Shining a spotlight on sarcopenia and myosteatosis in liver disease and liver transplantation

Muscle‐wasting and disease‐related malnutrition are highly prevalent in patients with chronic liver diseases (CLD) as well as in liver transplant (LT) candidates. Alterations of body composition (BC) such as sarcopenia, myosteatosis and sarcopenic obesity and associated clinical frailty were tied to inferior clinical outcomes including hospital admissions, length of stay, complications, mortality and healthcare costs in various patient cohorts and clinical scenarios. In contrast to other inherent detrimental individual characteristics often observed in these complex patients, such as comorbidities or genetic risk, alterations of the skeletal muscle and malnutrition are considered as potentially modifiable risk factors with a major clinical impact. Even so, there is only limited high‐level evidence to show how these pathologies should be addressed in the clinical setting. This review discusses the current state‐of‐the‐art on the role of BC assessment in clinical outcomes in the setting of CLD and LT focusing mainly on sarcopenia and myosteatosis. We focus on the disease‐related pathophysiology of BC alterations. Based on these, we address potential therapeutic interventions including nutritional regimens, physical activity, hormone and targeted therapies. In addition to summarizing existing knowledge, this review highlights novel trends, and future perspectives and identifies persisting challenges in addressing BC pathologies in a holistic way, aiming to improve outcomes and quality of life of patients with CLD awaiting or undergoing LT.


| INTRODUC TI ON
In 1989, Irwin Rosenberg introduced sarcopenia as a generalized loss of skeletal muscle mass in the elderly. 1 Based on this first description, various studies and definitions followed, predominantly to describe age-related alterations in body composition (BC).Much like sarcopenia, frailty was also described in geriatrics as a condition that precedes disability and indicates an increased vulnerability of a person. 2thological BC is an important component of clinical frailty and in the presence of these, patients have weakened resiliency and adaptive capacity to stressors including surgical trauma. 3,4Besides geriatric cohorts, BC pathologies and frailty are highly prevalent in patients with chronic liver disease (CLD). 5The European Working Group on Sarcopenia in Older People (EWGSOP) defines sarcopenia as the presence of low muscle strength combined with low muscle quantity or quality. 6Depending on the population and assessment strategies, the prevalence of sarcopenia is 40%-70% in patients with liver cirrhosis. 7Myosteatosis occurs in over 50% of cirrhotic patients evaluated for liver transplantation (LT). 8Sarcopenic obesity, the coexistence of both sarcopenia and obesity, is observed in 20%-40% of CLD patients awaiting LT. 8,9 In recent years, several studies have provided evidence that reduced muscle quantity (sarcopenia) as well as diminished muscle quality (myosteatosis) are both important predictors of higher complication-and mortality rates in CLD as well as in post-LT cohorts, [10][11][12][13][14] increased waiting list mortality [15][16][17] and lower graft-and patient survival after LT. [18][19][20][21][22][23] Ultimately these negative effects of pathological BC and associated frailty represent a significant burden for the healthcare system, due to the increased costs these patient populations generate compared to a not affected sub-population. 24[27] Even though there is a growing recognition of the role of diseaserelated malnutrition (DRM), pathological BC and frailty in LD and LT, we are still left with many important questions to answer regarding mechanisms, definitions and validation, and therapeutic approaches.
In this review, we provide a current overview of the complex muscle-liver interaction in liver disease (LD).Furthermore, we summarize the evidence regarding the impact of sarcopenia and myosteatosis on clinical outcomes in CLD, but the emphasis will be on waiting list candidates and the post-LT setting.Finally, as BC, DRM and frailty are considered as potentially modifiable risk factors, we will discuss treatment possibilities within the context of ongoing research and provide a brief outlook of future directions in the field.
The large variety of clinical assessment tools, heterogeneity of cutoff values and aspects of standardization are beyond the scope of the present article and have been reviewed recently by our group 5 and by others. 6,28,29

| PATHOPHYS IOLOGY
The pathophysiological axis between LD and pathological muscle alterations is complex and our understanding still remains fragmented.
Nevertheless, there are mechanisms in this multifactorial process which are well-described and can be approached with a therapeutic intention.It is known that LD promotes changes in the skeletal muscle (e.g.sarcopenia or myosteatosis) on the one hand, but sarcopenia/myosteatosis may also contribute to the progression of LD on the other hand. 5Besides, there are mechanisms, like insulin resistance, contributing to both pathological muscle alterations and CLD. 5 Figure 1 illustrates the main pathophysiological interactions.

| Cirrhosis and end-stage liver disease (ESLD) in general
Liver cirrhosis is characterized by multiple systemic consequences such as disease-related malnutrition, catabolism associated with body composition, frailty, liver disease, liver transplantation, myosteatosis, risk-factors, sarcopenia
• Alterations of body composition and the associated clinical frailty have shown to be robustly associated with inferior clinical outcomes in patients with liver disease.
• Body composition-based prognostic models could play an important role in the optimization of clinical management of waiting-list candidates in the future.
• Body composition alterations, frailty and disease-related malnutrition are potentially modifiable risk factors with a major clinical impact.
• Tailored patient selection, risk assessment and therapeutic interventions are paramount to optimize patient outcomes.low liver glycogen storage capacity, protein deficiency, hyperammonemia, endotoxemia, chronic inflammation, decreased growth hormone (GH) levels and increased myostatin. 7,30DRM affects 50%-90% of cirrhotic patients and is caused by clinical factors, such as inadequate nutrient and energy intake caused by nausea, intraabdominal pressure by ascites, gustatory and olfactory derangements and imbalance of orexigenic and anorexigenic hormones, in combination with intestinal maldigestion and malabsorption as well as inflammation-related disorders. 8,30,31The resulting energy deficit ultimately leads to catabolism and muscle depletion. 8In the diseased cirrhotic liver, reduced energy storage capacity and energy shortage induce protein catabolism, mainly by using up-branched chain amino acids (BCAAs) as substrates. 8,32Additionally, the progression of CLD induces gluconeogenesis which demands higher than usual protein intake by the patient. 30The result is an imbalance with reduced BCAA and increased aromatic amino acids (AAAs), which is associated with complications such as hepatic encephalopathy. 30,32e deficit of BCAA in turn diminishes protein synthesis and protein turnover and enhances muscle-wasting. 30,33main driver of muscle alterations in liver cirrhosis is hyperammonemia resulting from dysfunctional hepatocytes and portosystemic shunting, which in turn reduces ureagenesis. 7,8Muscle counteracts by forming glutamate and glutamine by using αketoglutarate from the tricarboxylic acid (TCA) cycle, also causing impaired adenosine triphosphate (ATP) production, energy shortage and diminished protein synthesis capacity in the muscle. 7,8,32,33As a former phenomenon, hyperammonemia contributes to mitochondrial dysfunction, which stimulates the generation of reactive oxygen species (ROS) and impairs fatty acid oxidation with accumulation of lipids observed in myosteatosis, decreased protein synthesis and autophagy-mediated proteolysis as consequences. 7,33,34Elevated ammonia uptake in the muscle promotes the transcription of myostatin, which reduces mammalian target of rapamycin complex 1 (mTORC1) signalling and upregulates adenosine monophosphateactivated catalytic subunit alpha 2 (AMPKa2) phosphorylation, contributing to impaired protein synthesis and elevated autophagic proteolysis. 7,8,32,33,35 liver cirrhosis, the anabolic hormones testosterone and GH are diminished, which contributes to deficient protein synthesis. 7,8,33ronic inflammation and elevated levels of inflammatory cytokines are characteristic in cirrhotic patients and, thus play an essential part in the interplay of LD and muscle pathologies.Less than 1% of patients with cirrhosis with acute decompensations do not have any evidence of systemic inflammation. 36

| Metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH)
The definitions in the field of steatotic liver disease have been rapidly changing over the past years and it represents one of the most common conditions in terms of malnutrition, BC and frailty with rapidly accumulating evidence. 37Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most recently proposed consensus term for the most common LD worldwide. 37Before this, in 2020 an expert panel created a novel term called metabolic dysfunction-associated fatty liver disease (MAFLD) to overcome the limitations related to the traditional terminology. 38The diagnosis of F I G U R E 1 Disease-related pathophysiology of sarcopenia and myosteatosis in chronic liver disease.Pathophysiology of sarcopenia and myosteatosis in liver disease (A).Potential therapeutic interventions and their targets (B).This figure was created using BioRe nder.com.AAA, aromatic amino acids; AMPKa2, adenosine monophosphate-activated catalytic subunit alpha 2; ATP, adenosine triphosphate; BCAA, branched-chain amino acids; FFA, free fatty acids; GH, growth hormone; IGF-1, insulin-like growth factor-1; IL1, interleukin-1; IL6, interleukin-6; LOLA, L-ornithine-L-aspartate; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; ROS, reactive oxygen species; TCA, tricarboxylic acid; TNFα, tumour necrosis factorα.
MAFLD is based on the presence of hepatic steatosis concomitantly with the presence of overweight or obesity and/or type 2 diabetes mellitus (T2DM). 39However, as concerns were raised by many, it led to a multi-stakeholder effort to resolve these issues and develop a new consensus and diagnostic criteria as described elsewhere. 37e 'old' term NAFLD was used in most studies concerning BC in this context, therefore we intend to still use this definition in this article when referring to previous studies.This was defined as the presence of steatosis in >5% of hepatocytes not caused by secondary fat accumulation as alcohol consumption or drug-induced and is associated with insulin resistance (IR). 40,41It can be divided into two pathologies: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). 40The underlying pathophysiological mechanisms for NAFLD and alterations of the skeletal muscle observed in this condition, are obesity, physical inactivity, chronic inflammation, IR, hepatokines, myokines and vitamin D deficiency. 5,42NAFLD has a prevalence of 25% globally 42 and 17%-46% in Western countries and is one of the three most frequent indications for LT. 40esity is one of the main factors contributing to LD and pathological changes in the skeletal muscle, especially myosteatosis. 5tably, the prevalence of overweight or obesity amounts to 60% in NAFLD and even 90% in NASH. 8The morbidity and mortality of sarcopenic obesity are higher compared to sarcopenia and obesity alone. 35Elevated free fatty acids (FFA) and triglycerides lead to NASH and myosteatosis by intracellular accumulation of lipid intermediates in liver and muscle. 5,35,42Furthermore, the increased lipotoxicity causes mitochondrial dysfunction, oxidative stress and production of ROS. 43,44esity contributes to higher levels of circulating inflammatory cytokines such as interleukin-6 (IL6), interleukin-1 (IL1), tumour necrosis factorα (TNFα), plasminogen activator inhibitor-1 and leptin, leading to chronic hepatic inflammation which in turn induces fibrogenesis. 36,42,43,45TNFα activates ROS production and results in oxidative stress and mitochondrial dysfunction. 36,42Moreover, it inactivates the AMP-activated protein kinase (AMPK) pathway, promoting the progression of NAFLD. 42Augmented TNFα and IL-6 levels correlate with reduced muscle mass and strength. 7,421 promotes the muscular protein catabolism. 35Leptin reduces the anabolic effect of insulin-like growth factor-1 (IGF-1). 42Overall, systemic inflammation seems to have a paramount significance, therefore some authors are tending to abandon the term 'pathological BC' and move towards a more holistic approach of 'pathological host phenotypes', in which muscle alterations interact with systemic inflammation having a stronger effect on clinical prognosis than any of these factors alone. 46key factor in the development and progression of NAFLD and a direct promoter of sarcopenia and myosteatosis is IR.8,42,44 Insulin is a main driver of glucose, lipid and protein metabolisms in hepatocytes.35 The reduced insulin sensitivity leads to impaired glucose uptake and glycogen synthesis.42 The augmented glucose is converted to triacylglycerol in the liver, leading to NAFLD.42 As an anabolic hormone insulin induces the muscle protein synthesis and suppresses the proteins catabolism in myocytes, thus the consequence of IR is the opposite of these, namely muscle-wasting.8,35 IR in skeletal muscle causes a diminished fatty acid oxidative capacity contributing to increased intracellular lipid accumulation in muscle and liver.5,45 The elevated cellular glucose availability that comes alongside IR also leads to augmented intrahepatic lipid content. 45 An oer-expression of hepatokines (e.g.LECT2 and Hepassocin) as endocrine proteins released by hepatocytes as well as the augmented secretion of myokines such as myostatin disturbs the metabolism in liver and muscle.8,42 Another factor involved in the development of sarcopenia and NAFLD is vitamin D deficiency.47 Vitamin D contributes to the homeostasis of skeletal muscles, cell regulation and proliferation.35,42 In hepatocytes, it reduces liver fibrosis by depressing the proliferation of fibroblasts and the collagen production.42

| Alcohol-related liver disease (ALD)
ALD is one of the main conditions leading to cirrhosis and one of the most frequent indications for LT. 48Several studies have provided evidence that ethanol directly and indirectly promotes muscle-wasting, and severe sarcopenia, more than what we see in other forms of LDs. 7,32,49It causes impaired protein synthesis by myostatin activation and by inhibiting mTOR. 50In the liver, it triggers direct and indirect profibrotic pathways. 35It is known that the ethanol oxidation to acetaldehyde is associated with increased ROS and oxidative stress, mitochondrial dysfunction, reduced ATP production and enhanced autophagy. 35As a key factor that aggravates liver and muscle damage, hyperammonemia is increased by impaired hepatic ureagenesis by acetaldehyde. 35Additionally, ethanol raises the muscle sensitivity to hyperammonemia by promoting the ammonia transport in the muscle. 7Another main driver for liver damage and muscle pathology is malnutrition and deficit in micronutrients and vitamins, as a result of the caloric value of ethanol. 32,35,41Notably, 90% of patients with advanced ALD are affected by anorexia, 30 while patients with alcoholic hepatitis and severe malnutrition are observed to have a one-year mortality up to 76%. 35

| Viral hepatitis, cirrhosis related to autoimmune-hepatitis, primary sclerosing cholangitis (PSC)/primary biliary cholangitis (PBC)
Cirrhosis due to viral hepatitis remains one of the three most common indications for LT, 48 even though its relative significance in the transplant setting has decreased over the past years through the introduction of adequate medical treatment.It has been reported that muscle depletion is independently associated with fibrosis intensity in chronic hepatitis B and C. 8,47 On the other hand, several studies have provided evidence that antiviral agents such as lamivudine, tenofovir and entecavir improve liver fibrosis. 47Chronic inflammation and elevated levels of pro-inflammatory cytokines in viral hepatitis, autoimmune hepatitis, PSC and PBC aggravate liver damage and muscle atrophy by protein catabolism, ROS production and oxidative stress. 30,35A further complication causally leading to muscle depletion and malabsorption is cholestasis, which is pathognomonic for PBC and PSC. 30

| Peri-operative, post-liver transplantation
Patients in the peri-operative and post-LT phase are at high risk regarding pathological muscle changes. 51Causally, physical inactivity, infections and perioperative complications are factors which contribute to progressing muscle loss, sarcopenia and myosteatosis after life-saving surgery. 32,41The most extended muscle loss occurs during the first year after LT, while sarcopenic obesity occurs more frequently in the subsequent period. 32,41,51munosuppressive agents such as corticosteroids, calcineurin inhibitors and mTOR inhibitors contribute to muscle atrophy and myosteatosis. 8,32

| CLINIC AL OUTCOME S
In recent decades, an increasing number of studies demonstrated the clinical impact of sarcopenia, myosteatosis and sarcopenic obesity in patients with LD (Table S1) and patients listed for or undergoing LT (Tables 1 and S2).

| Liver fibrosis and cirrhosis
A rather robust prognostic association between sarcopenia and mortality in patients with cirrhosis has been demonstrated by various authors using different study designs. 11,52,53In a meta-analysis conducted by Tantai et al., which included 22 studies and a total of 6965 cirrhotic patients, sarcopenic patients had a mortality rate that was twice as high compared to non-sarcopenic patients.The adjusted hazard ratio was calculated to be 2.30 in this setting. 54osteatosis was also detected as a strong predictor of mortality in patients with liver cirrhosis or NAFLD. 13,14,55,56Furthermore, alterations in BC are risk factors also for 'softer endpoints' including hospitalization, 57 health-related costs, 58 and cirrhosis-associated clinical complications. 10,56It has to be pointed out, that there is a strong association between pathological BC and hepatic encephalopathy in cirrhotic cohorts. 10,12,59,60In a study conducted by Bhanji et al.,   which involved 675 patients with liver cirrhosis, it was observed that 70% of the patients with myosteatosis had hepatic encephalopathy, while only 45% of the patients without myosteatosis exhibited this condition. 59 their large multicenter study with 2761 patients with NAFLD, a South Korean group by Lee et al. provided evidence, that sarcopenia is associated with liver fibrosis. 61Hsieh et al. additionally proved that myosteatosis is an independent predictive factor for significant fibrosis in NAFLD with an odds ratio of 1.65. 62In their study, the authors examined the additional benefits of measuring low muscle mass and myosteatosis in predicting liver fibrosis. 62rcopenia and LD often come along with frailty, which includes components such as sarcopenia, reduced physical function, reduced aerobic exercise capacity and physical disability. 63,64Notably, for quantifying frailty as predictor of clinical outcomes in cirrhotic patients, different frailty indices were designed.Williams et al. highlight   in their article two indices: the Clinical Frailty Scale and Liver Frailty Index (LFI) as practical and objective scores for predicting clinical outcomes and waiting list mortality in patients with ESLD. 63In their multicenter prospective study including 1405 patients, Kardashian et al. identified cutoff values for the LFI to predict an increased risk of 3-, 6-and 12-month mortality. 65

| Waiting list mortality, surgical outcomes and perioperative outcomes after liver transplantation
Risks in the setting of LT are a central topic in BC research, encompassing waiting list mortality, perioperative outcomes as well as long-term graft-and patient survival after LT (Table S1).Earlier studies examining the perioperative effect of sarcopenia suggested an association of BC parameters with the length of intensive care unit (ICU), hospital stay and time of ventilatory support, post-transplant infections and neurological complications. 21,22,51,66,67Our group analysed myosteatosis in the perioperative setting and could provide evidence of a longer ICU-and hospital stay, higher postoperative complication rates and higher estimated costs for transplanted patients with myosteatosis compared to those without. 68Several studies have recently confirmed these findings. 19,20rticularly the focus on pathological BC as an indicator of waiting list mortality contributed to the demand for a new score involving these variables to potentially improve evidence-based allocation and outcome prediction strategies in the near future (Tables 2 and   S3).In 2015, Montano-Loza et al. introduced the Model of End Stage Liver Disease (MELD)-sarcopenia score and demonstrated an improved prediction of 3-month mortality. 69The Dutch research group van Vugt et al. applied the same model reporting a limited prognostic value in predicting waiting list mortality. 16In the face of the accumulation of studies showing the independent negative impact of myosteatosis, Lattanzi et al. suggested a higher predictive accuracy for 3-and 6-month mortality by the MELD-Sarco-Myo-HE score. 13Moreover, a Japanese research group of Hamaguchi et al.   included alteration in muscle mass, muscle quality and visceral adiposity in a body composition-MELD score demonstrating a better value in predicting waiting list mortality. 70In 2021, the Italian research group of Professor Lai introduced the urgency Sarco-Model 2 score, by adding one extra point of MELDNa for each 0.5 cm 2 /m 2 reduction of total psoas area <6.0 cm 2 /m 2 . 71In their study with 1087 cirrhotic patients listed for LT, the authors demonstrated a better prediction of 3-month waiting list dropout in patients with MELDNa TA B L E 1 Reports on the prognostic role of sarcopenia and/or myosteatosis in patient cohorts undergoing deceased or living donor liver transplantation.S3).Abbreviations: AUC, area under the curve; BAR, balance of risk; BC, body composition; HE, hepatic encephalopathy; IMAC, intramuscular adipose tissue content; MELD, model of end-stage liver disease; PD, psoas density; SM-RA, skeletal muscle radiation attenuation; SMI, skeletal muscle index; TIPS, transjugular intrahepatic portosystemic shunt; TPA, total psoas area; TPMT, total psoas muscle thickness; VSR, visceral to subcutaneous adipose tissue ratio; WL, waiting list.

TA B L E 2 (Continued)
<20 with an impressive AUC = .93for the new model. 71Based on data indicating a superior prognostic value of muscle quality over muscle mass in the perioperative outcome, our group introduced the Balance-of Risk (BAR)-Myosteatosis-score, pointing out a better predictive value for 90-day morbidity and mortality compared to the original BAR-score. 68Taken together, including BC characteristics to conventional risk factors contributes to higher prognostic accuracy in most of the so far reported cases.Nevertheless, additional studies with larger patient cohorts and longer follow-ups are still warranted to identify the optimal model of risk stratification for patients on the waiting list and in LT.
These above-detailed findings clearly show the effects of pathological BC on clinical outcomes and the potential of its assessment in clinical risk-stratification. 5 Even though it would be highly desirable to optimize clinical decision making based on BC, frailty and nutritional biomarkers and phenotypes, currently data derived from BC assessment is mostly used only as a supplementary tool or information to identify patients at risk and guide interventions on the level of clinical nutrition or exercise (see e.g.EASL recommendations). 25is can be attributed to the fact that cutoffs and measurement approaches are heterogeneous, and not yet fully mature or validated; therefore, caution is warranted. 5For these reasons, we consider it premature to enmesh these factors with routine clinical decision making outside of clinical trials which might potentially define the whole individual therapeutic path and fate of an individual patient.
To the best of our knowledge, no national or international association has included these parameters in allocation policies yet with the aim to increase the priority of a patient on the waiting list or to define 'futility' in severe critical illness.
In such 'futile' cases, however, extreme sarcopenia or myosteatosis associated with clinical frailty might indeed play a significant role in the future in objectifying the decision, whether a critically ill and frail patient is 'fit or unfit for transplant'. 72

| The impact of body composition on hepatocellular carcinoma (HCC) recurrence after liver transplantation
Hepatocellular carcinoma (HCC) comprises 80% of primary liver cancers 73 and is known as a frequent indication for LT.Although to date high-quality clinical studies remain rare, current research focuses on the impact of sarcopenia on HCC recurrence. 73Guo et al.
describe in their comprehensive meta-analysis involving 57 studies a significant association between sarcopenia and a higher risk of HCC tumour recurrence. 74While multiple authors have provided evidence that sarcopenia and myosteatosis are independent risk factors for HCC recurrence after curative-intent hepatic resection, [75][76][77] studies which would show the clear effect of sarcopenia on tumour recurrence after LT remain extremely rare.Grat et al. reported no significant impact of low muscle mass on HCC recurrence after LT in their retrospective study including a small cohort of 77 patients. 78 contrast, the Korean research group Kim et al. demonstrated sarcopenia as one of the important host factors for tumour recurrence in a cohort of patients with advanced HCC undergoing living donor liver transplantation (LDLT). 79These rather controversial findings warrant further clinical investigation and demonstrate the need for high-level evidence.

| Predictive value of myosteatosis versus sarcopenia
A higher number of studies are focusing on the prognostic effect of low skeletal muscle mass than studies dealing with low-quality fatinfiltrated muscle as predictive parameter.Only a very small number of research groups compare the effect of sarcopenia with the impact of myosteatosis on clinical outcomes.In 2019, for the first time, our research group could show that a dismal muscle quality may even be a stronger predictor for an adverse perioperative outcome in deceased donor liver transplantation (DDLT) than low skeletal muscle mass. 68Supporting these findings, recent studies with different patient profiles confirmed these results and underlined the stronger prognostic value of myosteatosis. 18,19It should be noted, that myosteatosis seems to be a strong prognostic factor for perioperative outcomes as well as 1-year mortality or graft failure, 19 with worse predictive value for long-term outcomes. 18,80Of interest, myosteatosis seems to be a key factor in and a potential prognostic marker for NASH. 81,82The dimension of muscular fat content reflects the severity of NAFLD in obese patients. 81Recently, Ebadi et al. demonstrated in their retrospective study including 855 cirrhotic patients that the concurrent presence of myosteatosis and sarcopenia may have an additive effect with the worst survival, predicting the cumulative incidence of mortality with a hazard ratio of 2.22. 56

| The role of sex in body composition and clinical outcomes
Sex has an important role in liver disease biology and progression. 83,84This certainly includes sex-based differences in BC and frailty as well.Sex-associated disparities are increasingly recognized in the field of hepatology and transplantation, leading to improved selection criteria adjusted for sex (e.g.MELD 3.0). 85ere are multiple studies which have aimed to analyse the sexdependent differences of BC and its impact on clinical outcomes in various cohorts which have been reviewed extensively by various groups. 86,87Briefly, a systematic review by Guarino et al. on behalf of the Italian Association for the Study of the Liver could show a higher prevalence of sarcopenia in males with CLD, suggesting worse clinical outcomes in the peri-and post-operative setting in sarcopenic male patients undergoing LT. 88 In general, sex hormones play an important role in BC and skeletal muscle homeostasis.While testosterone is a potent anabolic hormone, estrogens also play a crucial role in muscle mass maintenance, regeneration and anti-inflammation. 89,90erefore, the sex-related effects on BC are multifactorial, complex and not yet well characterized. 86This underlines the need for further research on the role of sex in BC and frailty in the context of liver disease.

| TRE ATMENT AND INTERVENTI ON S
As described above, frailty, pathological BC and malnutrition are risk factors with major clinical impact in the LT and ESLD population.
In contrast to many other clinical variables which might influence outcomes, all these are potentially modifiable by therapeutic interventions.Even so, high-level evidence from randomized controlled trials (RCTs) using therapeutic interventions still remains limited as summarized in Tables 3 and S4.
Figure 1 briefly shows therapeutic approaches in the context of pathophysiology.Furthermore, to better visualize the rather complex clinical management, Figure 2  Conservative treatment options such as nutritional regimes and physical activity play an essential part in reducing muscle depletion and promoting protein synthesis. 5,93Malnutrition as a corollary of inadequate nutrient and energy intake by a cirrhotic patient, particularly in ALD, can be counteracted by three meals and three snacks including a late-evening snack daily, representing an energy intake of at least 35 kcal/bwkg and a protein intake of 1.2-1.2g/bwkg/day 25,26,64 (Figure 2).Short-term adequate nutrition regime after LT such as enteral or, if not possible, parenteral nutrition within 12-24 h postoperatively contributes to decreased bile duct complications, infection rate and length of ICU stay. 5,25,41e EASL practice guidelines on nutrition in CLD recommend early oral food intake or enteral tube feeding within 12-14 h postoperatively. 25ysical activity regimes should contain resistance (e.g. 2 days/ week) as well as endurance exercises (e.g. 4 days/week) combined with flexibility and balance (e.g. 2 days/week). 25,94,95Several studies provided evidence that physical training in cirrhotic patients awaiting LT increases muscle mass, strength and functional capacity 96 and furthermore decreases posttransplant mortality and morbidity. 25,94,95In obese NASH patients, dietary regimes play a key role in addressing myosteatosis and sarcopenia as well as com-

TA B L E 3 (Continued)
activity, energy restriction (e.g.500-1000 kcal) and a macronutrient composition including high-protein intake. 40cusing on the impaired protein synthesis, the autophagyrelated proteolysis and the following decrease in BCAA levels, high protein supplements are considered as specific therapeutic options with increasing evidence. 25BCAAs are not only used as substrates for protein synthesis but also improve nitrogen imbalance. 50,97rthermore, the amino group from the BCAAs is utilized to form glutamate and to detoxify ammonia. 98Leucin and HMB-enriched amino acid supplements additionally promote protein synthesis and diminish autophagy in the skeletal muscle by stimulating mTOR/ mTOR1 signalling. 30,33,50,97,99,100Recent sources demonstrated decreased fat accumulation in skeletal muscle, improved glucose sensitivity and increased muscle mass when using BCAA. 31,101Several studies provided evidence that BCAA supplementation in advanced cirrhosis reduces the progression of liver failure, hepatic encephalopathy, hospital admission rate and mortality and improves the cognitive status and health-related quality of life in ESLD. 30,91,98,102though promising sources confirmed these findings, the positive impact on mortality remains unclear. 103L-carnitine as a metabolite produced by the degradation of lysine is utilized as carrier of the mitochondrial membrane for short-chain fatty acids and is highly relevant in fatty acid oxidation. 50,98Published data suggest that L-carnitine supplementation (e.g.[106] Ammonia-lowering strategies are showing promising results in counteracting muscle depletion and preventing LD progression and clinical consequences such as hepatic encephalopathy. 107,108Some studies suggest a potential reduction in sarcopenia by lactulose, rifaximin and L-ornithine L-aspartate (LOLA). 107,109,110Rifaximin additionally may decrease myostatin and release BCAA. 107,109 the face of decreased testosterone and GH levels and response in sarcopenia and LD, hormone therapy is of interest. 33 is known that anabolic hormones improve muscle mass by stimulating mTORC1 signalling and myostatin inhibition. 30,33though various sources suggest the improvement of muscle mass and function as well as the reduction in fat mass by androgen and testosterone treatment, 32,111 other authors report the lack of therapeutic benefits by hormone treatments in some cohorts. 30,33,93,109,112,113Further high-level randomized evidence is warranted to find the right place for these treatment strategies in the clinical algorithms.
Recently, some next-generation targets showed promising results.mTOR1 signalling is a targetable axis leading to inhibited autophagy-mediated proteolysis, increased protein synthesis and counteracts anabolic resistance, all contributing to improved muscle mass. 30,100,114Myostatin antagonists are further candidates which might reduce skeletal muscle atrophy. 109Additionally, they not only prevent hepatic steatosis but also promote insulin sensitivity. 42Examples which target this particular axis are IGF-1, follistatin and anti-myostatin antibodies. 107,109Mitochondrial protective agents such as Dynamin-related protein 1 (DRP1) inhibitors are interesting targets with therapeutic potential to be examined. 109 and transcriptomic remodelling in myosteatosis. 116Notably, systems biology and the analysis of multi-omics data are promising technologies to be able to use a complex approach not only for diagnostic purposes as biomarkers, but also to identify therapeutic targets using integrated 'molecular-metabolic approaches' as described by Tandon et al. 86,117 Importantly, system biology and panomics analysis potentially provide the basis for future targeted therapies that are more specific to the underlying LD, for instance, HMB for ALD or Zexie-Baizhu decoction, a Chinese classical formula containing several bioactive monomers, to treat body fluid disorders, for NAFLD. 118,119Artificial intelligence and machine learning have a strong potential to improve the utilization of such complex data in daily clinical practice in the future. 120t only for uncovering molecular pathomechanisms and diagnostic tools but also for identifying therapeutic strategies, animal models are still important and indispensable in BC and nutrition research. 121,122In this context, sarcopenia mouse models are widely used in the setting of various studies. 123 date, no consistent high-level validation for sarcopenia, myosteatosis and sarcopenic obesity exists in the LD population.patients after LT, using a robotic platform for daily interaction with a transplant specialist which assessed vital parameters, asked about immunosuppressant medication use and exercise and furthermore recommended rehabilitation exercises. 127The results showed better self-management, medication adherence, lower readmission rates and improved health-related quality of life. 127The multicenter, ran- Investigations with more clinically relevant endpoints are warranted.
To provide personalized interventional strategies, adapted to the underlying disease and patient characteristics, population studies are indispensable.It is also necessary to look beyond the currently prevailing 'deficiency-replacement' based therapy approaches and focus more on mechanism-based as well as causal therapies. 86[134] The field is rapidly changing with multiple highly productive groups.With this review, we gave a comprehensive perspective on the current state of the art and a challenging but also realistic depiction of future perspectives on this evolving area of research.
was designed to summarize possible clinical aims, diagnostic steps and interventions based on disease stage, history and progression.As an example, the Italian group by Marchesini et al. could show in their multicenter, double-blinded RCT that BCAA supplementation reduces the hospital admission rate, decreases the Child-Pugh score and improves anorexia and health-related quality of life in patients with advanced liver cirrhosis. 91Kamo et al. provided evidence that postoperative administration of β-hydroxyβ-methylbutyrate (HMB)-enriched formula after LT shortens the length of hospital stay. 92

•
plications coming along with obesity, IR and steatosis.The joint EASL, European Association for the Study of Diabetes (EASD) and European Association of Obesity (EASO) Clinical Practice Guidelines for the management of NAFLD suggest a combination of physical TA B L E 3 Randomized controlled trials on therapeutic interventions.Low sample size (L) • Single-centre, open-label study (L) • Difficult to determine whether effects of the treatment are attributable to BCAA or nutritional improvement (L) Meena et al. non-trivial possible positive long-term effects of a short-term training program (S) • Low sample size (L) • Little access to lifestyle data (L) Mohta et al. follow-up period of 12 months (S) • Single-centre, open-label study (L) • Low sample size (L) • Daily physical activity was not investigated in detail (

F I G U R E 2
Possible suggestions for the clinical management over the course of disease history and progression.This figure was created using BioRe nder.com.This figure serves as an orientation for the reader on the clinical management of 'fictional' patients based on the author's own experience and literature sources and does not intended to serve as official clinical guidance.For clinical recommendations follow international practice guidelines and consensus-based guidance statements.BCAAs, branched-chain amino acids; BC, body composition; BIA, bioelectrical impedance analysis; bw, body weight; CT, computed tomography; DEXA, dual x-ray absorptiometry; ERAS, enhanced recovery after surgery; JT, jejunal tube; LES, late evening snack; LFI, liver frailty index; LT, liver transplantation; MRI, magnetic resonance imaging; SGA, subjective global assessment; TPN, total parenteral nutrition.

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Although, multiple studies show promising results in geriatric populations, further well-designed trials are warranted to show the clinical impact of these next-generation targeted therapies.CON CLUS I ON AND OUTLOOK Sarcopenia, myosteatosis and associated frailty are alterations which are almost omnipresent in the populations of patients with CLD.They represent a manifest and important phenomenon in ESLD cirrhotic cohorts and patients awaiting as well as undergoing LT.Exploiting their multi-faceted pathophysiology, diverse opportunities for therapeutic interventions occur.Figure 3 shines the spotlight on future perspectives in this field, aiming to counteract the paramount consequences of these conditions on clinical outcomes.Still, there is a need for a better understanding of the complex molecular interactions behind the poorly explored liver-to-muscle and muscle-to-liver axis, aiming to identify novel targets for therapeutic interventions.Advanced technologies, such as single-cell sequencing allow a better understanding of individual cellular features and cell typespecific interaction and adaption to various stimuli. 115Lovric et al. examined transcriptional features of fast-and slow-twitch muscle fibres by physical activity. 115A Chinese group by Xu et al. applied single-cell RNA sequencing to determine cell dynamics, lipidomic F I G U R E 3 Current directions of research and future perspectives in investigating the role of body composition in liver disease and liver transplantation.This figure was created using BioRe nder.com.AIH, autoimmune hepatitis; ALD, alcoholic liver disease; ASH, alcoholic steatohepatitis; MASLD, metabolic dysfunction associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.
Besides, the majority of current definitions include only gender in determining cutoff points.Specific characteristics such as ethnicity, age or clinical attributes and acuity are not considered as factors when defining cutoff values.A standardization in disease-specific cutoffs and definitions adapted to the patient's individual characteristics is still lacking.We and other groups recommend that the assessment of BC and advanced nutritional screening be included in the routine clinical care in cirrhotic patients and especially for LT candidates.As mentioned already, artificial intelligence and its sub-fields of machine-and deep learning are gaining more and more interest and use in the clinical setting.120Fully automated AI-based BC analysis has a great potential to replace current manual and semi-automated techniques.124Machine learning-based segmentation approaches for BC metrics combined with adjustment for characteristics such as gender, race and age could represent a strong improvement in clinical risk stratification.124AI-based BC analysis may enable the routine implementation of BC analysis for populational screening with proper standardization.125This might facilitate the inclusion of these risk factors into models which are used in allograft allocation and risk prediction.Digitalization and telemedicine are emerging fields and hold promise to improve access to high-level care around the globe despite the increasing scarcity of skilled human resources.Teixeira et al. developed a portable digital monitoring system for sarcopenia screening based on the EWGSOP2 algorithm using clinical parameters provided by the patients in an app.126A Chinese group by Tian et al. introduced follow-up management by telemedicine for domized controlled clinical trial EVIDENT 3 demonstrated the effect of mobile health (mHealth) on BC for obese patients, adding a selfreporting app and a wearable smart tracking device.128Tele-exercise as effective intervention method for video-based supervised physical exercise and resistance training showed promising results like improvement in skeletal muscle mass and physical function in elderly patients.129More research is needed for the optimal integration of technologies like telemedicine and home-based tele-exercise into routine clinical care for liver patients.The last topic we point out is the urgent need for prophylactic and therapeutic intervention strategies.Validated protocols comprising nutritional regimes and physical activity exist.Furthermore, studies suggesting the therapeutic impact of high protein supplementation, primarily the substitution of BCAA and leucine-enriched amino acid supplements, are available.130,131However, thus far these studies have mostly focusing on the structural improvement in muscle mass and some cases muscle function.Studies evaluating the effect on clinical outcomes in cirrhotic patients and in LT are lacking.