Current treatment strategies and future possibilities for sarcopenia in cirrhosis

Sarcopenia is a common skeletal muscle abnormality in patients with cirrhosis which is associated with a high incidence of complications both pre- and post-liver transplantation. The pathogenesis of sarcopenia in cirrhosis is multifactorial; however, hyperammonemia, elevated muscle autophagy, insulin resistance, inflammation, lower levels of testosterone, growth hormones or branched-chain amino acids (BCAAs), are considered to be the main factors responsible for sarcopenia in cirrhosis.[1]Ebadi M. Bhanji R.A. Mazurak V.C. Montano-Loza A.J. Sarcopenia in cirrhosis: from pathogenesis to interventions.J Gastroenterol. 2019; 54: 845-859Crossref PubMed Scopus (147) Google Scholar The prevalence of sarcopenia in cirrhosis varies between 40 to 70%.[2]Kim G. Kang S.H. Kim M.Y. Baik S.K. Prognostic value of sarcopenia in patients with liver cirrhosis: a systematic review and meta-analysis.PLoS One. 2017; 12e0186990Crossref Scopus (240) Google Scholar A possible explanation for this wide variation could be attributed to the different modalities and cut-off points used to measure muscle mass, and other skeletal muscle parameters such as strength or function. In addition, sex, ethnicity, and degree of liver failure should be considered as important determinants. These controversies pose a challenge when designing trials to assess interventions for sarcopenia in cirrhosis. The clinical implications of sarcopenia in cirrhosis have been well documented,[3]Tantai X. Liu Y. Yeo Y.H. Praktiknjo M. Mauro E. Hamaguchi Y. et al.Effect of sarcopenia on survival in patients with cirrhosis: a meta-analysis.J Hepatol. 2022; 76: 588-599Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar however, there are limited data on treatment strategies for sarcopenia in this population (Fig. 1); such strategies are mainly in investigational stages. Although exercise, particularly resistance training, has been considered the main strategy to prevent sarcopenia in various populations, nutritional interventions to support resistance exercise have attracted significant attention in recent years. Daily energy intake of at least 35 kcal/kg body weight in non-obese patients and a protein intake of 1.2–1.5 g/kg,[4]Lai J.C. Tandon P. Bernal W. Tapper E.B. Ekong U. Dasarathy S. et al.Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American association for the study of liver diseases.Hepatology. 2021; 74: 1611-1644Crossref PubMed Scopus (185) Google Scholar including small frequent meals and a late evening snack,[5]Plank L.D. Gane E.J. Peng S. Muthu C. Mathur S. Gillanders L. et al.Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial.Hepatology. 2008; 48: 557-566Crossref PubMed Scopus (234) Google Scholar are recommended in patients with chronic liver diseases. In addition to adequate dietary intake and moderate-intensity physical activity, potential nutritional supplements have been investigated in small clinical trials or pilot studies; however, large, randomized trials to support their efficacy in cirrhosis are currently lacking. BCAAs including valine, leucine, and isoleucine serve as substrates for energy production, protein synthesis and ammonia detoxification in skeletal muscles. Although lower levels of serum BCAAs have been reported in patients with cirrhosis, the impact of BCAA supplementation on muscle mass and function in cirrhosis is controversial.[6]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: 427-437Crossref PubMed Scopus (103) Google Scholar,[7]Uojima H. Sakurai S. Hidaka H. Kinbara T. Sung J.H. 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: 1402-1407Crossref PubMed Scopus (32) Google Scholar This might be related to various confounding factors including study design, dose, duration and frequency of intervention, dosing based on body weight, time of administration, concurrent interventions, and relative percentage of each individual BCAA, palatability, ethnicity, different clinical outcomes, as well as the presence of malnutrition and the severity of cirrhosis complications. Moreover, patient’s total energy and protein intake, physical activity, and adherence to the intervention were not assessed in all the studies. Two recent meta-analyses demonstrated that BCAAs improved muscle mass[8]Ismaiel A. Bucsa C. Farcas A. Leucuta D.C. Popa S.L. Dumitrascu D.L. Effects of branched-chain amino acids on parameters evaluating sarcopenia in liver cirrhosis: systematic review and meta-analysis.Front Nutr. 2022; 9749969Crossref PubMed Scopus (10) Google Scholar,[9]Konstantis G. Pourzitaki C. Chourdakis M. Kitsikidou E. Germanidis G. Efficacy of branched chain amino acids supplementation in liver cirrhosis: a systematic review and meta-analysis.Clin Nutr. 2022; 41: 1171-1190Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar but not strength;[8]Ismaiel A. Bucsa C. Farcas A. Leucuta D.C. Popa S.L. Dumitrascu D.L. Effects of branched-chain amino acids on parameters evaluating sarcopenia in liver cirrhosis: systematic review and meta-analysis.Front Nutr. 2022; 9749969Crossref PubMed Scopus (10) Google Scholar nevertheless, the majority of included studies were observational with methodological limitations. Superior enhancement of muscle mass and strength was observed when BCAA supplementation and physical activity were combined.[10]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: 1416-1423Crossref PubMed Scopus (102) Google Scholar Among BCAAs, a significant benefit on mammalian target of rapamycin (mTOR) signaling was noticed with leucine; however, supplementation with leucine-enriched BCAAs was associated with a decline in plasma levels of other essential amino acids, supporting the need to include all essential amino acids in supplements in order to enhance muscle protein synthesis.[11]Tsien C. Davuluri G. Singh D. Allawy A. Ten Have G.A. 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: 2018-2029Crossref PubMed Scopus (167) Google Scholar Leucine’s active metabolite, b-hydroxy-b-methyl butyrate, was shown to improve muscle function, measured by chair stand and six-minute walk tests, in a pilot randomized-controlled trial.[12]Lattanzi B. Bruni A. Di Cola S. Molfino A. De Santis A. Muscaritoli M. et al.The effects of 12-week beta-hydroxy-beta-methylbutyrate supplementation in patients with liver cirrhosis: results from a randomized controlled single-blind pilot study.Nutrients. 2021; 13Crossref Scopus (11) Google Scholar L-carnitine, a fundamental nutrient in fatty acid metabolism, has the ability to prevent muscle loss in a dose-dependent manner (≥1,274 mg/day) through its anti-inflammatory and ammonia-lowering effects.[13]Hiramatsu A. Aikata H. Uchikawa S. Ohya K. Kodama K. Nishida Y. et al.Levocarnitine use is associated with improvement in sarcopenia in patients with liver cirrhosis.Hepatol Commun. 2019; 3: 348-355Crossref PubMed Scopus (36) Google Scholar A dose of 1,500-3,000 mg/day appeared to be sufficient to prevent sarcopenia progression in two Japanese studies.[13]Hiramatsu A. Aikata H. Uchikawa S. Ohya K. Kodama K. Nishida Y. et al.Levocarnitine use is associated with improvement in sarcopenia in patients with liver cirrhosis.Hepatol Commun. 2019; 3: 348-355Crossref PubMed Scopus (36) Google Scholar,[14]Ohashi K. Ishikawa T. Hoshii A. Hokari T. Suzuki M. Noguchi H. et al.Effect of levocarnitine administration in patients with chronic liver disease.Exp Ther Med. 2020; 20: 94Crossref PubMed Google Scholar However, in these two retrospective experiences, the yearly relative change in muscle area equal to or above 0% was considered an increase in muscle mass. The results of these studies should be interpreted thoughtfully as a change between -2% and 2% signifies tissue stability in consecutive CT images.[15]Mourtzakis M. Prado C.M. Lieffers J.R. Reiman T. McCargar L.J. Baracos V.E. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care.Appl Physiol Nutr Metab. 2008; 33: 997-1006Crossref PubMed Scopus (1470) Google Scholar Prospective clinical trials are required to identify the clinically beneficial dose of L-carnitine that can prevent muscle loss, using an accepted change for muscle cross-sectional area of greater than 2% on CT scans in patients with cirrhosis. Interventions with other nutritional supplements including long-chain n-3 polyunsaturated fatty acids or vitamin D supplementation alone or in combination with anabolic stimuli, such as amino acids, have recently garnered interest as a therapy for sarcopenia in geriatric or oncological populations, yet their association with sarcopenia prevention or treatment in cirrhosis has not been investigated. Multidisciplinary nutritional approaches have been the focus of prior studies, but pharmacological treatments have not been studied frequently. Hyperammonemia plays a multifactorial role in skeletal muscle abnormalities in cirrhosis and therefore, ammonia-lowering therapies may offer a reasonable target for preventing or reversing sarcopenia. Ammonia-lowering therapy with a combination of rifaximin and L-ornithine L-aspartate[16]Kumar A. Davuluri G. Silva R.N.E. Engelen M. Ten Have G.A.M. Prayson R. et al.Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis.Hepatology. 2017; 65: 2045-2058Crossref PubMed Scopus (141) Google Scholar increased muscle mass in a pre-clinical model of hyperammonemia by lowering the levels of intramuscular myostatin and pro-inflammatory cytokines.[17]Murata K. Kaji K. Nishimura N. Enomoto M. Fujimoto Y. Takeda S. et al.Rifaximin enhances the L-carnitine-mediated preventive effects on skeletal muscle atrophy in cirrhotic rats by modulating the gut-liver-muscle axis.Int J Mol Med. 2022; 50Crossref PubMed Google Scholar Combined administration of rifaximin with L-carnitine efficiently improved the inhibitory effects of L-carnitine on skeletal muscle wasting in cirrhotic rats with steatohepatitis.[17]Murata K. Kaji K. Nishimura N. Enomoto M. Fujimoto Y. Takeda S. et al.Rifaximin enhances the L-carnitine-mediated preventive effects on skeletal muscle atrophy in cirrhotic rats by modulating the gut-liver-muscle axis.Int J Mol Med. 2022; 50Crossref PubMed Google Scholar This suppression of muscle atrophy was associated with improvement in serum and liver levels of insulin-like growth factor-1 (IGF-1), an effective myotrophic factor, as well as skeletal muscle mitochondrial biogenesis. The ability of rifaximin alone or in combination with L-carnitine to treat cirrhosis-associated sarcopenia and the clinical doses have not been explored in clinical trials of patients with cirrhosis. Protein-calorie malnutrition in patients with cirrhosis and portal hypertension contributes to sarcopenia. The reduction in portal hypertension induced by transjugular intrahepatic portosystemic shunt (TIPS) has been shown to ameliorate nutritional status and improve muscle mass.[18]Tsien C. Shah S.N. McCullough A.J. Dasarathy S. Reversal of sarcopenia predicts survival after a transjugular intrahepatic portosystemic stent.Eur J Gastroenterol Hepatol. 2013; 25: 85-93Crossref PubMed Scopus (154) Google Scholar Increased muscle mass following TIPS was also associated with lower levels of blood ammonia and risk of hepatic encephalopathy post-TIPS.[19]Gioia S. Merli M. Nardelli S. Lattanzi B. Pitocchi F. Ridola L. et al.The modification of quantity and quality of muscle mass improves the cognitive impairment after TIPS.Liver Int. 2019; 39: 871-877Crossref PubMed Scopus (50) Google Scholar Preliminary evidence from a retrospective study has suggested that partial splenic embolization may be associated with a reduced rate of skeletal muscle mass loss in cirrhosis.[20]Hirooka M. Koizumi Y. Tanaka T. Nakamura Y. Sunago K. Yukimoto A. et al.Treatment on the spleen prevents the progression of secondary sarcopenia in patients with liver cirrhosis.Hepatol Commun. 2020; 4: 1812-1823Crossref PubMed Scopus (5) Google Scholar In patients with cirrhosis, lower levels of anabolic hormones, IGF-1 and testosterone, which likely contribute to elevated myostatin expression and impaired protein synthesis, have been observed. A significant improvement in muscle mass was observed following intramuscular testosterone administration to men with cirrhosis and low serum testosterone levels in a 1-year double-blind, placebo-controlled trial.[21]Sinclair M. Grossmann M. Hoermann R. Angus P.W. Gow P.J. Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial.J Hepatol. 2016; 65: 906-913Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar IGF-1 production is regulated by human growth hormone and its deficiency correlates with a reduction in muscle mass, strength and impairment in physical function in cirrhosis through mTOR pathway inactivation, enhanced proteolysis and suppressed satellite cell proliferation.[22]Saeki C. Kanai T. Nakano M. Oikawa T. Torisu Y. Saruta M. et al.Low serum branched-chain amino acid and insulin-like growth factor-1 levels are associated with sarcopenia and slow gait speed in patients with liver cirrhosis.J Clin Med. 2020; 9Crossref Scopus (14) Google Scholar Small trials in patients with various chronic diseases have investigated the impact of growth hormone or IGF-1 administration on muscle mass with conflicting results. Four months of IGF-1 treatment tended to improve energy metabolism with no changes in muscle mass and strength in patients with cirrhosis and subnormal IGF-I levels in a randomized double-blind placebo-controlled clinical trial.[23]Conchillo M. de Knegt R.J. Payeras M. Quiroga J. Sangro B. Herrero J.I. et al.Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial.J Hepatol. 2005; 43: 630-636Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar The safety, efficacy and long-term outcomes associated with growth hormone or IGF-1 replacement therapies should be investigated in patients with cirrhosis, considering their main side effect of fluid retention and high cost. Ghrelin hormone can stimulate growth hormone secretion and appetite. A single administration of human ghrelin improved muscle mass, strength and performance in a non-cirrhotic population.[24]Nagaya N. Itoh T. Murakami S. Oya H. Uematsu M. Miyatake K. et al.Treatment of cachexia with ghrelin in patients with COPD.Chest. 2005; 128: 1187-1193Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar Existing pharmaceutical options for sarcopenia in cirrhosis are limited in terms of the presented clinical evidence; novel therapeutic strategies are required to improve muscle mass and function. Myostatin is one of the main myokines in muscle and its upregulation plays a major role in muscle atrophy in various chronic diseases including cirrhosis. Therapies targeting myostatin have attracted attention in recent years. The effect of monoclonal antibodies directly targeting myostatin, including landogrozumab and bimagrumab, on muscle parameters is currently being investigated;[25]Feike Y. Zhijie L. Wei C. Advances in research on pharmacotherapy of sarcopenia.Aging Med (Milton). 2021; 4: 221-233Crossref PubMed Scopus (21) Google Scholar they could be promising treatments for sarcopenia in cirrhosis. Myostatin activation by hyperammonemia and the reduction in crucial myostatin inhibitors, follistatin, IGF-1 and testosterone in cirrhosis demonstrate the importance of conducting research through preclinical and clinical studies to determine the safety and efficacy of monoclonal antibodies as a potential therapeutic option for sarcopenia in cirrhosis. Early and large-scale treatment interventions for sarcopenia in cirrhosis are needed to improve the prognosis and quality of life of affected patients. However, considering methodological limitations of previous studies, such as small sample sizes, varying study doses, durations, primary endpoints (including evaluation of muscle mass or strength with or without functional assessment), disease stages and the lack of control arms in several studies, interpretation of current data remains complicated. Among several uncovered issues in previous studies, lack of clear statements on the goals of the intervention (maintaining and preventing further decline of muscle parameters or reversal of presenting sarcopenia) in the specific target population (only confirmed sarcopenic vs. random sample regardless of sarcopenic status) are major limitations. Moreover, it is not clear whether sarcopenia prevention or reversal is associated with improvement in important clinical outcomes in patients with cirrhosis, such as mortality before or after liver transplant, risk of decompensation or hospital admissions. There is no doubt that future well-designed clinical trials are required to verify the preliminary data, yet potential trials in cirrhosis pose challenges. Firstly, preventive or treatment trials for skeletal muscle abnormalities necessitate an effective evaluation of the abnormality at single time points as well as reversal assessment in longitudinal studies. Beyond the consistency and sensitivity of modalities, the progressive nature of sarcopenia over time, cost, accessibility and practicability of techniques to quantify changes should be considered, mainly in large or longitudinal studies. A clinically significant increase in muscle mass, which is a change greater than 2%,[15]Mourtzakis M. Prado C.M. Lieffers J.R. Reiman T. McCargar L.J. Baracos V.E. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care.Appl Physiol Nutr Metab. 2008; 33: 997-1006Crossref PubMed Scopus (1470) Google Scholar should be used in prospective clinical trials. Secondly, preventative strategies in early-stages and therapeutic approaches in moderate-to-severe stages of sarcopenia might differ.[26]Ebadi M. Bhanji R.A. Dunichand-Hoedl A.R. Mazurak V.C. Baracos V.E. Montano-Loza A.J. Sarcopenia severity based on computed tomography image analysis in patients with cirrhosis.Nutrients. 2020; 12Crossref Scopus (20) Google Scholar Therefore, the best target population, specific types of therapy for each stage of sarcopenia, an appropriate time to initiate interventions, as well as tolerable clinical doses, should be identified. When designing studies, a lack of consideration of other confounding variables – including the time point of the disease’s trajectory, the etiology and severity of the disease, sex, age, ethnicity, polypharmacy, adjustment to dietary intake or physical activity levels –may lead to bias in assessing the impact of an intervention on skeletal muscle abnormalities. Control for confounders can be achieved by designing a well-adjusted distribution using analytic strategies to identify the optimal number of patients in order to detect a clinically meaningful difference in a homogeneous population. Patients’ adherence to the intervention is another essential concern in prospective clinical trials which could be enhanced by optimizing the dose, frequency of dosing, palatability and instructions for use. Lastly, the practical application and the potential efficacy of single or combined treatments to ameliorate skeletal muscle abnormalities are questions that need to be answered. Considering the aforementioned factors in the design of future trials examining the potential of both pharmacological and non-pharmacological interventions to prevent or reverse skeletal muscle abnormalities may have beneficial consequences for patients with cirrhosis. The authors received no financial support to produce this manuscript. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Search and selection of abstracts, review of the full-length articles and writing the final version of the manuscript was performed by Maryam Ebadi and Aldo J. Montano-Loza. Patrizia Burra, and Alberto Zanetto contributed to revising the manuscript. All authors have commented on the manuscript and approved the final version. The following are the supplementary data to this article: Download .pdf (.35 MB) Help with pdf files Multimedia component 1