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Sarcopenia in the Cirrhotic Patient: Current Knowledge and Future Directions

  • Edgewood R. Warner II
    Affiliations
    Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, 300 Community Drive, Manhasset, NY, 11030, USA
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  • Sanjaya K. Satapathy
    Correspondence
    Address for correspondence: Sanjaya K. Satapathy, MD, DM, MS(Epi), FACG, AGAF, FASGE, FAASLD, Interim Division Chief of Hepatology and Medical Director, Liver Transplantation Northwell Health Center for Liver Diseases & Transplantation, Professor Donald and Barbara Zucker School of Medicine, Department of Medicine, Northshore University Hospital/Northwell Health, 400 Community Drive, Manhasset, NY 11030 USA.
    Affiliations
    Division of Hepatology and Northwell Health Center for Liver Diseases and Transplantation, Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, 300 Community Drive, Manhasset, NY, 11030, USA
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      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

      Abbreviations:

      ACE (angiotensin-converting enzyme), ACE-I (angiotensin-converting enzyme inhibitor), AKI (acute kidney injury), ARB (angiotensin receptor blocker), ALM (appendicular lean mass), 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), GnRH (gonadotrophin-releasing hormone), GTP (guanosine-5′-triphosphate), 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), mTOR (mammalian target of rapamycin), 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)
      Liver cirrhosis is a complex pathophysiological condition that produces many different metabolic imbalances. One of the most notable derangements is a significant alteration in energy homeostasis. A combination of factors, including abnormal energy utilization, altered hormonal balance, and increased inflammation, in the context of decreased hepatic functional capacity, can result in a depletion of functional skeletal muscle mass; this is known as sarcopenia.
      • Santilli V.
      • Bernetti A.
      • Mangone M.
      • Paoloni M.
      Clinical definition of sarcopenia.
      Sarcopenia is a disorder of immense clinical interest because of its implications in the cirrhotic patient; it can result in multiple adverse outcomes ranging from severe debility to increased risk of injury and death.
      • Santilli V.
      • Bernetti A.
      • Mangone M.
      • Paoloni M.
      Clinical definition of sarcopenia.
      The purpose of this paper is as follows: (1) define sarcopenia; (2) describe the pathogenic processes that contribute to the generation of sarcopenia; (3) identify criteria for diagnosing sarcopenia; (4) discuss biomarkers of potential interest in sarcopenia; (5) explain current approaches for the management of sarcopenia; (6) introduce biomarkers that may be utilized to further characterize sarcopenia.

      Definition of Sarcopenia

      Sarcopenia is a physical state defined by the loss of functional skeletal muscle mass.
      • Studenski S.A.
      • Peters K.W.
      • Alley D.E.
      • et al.
      The FNIH sarcopenia project: rationale, study, description, conference recommendations and final estimates.
      It is a multifactorial process that is typically seen as part of the normal aging process in the setting of age-related metabolic changes. However, it becomes a pathological process when precipitated by the conditions of abnormal metabolism, such as cirrhosis. This depletion of skeletal muscle mass contributes to marked physical limitation, weakness, and frailty, which results in an increased risk of disability, morbidity, and mortality.
      • Studenski S.A.
      • Peters K.W.
      • Alley D.E.
      • et al.
      The FNIH sarcopenia project: rationale, study, description, conference recommendations and final estimates.
      While it has a clear definition, there remains ambiguity regarding the clinical metrics that need to be observed to make a diagnosis. Multiple authoritative bodies, most notably the European Working Group on Sarcopenia in Older People (EWGSOP), have created criteria by which sarcopenia may be identified; the diagnostic criteria encompass a combination of decreased muscle strength, mass, and function (Table 1).
      • Santilli V.
      • Bernetti A.
      • Mangone M.
      • Paoloni M.
      Clinical definition of sarcopenia.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      • Gould H.
      • Brennan S.L.
      • Kotowicz M.A.
      • Nicholson G.C.
      • Pasco J.A.
      Total and appendicular lean mass reference ranges for Australian men and womenL the Geelong osteoporosis study.
      • Studenski S.A.
      • Peters K.W.
      • Alley D.E.
      • et al.
      The FNIH sarcopenia project: rationale, study, description, conference recommendations and final estimates.
      • Cawthon P.M.
      • Peters K.W.
      • Shardell M.D.
      • et al.
      Cutpoints for low appendicular lean mass that identify older adults with clinically significant weakness.
      • Dent E.
      • Morley J.E.
      • Cruz-Jentoft A.J.
      • et al.
      International clinical practice guidelines for sarcopenia (ICFSR): screening, diagnosis, and management.
      • Chen L.
      • Woo J.
      • Assantachi P.
      • et al.
      Asian working group for sarcopenia: 2019 consensus update on sarcopenia diagnosis and treatment.
      • Chen L.K.
      • Liu L.K.
      • Woo J.
      • et al.
      Sarcopenia in Asia: consensus report of the Asian working group for sarcopenia.
      • Cederholm T.
      • Barazzoni R.
      • Austin P.
      • et al.
      ESPEN guidelines on definitions and terminology of clinical nutrition.
      • Wen X.
      • An P.
      • Chen W.C.
      • Lv Y.
      • Fu Q.
      Comparisons of sarcopenia prevalence based on different diagnostic criteria in Chinese older adults.
      Table 1Diagnostic Criteria for Sarcopenia by Organization.
      OrganizationDiagnostic criteria
      EWGSOP, version 2Low muscle strength (grip strength <27 kg in males and <16 in females)

      Low skeletal muscle mass (in terms of appendicular skeletal mass per height; <7.0 kg/m2 in males or <5.5 kg/m2 in females) (2 standard deviations below the reference range of 8.8 kg/m2 for males and 6.84 kg/m2 for females)

      For the diagnosis of severe sarcopenia, low muscle performance (gait speed of ≤0.8 m/s or SPPB of ≤8)
      ESPEN-SIGLow skeletal muscle mass (in terms of appendicular skeletal mass per height; <7.26/m2 in males and <5.5 kg/m2 in females (2 standard deviations below reference range of 8.6 kg/m2 for males and 7.3 kg/m2 for females) and one of the following:

      Low skeletal muscle strength (grip strength <30 kg in males and <20 kg in females)

      Low muscle performance (gait speed <0.8–1.0 m/s)
      IWGSLow skeletal muscle mass (in terms of appendicular skeletal muscle mass per height; 7.23 kg/m2 in males and 5.67 kg/m2 in females) (lowest 20% of distribution for each sex)

      Low muscle performance (gait speed <1 m/s)
      FNIHLow muscle strength (grip strength <26 kg in males and <16 kg in females)

      Low muscle mass (in terms of appendicular lean mass per BMI; <0.789 in males and <0.512 kg in females) (established by regression analysis)
      AWGSLow skeletal muscle mass (in terms of appendicular skeletal mass per height; <7.0 kg/m2 in males or 5.4 kg/m2 in females by DEXA or 5.7 kg/m2 by BIA) and one of the following:

      Low muscle strength (grip strength <28 kg for males and <18 for females) or

      Low muscle performance (gait speed <1 m/s or SPPB ≤9)
      International Conference on Frailty and Sarcopenia ResearchPer EWGSOP, FNIH, IWGS, or AWGS diagnostic criteria
      EWGSOP, European Working Group on Sarcopenia in Older People; ESPEN-SIG, European Society for Clinical Nutrition and Metabolism Special Interest Groups; IWGS, International Working Group on Sarcopenia; FNIH, Foundations for the National Institutes of Health; AWGS, Asian Working Group for Sarcopenia, SPPB, Short Performance Physical Battery; BIA, bioelectrical impedance analysis; DEXA, dual energy X-ray absorptiometry; BMI, body mass index.

      Pathogenesis of Sarcopenia in Cirrhosis

      The manifestation of sarcopenia is a complex interaction of numerous defective metabolic pathways in the cirrhotic patient, evident on a macroscopic (as evidenced by outwardly visible symptoms) and microscopic scale (within pathways affecting the hepatocyte and the myocyte), described in more detail below:

      Decreased Oral Intake due to Manifestations of Decompensated Cirrhosis

      One of the most apparent impacts of cirrhosis, specifically decompensated cirrhosis, on sarcopenia is decreased oral intake. Decompensated cirrhosis is heralded by any of the following conditions: bleeding varices (typically esophageal), ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatocellular carcinoma (HCC).
      • Chapman B.
      • Sinclair M.
      • Gow P.J.
      • Testro A.G.
      Malnutrition in cirrhosis: more food for thought.
      These complications, whether acute or chronic, drive anorexia through different modalities.
      Ascites—Ascites is a consequence of 3 pathophysiological processes working in tandem—increased portal pressures, vasodilation, and fluid retention. First, liver inflammation and injury, whether caused by chronic hepatitis viral infection, an autoimmune condition, chronic alcohol use, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH) lead to distortion of liver architecture and conversion of the hepatic portal system converting from low-resistance to a high-resistance system.
      • Moore C.M.
      • Theil D.H.V.
      Cirrhotic ascites review: pathophysiology, diagnosis, management.
      The body attempts to compensate by secreting vasodilatory substances, such as nitric oxide, to facilitate flow through splanchnic circulation. This increases splanchnic venous blood pooling and causes a relative deficiency in venous return, cardiac output, and renal blood flow. The renin-angiotensin-aldosterone system (RAAS) is activated, stimulating increased sodium and water retention. Overall, the combination of increased vascular (hydrostatic) pressure, increased fluid retention and accumulation in vessels in conjunction with inflammatory marker-mediated vascular permeability, and decreased oncotic pressure from albumin deficiency contributes to the generation of abdominal ascites.
      • Moore C.M.
      • Theil D.H.V.
      Cirrhotic ascites review: pathophysiology, diagnosis, management.
      The ascites exerts pressure on the abdominal compartment, particularly compressing the stomach; this leads to early satiety and decrease oral intake.
      • Moore C.M.
      • Theil D.H.V.
      Cirrhotic ascites review: pathophysiology, diagnosis, management.
      ,
      • Cheung K.
      • Lee S.S.
      • Raman M.
      Prevalence and mechanisms of malnutrition in patients with advanced liver disease, and nutrition management strategies.
      Hepatic encephalopathy—Hepatic encephalopathy is a spectrum of neurocognitive dysfunction that results from acute or chronic liver disease; patients may be asymptomatic or demonstrate symptoms ranging from confusion to coma.
      • Warner II,
      • Aloor F.Z.
      • Satapathy S.K.
      A narrative review of nutritional abnormalities, complications, and optimization in the cirrhotic patient.
      Nitrogen in the form of ammonia is metabolized to urea in the liver; urea may then be excreted into urine as waste. However, the inability of the cirrhotic liver to convert ammonia to urea and shunting of blood away from the liver through collateral circulation leads to hyperammonemia.
      • Bemeur C.
      • Desjardins P.
      • Butterworth R.F.
      Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure.
      The ammonia is typically rerouted to skeletal muscle (described below in the Ammonia Dysmetabolism section) or to the brain.
      • Bemeur C.
      • Desjardins P.
      • Butterworth R.F.
      Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure.
      ,
      • Butterworth R.F.
      Hepatic encephalopathy in cirrhosis: pathology and pathophysiology.
      While in the brain, ammonia induces hepatic encephalopathy via mechanisms: (1) it is converted to glutamine and taken up by astrocytes causing astrocyte swelling and dysfunction; (2) ammonia disrupts the citric acid cycle and disrupts ATP production in the brain; (3) may promote the conversion of tryptophan to serotonin; (4) activates the gamma-amino-n-butyric acid pathway.
      • Bemeur C.
      • Desjardins P.
      • Butterworth R.F.
      Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure.
      • Butterworth R.F.
      Hepatic encephalopathy in cirrhosis: pathology and pathophysiology.
      • John S.
      • Thuluvath P.J.
      Hyponatremia in cirrhosis: pathophysiology and management.
      • Jindal A.
      • Jagdish R.K.
      Sarcopenia: ammonia metabolism and hepatic encephalopathy.
      Patients who experience the neurocognitive effects of hepatic encephalopathy are unable to adequately perform their activities of daily living, including preparing meals and adhering to a regular schedule of food consumption, with mild symptoms and may have a complete inability to consume food with moderate to severe symptoms.
      • Chapman B.
      • Sinclair M.
      • Gow P.J.
      • Testro A.G.
      Malnutrition in cirrhosis: more food for thought.
      As such, hepatic encephalopathy creates a significant risk for malnutrition and resultant sarcopenia.

      Hepatocyte Dysfunction

      Glucose dysmetabolism—When excess calories are consumed during a meal, the liver can synthesize glycogen (a polymer of glucose) for use during times of decreased availability of exogenous energy substrates (i.e. overnight fasting or starvation).
      • Han H.S.
      • Kang G.
      • Kim J.S.
      • Choi B.H.
      • Koo S.H.
      Regulation of glucose metabolism from a liver-centric perspective.
      During these fasting states and under the direction of hormonal control, the glycogen is broken down into individual glucose molecules that can be utilized by hungry tissues (brain, muscle) by means of glycolysis. The depletion of glycogen stores after prolonged period of starvation (greater than 24 h) triggers hepatic synthesis of glucose from alternate substrates, specifically amino acids and lactate; the amino acids, particularly the glucogenic amino acids glutamine and alanine, are sourced from the catabolism of skeletal muscle.
      • Argilés J.M.
      • Campos N.
      • Lopez-Pedrosa J.M.
      • Rueda R.
      • Rodriguez-Mañas L.
      Skeletal muscle regulates metabolism via interorgan crosstalk: roles in health and disease.
      This process is temporary until the glycogen stores are replenished. The destruction of liver architecture in cirrhosis, however, leads to persistent compromise of function, of which includes the capacity for glycogen metabolism; as such, glycogen stores are noted to be decreased in cirrhotic patients.
      • Sinclair M.
      • Gow P.J.
      • Grossman M.
      • Angus P.W.
      Review article: sarcopenia in cirrhosis – aetiology, implications, and potential therapeutic interventions.
      This decrease is related to a decline in the activity of glucokinase, the enzyme within the liver that is responsible for phosphorylating glucose as a first step in hepatic glycolysis.
      • Chang M.
      • Yang S.
      Metabolic signature of hepatic fibrosis: from individual pathways to systems biology.
      This depletion of glycogen causes an increased reliance on gluconeogenesis, which is powered by amino acids sourced from protein catabolism.
      • Meyer F.
      • Bannert K.
      • Wiese M.
      • et al.
      Molecular mechanism contributing to malnutrition and sarcopenia in patients with liver cirrhosis.
      Hyperammonemia—Ammonia, generated from protein catabolism and intestinal bacterial metabolism, is typically transported via alanine and glutamine to the liver where it is converted by the liver into urea via the hepatic urea cycle and excreted by the kidneys.
      • Lee D.Y.
      • Kim E.H.
      Therapeutic effects of amino acids in liver diseases: current studies and future perspectives.
      Pyruvate and α-ketoglutarate, the products of deamination of alanine and glutamine, respectively, can then enter the Krebs cycle for utilization where appropriate.
      • Lee D.Y.
      • Kim E.H.
      Therapeutic effects of amino acids in liver diseases: current studies and future perspectives.
      However, compromised hepatic function and shunting from the liver due to portal hypertension results in increased serum ammonia levels.
      • Bemeur C.
      • Desjardins P.
      • Butterworth R.F.
      Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure.
      ,
      • Dasarathy S.
      • Hatzoglou M.
      Hyperammonemia and proteostasis in cirrhosis.
      The ammonia is subsequently routed to skeletal muscle, where it combines with α-ketoglutarate to form glutamate and glutamine; the depletion of α-ketoglutarate creates a deficit of substrates for the citric acid cycle, which can negatively impact mitochondrial function (specifically generation of ATP) and cause muscle injury and wasting (Figure 1).
      • Dasarathy S.
      • Hatzoglou M.
      Hyperammonemia and proteostasis in cirrhosis.
      • Dasarathy S.
      Myostatin and beyond in cirrhosis: all roads lead to sarcopenia.
      • Holecek 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.
      As muscle mass decreases, excess ammonia circulates to the brain, where it produces the effects of hepatic encephalopathy described in the Hepatic Encephalopathy section.
      Figure 1
      Figure 1Illustration 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.

      Vitamin D Deficiency

      Vitamin D is a fat-soluble vitamin that is derived from cholesterol; it undergoes transformation to 7-dehydrocholesterol (in the liver), cholecalciferol (through sun exposure), 25-hydroxy-vitamin D (in the liver), and then to the active form, 1,25-dihydroxy-vitamin D, after which it exerts its effects on multiple target organs, such as the intestines, bones, and skeletal muscle.
      • Remelli F.
      • Vitali A.
      • Zurlo A.
      • Volpato S.
      Vitamin D deficiency and sarcopenia in older persons.
      Vitamin D specifically impacts skeletal muscle through upregulation of insulin-like growth factors (IGFs), specifically IGF-1 and follistatin, molecules that promote muscle cell differentiation and proliferation; it also inhibits myostatin, a myokine that suppresses muscle growth.
      • Remelli F.
      • Vitali A.
      • Zurlo A.
      • Volpato S.
      Vitamin D deficiency and sarcopenia in older persons.
      The etiology of vitamin D deficiency in cirrhosis is multifactorial; it includes lack of exposure to sunlight, low oral intake from external sources due to anorexia, and failure of chemical conversion due to defective hepatocyte activity. Therefore, vitamin D deficit promotes sarcopenia by limiting the extent of muscle proliferation and growth.
      • Konstantakis C.
      • Tselekouni P.
      • Kalafateli M.
      • Triantos C.
      Vitamin D deficiency in patients with liver cirrhosis.
      Of note, vitamin D deficiency is about 60–90% more prevalent in patients with chronic liver disease than in patients without such liver disorders.
      • Konstantakis C.
      • Tselekouni P.
      • Kalafateli M.
      • Triantos C.
      Vitamin D deficiency in patients with liver cirrhosis.

      Hormonal Imbalance

      Leptin and ghrelin—Hormones involved in the regulation of appetite may also become imbalanced. Leptin, a hormone secreted by adipose tissue, modulates appetite by stimulating the reduction of food consumption, while ghrelin, produced by the stomach, stimulates appetite.
      • Kelesidis T.
      • Kelesidis I.
      • Chou S.
      • Mantzoros C.S.
      Narrative Review: the role of leptin in human physiology: emerging clinical applications.
      • Elaghori A.
      • Salem P.E.S.
      • Azzam E.
      • Elfotoh N.A.
      Ghrelin levels in patients with liver cirrhosis.
      • Kalaitzakis E.
      • Bosaeus I.
      • Ohman L.
      • Bjornsson E.
      Altered postprandial glucose, insulin, leptin and ghrelin in liver cirrhosis: correlations with energy intake and resting energy expenditure.
      Patients with cirrhosis are demonstrated to have increased levels of leptin, which serves to decrease oral intake; it is noted that leptin levels may fluctuate depending on the amount of fat tissue.
      • Chapman B.
      • Sinclair M.
      • Gow P.J.
      • Testro A.G.
      Malnutrition in cirrhosis: more food for thought.
      ,
      • Rachakonda V.
      • Borhani A.A.
      • Dunn M.A.
      • Andrzejewski M.
      • Martin K.
      • Behari J.
      Serum leptin is a biomarker of malnutrition in decompensated cirrhosis.
      ,
      • Kohara K.
      • Ochi M.
      • Tabara Y.
      • Nagai T.
      • Igase M.
      • Miki T.
      Leptin in sarcopenic visceral obesity: possible link between adipocytes and myocytes.
      Additionally, compared to non-cirrhotic patients, cirrhotic patients are noted to have decreased ghrelin levels which can also adversely impact oral intake; levels are further decreased in decompensated cirrhotic patients compared to compensated cirrhotic patients.
      • Chapman B.
      • Sinclair M.
      • Gow P.J.
      • Testro A.G.
      Malnutrition in cirrhosis: more food for thought.
      ,
      • Elaghori A.
      • Salem P.E.S.
      • Azzam E.
      • Elfotoh N.A.
      Ghrelin levels in patients with liver cirrhosis.
      ,
      • Kalaitzakis E.
      • Bosaeus I.
      • Ohman L.
      • Bjornsson E.
      Altered postprandial glucose, insulin, leptin and ghrelin in liver cirrhosis: correlations with energy intake and resting energy expenditure.
      ,
      • Diz-Lois M.T.
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      • Suarez F.
      • Sangiao-Alvarellos S.
      • Vidal O.
      • Cordido F.
      Altered fasting and postprandial plasma ghrelin levels in patients with liver failure are normalized after liver transplantation.
      Insulin—A major function of insulin to decrease proteolysis and increase protein synthesis by means of the Akt/mammalian target of rapamycin (mTOR) pathway in the presence of essential amino acids (EAAs), especially with higher insulin levels and a robust supply of EAA after meals (Figure 2)
      • Everman S.
      • Meyer C.
      • Tran L.
      • et al.
      Insulin does not stimulate muscle protein synthesis during increased plasma branched-chain amino acids alone but still decreases whole body proteolysis in humans.
      ,
      • Robinson M.M.
      • Soop M.
      • Sohn T.S.
      • et al.
      High insulin combined with essential amino acids stimulates skeletal muscle mitochondrial protein synthesis while decreasing insulin sensitivity in healthy humans.
      ; therefore, a decreased consumption of substrates for synthesis blunts insulin's muscle synthetic activity, even when insulin levels are elevated.
      • James H.A.
      • O'Neill B.T.
      • Nair K.S.
      Insulin regulation of proteostasis and clinical implications.
      Additionally, cirrhosis predisposes to insulin resistance due to decreased hepatic clearance, shunting around the hepatic portal venous system, and increased pancreatic secretions.
      • Najjar S.M.
      • Perdomo G.
      Hepatic insulin clearance: mechanism and physiology.
      • Erice E.
      • Llop E.
      • Berzigotti A.
      • et al.
      Insulin resistance in patients with cirrhosis and portal hypertension.
      • Kawaguchi T.
      • Taniguchi E.
      • Itou M.
      • Sakata M.
      • Sumie S.
      • Sata M.
      Insulin resistance and chronic liver disease.
      Insulin resistance has been noted in a high proportion of cirrhotic patients, regardless of etiology, even when traditional measures of glycemic status (i.e. hemoglobin A1c and fasting plasma glucose) are within normal limits (euglycemic cirrhosis).
      • Deep H.S.
      • Babbar N.
      • Mahajan D.S.
      Prevalence of insulin resistance in cirrhosis of liver.
      ,
      • Goswami A.
      • Bhargava N.
      • Dadhich S.
      • Kulamarva G.
      Insulin resistance in euglycemic cirrhosis.
      Specifically, insulin resistance can directly lead to muscle wasting due to reduction in the activity of the phosphatidylinositol 3-kinase, Akt, and mTOR pathways; this results in a combination of decreased muscle synthesis and increased activity of the ubiquitin-proteosome degradation pathway within muscle, which can accelerate loss of muscle mass.
      • James H.A.
      • O'Neill B.T.
      • Nair K.S.
      Insulin regulation of proteostasis and clinical implications.
      ,
      • Wang X.
      • Hu Z.
      • Hu J.
      • Du J.
      • Mitch W.E.
      Insulin resistance accelerates muscle protein degradation: activation of the ubiquitin-proteosome pathway by defects in muscle cell signaling.
      Figure 2
      Figure 2Illustration 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.
      Glucagon—Liver dysfunction is a catalyst for hyperglucagonemia. One of the functions of insulin is to suppress glucagon secretion; insulin resistance, however, attenuates the suppressive effects of insulin on glucagon, which leads to overall higher glucagon levels.
      • Thiessen S.E.
      • Derde S.
      • Derese I.
      • et al.
      Role of glucagon in catabolism and muscle wasting of critical illness and modulation by nutrition.
      There is also a measure of glucagon resistance. A high concentration of glucagon receptors are located in the liver due to the organ's glycogenolytic and gluconeogenic functions.
      • Qaid M.M.
      • Abdelrahman M.M.
      Role of insulin and other related hormones in energy metabolism – a review.
      ,
      • Albrechtsen N.J.W.
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      • Pederson J.
      • Knop F.K.
      • Holst J.J.
      The biology of glucagon and the consequences of hyperglucagonemia.
      Cirrhosis causes reduced functional hepatic mass, which reduces capacity for glycogenesis and glycolysis; this, in turn, reduces the efficacy of glucagon on the liver.
      • Suppli M.P.
      • Bagger J.I.
      • Lund A.
      • et al.
      Glucagon resistance at the level of amino acid turnover in obese subjects with hepatic steatosis.
      ,
      • Calmet F.
      • Martin P.
      • Pearlman M.
      Nutrition in patients with cirrhosis.
      Additionally, increased levels of glucagon cause accelerated muscle catabolism; the breakdown of muscle generates the amino acids necessary for gluconeogenesis and maintenance of hepatic glucose in the setting of decreased glycogenolysis.
      • Thiessen S.E.
      • Derde S.
      • Derese I.
      • et al.
      Role of glucagon in catabolism and muscle wasting of critical illness and modulation by nutrition.
      ,
      • Adeva-Andany M.M.
      • Funcasta-Calderon R.
      • Fernandez-Fernandez C.
      • Castro-Quintela E.
      • Carneiro-Freire N.
      Metabolic effects of glucagon in humans.
      Estrogen and testosterone—Cirrhosis is noted to impact the sex hormone levels. Testosterone is decreased due to abnormalities in the hypothalamic-pituitary-testicular axis; this specifically occurs through the suppression of gonadotrophin-releasing hormone and luteinizing hormone.
      • Sinclair M.
      • Grossmann M.
      • Gow P.J.
      • Angus P.W.
      Testosterone in men with advanced liver disease: abnormalities and implications.
      These changes cause a decrease in the level of testosterone, which is a critical stimulus of the Akt/mTOR pathway for muscle synthesis and maintenance (Figure 2).
      • Sinclair M.
      • Grossmann M.
      • Gow P.J.
      • Angus P.W.
      Testosterone in men with advanced liver disease: abnormalities and implications.
      ,
      • White J.P.
      • Gao S.
      • Puppa M.J.
      • Sato S.
      • Welle S.L.
      • Carson J.A.
      Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle.
      Furthermore, estrogen is also increased in cirrhosis as a result of decreased metabolism in the liver and increased conversion of testosterone peripherally.
      • Sinclair M.
      • Grossmann M.
      • Gow P.J.
      • Angus P.W.
      Testosterone in men with advanced liver disease: abnormalities and implications.
      Lastly, increased estrogen and decreased testosterone also generate increased levels of sex hormone binding globulin, which has a stronger affinity to testosterone; this serves to magnify the relative and absolute testosterone deficiency.
      • Sinclair M.
      • Grossmann M.
      • Gow P.J.
      • Angus P.W.
      Testosterone in men with advanced liver disease: abnormalities and implications.

      Proinflammatory State

      Damaged liver tissue attracts immune cells such as macrophages and neutrophils; both entities generate cytokines that result in significant localized and systemic inflammation.
      • Irving K.M.
      • Ratnasekera I.
      • Powell E.E.
      • Hume D.A.
      Causes and consequences of innate immune dysfunction in cirrhosis.
      ,
      • Dirchwolf M.
      • Ruf A.E.
      Role of systemic inflammation in cirrhosis: from pathogenesis to prognosis.
      Decreased hepatic function also compromises its immunological function, a condition called cirrhosis-associated immune dysfunction; this is characterized by immune cell dysfunction, increased oxidative stress, and augmented risk for bacterial infection.
      • Irving K.M.
      • Ratnasekera I.
      • Powell E.E.
      • Hume D.A.
      Causes and consequences of innate immune dysfunction in cirrhosis.
      • Dirchwolf M.
      • Ruf A.E.
      Role of systemic inflammation in cirrhosis: from pathogenesis to prognosis.
      • Noor M.T.
      • Manoria P.
      Immune dysfunction in cirrhosis.
      Circulating inflammatory cytokines, specifically interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), activate the ubiquitin-proteosome degradation pathway in the muscle, causing wasting.
      • Bojko M.
      Causes of sarcopenia in liver cirrhosis.

      Hypermetabolism

      Cirrhosis is a hypermetabolic state which is mediated largely in part by an over activation of the sympathetic nervous system (SNS); individuals with cirrhosis are noted to have increased levels of epinephrine and norepinephrine as well as increased SNS nerve conduction.
      • Eghtesad S.
      • Poustchi H.
      • Malekzadeh R.
      Malnutrition in liver cirrhosis: the influence of protein and sodium.
      ,
      • Amir M.
      • Yu M.
      • He P.
      • Srinivasan S.
      Hepatic autonomic nervous system and neurotrophic factors regulate the pathogenesis and progression of non-alcoholic fatty liver disease.
      The catecholamines act in a similar capacity to glucagon, stimulating gluconeogenesis through amino acids abstracted from muscle catabolism.
      • Eghtesad S.
      • Poustchi H.
      • Malekzadeh R.
      Malnutrition in liver cirrhosis: the influence of protein and sodium.
      ,
      • Dufour S.
      • Lebon V.
      • Shulman G.I.
      • Petersen K.F.
      Regulation of net hepatic glycogenolysis and gluconeogenesis by epinephrine in humans.
      This SNS hyperstimulation also causes a higher resting energy expenditure, which requires increased tissue catabolism (specifically muscle) to support the increased metabolic needs.
      • Bojko M.
      Causes of sarcopenia in liver cirrhosis.
      ,
      • Eghtesad S.
      • Poustchi H.
      • Malekzadeh R.
      Malnutrition in liver cirrhosis: the influence of protein and sodium.
      Table 2 demonstrates a summary of metabolic predisposing factors to sarcopenia in cirrhosis.
      Table 2Metabolic Predisposing Factors and Mechanisms of Contribution to Sarcopenia in Cirrhosis.
      FactorMechanismOutcome
      Physical – decompensated cirrhosisReduced oral intakeReduced available amino acids for protein synthesis/maintenance
      Hepatocyte dysfunctionReduced glycogen storage

      Consumption of ketoacids for ammonia metabolism

      Ammonia upregulation of myostatin
      Increased muscle catabolism and increased use of amino acids for gluconeogenesis

      Mitochondrial dysfunction

      Decreased protein synthesis and increased muscle autophagy
      Increased ammonia production in kidneyHepatic encephalopathy
      Hormonal:

      Increased leptin

      Decreased ghrelin

      Insulin resistance

      Increased glucagon
      Reduced oral intake

      Reduced oral intake

      Decreased Akt and mTOR pathway activity

      Amino acid utilization for gluconeogenesis
      Reduced available amino acids for protein synthesis/maintenance

      Reduced available amino acids for protein synthesis/maintenance

      Decreased protein synthesis and increased muscle autophagy

      Decreased muscle mass
      Decreased testosterone, increased estrogenDecreased HPT axis, increased SHBG; decreased Akt and mTOR pathway activityDecreased protein synthesis
      InflammationIncreased inflammatory pathway activityDecreased protein synthesis and increased muscle autophagy
      HypermetabolismHigher resting energy expenditureIncreased muscle autophagy
      mTOR, mammalian target of rapamycin; HPT, hypothalamic-pituitary-testicular; SHBG, sex hormone binding globulin.

      Sarcopenia, Cirrhosis, and Impact on Outcomes

      The assessment of the presence of sarcopenia is of great import for clinicians who manage cirrhotic patients, given the predisposing pathophysiology and the high incidence of sarcopenia in this population (40–70% of patients).
      • Ebadi M.
      • Bhanji R.A.
      • Mazurak V.C.
      • Montano-Loza A.J.
      Sarcopenia in cirrhosis: from pathogenesis to interventions.
      Additionally, sarcopenia portends increased risk for complications and poor clinical outcomes in cirrhotic patient, specifically hepatic encephalopathy, sepsis, and overall mortality; it is also associated with worse outcomes after liver transplantation, including increased ICU length of stay, dependence on mechanical ventilation, organ injury, and post-operative mortality.
      • Montano-Loza A.J.
      Clinical relevance of sarcopenia in patients with cirrhosis.
      ,
      • Duong N.
      • Sadowski B.
      • Rangnekar A.S.
      The impact of frailty, sarcopenia, and malnutrition on liver transplant outcomes.
      Additionally, sarcopenia itself is a significant independent risk factor for NAFLD/NASH and fibrosis, which can exacerbate liver disease and accelerate progression to or worsening of cirrhosis.
      • Li A.A.
      • Kim D.
      • Ahmen A.
      Association of sarcopenia and NAFLD.
      Patients with sarcopenia were noted to have nearly twice the rates of NASH with fibrosis and 2.5 times the risk of developing NASH with fibrosis than patients without sarcopenia.
      • Li A.A.
      • Kim D.
      • Ahmen A.
      Association of sarcopenia and NAFLD.
      Sarcopenia further exacerbates insulin resistance as muscle-mediated glucose metabolism decreases due to decreased skeletal muscle mass; insulin resistance facilitates fatty acid release from adipose tissue into circulation and deposition into body tissues, including muscle and liver.
      • Azevedo V.Z.
      • Silaghi C.A.
      • Maurel T.
      • Silaghi H.
      • Ratziu V.
      • Pais R.
      Impact of sarcopenia on the severity of the liver damage in patients with non-alcoholic fatty liver disease.
      Increased deposition into the liver will promote inflammation and worsen already present liver disease. Thus, early and accurate identification of patients who are at increased risk of sarcopenia is important for the purpose of executing interventions that direct the clinical course toward a more favorable trajectory. This is facilitated by monitoring for biomarkers that suggest the presence of sarcopenia.

      Biomarkers of Interest and Their Implications in Sarcopenia

      Indicators of Muscle Integrity

      The assessment of muscle integrity is one of the primary mechanisms utilized to identify the presence of sarcopenia. These indicators of muscle integrity are typically divided into 3 categories: strength, quantity, and function (the criteria by which sarcopenia is diagnosed per the EWGSOP).
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      Muscle strength—Muscle strength is typically utilized as a screening test for sarcopenia. It is assessed by handgrip strength for upper body or the chair rise test for lower body (an assessment of how long it takes an individual to rise from a chair 5 times).
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      Per the revised EWGSOP2 guidelines, sarcopenia can be suspected with males with less than 27 kg of handgrip strength or females with less than 16 kg; this represents 2.5 standard deviations below the peak mean value for each respective gender.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      ,
      • Dodds R.M.
      • Syddall H.E.
      • Cooper R.
      • et al.
      Grip strength across the life course: normative data from twelve British Studies.
      Regarding the chair rise test, sarcopenia is suspected in an individual who takes longer than 15 s to rise out of a chair five times.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      Muscle mass—Muscle mass/quantity (particularly decreased mass) serves as a confirmation of the presence of sarcopenia. Multiple modalities can be employed to assess muscle mass; these include dual energy X-ray absorptiometry (DEXA) scan (which assess for approximate appendicular muscle mass), bioelectrical impedance analysis (BIA), and CT scanning of the skeletal muscle index (SMI; total area of muscle at L3 divided by height in meters squared) and/or right psoas muscle thickness at the level of the umbilicus divided by height in meters (PMTH).
      • Su H.
      • Ruan J.
      • Chen T.
      • Lin E.
      • Shi L.
      CT-assessed sarcopenia is a predictive factor for both long-term and short-term outcomes in gastrointestinal oncology patients: a systematic review and meta-analysis.
      ,
      • Han A.
      • Bokshan S.L.
      • Marcaccio S.E.
      • DePasse J.M.
      • Daniels A.H.
      Diagnostic criteria and clinical outcomes in sarcopenia research: a literature review.
      Appendicular skeletal mass (ASM) is one of the most favored metrics in this regard; values of less than 20 kg in males or less than 15 kg in females, or ASM index (appendicular muscle mass per height squared) of less than 7 kg/m2 in males or 5.5 kg/m2 in females is considered low muscle quantity according to EWGSOP2.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      These values are the result of a study designed to establish reference metrics for appendicular lean mass in a randomly selected southeastern Australian population; they correlate approximately to 2 standard deviations below the mean score of 8.8 kg/m2 for males and 6.84 kg/m2 for females in this normal population.
      • Gould H.
      • Brennan S.L.
      • Kotowicz M.A.
      • Nicholson G.C.
      • Pasco J.A.
      Total and appendicular lean mass reference ranges for Australian men and womenL the Geelong osteoporosis study.
      Other organizations have established cutoffs for low muscle mass as well. The Foundation for the National Institutes of Health utilized classical and regression tree analysis in a pooled population from 9 collaborating studies (Age, Gene/Environment Susceptibility-Reykjavik Study; Boston Puerto Rican Health Study; Clinical Trials; Framingham Heart Study; Health, Aging, and Body Composition Study; Invecchiare in Chianti; Osteoporotic Fractures in Men Study; Rancho Bernardo Study; and Study of Osteoporotic Fractures) to define low muscle mass as an appendicular lean mass of less than 0.789 kg/m2 in males or less than 0.512 kg/m2 in females.
      • Cawthon P.M.
      • Peters K.W.
      • Shardell M.D.
      • et al.
      Cutpoints for low appendicular lean mass that identify older adults with clinically significant weakness.
      The European Society for Clinical Nutrition and Metabolism Special Interests Groups has established the values of 7.26 kg/m2 for males and 5.5 kg/m2 for females, which is 2 standard deviations below the reference ranges of the healthy 18-40 year-old participants in the Rosetta Study.
      • Baumgartner R.N.
      • Koehler K.M.
      • Gallagher D.
      • et al.
      Epidemiology of Sarcopenia among the elderly in New Mexico.
      The Asian Working Group for Sarcopenia (AWGS) recommended a skeletal muscle mass cutoff of 7.0 kg/m2 in males and 5.4 kg/m2 in females using DEXA or 5.7 kg/m2 using BIA; this is based on various studies on Asian subpopulations producing values ranging from 5.72 to 8.87 kg/m2 for males and from 4.82 to 6.42 kg/m2 for females.
      • Chen L.K.
      • Liu L.K.
      • Woo J.
      • et al.
      Sarcopenia in Asia: consensus report of the Asian working group for sarcopenia.
      The International Working Group for Sarcopenia (IWGS) established cutoff values for those who were in the bottom 20% of the healthy 1435 males and 1549 females included in the study; this corresponds to values of 7.23 kg/m2 for males and 5.67 kg/m2 for females.[
      • Fielding R.A.
      • Vellas B.
      • Evans W.J.
      • et al.
      Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International Working Group on Sarcopenia.
      ,
      • Newman A.B.
      • Kupelian V.
      • Visser M.
      • et al.
      Sarcopenia: alternative definitions and associations with lower extremity function.
      ] The values established by EWGSOP2, AWGS, and IWGS were validated through the assessment of anthropomorphic metrics of 756 healthy Japanese individuals utilizing DEXA and 1884 healthy Japanese individuals using BIA.
      • Yamada Y.
      • Yamada M.
      • Yoshida T.
      • Miyachi M.
      • Arai H.
      Validating muscle mass cutoffs of four international sarcopenia-working groups in Japanese people using DXA and BIA.
      Muscle function—Muscle function is a marker of severity of sarcopenia, meaning that any functional impairment is an indication of severe sarcopenia.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      As per EWGSOP2 guidelines, a walking speed of less than 0.8 m/s should increase the suspicion of severe sarcopenia.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      Another assessment is the short performance physical battery test, which uses a scoring system based on balance, gait, and chair standing to estimate lower extremity strength (Table 3); scores of less than or equal to 8 signify diminished functionality.
      • Veronese N.
      • Bolzetta F.
      • Toffanello E.D.
      • et al.
      Association between short physical performance battery and falls in older people: the Progetto Veneto Anziani study.
      Table 3Components, Definitions, Cutoffs, and Scoring of the SPPB Test.
      ComponentDefinitionCut-off and scoring
      Gait speedBest speed achieved while walking down a 4-meter corridor in 2 attempts (speed in meters per second)
      • ≤0.42 m/s – 1 point
      • 0.42–0.58 m/s – 2 points
      • 0.58–0.75 m/s – 3 points
      • >0.75 m/s – 4 points
      Timed chair standsTotal time required to sit and stand from a chair five times (time in seconds)
      • ≥16.7 s–1 point
      • 13.7–16.7 s – 2 points
      • 11.2–13.7 s – 3 points
      • <11.2 s–4 points
      Tandem testTime in which balance is maintained in each of 3 positions—feet directly side by side, semi-tandem (one foot slightly ahead of the other), and tandem (one foot directly in front of the other) (time in seconds)
      • Side-by-side 10 s and semi-tandem <10 s–1 point
      • Semi-tandem 10 s and tandem 0–2 s – 2 points
      • Semi-tandem 10 s and tandem 3–9 s – 3 points
      • Tandem 10 s–4 points
      SPPB, Short Performance Physical Battery.
      Figure 3 illustrates a schematic for diagnosing sarcopenia according to the EWGSOP.
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      Figure 3
      Figure 3Flowchart 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.

      Body Mass Index

      While body mass index (BMI) can provide essential information about a patient's clinical status, dependence on this metric on its own can create an inaccurate picture of health. Low BMI, among other surrogates of nutrition, signifies an increased predisposition for the development of sarcopenia.
      • Nasimi N.
      • Dabbaghmanesh M.H.
      • Sohrabi Z.
      Nutritional status and body fat mass: determinants of sarcopenia in community-dwelling older adults.
      However, metabolic changes in cirrhosis create pathophysiological changes that can impact (specifically increase) BMI. For example, decompensated cirrhosis can artificially increase BMI, particularly in the setting of large-volume ascites.
      • Eslamparast T.
      • Montano-Loza A.J.
      • Raman M.
      • Tandon P.
      Sarcopenic obesity in cirrhosis – the confluence of 2 prognostic titans.
      Additionally, hormonal derangements, specifically insulin resistance, age-related changes, and other processes tend to cause an increased deposition of fat tissue in addition to the loss of muscle mass, which may create BMI values that obscure the presence of sarcopenia.
      • Wannamethee S.G.
      • Atkins J.L.
      Muscle loss and obesity: the health implications of sarcopenia and sarcopenic obesity.
      Therefore, BMI should be considered in conjunction with ancillary measurements such as muscle mass and fat mass obtained from imagine such as DEXA to generate an accurate estimation of a patient's risk for sarcopenia. This complete approach is critical for identifying patients who may have sarcopenic obesity, a combination of muscle wasting and fat accumulation; according to the National Health and Nutritional Examination Survey number 3 (NHANES III), sarcopenic obesity is diagnosed in a male with a skeletal mass per height of less than 9.12 kg/m2 and a body fat percentage of greater than 37.16% or in a female with a skeletal mass per height less than 6.53 kg/m2 and a body fat percentage greater than 40.01%.
      • Eslamparast T.
      • Montano-Loza A.J.
      • Raman M.
      • Tandon P.
      Sarcopenic obesity in cirrhosis – the confluence of 2 prognostic titans.
      ,
      • Stenholm S.
      • Harris T.B.
      • Rantanen T.
      • Visser M.
      • Kritchevsky S.B.
      • Ferrucci L.
      Sarcopenic obesity – definition, etiology, and consequences.
      Patients have much worse outcomes than those with a normal proportions of fat and muscle, including increased risk for worsening of liver disease, a decreased median survival period, and a 24% increased risk of all-cause mortality.
      • Eslamparast T.
      • Montano-Loza A.J.
      • Raman M.
      • Tandon P.
      Sarcopenic obesity in cirrhosis – the confluence of 2 prognostic titans.

      Muscle Composition and Quality

      Increased deposition of fat in muscle, termed myosteatosis, has been noted to have an impact on muscle structure, function, and quality.
      • Zamboni M.
      • Gattazzo S.
      • Rossi A.P.
      Myosteatosis: a relevant, yet poorly explored element of sarcopenia.
      Muscle quality is a ratio of muscle strength to mass. The deposition of fat between muscle fibers (intermuscular fat) and within muscle fibers (intramuscular fat) distorts skeletal muscle fiber architecture, leading to a decreased muscle strength and quality and increased frailty, morbidity, and mortality.
      • Zamboni M.
      • Gattazzo S.
      • Rossi A.P.
      Myosteatosis: a relevant, yet poorly explored element of sarcopenia.
      ,
      • Correa-de-Araujo R.
      • Addison O.
      • Miljkovic I.
      • et al.
      Myosteatosis in the context of skeletal muscle function deficit: an interdisciplinary workshop at the National Institute on Aging.
      The pathogenic process responsible for increased deposition into muscle has not been elucidated, but there is a positive correlation with insulin resistance related to metabolic syndrome (particularly diabetes), fatty acid dysmetabolism, and inflammatory mediators, specifically IL-6, TNF-α, and C-reactive protein.
      • Miljkovic I.
      • Zmuda J.M.
      Epidemiology of myosteatosis.

      Amino Acids

      The branched chained amino acids (BCAA; of which include leucine, isoleucine, and valine) are critical for muscle synthesis; these amino acids, when present in appropriate quantities, stimulate the production of multiple muscle components, including proteins comprising the myofibrils, sarcoplasm, and mitochondria.
      • Zhang Z.
      • Monleon D.
      • Verhamme P.
      • Staessen J.A.
      Branched-chain amino acids as critical switches in health and disease.
      A characteristic amino acid pattern can be observed in patients with sarcopenia. According to the BIOSPHERE project, BCAAs were noted to be decreased in an observed sarcopenic population.
      • Calvani R.
      • Picca A.
      • Marini F.
      • et al.
      A distinct pattern of circulating amino acids characterizes older persons with physical frailty and sarcopenia: results from the BIOSPHERE Study.
      ,
      • Xu Z.
      • Tan Z.
      • Zhang Q.
      • Gui Q.
      • Yang Y.
      The effectiveness of leucine on muscle protein synthesis, lean body mass, and leg lean mass accretion in older people: a systematic review and meta-analysis.
      In fact, EAAs, including the BCAAs and methionine, are typically low in sarcopenia; this is likely a result of poor oral intake and abnormal protein processing as these BCAAs are EEAs and are obtained primarily through diet.
      • Calvani R.
      • Picca A.
      • Marini F.
      • et al.
      A distinct pattern of circulating amino acids characterizes older persons with physical frailty and sarcopenia: results from the BIOSPHERE Study.
      A deficiency of BCAAs, specifically leucine, leads to decreased activity of the mTOR signaling pathway responsible for protein synthesis[80.82,83]. In the absence of sufficient quantities of these BCAAs, the body responds by abstracting these amino acids from skeletal muscle repositories to allow for continued protein synthesis essential for other body functions; however, this catabolism of skeletal muscle exacerbates the degree of sarcopenia.
      • Zhang Z.
      • Monleon D.
      • Verhamme P.
      • Staessen J.A.
      Branched-chain amino acids as critical switches in health and disease.

      Creatinine

      Creatinine is generated from creatine and creatine phosphate, which are found almost exclusively in muscle; therefore, creatinine levels correlate with muscle mass. It is filtered (and slightly secreted) by the kidney without reabsorption, making it an excellent measurement to approximate glomerular filtration rate.
      • Thongprayoon C.
      • Cheungpasitporn W.
      • Kashani K.
      Serum creatinine, a surrogate of muscle mass, predict mortality in critically ill patients.
      When renal function is stable, it provides a reliable estimate of muscle mass.
      • Thongprayoon C.
      • Cheungpasitporn W.
      • Kashani K.
      Serum creatinine, a surrogate of muscle mass, predict mortality in critically ill patients.
      Therefore, patients with decreased muscle mass due to sarcopenia would be expected to have a lower creatinine level.
      • Thongprayoon C.
      • Cheungpasitporn W.
      • Kashani K.
      Serum creatinine, a surrogate of muscle mass, predict mortality in critically ill patients.
      Values may also be influenced by cirrhosis pathophysiology, specifically poor oral intake (specifically protein intake), abnormal fluid states, and decreased synthesis of creatine in the liver.
      • Thongprayoon C.
      • Cheungpasitporn W.
      • Kashani K.
      Serum creatinine, a surrogate of muscle mass, predict mortality in critically ill patients.
      It is noted that creatinine may be an appropriate biomarker in the absence of any intrinsic kidney disease. Just like BMI, creatinine may be increased by concomitant medical conditions, such as acute kidney injury or chronic kidney disease, which may complicate the reliability of this marker as an indicator of sarcopenia.

      Myostatin

      Myostatin, as briefly stated, is a protein secreted by muscle cells that inhibits muscle synthesis and differentiation and promotes muscle degradation.
      • Lee D.Y.
      • Kim E.H.
      Therapeutic effects of amino acids in liver diseases: current studies and future perspectives.
      ,
      • Kim Y.
      Emerging treatment options of sarcopenia in chronic liver disease.
      It is primarily activated by elevated ammonia levels precipitated by cirrhosis, though other stimuli include decreased testosterone and increased TNF-α.
      • Lee D.Y.
      • Kim E.H.
      Therapeutic effects of amino acids in liver diseases: current studies and future perspectives.
      Specifically, ammonia activates nuclear factor κβ, which, in turn, stimulates the production of myostatin.
      • Qiu J.
      • Thapaliya S.
      • Runkana A.
      • et al.
      Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κβ mediated mechanism.
      Myostatin exerts its action through multiple modalities: (1) it inhibits the Akt and mTOR pathways involved in muscle growth and differentiation and; (2) it induces the proteosome–ubiquitin complex (and muscle breakdown) through the activation of effectors of the proteosome such as atrogin-1 and muscle RING-finger-1 (Figure 2).
      • Lee D.Y.
      • Kim E.H.
      Therapeutic effects of amino acids in liver diseases: current studies and future perspectives.
      ,
      • Yoon M.
      mTOR as a key regulator in maintaining skeletal muscle mass.

      Metrics of Bone Health

      Altered skeletal and bone physiology can increase the degree of frailty in cirrhotic patients. There is strong link between sarcopenia and osteoporosis. For example, some studies show that those with sarcopenia have a 5-fold greater risk of developing osteoporosis than those that do not; additionally, sarcopenia is a significant risk factor for the development of fractures.
      • Greco E.A.
      • Pietschmann P.
      • Migliaccio S.
      Osteoporosis and sarcopenia increase frailty syndrome in the elderly.
      Additionally, studies show that men in the lowest quartile of 25-hydroxy-vitamin D levels have an increased risk of developing sarcopenia than those in the highest quartile.
      • Bruyere O.
      • Cavalier E.
      • Reginster J.Y.
      Vitamin D and osteosarcopenia: an update from epidemiological studies.
      This is expected given the importance of the role in vitamin D in skeletal and bone health. Therefore, assessing metric of bone integrity, specifically the presence of osteopenia and osteoporosis via DEXA and serum vitamin D levels, are essential for the diagnosis, treatment, and prevention of any bone disease.

      Angiotensin II

      It is known that the portal hypertension evident in cirrhosis precipitates a vasodilatory state that results in activation of the RAAS system; effectors of this system, specifically angiotensin II and aldosterone, stimulates salt and water reabsorption. In addition to its impact on fluid retention, angiotensin II has a number of other physiological effects, including skeletal muscle which is owed to the presence of angiotensin II receptors on skeletal muscle.
      • Deminice R.
      • Hyatt H.
      • Yoshihara T.
      • et al.
      Human and rodent skeletal muscles express angiotensin II type 1 receptors.
      It is a modulator of the inflammatory process; it stimulates the activity of nicotinamide adenine dinucleotide phosphate oxidase, which increases the generation of reactive oxygen species, leading to muscle injury.
      • Sukhanov S.
      • Semprun-Prieto L.
      • Yoshida T.
      • et al.
      Angiotensin II, oxidative stress and skeletal muscle wasting.
      ,
      • Kadoguchi T.
      • Shimada K.
      • Koide H.
      • et al.
      Possible role of NADPH oxidase 4 in angiotensin II-induced muscle wasting in mice.
      Angiotensin II inhibits muscle growth through the disruption binding of IGF-1 and insulin to their receptors, which results in decreased activity of the mTOR and AKT pathways; it also reduces the volume and growth of satellite progenitor cells that replace injured muscle.
      • Kadoguchi T.
      • Shimada K.
      • Koide H.
      • et al.
      Possible role of NADPH oxidase 4 in angiotensin II-induced muscle wasting in mice.
      ,
      • Yoshida T.
      • Galvez S.
      • Tiwari S.
      • et al.
      Angiotensin II inhibits satellite cell proliferation and prevents skeletal muscle regeneration.
      Angiotensin II also promotes muscle degradation by increasing levels of atrogin-1 and muscle RING-finger-1, effectors of the ubiquitin-proteosome complex.
      • Du Bois P.
      • Tortola C.P.
      • Lodka D.
      • et al.
      Angiotensin II induces skeletal muscle atrophy by activating TFEB-mediated MuRF1 expression.
      It also has the effect of increasing cortisol levels, which itself is an agent of skeletal muscle catabolism.
      • Deminice R.
      • Hyatt H.
      • Yoshihara T.
      • et al.
      Human and rodent skeletal muscles express angiotensin II type 1 receptors.
      Additionally, angiotensin II can induce muscle vasculature constriction, which may compromise delivery of nutrients and oxygen to muscle and lead to muscle injury and compromised muscle function.
      • Chai W.
      • Wang W.
      • Liu J.
      • et al.
      Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use.
      These pathways are mediated through the angiotensin II's activation of the angiotensin type 1 receptor (AT1R) and directly contribute to sarcopenia.
      • Sukhanov S.
      • Semprun-Prieto L.
      • Yoshida T.
      • et al.
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      Possible role of NADPH oxidase 4 in angiotensin II-induced muscle wasting in mice.
      • Yoshida T.
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      Angiotensin II inhibits satellite cell proliferation and prevents skeletal muscle regeneration.
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      Angiotensin II induces skeletal muscle atrophy by activating TFEB-mediated MuRF1 expression.
      • Chai W.
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      • et al.
      Angiotensin II type 1 and type 2 receptors regulate basal skeletal muscle microvascular volume and glucose use.

      Current Approach to Management of Sarcopenia

      Sarcopenia is an intriguing disease state that requires more investigation to be fully understood. Currently, interventions are aimed to minimize the risk factors that predispose cirrhotic patients to sarcopenia. Those interventions fall under the following categories: nutrition, physical activity, and pharmacotherapy (Figure 4).
      Figure 4
      Figure 4Nutritional, exercise, and pharmacological approach to management of sarcopenia in cirrhosis.
      Nutrition—One of the major risk factors for sarcopenia is the inadequate intake of essential nutrients, particularly protein. The identification of these patients can be executed via the EWGSOP diagnostic criteria with the requisite lab work and imaging to evaluate the biomarkers. Once identified, patients obtain nutrition consults to ensure optimization of their diets. The nutritional management of patients with cirrhosis is focused on ensuring adequate consumption of calories, including proteinaceous foods containing proper quantities of BCAA. Clinical guidelines recommend consumption of 1.2–1.5 g/kg/day for compensated cirrhotic patients and about 2 g/kg/day for decompensated cirrhotic patients to counteract the avid protein catabolism.
      • Dhaliwal A.
      • Armstrong M.J.
      Sarcopenia in cirrhosis: a practical overview.
      Studies show that proper supplementation of BCAA can enhance protein synthesis, attenuate insulin resistance, and improve lipid and glucose metabolism.
      • Naseer M.
      • Turse E.P.
      • Syed A.
      • Dailey F.E.
      • Zatreh M.
      • Tahan V.
      Interventions to improve sarcopenia in cirrhosis: a systematic review.
      Patients are also advised to supplement vitamins to correct or prevent any vitamin or mineral deficiencies.
      Exercise—Exercise serves several purposes—general conditioning, muscle strength building, and size reduction to a healthy weight. Patients are screened for exercise tolerance and mentored about specific comorbidities before being provided with an exercise plan.
      • Tandon P.
      • Ismond K.P.
      • Riess K.
      • et al.
      Exercise in cirrhosis: translating evidence and experience to practice.
      Patients are encouraged to undergo a combination of aerobic and resistance exercises. In the cirrhotic patient, exercise can increase muscle strength and blood flow, decrease body fat, increase insulin sensitivity, and fortify bones; it also has the benefit of improving cardiac and pulmonary function, enhancing vascular compliance, and lowering hepatic portal pressures.
      • Tandon P.
      • Ismond K.P.
      • Riess K.
      • et al.
      Exercise in cirrhosis: translating evidence and experience to practice.
      Weight loss can also slow the progression of liver disease by reducing inflammation and fibrosis.
      • Kumar N.
      • Choudhary N.S.
      Treating morbid obesity in cirrhosis: a quest of holy grail.
      Pharmacotherapy—Cirrhosis-targeted medications are required to prevent complications such as hepatic encephalopathy and ascites. Lactulose and rifaximin decreases the ammonia load on the body, which, in turn, can limit ammonia shunting to the muscle and reduce muscle catabolism; it also prevents accumulation the brain, which can precipitate hepatic encephalopathy.
      • Dasarathy S.
      • Hatzoglou M.
      Hyperammonemia and proteostasis in cirrhosis.
      ,
      • Dasarathy S.
      Myostatin and beyond in cirrhosis: all roads lead to sarcopenia.
      ,
      • Flamm S.L.
      Rifaximin treatment for reduction of risk of overt hepatic encephalopathy occurrence.
      ,
      • Wijarnpreecha K.
      • Werlang M.
      • Panjawatanan P.
      • et al.
      Association between sarcopenia and hepatic encephalopathy: a systematic review and meta-analysis.
      Diuretics also help to counteract the reabsorption of fluid due to RAAS activation and, therefore, reduce ascites; this prevents the formation of ascites and resultant abdominal mechanical obstruction that can lead to anorexia.

      Future approaches for the Assessment and Characterization of Cirrhosis

      The predisposition of cirrhotic patients to sarcopenia should influence the manner in which cirrhosis is evaluated and managed. In addition to the diagnosis of cirrhosis and medical management, patients should automatically be screened for the presence of sarcopenia. In addition to testing the aforementioned indicators of muscle integrity, other tests may also be employed. The DEXA scan is an invaluable tool because it can assess multiple anthropometric components, specifically muscle mass, fat content, and bone mineral density. The primary limitation is the time interval for testing; multiple bodies recommend that testing occur at 2-3-year intervals, though shorter intervals may be utilized if significant bone disease or certain risk factors are present.
      • Patel N.
      • Munoz S.J.
      Bone disease in cirrhosis.
      ,
      • Craig K.W.
      • Stevermer J.J.
      DEXA screening – are we doing too much?.
      While the annual assessments for sarcopenia screening are ideal, the frequency at which it can be used to obtain muscle mass and fat content to assess the degrees of sarcopenia is largely tied to the aforementioned intervals used for bone density testing, which may not provide the opportunities for the frequency of testing potentially desired in this population of patients. Nonetheless, the assessment of muscle integrity using strength and function testing, especially as part of screening tests such as the SARC-F (Strength, Assistance with walking, Rise from a chair, Climb stairs, and Falls) can be performed as frequently as necessary to monitor physical capacity in setting suspected sarcopenia.
      • Xie W.Q.
      • Xiao G.L.
      • Hu P.W.
      • He Y.Q.
      • Lv S.
      • Xiao W.F.
      Possible sarcopenia: early screening and intervention – narrative review.
      Liver Frailty Index, developed by University of California San Francisco consisting of three performance-based tests (grip, chair stands, balance), that assess frailty has been validated in multiple studies and could be very useful in cirrhosis patients.
      • Lai J.C.
      • Covinsky K.E.
      • Dodge J.L.
      • et al.
      Development of a novel frailty index to predict mortality in patient with end-stage liver disease.
      A diagnosis of sarcopenia should be accompanied by a sarcopenia score that can give insight into the risk of adverse outcome. This score would be a composite of several critical physical biomarkers discussed, specifically muscle mass and BMI. The sarcopenia score would be compared to a reference score of a healthy individual with similar characteristics (age group, BMI, etc) to assess gross deviation due to illness in the setting of sarcopenia. Serial assessments of this score can be utilized to create a trend to identify clinical deterioration or improvement while undergoing therapeutic intervention. There have been different models investigated to meet this goal—the ratio of ASM to height squared (ASM/ht2; ASM in kg, height in meters), ASM/weight (weight in kg), and ASM/BMI.
      • Kim K.M.
      • Jang H.C.
      • Lim S.
      Differences among skeletal muscle mass indices derived from height-, weight-, and body mass index-adjusted models in assessing sarcopenia.
      However, studies show that there are widely disparate values of prevalence of class 2 sarcopenia (defined when values are greater than 2 standard deviations below the reference level) amongst the 3 indices.
      • Kim K.M.
      • Jang H.C.
      • Lim S.
      Differences among skeletal muscle mass indices derived from height-, weight-, and body mass index-adjusted models in assessing sarcopenia.
      Multiple international organizations, including the EWGSOP, IWGS, and the AWGS recommended the use of the ASM/ht2 index, with cut-offs for low muscle mass being 2 standard deviations below the mean reference levels of healthy adults or the lowest quintile of the ASM/ht2 index.
      • Kim K.M.
      • Jang H.C.
      • Lim S.
      Differences among skeletal muscle mass indices derived from height-, weight-, and body mass index-adjusted models in assessing sarcopenia.
      However, other studies intimate that ASM/BMI is more closely related to cardiovascular risk factors, such as insulin resistance and metabolic syndrome that are intimately associated with sarcopenia and sarcopenic obesity.
      • Kim T.N.
      • Park M.S.
      • Lee E.J.
      • et al.
      Comparisons of three different methods for defining sarcopenia: an aspect of cardiometabolic risk.
      There is more research that has to be conducted to ascertain which index would be the optimal index for this purpose.
      Another metric that can be utilized is the PMTH and psoas muscle index (PMI; the total psoas muscle area in centimeters squared divided by the patient's height in meters squared).
      • Sempokuya T.
      • Yokoyama-Arakaki L.
      • Wong L.L.
      • Kalathil S.
      A pilot stydt of racial differences in the current definition of sarcopenia among liver transplant candidates.
      The psoas muscle is viewed as ideal muscle to assess because its size was not influenced by activity and thus was more likely to represent the overall state of health of the body's musculature; furthermore, it is less susceptible to structural alterations (i.e. fat infiltration as seen in myosteatosis) than other more proximal muscles such as the gluteal muscles.
      • Correa-de-Araujo R.
      • Addison O.
      • Miljkovic I.
      • et al.
      Myosteatosis in the context of skeletal muscle function deficit: an interdisciplinary workshop at the National Institute on Aging.
      ,
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      ,
      • Kim T.Y.
      • Kim M.Y.
      • Sohn J.H.
      • et al.
      Sarcopenia as a useful predictor for long-term mortality in cirrhotic patients with ascites.
      The PMTH cutoff for sarcopenia was determined to be less than 16.8 mm/m (measured at the level of the umbilicus); this value was established from the analysis of 653 liver cirrhosis patients evaluated at the Korea University Anam, Soonchunhyang University Bucheon, and Wonju Hospitals.
      • Gu D.H.
      • Kim M.Y.
      • Seo Y.S.
      • et al.
      Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis.
      PMI sarcopenia cutoffs of 6.87 cm2/m2 for men and 4.12 cm2/m2 for women were established through the analysis of 102 patients who were treated at Honolulu's Queens Medical Center and placed on the liver transplantation list through referral with the United Network of Organ Sharing; this is relatively consistent with other PMI values established through studies with other populations of patients with liver disease.
      • Sempokuya T.
      • Yokoyama-Arakaki L.
      • Wong L.L.
      • Kalathil S.
      A pilot stydt of racial differences in the current definition of sarcopenia among liver transplant candidates.
      ,
      • Tan Y.
      • Duan T.
      • Li B.
      • et al.
      Sarcopenia defined by psoas muscle index independently predicts long-term survival after living donor liver transplantation in male recipients.
      Within this population, 10 patients were noted to have sarcopenia as defined by PMI – 2 white patients, 6 Asian patients, and 2 Native Hawaiians and Other Pacific Islanders. There was no noted statistical difference in the prevalence of sarcopenia in this group according to the PMI criteria but the small sample size is likely a contributing factor. It should be noted that differences in body composition amongst different ethnicities may impact the ability of PMI to accurately identify sarcopenia. Therefore, if PMI is to be utilized as a diagnostic metric, there may be a need for algorithms to account for ethnic differences to ensure that outputs are standardized across a heterogenous population; this is also true for the muscle strength and mass values established by the various governing bodies in the assessment of sarcopenia.
      Additionally, more specialized tests can be made more mainstream for definitive diagnosis in cases of high suspicion with equivocal workup. For example, amino acid profile can be utilized to characterize the extent of BCAA deficiencies (specifically in terms of decreased BCAA-to-tyrosine levels) and potentially monitor improvement with a proper BCAA supplementation.
      • Nishikawa H.
      • Enomoto H.
      • Ishii A.
      • et al.
      Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis.
      Myostatin levels may be potentially helpful in providing prognostic values for outcomes in the same manner as the model for end-stage liver disease score. Increased levels have been shown to be associated with different adverse outcomes, including the increased risk for decompensated cirrhosis, complications such as HCC and lower survival rates.
      • Nishikawa H.
      • Enomoto H.
      • Ishii A.
      • et al.
      Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis.
      ,
      • Kim J.H.
      • Kang S.H.
      • Lee M.
      • et al.
      Serum myostatin predicts the risk of hepatocellular carcinoma in patients with alcoholic cirrhosis: a multicenter study.
      With regards to future pharmacological interventions, there is much more research that needs to be done to determine which particular pathways can be manipulated to inhibit the sarcopenic process. However, there are pathways that show great promise as targets for treatment. For example, insulin resistance is noted to be a major contributor to the development of sarcopenia. Metformin is an agent that helps to sensitize the body to insulin; it also is effective as a weight-loss medication in non-diabetic obese and non-obese patients.
      • Campins L.
      • Camps M.
      • Riera A.
      • Pleguezuelos E.
      • Yebenes J.C.
      • Serra-Prat M.
      Oral drugs related with muscle wasting and sarcopenia: a review.
      ,
      • Seifarth C.
      • Schehler B.
      • Schneider H.J.
      Effectiveness of metformin on weight loss in non-diabetic individuals with obesity.
      There may be a role for metformin to counteract cirrhosis-related sarcopenia as there are studies that demonstrate that treatment results in fewer circulating inflammatory agents regardless of glycemic status.
      • Campins L.
      • Camps M.
      • Riera A.
      • Pleguezuelos E.
      • Yebenes J.C.
      • Serra-Prat M.
      Oral drugs related with muscle wasting and sarcopenia: a review.
      Carnitine has also demonstrated significant promise regarding outcomes in sarcopenia. Carnitine, specifically l-carnitine, is synthesized from methionine and lysine in the liver and primarily stored in the skeletal muscle and heart; its role is to transport fatty acids into the mitochondria for β-oxidation and energy production.
      • Sakai Y.
      • Nishikawa H.
      • Enomoto H.
      • et al.
      Effect of L-carnitine in patients with liver cirrhosis on energy metabolism using indirect calorimetry: a pilot study.
      ,
      • Fielding R.
      • Riede L.
      • Lugo J.P.
      • Bellamine A.
      L-carnitine supplementation in recovery after exercise.
      l-carnitine has been demonstrated to have multiple impactful metabolic effects, such as serving as a free radical scavenger, reducing oxidative stress, modulating fatty acid oxidation (and by proxy, reducing deposition in tissues such as muscle and the liver), and facilitating growth of muscle by increasing blood supply.
      • Fielding R.
      • Riede L.
      • Lugo J.P.
      • Bellamine A.
      L-carnitine supplementation in recovery after exercise.
      ,
      • Li N.
      • Zhao H.
      Role of carnitine in non-alcoholic fatty liver disease and other related disease: an update.
      l-carnitine has other beneficial effects in liver disease, specifically improved albumin levels, decreased the incidence of hepatic encephalopathy, improvement of hyperammonemia, and reduced muscle cramping.
      • Sato S.
      • Namisaki T.
      • Furukawa M.
      • et al.
      Effect of L-carnitine on health-related quality of life on patients with cirrhosis.
      Myostatin, due to its prominent role in sarcopenia, may also be a prominent target. Studies show that follistatin, an endogenous myostatin antagonist and activator of skeletal muscle hypertrophy and growth via the Akt/mTOR pathway, may be a therapeutic intervention to counteract muscle wasting and promote development of muscle mass.
      • Sepulveda P.V.
      • Lamon S.
      • Hagg A.
      • et al.
      Evaluation of follistatin as a therapeutic in models of skeletal muscle atrophy associated with denervation and tenotomy.
      ,
      • Winbanks C.E.
      • Weeks K.L.
      • Thomson R.E.
      • et al.
      Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.
      Glucagon-like peptide-1 (GLP-1) receptor agonists, specifically dulaglutide, were also demonstrated to reduce muscle wasting and improved several metrics of muscle strength in a Duchenne muscular dystrophy mouse model through the suppression of myostatin and other muscle inhibiting factors and augmentation of insulin sensitivity.
      • Hong Y.
      • Lee J.H.
      • Jeong K.W.
      • Choi C.S.
      • Jun H.
      Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy.
      RAAS inhibition appears to be a promising prospect as well. For one, inhibition of angiotensin-converting enzyme (ACE) with ACE inhibitors (ACE-I) serves to prevent the conversion of angiotensin I to angiotensin II; with the inhibition of ACE, angiotensin I is converted to angiotensin (1–9) by ACE2 and then subsequently to angiotensin (1–7) by ACE.
      • Sartiani L.
      • Spinelli V.
      • Laurino A.
      • et al.
      Pharmacological perspectives in sarcopenia: a potential role for renin-angiotensin system blockers?.
      Angiotensin (1–7) activates the angiotensin type 2 receptor (AT2R), which has the opposite effects of the AT1R; those effects include anti-inflammatory actions, increased insulin sensitivity and glucose uptake, vasodilation of the skeletal muscle vasculature, which facilitates the delivery of oxygen and nutrients to the muscle, and increased growth and differentiation of muscle satellite cells.
      • Sartiani L.
      • Spinelli V.
      • Laurino A.
      • et al.
      Pharmacological perspectives in sarcopenia: a potential role for renin-angiotensin system blockers?.
      • Echeverria-Rodriguez O.
      • Gallardo-Ortiz I.A.
      • Del Valle-Mondragon L.
      • Villalobos-Molina R.
      Angiotensin-(1-7) participates in enhanced skeletal muscle insulin sensitivity after a bout of exercise.
      • Touyz R.M.
      • Montezano A.C.
      Angiotensin-(1-7) and vascular function.
      • Yoshida T.
      • Huq T.S.
      • Delafontaine P.
      Angiotensin type 2 receptor signaling in satellite cells potentiates skeletal muscle regeneration.
      Angiotensin (1–7) also activates the MasR receptor, which exerts effects similar to AT2R. Additionally, angiotensin receptor blockers (ARBs) can inhibit the effects of angiotensin at its AT1R.
      • Sartiani L.
      • Spinelli V.
      • Laurino A.
      • et al.
      Pharmacological perspectives in sarcopenia: a potential role for renin-angiotensin system blockers?.
      This directs angiotensin II to the AT2R and MasR receptors, which would serve to promote skeletal muscle growth through effects opposite to those of the AT1R.
      • Sartiani L.
      • Spinelli V.
      • Laurino A.
      • et al.
      Pharmacological perspectives in sarcopenia: a potential role for renin-angiotensin system blockers?.
      ,
      • Touyz R.M.
      • Montezano A.C.
      Angiotensin-(1-7) and vascular function.
      Aside from their noted role in the prevention of pathological cardiac remodeling in heart disease, ACE-I and ARB have been demonstrated to have positive effects on indicators of muscle integrity. One study demonstrates that the odds of having reduced hand grip strength is 75% less in a population of chronic hemodialysis patients who received ARB compared to those who did not use ARB; this is significant because end-stage renal disease, like cirrhosis, can result in sarcopenia as well.
      • Lin Y.L.
      • Chen S.Y.
      • Lai Y.H.
      • et al.
      Angiotensin II receptor blockade is associated with preserved muscle strength in chronic hemodialysis patients.
      ,
      • Sabatino A.
      • Cuppari L.
      • Stenvinkel P.
      • Lindholm B.
      • Avesani C.M.
      Sarcopenia in chronic kidney disease what have we learned so far?.
      Another study also demonstrates that patients taking perindopril were able to travel a farther distance in the 6-minute walk test compared to the placebo group.
      • Witham M.D.
      • Sumukadas D.
      • McMurdo M.
      ACE inhibitors for sarcopenia – as good as exercise training?.
      However, much more research is required because other research demonstrates a minimal impact of RAAS inhibitors on indicators of muscle integrity.
      • Caulfield L.
      • Heslop P.
      • Walesby K.E.
      • Sumukadas D.
      • Sayer A.A.
      • Witham M.D.
      Effect of angiotensin system inhibitors on physical performance in older people – a systematic review and meta-analysis.
      • Sumukadas D.
      • Band M.
      • Miller S.
      • et al.
      Do ACE inhibitors improve the response to exercise training in functionally impaired older adults? A randomized controlled trial.
      • Achison M.
      • Adamson S.
      • Akpan A.
      • et al.
      The LACE Study Group
      Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.
      Sex hormonal pathways may also be a consideration for therapeutic intervention, especially given the impact of testosterone on muscle synthesis and the relative deficiency of testosterone in cirrhosis. However, studies are inconsistent with regards to the impact of androgen replacement, given the differences in approach and investigation methods; additionally, the side effects may pose a concern as to the safety of this potential therapy.
      • Shin M.J.
      • Jeon Y.K.
      • Kim I.J.
      Testosterone and sarcopenia.
      Sarcopenia is the result of the interactions of multiple metabolic pathways pathologically altered by the cirrhotic liver; conversely, sarcopenia can also promote conditions that can worsen liver disease. Though extremely complex, these pathways represent targets for interventions that can counteract this disease state, specifically those involving insulin resistance and the effectors of muscle inhibition and degradation. It is noted that the connections between and within each pathway are constantly evolving. Thus, much more research is required to further elucidate these relationships to advance the understanding of the association between cirrhosis and sarcopenia. Nonetheless, a combination of appropriate diagnosis and management in terms of nutrition, exercise, and treatment of the cirrhosis remains the best means by which to achieve favorable outcomes in affected patients.

      Credit authorship contribution statement

      ERW collected the data and wrote the paper; SKS provided the concept and supervised the production and revision of the paper.

      Conflicts of interest

      All authors have none to declare.

      Funding

      None

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