri P, Dhiman RK, Taneja S, Tandon P, Merli M, Anand AC, et al. Nutrition in Chronic Liver Disease: Consensus Statement of the Indian National Association for Study of the Liver. J Clin Exp Hepatol 2021;11(1):97-143 View Article PubMed/NCBI
  45. Eslamparast T, Montano-Loza AJ, Raman M, Tandon P. Sarcopenic obesity in cirrhosis-The confluence of 2 prognostic titans. Liver Int 2018;38(10):1706-1717 View Article PubMed/NCBI
  46. Krähenbühl L, Lang C, Lüdes S, Seiler C, Schäfer M, Zimmermann A, et al. Reduced hepatic glycogen stores in patients with liver cirrhosis. Liver Int 2003;23(2):101-109 View Article PubMed/NCBI
  47. Figueiredo FA, De Mello Perez R, Kondo M. Effect of liver cirrhosis on body composition: evidence of significant depletion even in mild disease. J Gastroenterol Hepatol 2005;20(2):209-216 View Article PubMed/NCBI
  48. Anand AC. Nutrition and Muscle in Cirrhosis. J Clin Exp Hepatol 2017;7(4):340-357 View Article PubMed/NCBI
  49. Allen SL, Quinlan JI, Dhaliwal A, Armstrong MJ, Elsharkawy AM, Greig CA, et al. Sarcopenia in chronic liver disease: mechanisms and countermeasures. Am J Physiol Gastrointest Liver Physiol 2021;320(3):G241-G257 View Article PubMed/NCBI
  50. Dasarathy S. Cause and management of muscle wasting in chronic liver disease. Curr Opin Gastroenterol 2016;32(3):159-165 View Article PubMed/NCBI
  51. Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. J Gastroenterol Hepatol 2012;27(3):430-441 View Article PubMed/NCBI
  52. Kim JA, Choi KM. Sarcopenia and fatty liver disease. Hepatol Int 2019;13(6):674-687 View Article PubMed/NCBI
  53. Thapaliya S, Runkana A, McMullen MR, Nagy LE, McDonald C, Naga Prasad SV, et al. Alcohol-induced autophagy contributes to loss in skeletal muscle mass. Autophagy 2014;10(4):677-690 View Article PubMed/NCBI
  54. Walker V. Ammonia metabolism and hyperammonemic disorders. Adv Clin Chem 2014;67:73-150 View Article PubMed/NCBI
  55. Olde Damink SW, Deutz NE, Dejong CH, Soeters PB, Jalan R. Interorgan ammonia metabolism in liver failure. Neurochem Int 2002;41(2-3):177-188 View Article PubMed/NCBI
  56. Qiu J, Thapaliya S, Runkana A, Yang Y, Tsien C, Mohan ML, et al. Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB-mediated mechanism. Proc Natl Acad Sci U S A 2013;110(45):18162-18167 View Article PubMed/NCBI
  57. Dasarathy S, Muc S, Hisamuddin K, Edmison JM, Dodig M, McCullough AJ, et al. Altered expression of genes regulating skeletal muscle mass in the portacaval anastomosis rat. Am J Physiol Gastrointest Liver Physiol 2007;292(4):G1105-G1113 View Article PubMed/NCBI
  58. Qiu J, Tsien C, Thapalaya S, Narayanan A, Weihl CC, Ching JK, et al. Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab 2012;303(8):E983-E993 View Article PubMed/NCBI
  59. Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 2002;277(34):30409-30412 View Article PubMed/NCBI
  60. Davuluri G, Allawy A, Thapaliya S, Rennison JH, Singh D, Kumar A, et al. Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. J Physiol 2016;594(24):7341-7360 View Article PubMed/NCBI
  61. Tsiaousi ET, Hatzitolios AI, Trygonis SK, Savopoulos CG. Malnutrition in end stage liver disease: recommendations and nutritional support. J Gastroenterol Hepatol 2008;23(4):527-533 View Article PubMed/NCBI
  62. Owen OE, Trapp VE, Reichard GA, Mozzoli MA, Moctezuma J, Paul P, et al. Nature and quantity of fuels consumed in patients with alcoholic cirrhosis. J Clin Invest 1983;72(5):1821-1832 View Article PubMed/NCBI
  63. Nakaya Y, Harada N, Kakui S, Okada K, Takahashi A, Inoi J, et al. Severe catabolic state after prolonged fasting in cirrhotic patients: effect of oral branched-chain amino-acid-enriched nutrient mixture. J Gastroenterol 2002;37(7):531-536 View Article PubMed/NCBI
  64. Tajiri K, Shimizu Y. Branched-chain amino acids in liver diseases. World J Gastroenterol 2013;19(43):7620-7629 View Article PubMed/NCBI
  65. Holeček M. The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases. Physiol Res 2021;70(3):293-305 View Article PubMed/NCBI
  66. Nishitani S, Matsumura T, Fujitani S, Sonaka I, Miura Y, Yagasaki K. Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun 2002;299(5):693-696 View Article PubMed/NCBI
  67. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000;6(5):1099-1108 View Article PubMed/NCBI
  68. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep 2016;17(10):1374-1395 View Article PubMed/NCBI
  69. Tsien C, Davuluri G, Singh D, Allawy A, Ten Have GA, Thapaliya S, et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology 2015;61(6):2018-2029 View Article PubMed/NCBI
  70. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009;136(3):521-534 View Article PubMed/NCBI
  71. Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005;26(6):833-876 View Article PubMed/NCBI
  72. Moctezuma-Velázquez C, Low G, Mourtzakis M, Ma M, Burak KW, Tandon P, et al. Association between Low Testosterone Levels and Sarcopenia in Cirrhosis: A Cross-sectional Study. Ann Hepatol 2018;17(4):615-623 View Article PubMed/NCBI
  73. Cuneo RC, Hickman PE, Wallace JD, Teh BT, Ward G, Veldhuis JD, et al. Altered endogenous growth hormone secretory kinetics and diurnal GH-binding protein profiles in adults with chronic liver disease. Clin Endocrinol (Oxf) 1995;43(3):265-275 View Article PubMed/NCBI
  74. Møller S, Becker U. Insulin-like growth factor 1 and growth hormone in chronic liver disease. Dig Dis 1992;10(4):239-248 View Article PubMed/NCBI
  75. Liu W, Thomas SG, Asa SL, Gonzalez-Cadavid N, Bhasin S, Ezzat S. Myostatin is a skeletal muscle target of growth hormone anabolic action. J Clin Endocrinol Metab 2003;88(11):5490-5496 View Article PubMed/NCBI
  76. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 2001;3(11):1009-1013 View Article PubMed/NCBI
  77. Johnson DG, Alberti KG, Faber OK, Binder C. Hyperinsulinism of hepatic cirrhosis: Diminished degradation or hypersecretion?. Lancet 1977;1(8001):10-13 View Article PubMed/NCBI
  78. Letiexhe MR, Scheen AJ, Gérard PL, Bastens BH, Pirotte J, Belaiche J, et al. Insulin secretion, clearance, and action on glucose metabolism in cirrhotic patients. J Clin Endocrinol Metab 1993;77(5):1263-1268 View Article PubMed/NCBI
  79. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?. Diabetes Care 2008;31(Suppl 2):S262-S268 View Article PubMed/NCBI
  80. Petrides AS, Groop LC, Riely CA, DeFronzo RA. Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis. J Clin Invest 1991;88(2):561-570 View Article PubMed/NCBI
  81. Müller MJ, Fenk A, Lautz HU, Selberg O, Canzler H, Balks HJ, et al. Energy expenditure and substrate metabolism in ethanol-induced liver cirrhosis. Am J Physiol 1991;260(3 Pt 1):E338-E344 View Article PubMed/NCBI
  82. Srikanthan P, Hevener AL, Karlamangla AS. Sarcopenia exacerbates obesity-associated insulin resistance and dysglycemia: findings from the National Health and Nutrition Examination Survey III. PLoS One 2010;5(5):e10805 View Article PubMed/NCBI
  83. Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology 2006;147(9):4160-4168 View Article PubMed/NCBI
  84. Barchetta I, De Bernardinis M, Capoccia D, Baroni MG, Fontana M, Fraioli A, et al. Hypovitaminosis D is independently associated with metabolic syndrome in obese patients. PLoS One 2013;8(7):e68689 View Article PubMed/NCBI
  85. Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol 2022;10(4):284-296 View Article PubMed/NCBI
  86. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56(7):1761-1772 View Article PubMed/NCBI
  87. Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143(4):913-6.e7 View Article PubMed/NCBI
  88. Ahluwalia V, Betrapally NS, Hylemon PB, White MB, Gillevet PM, Unser AB, et al. Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis. Sci Rep 2016;6:26800 View Article PubMed/NCBI
  89. Gojda J, Cahova M. Gut Microbiota as the Link between Elevated BCAA Serum Levels and Insulin Resistance. Biomolecules 2021;11(10):1414 View Article PubMed/NCBI
  90. Yamamoto K, Ishizu Y, Honda T, Ito T, Imai N, Nakamura M, et al. Patients with low muscle mass have characteristic microbiome with low potential for amino acid synthesis in chronic liver disease. Sci Rep 2022;12(1):3674 View Article PubMed/NCBI
  91. Montano-Loza AJ, Duarte-Rojo A, Meza-Junco J, Baracos VE, Sawyer MB, Pang JX, et al. Inclusion of Sarcopenia Within MELD (MELD-Sarcopenia) and the Prediction of Mortality in Patients With Cirrhosis. Clin Transl Gastroenterol 2015;6:e102 View Article PubMed/NCBI
  92. Merli M, Giusto M, Lucidi C, Giannelli V, Pentassuglio I, Di Gregorio V, et al. Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study. Metab Brain Dis 2013;28(2):281-284 View Article PubMed/NCBI
  93. Nardelli S, Lattanzi B, Torrisi S, Greco F, Farcomeni A, Gioia S, et al. Sarcopenia Is Risk Factor for Development of Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt Placement. Clin Gastroenterol Hepatol 2017;15(6):934-936 View Article PubMed/NCBI
  94. Kim TY, Kim MY, Sohn JH, Kim SM, Ryu JA, Lim S, et al. Sarcopenia as a useful predictor for long-term mortality in cirrhotic patients with ascites. J Korean Med Sci 2014;29(9):1253-1259 View Article PubMed/NCBI
  95. Masuda T, Shirabe K, Ikegami T, Harimoto N, Yoshizumi T, Soejima Y, et al. Sarcopenia is a prognostic factor in living donor liver transplantation. Liver Transpl 2014;20(4):401-407 View Article PubMed/NCBI
  96. Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, et al. Sarcopenia, intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma. J Hepatol 2015;63(1):131-140 View Article PubMed/NCBI
  97. Kaido T, Ogawa K, Fujimoto Y, Ogura Y, Hata K, Ito T, et al. Impact of sarcopenia on survival in patients undergoing living donor liver transplantation. Am J Transplant 2013;13(6):1549-1556 View Article PubMed/NCBI
  98. Montano-Loza AJ, Meza-Junco J, Baracos VE, Prado CM, Ma M, Meeberg G, et al. Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation. Liver Transpl 2014;20(6):640-648 View Article PubMed/NCBI
  99. Kang SH, Jeong WK, Baik SK, Cha SH, Kim MY. Impact of sarcopenia on prognostic value of cirrhosis: going beyond the hepatic venous pressure gradient and MELD score. J Cachexia Sarcopenia Muscle 2018;9(5):860-870 View Article PubMed/NCBI
  100. Beaudart C, Zaaria M, Pasleau F, Reginster JY, Bruyère O. Health Outcomes of Sarcopenia: A Systematic Review and Meta-Analysis. PLoS One 2017;12(1):e0169548 View Article PubMed/NCBI
  101. Saeki C, Tsubota A. Influencing Factors and Molecular Pathogenesis of Sarcopenia and Osteosarcopenia in Chronic Liver Disease. Life (Basel) 2021;11(9):899 View Article PubMed/NCBI
  102. Calmet F, Martin P, Pearlman M. Nutrition in Patients With Cirrhosis. Gastroenterol Hepatol (N Y) 2019;15(5):248-254 PubMed/NCBI
  103. Dejong CH, van de Poll MC, Soeters PB, Jalan R, Olde Damink SW. Aromatic amino acid metabolism during liver failure. J Nutr 2007;137(6 Suppl 1):1579S-1585S View Article PubMed/NCBI
  104. Miwa T, Hanai T, Nishimura K, Maeda T, Ogiso Y, Imai K, et al. Handgrip strength stratifies the risk of covert and overt hepatic encephalopathy in patients with cirrhosis. JPEN J Parenter Enteral Nutr 2022;46(4):858-866 View Article PubMed/NCBI
  105. Nardelli S, Lattanzi B, Merli M, Farcomeni A, Gioia S, Ridola L, et al. Muscle Alterations Are Associated With Minimal and Overt Hepatic Encephalopathy in Patients With Liver Cirrhosis. Hepatology 2019;70(5):1704-1713 View Article PubMed/NCBI
  106. García-Compeán D, Orsi E, Kumar R, Gundling F, Nishida T, Villarreal-Pérez JZ, et al. Clinical implications of diabetes in chronic liver disease: Diagnosis, outcomes and management, current and future perspectives. World J Gastroenterol 2022;28(8):775-793 View Article PubMed/NCBI
  107. Zhang H, Lin S, Gao T, Zhong F, Cai J, Sun Y, et al. Association between Sarcopenia and Metabolic Syndrome in Middle-Aged and Older Non-Obese Adults: A Systematic Review and Meta-Analysis. Nutrients 2018;10(3):E364 View Article PubMed/NCBI
  108. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012;8(8):457-465 View Article PubMed/NCBI
  109. Perakakis N, Triantafyllou GA, Fernández-Real JM, Huh JY, Park KH, Seufert J, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 2017;13(6):324-337 View Article PubMed/NCBI
  110. Schutte JE, Longhurst JC, Gaffney FA, Bastian BC, Blomqvist CG. Total plasma creatinine: an accurate measure of total striated muscle mass. J Appl Physiol Respir Environ Exerc Physiol 1981;51(3):762-766 View Article PubMed/NCBI
  111. Ichikawa T, Miyaaki H, Miuma S, Motoyoshi Y, Yamashima M, Yamamichi S, et al. Indices calculated by serum creatinine and cystatin C as predictors of liver damage, muscle strength and sarcopenia in liver disease. Biomed Rep 2020;12(3):89-98 View Article PubMed/NCBI
  112. Bischoff SC, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T, et al. ESPEN practical guideline: Clinical nutrition in liver disease. Clin Nutr 2020;39(12):3533-3562 View Article PubMed/NCBI
  113. Kumar A, Davuluri G, Silva RNE, Engelen MPKJ, Ten Have GAM, Prayson R, et al. Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis. Hepatology 2017;65(6):2045-2058 View Article PubMed/NCBI
  114. Hiraoka A, Michitaka K, Kiguchi D, Izumoto H, Ueki H, Kaneto M, et al. Efficacy of branched-chain amino acid supplementation and walking exercise for preventing sarcopenia in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2017;29(12):1416-1423 View Article PubMed/NCBI
  115. Uojima H, Sakurai S, Hidaka H, Kinbara T, Sung JH, Ichita C, et al. Effect of branched-chain amino acid supplements on muscle strength and muscle mass in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2017;29(12):1402-1407 View Article PubMed/NCBI
  116. Kitajima Y, Takahashi H, Akiyama T, Murayama K, Iwane S, Kuwashiro T, et al. Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis. J Gastroenterol 2018;53(3):427-437 View Article PubMed/NCBI
  117. Ruiz-Margáin A, Macías-Rodríguez RU, Ríos-Torres SL, Román-Calleja BM, Méndez-Guerrero O, Rodríguez-Córdova P, et al. Effect of a high-protein, high-fiber diet plus supplementation with branched-chain amino acids on the nutritional status of patients with cirrhosis. Rev Gastroenterol Mex (Engl Ed) 2018;83(1):9-15 View Article PubMed/NCBI
  118. Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 2003;124(7):1792-1801 View Article PubMed/NCBI
  119. Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, et al. Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. Am J Gastroenterol 2011;106(6):1081-1088 View Article PubMed/NCBI
  120. Sinclair M, Grossmann M, Hoermann R, Angus PW, Gow PJ. Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial. J Hepatol 2016;65(5):906-913 View Article PubMed/NCBI
  121. Wallace JD, Abbott-Johnson WJ, Crawford DH, Barnard R, Potter JM, Cuneo RC. GH treatment in adults with chronic liver disease: a randomized, double-blind, placebo-controlled, cross-over study. J Clin Endocrinol Metab 2002;87(6):2751-2759 View Article PubMed/NCBI
  122. Kim Y. Emerging Treatment Options for Sarcopenia in Chronic Liver Disease. Life (Basel) 2021;11(3):250 View Article PubMed/NCBI
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  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

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Sarcopenia in Chronic Liver Disease: A Metabolic Perspective

Ramesh Kumar, Sabbu Surya Prakash, Rajeev Nayan Priyadarshi, Utpal Anand
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